Expert Interview

slituswehedicluchihaspahathoswiclugashuvotriwibosigijunushephostaclatredaprostipotruthujepephuhejibrisopralaclislegupistof

How does the presence of the JAK2 V617F mutation affect the diagnosis and classification of myeloproliferative neoplasms?

Dr. Richard: The JAK2 V617F mutation is found in > 90% of patients with polycythemia vera (PV). The remaining patients with PV have mutations in a different portion of the JAK2 gene. Since JAK2 mutations are found in virtually all patients with PV, having the mutation helps make the diagnosis, but does not carry prognostic significance. Some studies suggest that the allele burden of the mutated JAK2 V617F could be used to identify aggressive disease, but that finding is not universally accepted across all health care entities or practitioners. Variations in acceptance may be due to factors such as evolution of knowledge based on the latest evidence, clinical practice variability and priorities, availability of testing, and complexity of disease management.

This is not true of the 2 other classical myeloproliferative neoplasms (MPNs) that we see commonly in our clinics: essential thrombocytosis (ET) and myelofibrosis (MF). The CALR mutation can be seen in patients with ET and MF and signals a less aggressive form of the disease.

The presence of JAK2 V617F is critical for prognosis. Although it does not directly help to inform the patient of what to expect, identifying the mutation provides us with important information about the patient’s prognosis, which helps guide treatment decisions such as the intensity of therapy and monitoring for thrombotic events.

What are the potential implications of the JAK2 V617F mutation in the treatment of PV?

Dr. Richard: The discovery of the JAK2 V617F mutation in MPNs in 2005 led to the hope that perhaps there would be targeted therapy that could result in disease remissions. We had all hoped that the spectacular responses observed in patients with chronic myelogenous leukemia (CML) treated with imatinib could be replicated with JAK2 inhibitors. It turned out that blocking JAK2 was insufficient to reverse the disease. Studies are still ongoing whether drugs that can decrease the JAK2 V617F allele burden could be used to achieve a type of remission. Perhaps combination therapies will need to be developed.

I am hopeful that in the future we do see advancements that provide improved diagnosis and monitoring to help facilitate early detection, personalized treatment approaches to offer more effective and well tolerated therapies, risk stratification and prognostication to help identify higher risk progression, combination therapies to possibly improve efficacy and adherence, and novel therapeutic targets to help discover new treatments and provide improved outcomes.

How can JAK2 V617F lead to 3 different forms of myeloproliferative neoplasms?

Dr. Richard: The short answer is no one knows exactly. The phenotypic differences between PV and the other 2 MPN variants are most likely determined by the integration of other signaling pathways that are activated by the corresponding driver mutation, and interactions with other mutations. What also seems to matter is the sequence in which the individual mutations are acquired.

There have been documented cases of post-polycythemic leukemia that no longer have the JAK2 V617F mutation. However, at some point that mutation was lost, and the cells acquired other driver mutations that resulted in leukemia.

What we do know now is that there are several potential interactions that can coexist with JAK2 V617F. There is MPL mutation, which contributes to disease pathogenesis and thrombotic risk. Independent of JAK2 V617F pathways is CALR mutation, which is another driver of MPNs. In addition are other JAK mutations, epigenetic alterations, and microenvironmental factors. All of these have the potential to influence clinical manifestations by impacting clinical outcomes, affecting expression patterns and signaling inflammation within the bone marrow microenvironment.

Are there any ongoing research efforts or clinical trials exploring targeted therapies that specifically address the JAK2 V617F mutation in patients with PV?

Dr. Richard: The ongoing research efforts to address JAK2-targeted therapies are looking at options like novel JAK inhibitors, combination therapies, resistance mechanisms, improved safety profiles, biomarker identification, exploring new indications, and preclinical studies that involve the development and testing of new JAK inhibitors.

Other JAK2-targeted therapies continue to be in development. At this time, we have ruxolitinib, pacritinib, fedratinib, and momelotinib. None of them appear to be a magic bullet the way imatinib was with CML. Perhaps a better disease comparison is chronic lymphocytic leukemia (CLL). In CLL, targeted therapies against Bruton tyrosine kinase and BCL2 are being combined to result in many years of disease control. JAK2 inhibition may need to be combined with another active drug, perhaps against a mutation or pathway that has not yet been identified.

slituswehedicluchihaspahathoswiclugashuvotriwibosigijunushephostaclatredaprostipotruthujepephuhejibrisopralaclislegupistof

How does the presence of the JAK2 V617F mutation affect the diagnosis and classification of myeloproliferative neoplasms?

Dr. Richard: The JAK2 V617F mutation is found in > 90% of patients with polycythemia vera (PV). The remaining patients with PV have mutations in a different portion of the JAK2 gene. Since JAK2 mutations are found in virtually all patients with PV, having the mutation helps make the diagnosis, but does not carry prognostic significance. Some studies suggest that the allele burden of the mutated JAK2 V617F could be used to identify aggressive disease, but that finding is not universally accepted across all health care entities or practitioners. Variations in acceptance may be due to factors such as evolution of knowledge based on the latest evidence, clinical practice variability and priorities, availability of testing, and complexity of disease management.

This is not true of the 2 other classical myeloproliferative neoplasms (MPNs) that we see commonly in our clinics: essential thrombocytosis (ET) and myelofibrosis (MF). The CALR mutation can be seen in patients with ET and MF and signals a less aggressive form of the disease.

The presence of JAK2 V617F is critical for prognosis. Although it does not directly help to inform the patient of what to expect, identifying the mutation provides us with important information about the patient’s prognosis, which helps guide treatment decisions such as the intensity of therapy and monitoring for thrombotic events.

What are the potential implications of the JAK2 V617F mutation in the treatment of PV?

Dr. Richard: The discovery of the JAK2 V617F mutation in MPNs in 2005 led to the hope that perhaps there would be targeted therapy that could result in disease remissions. We had all hoped that the spectacular responses observed in patients with chronic myelogenous leukemia (CML) treated with imatinib could be replicated with JAK2 inhibitors. It turned out that blocking JAK2 was insufficient to reverse the disease. Studies are still ongoing whether drugs that can decrease the JAK2 V617F allele burden could be used to achieve a type of remission. Perhaps combination therapies will need to be developed.

I am hopeful that in the future we do see advancements that provide improved diagnosis and monitoring to help facilitate early detection, personalized treatment approaches to offer more effective and well tolerated therapies, risk stratification and prognostication to help identify higher risk progression, combination therapies to possibly improve efficacy and adherence, and novel therapeutic targets to help discover new treatments and provide improved outcomes.

How can JAK2 V617F lead to 3 different forms of myeloproliferative neoplasms?

Dr. Richard: The short answer is no one knows exactly. The phenotypic differences between PV and the other 2 MPN variants are most likely determined by the integration of other signaling pathways that are activated by the corresponding driver mutation, and interactions with other mutations. What also seems to matter is the sequence in which the individual mutations are acquired.

There have been documented cases of post-polycythemic leukemia that no longer have the JAK2 V617F mutation. However, at some point that mutation was lost, and the cells acquired other driver mutations that resulted in leukemia.

What we do know now is that there are several potential interactions that can coexist with JAK2 V617F. There is MPL mutation, which contributes to disease pathogenesis and thrombotic risk. Independent of JAK2 V617F pathways is CALR mutation, which is another driver of MPNs. In addition are other JAK mutations, epigenetic alterations, and microenvironmental factors. All of these have the potential to influence clinical manifestations by impacting clinical outcomes, affecting expression patterns and signaling inflammation within the bone marrow microenvironment.

Are there any ongoing research efforts or clinical trials exploring targeted therapies that specifically address the JAK2 V617F mutation in patients with PV?

Dr. Richard: The ongoing research efforts to address JAK2-targeted therapies are looking at options like novel JAK inhibitors, combination therapies, resistance mechanisms, improved safety profiles, biomarker identification, exploring new indications, and preclinical studies that involve the development and testing of new JAK inhibitors.

Other JAK2-targeted therapies continue to be in development. At this time, we have ruxolitinib, pacritinib, fedratinib, and momelotinib. None of them appear to be a magic bullet the way imatinib was with CML. Perhaps a better disease comparison is chronic lymphocytic leukemia (CLL). In CLL, targeted therapies against Bruton tyrosine kinase and BCL2 are being combined to result in many years of disease control. JAK2 inhibition may need to be combined with another active drug, perhaps against a mutation or pathway that has not yet been identified.

slituswehedicluchihaspahathoswiclugashuvotriwibosigijunushephostaclatredaprostipotruthujepephuhejibrisopralaclislegupistof

How does the presence of the JAK2 V617F mutation affect the diagnosis and classification of myeloproliferative neoplasms?

Dr. Richard: The JAK2 V617F mutation is found in > 90% of patients with polycythemia vera (PV). The remaining patients with PV have mutations in a different portion of the JAK2 gene. Since JAK2 mutations are found in virtually all patients with PV, having the mutation helps make the diagnosis, but does not carry prognostic significance. Some studies suggest that the allele burden of the mutated JAK2 V617F could be used to identify aggressive disease, but that finding is not universally accepted across all health care entities or practitioners. Variations in acceptance may be due to factors such as evolution of knowledge based on the latest evidence, clinical practice variability and priorities, availability of testing, and complexity of disease management.

This is not true of the 2 other classical myeloproliferative neoplasms (MPNs) that we see commonly in our clinics: essential thrombocytosis (ET) and myelofibrosis (MF). The CALR mutation can be seen in patients with ET and MF and signals a less aggressive form of the disease.

The presence of JAK2 V617F is critical for prognosis. Although it does not directly help to inform the patient of what to expect, identifying the mutation provides us with important information about the patient’s prognosis, which helps guide treatment decisions such as the intensity of therapy and monitoring for thrombotic events.

What are the potential implications of the JAK2 V617F mutation in the treatment of PV?

Dr. Richard: The discovery of the JAK2 V617F mutation in MPNs in 2005 led to the hope that perhaps there would be targeted therapy that could result in disease remissions. We had all hoped that the spectacular responses observed in patients with chronic myelogenous leukemia (CML) treated with imatinib could be replicated with JAK2 inhibitors. It turned out that blocking JAK2 was insufficient to reverse the disease. Studies are still ongoing whether drugs that can decrease the JAK2 V617F allele burden could be used to achieve a type of remission. Perhaps combination therapies will need to be developed.

I am hopeful that in the future we do see advancements that provide improved diagnosis and monitoring to help facilitate early detection, personalized treatment approaches to offer more effective and well tolerated therapies, risk stratification and prognostication to help identify higher risk progression, combination therapies to possibly improve efficacy and adherence, and novel therapeutic targets to help discover new treatments and provide improved outcomes.

How can JAK2 V617F lead to 3 different forms of myeloproliferative neoplasms?

Dr. Richard: The short answer is no one knows exactly. The phenotypic differences between PV and the other 2 MPN variants are most likely determined by the integration of other signaling pathways that are activated by the corresponding driver mutation, and interactions with other mutations. What also seems to matter is the sequence in which the individual mutations are acquired.

There have been documented cases of post-polycythemic leukemia that no longer have the JAK2 V617F mutation. However, at some point that mutation was lost, and the cells acquired other driver mutations that resulted in leukemia.

What we do know now is that there are several potential interactions that can coexist with JAK2 V617F. There is MPL mutation, which contributes to disease pathogenesis and thrombotic risk. Independent of JAK2 V617F pathways is CALR mutation, which is another driver of MPNs. In addition are other JAK mutations, epigenetic alterations, and microenvironmental factors. All of these have the potential to influence clinical manifestations by impacting clinical outcomes, affecting expression patterns and signaling inflammation within the bone marrow microenvironment.

Are there any ongoing research efforts or clinical trials exploring targeted therapies that specifically address the JAK2 V617F mutation in patients with PV?

Dr. Richard: The ongoing research efforts to address JAK2-targeted therapies are looking at options like novel JAK inhibitors, combination therapies, resistance mechanisms, improved safety profiles, biomarker identification, exploring new indications, and preclinical studies that involve the development and testing of new JAK inhibitors.

Other JAK2-targeted therapies continue to be in development. At this time, we have ruxolitinib, pacritinib, fedratinib, and momelotinib. None of them appear to be a magic bullet the way imatinib was with CML. Perhaps a better disease comparison is chronic lymphocytic leukemia (CLL). In CLL, targeted therapies against Bruton tyrosine kinase and BCL2 are being combined to result in many years of disease control. JAK2 inhibition may need to be combined with another active drug, perhaps against a mutation or pathway that has not yet been identified.

avaho_image_partnership.jpg

rrichard_feb_2023_1.jpeg

There are several new therapies on the horizon for polycythemia vera. What is the potential impact of these treatments coming to market?

Dr. Richard: There are a number of emerging therapies for polycythemia vera (PV), such as PTG-300, idasanutlin, and givinostat. PTG-300, or rusfertide, is a hepcidin mimetic that works by regulating iron metabolism and potentially controlling erythropoiesis, limiting the need for phlebotomy. Idasanutlin, a selective MDM2 inhibitor, targets p53 activity. Even though this drug is early in its development, everyone who treats patients with cancer has been hoping for a drug that works through p53. If it is effective here, who knows where else it could be effective across various other conditions.

Givinostat is well along the development pathway in advanced trials. This drug shows promise in modulating gene expression and reducing the inflammation and fibrosis associated with PV, potentially improving patient outcomes and quality of life. Everyone is hopeful that givinostat could show some effect on disease control and potentially an effect on the myeloproliferative clone. However, rigorous clinical trials and further research are necessary to validate their efficacy, safety profiles, and long-term impacts on patients with PV.

Now, with the approval of peginterferon, the next step is going to be to see how effective it will be and what the adverse events might be. I think we will be getting more data as it starts to be used more. My prediction is that there will be a slow uptake, largely because many older physicians such as myself remember the significant side effects from interferon in the past. Despite being an FDA-approved treatment, it remains an emerging therapy, particularly in the United States. Its adoption and efficacy will become clearer as time progresses.

Another promising drug early in its development is bomedemstat, which functions through a different mechanism as a deacetylase. While the potential effect of histone deacetylase drugs on patient treatment outcomes remains uncertain this year, there might be significant data—either positive or negative—that accelerate the progress of these drugs in their developmental trajectory.

We know that ruxolitinib can be used effectively for patients once they fail hydroxyurea. And now there has been the development of other JAK2 inhibitors that are approved for myelofibrosis. I am not quite sure how they can be evaluated in PV, since we are talking about relatively small numbers of patients, but they do seem to have some slight differences that may be significant and could be used in this space.

Those are the main therapies that I will have my eye on this year.

What is the potential significance of an accelerated dosing schedule for BESREMi (ropeginterferon-alfa-2b-njft), which is being investigated in the ECLIPSE PV phase 3b clinical trial?

Dr. Richard: The potential significance of an accelerated dosing schedule for BESREMi, as investigated in the ECLIPSE PV phase 3b clinical trial, lies in its capacity to enhance treatment efficacy and outcomes for patients with PV. I am incredibly pleased that it is being done as a trial, partly because a lot of people assume that once a phase 3 study is complete and a drug receives FDA approval, everything is finished and done, and we will move on to the next thing. I really appreciate it when phase 3b or 4 studies are performed, and the data get collected and published.

This study is going to follow a group of patients closely for adverse events and for the JAK2 signal. By administering BESREMi at an accelerated pace, researchers can evaluate its ability to better control hematocrit levels and symptoms associated with PV. In addition, an accelerated dosing schedule could potentially offer patients more efficient symptom management and disease control, leading to improved quality of life and reduced complications associated with PV. I believe that findings from this trial could thus pave the way for optimized treatment strategies and better outcomes for individuals living with PV.

What should future trials focus on to help improve prognosis and survival for patients with PV?

Dr. Richard: We are starting to move increasingly into finding better therapies for patients with PV, and I’ll add in essential thrombocytosis, which are based on informed prognostication. I would love to see studies that just pull out the patients at the highest risk, where the survival is down around 5 years—those are small numbers of patients. To conduct a study like that is exceedingly difficult to do. We are seeing increased consortiums of myeloproliferative neoplasm physicians. Europe has always been particularly good at this. The United States is getting better at it, so it is possible that a trial like that could be pulled together, where centers put in 1 or 2 patients at a time.

Future trials aimed at improving prognosis and survival for PV should prioritize several critical areas. First, there is a need for comprehensive studies to better understand the molecular mechanisms underlying PV pathogenesis, including the JAK2 mutation and its downstream effects. Exploring new therapeutic implications and improve long-term outcomes. Additionally, identifying reliable biomarkers for disease progression and treatment response can facilitate early intervention and personalized treatment approaches. Finally, trials should focus on assessing the impact of treatment on quality of life and addressing the unique needs of patients with PV to optimize overall prognosis and survival.

I have always held hope that the Veterans Administration could serve as a platform for conducting some of these studies, given that we possess the largest healthcare system in the country. Whether we participate in larger studies or conduct our research internally, this is something I have long envisioned.

avaho_image_partnership.jpg

rrichard_feb_2023_1.jpeg

There are several new therapies on the horizon for polycythemia vera. What is the potential impact of these treatments coming to market?

Dr. Richard: There are a number of emerging therapies for polycythemia vera (PV), such as PTG-300, idasanutlin, and givinostat. PTG-300, or rusfertide, is a hepcidin mimetic that works by regulating iron metabolism and potentially controlling erythropoiesis, limiting the need for phlebotomy. Idasanutlin, a selective MDM2 inhibitor, targets p53 activity. Even though this drug is early in its development, everyone who treats patients with cancer has been hoping for a drug that works through p53. If it is effective here, who knows where else it could be effective across various other conditions.

Givinostat is well along the development pathway in advanced trials. This drug shows promise in modulating gene expression and reducing the inflammation and fibrosis associated with PV, potentially improving patient outcomes and quality of life. Everyone is hopeful that givinostat could show some effect on disease control and potentially an effect on the myeloproliferative clone. However, rigorous clinical trials and further research are necessary to validate their efficacy, safety profiles, and long-term impacts on patients with PV.

Now, with the approval of peginterferon, the next step is going to be to see how effective it will be and what the adverse events might be. I think we will be getting more data as it starts to be used more. My prediction is that there will be a slow uptake, largely because many older physicians such as myself remember the significant side effects from interferon in the past. Despite being an FDA-approved treatment, it remains an emerging therapy, particularly in the United States. Its adoption and efficacy will become clearer as time progresses.

Another promising drug early in its development is bomedemstat, which functions through a different mechanism as a deacetylase. While the potential effect of histone deacetylase drugs on patient treatment outcomes remains uncertain this year, there might be significant data—either positive or negative—that accelerate the progress of these drugs in their developmental trajectory.

We know that ruxolitinib can be used effectively for patients once they fail hydroxyurea. And now there has been the development of other JAK2 inhibitors that are approved for myelofibrosis. I am not quite sure how they can be evaluated in PV, since we are talking about relatively small numbers of patients, but they do seem to have some slight differences that may be significant and could be used in this space.

Those are the main therapies that I will have my eye on this year.

What is the potential significance of an accelerated dosing schedule for BESREMi (ropeginterferon-alfa-2b-njft), which is being investigated in the ECLIPSE PV phase 3b clinical trial?

Dr. Richard: The potential significance of an accelerated dosing schedule for BESREMi, as investigated in the ECLIPSE PV phase 3b clinical trial, lies in its capacity to enhance treatment efficacy and outcomes for patients with PV. I am incredibly pleased that it is being done as a trial, partly because a lot of people assume that once a phase 3 study is complete and a drug receives FDA approval, everything is finished and done, and we will move on to the next thing. I really appreciate it when phase 3b or 4 studies are performed, and the data get collected and published.

This study is going to follow a group of patients closely for adverse events and for the JAK2 signal. By administering BESREMi at an accelerated pace, researchers can evaluate its ability to better control hematocrit levels and symptoms associated with PV. In addition, an accelerated dosing schedule could potentially offer patients more efficient symptom management and disease control, leading to improved quality of life and reduced complications associated with PV. I believe that findings from this trial could thus pave the way for optimized treatment strategies and better outcomes for individuals living with PV.

What should future trials focus on to help improve prognosis and survival for patients with PV?

Dr. Richard: We are starting to move increasingly into finding better therapies for patients with PV, and I’ll add in essential thrombocytosis, which are based on informed prognostication. I would love to see studies that just pull out the patients at the highest risk, where the survival is down around 5 years—those are small numbers of patients. To conduct a study like that is exceedingly difficult to do. We are seeing increased consortiums of myeloproliferative neoplasm physicians. Europe has always been particularly good at this. The United States is getting better at it, so it is possible that a trial like that could be pulled together, where centers put in 1 or 2 patients at a time.

Future trials aimed at improving prognosis and survival for PV should prioritize several critical areas. First, there is a need for comprehensive studies to better understand the molecular mechanisms underlying PV pathogenesis, including the JAK2 mutation and its downstream effects. Exploring new therapeutic implications and improve long-term outcomes. Additionally, identifying reliable biomarkers for disease progression and treatment response can facilitate early intervention and personalized treatment approaches. Finally, trials should focus on assessing the impact of treatment on quality of life and addressing the unique needs of patients with PV to optimize overall prognosis and survival.

I have always held hope that the Veterans Administration could serve as a platform for conducting some of these studies, given that we possess the largest healthcare system in the country. Whether we participate in larger studies or conduct our research internally, this is something I have long envisioned.

avaho_image_partnership.jpg

rrichard_feb_2023_1.jpeg

There are several new therapies on the horizon for polycythemia vera. What is the potential impact of these treatments coming to market?

Dr. Richard: There are a number of emerging therapies for polycythemia vera (PV), such as PTG-300, idasanutlin, and givinostat. PTG-300, or rusfertide, is a hepcidin mimetic that works by regulating iron metabolism and potentially controlling erythropoiesis, limiting the need for phlebotomy. Idasanutlin, a selective MDM2 inhibitor, targets p53 activity. Even though this drug is early in its development, everyone who treats patients with cancer has been hoping for a drug that works through p53. If it is effective here, who knows where else it could be effective across various other conditions.

Givinostat is well along the development pathway in advanced trials. This drug shows promise in modulating gene expression and reducing the inflammation and fibrosis associated with PV, potentially improving patient outcomes and quality of life. Everyone is hopeful that givinostat could show some effect on disease control and potentially an effect on the myeloproliferative clone. However, rigorous clinical trials and further research are necessary to validate their efficacy, safety profiles, and long-term impacts on patients with PV.

Now, with the approval of peginterferon, the next step is going to be to see how effective it will be and what the adverse events might be. I think we will be getting more data as it starts to be used more. My prediction is that there will be a slow uptake, largely because many older physicians such as myself remember the significant side effects from interferon in the past. Despite being an FDA-approved treatment, it remains an emerging therapy, particularly in the United States. Its adoption and efficacy will become clearer as time progresses.

Another promising drug early in its development is bomedemstat, which functions through a different mechanism as a deacetylase. While the potential effect of histone deacetylase drugs on patient treatment outcomes remains uncertain this year, there might be significant data—either positive or negative—that accelerate the progress of these drugs in their developmental trajectory.

We know that ruxolitinib can be used effectively for patients once they fail hydroxyurea. And now there has been the development of other JAK2 inhibitors that are approved for myelofibrosis. I am not quite sure how they can be evaluated in PV, since we are talking about relatively small numbers of patients, but they do seem to have some slight differences that may be significant and could be used in this space.

Those are the main therapies that I will have my eye on this year.

What is the potential significance of an accelerated dosing schedule for BESREMi (ropeginterferon-alfa-2b-njft), which is being investigated in the ECLIPSE PV phase 3b clinical trial?

Dr. Richard: The potential significance of an accelerated dosing schedule for BESREMi, as investigated in the ECLIPSE PV phase 3b clinical trial, lies in its capacity to enhance treatment efficacy and outcomes for patients with PV. I am incredibly pleased that it is being done as a trial, partly because a lot of people assume that once a phase 3 study is complete and a drug receives FDA approval, everything is finished and done, and we will move on to the next thing. I really appreciate it when phase 3b or 4 studies are performed, and the data get collected and published.

This study is going to follow a group of patients closely for adverse events and for the JAK2 signal. By administering BESREMi at an accelerated pace, researchers can evaluate its ability to better control hematocrit levels and symptoms associated with PV. In addition, an accelerated dosing schedule could potentially offer patients more efficient symptom management and disease control, leading to improved quality of life and reduced complications associated with PV. I believe that findings from this trial could thus pave the way for optimized treatment strategies and better outcomes for individuals living with PV.

What should future trials focus on to help improve prognosis and survival for patients with PV?

Dr. Richard: We are starting to move increasingly into finding better therapies for patients with PV, and I’ll add in essential thrombocytosis, which are based on informed prognostication. I would love to see studies that just pull out the patients at the highest risk, where the survival is down around 5 years—those are small numbers of patients. To conduct a study like that is exceedingly difficult to do. We are seeing increased consortiums of myeloproliferative neoplasm physicians. Europe has always been particularly good at this. The United States is getting better at it, so it is possible that a trial like that could be pulled together, where centers put in 1 or 2 patients at a time.

Future trials aimed at improving prognosis and survival for PV should prioritize several critical areas. First, there is a need for comprehensive studies to better understand the molecular mechanisms underlying PV pathogenesis, including the JAK2 mutation and its downstream effects. Exploring new therapeutic implications and improve long-term outcomes. Additionally, identifying reliable biomarkers for disease progression and treatment response can facilitate early intervention and personalized treatment approaches. Finally, trials should focus on assessing the impact of treatment on quality of life and addressing the unique needs of patients with PV to optimize overall prognosis and survival.

I have always held hope that the Veterans Administration could serve as a platform for conducting some of these studies, given that we possess the largest healthcare system in the country. Whether we participate in larger studies or conduct our research internally, this is something I have long envisioned.

rrichard_feb_2023.jpeg

Dr. Richard: The first thing we as physicians are worried about is patients with PV developing thrombosis. We start prophylaxis with aspirin, as aspirin remains the best treatment for reducing this risk. It is essential to make sure patients with PV understand the importance of taking an aspirin, even at a low dosage.

The second step is trying to control patients’ red blood cell counts. Phlebotomy has been used for this purpose for many decades and continues to be effective. You will find some experts in the field who consider phlebotomy to be the mainstay of treatment for patients with PV, and that it has benefits in and of itself.

However, despite the benefits, phlebotomy can be a little tough on patients. For instance, patients with PV cannot donate blood at a traditional blood center such as Red Cross, and therefore need to go to an actual infusion center. They also must stop their day and travel to a site to receive therapeutic phlebotomy treatment, which is most effective for patients with a blood disorder. I work in Seattle taking care of patients throughout the Northwest, and it is not always easy to find a close location to send patients for phlebotomy. Nevertheless, phlebotomy should be part of the treatment options for patients with PV, especially patients in the high-risk range who have high hemoglobin and hematocrit values.

The third step is controlling hemoglobin and hematocrit levels. Hydroxyurea is our standard of care with strong beneficial data for this purpose.

These are the 3 approaches to treatment we initially discuss with our patients during their first visit. These 3 strategies can improve a patient's life and reduce their risk for thrombosis.

Which treatment do you recommend depending on the patient’s symptoms?

Dr. Richard: The treatment that we offer can vary. The first thing I want to know is how their symptoms respond to aspirin. For instance, symptoms such as erythromelalgia oftentimes respond beautifully to aspirin. Most patients do not have massive splenomegaly—that would give me a high suspicion for myelofibrosis—but they can develop and present with some level of splenomegaly.

If the symptoms are bothersome to the patient, I will probably want to get them on some kind of cytoreduction to see if that is effective. Hydroxyurea, although not as effective as aspirin and associated with adverse effects in some patients, is a good medication to start cytoreductive therapy. The National Comprehensive Cancer Network® (NCCN®) Guidelines suggest that if a patient taking hydroxyurea experiences severe gastrointestinal (GI) toxicity, go ahead and move to a Janus kinase 2 (JAK2) inhibitor or try interferon. JAK2 inhibition with ruxolitinib, in this case, is effective, at least initially for treating splenomegaly. Unfortunately, symptoms sometimes get confused with effects from the medications. You have to use an individualized treatment approach and see what works for each patient.
 

What are some of the common adverse effects of treatment?

Dr. Richard: As you probably can tell, I never skip aspirin since it is such an important part of treatment for patients with PV. However, I do talk to patients about GI upset and the bleeding risks, such as the potential for GI bleed. Obviously, clotting is what causes an increase in morbidity and mortality, but bleeding can be an important adverse effect with platelets that do not function, or for other issues.

Hydroxyurea is generally well tolerated, but some patients can develop skin issues or ulcers due to GI toxicity. I have a lot of confidence in the use of hydroxyurea, and I use it without hesitation. However, you may have a patient who already has a relatively low neutrophil count or has some level of thrombocytopenia from either liver disease or some other issue, and they just cannot tolerate hydroxyurea. Some other bothersome symptoms include change of taste, skin changes, and brittle nails. It can be tricky. I will attempt hydroxyurea, if needed, but sometimes they just cannot tolerate it.

What happens when a patient cannot tolerate one or all the medications you mentioned?

Dr. Richard: Now that we have JAK2 inhibitors, ruxolitinib is generally my choice for patients who cannot tolerate hydroxyurea, which is more common than maybe we would like. Other problems with hydroxyurea include that it might not work, or phlebotomy combined with hydroxyurea results in cytopenias, or patients have a particularly aggressive form of PV.

There are numerous other JAK2 drug inhibitors on the market for myelofibrosis. The assumption is they probably work as well as ruxolitinib for PV, but right now ruxolitinib is what is approved by the US Food and Drug Administration for these patients.

The other drug that we do not use much is interferon, or now, pegylated interferon. It is a drug that has been around for a long time and worked well in chronic myelogenous leukemia before we had the tyrosine kinase inhibitors. Pegylated interferon is a well-tolerated drug that can be used for patients with PV who are pregnant or could get pregnant. It is not the interferon of our parents or grandparents. We now have options for controlling the disease and its complications, but the hardest thing is to tell patients that none of these treatments are going to cure them or reverse the overproduction of red blood cells in their bone marrow. There has always been discussion about whether there could be some effect of interferon on the actual tumor burden, but that remains to be proven.

Can you go a little bit more into your recommended approach to managing newly diagnosed patients with PV in your day-to-day practice?

Dr. Richard: Oftentimes these patients are identified through our consultation service. It can be hard on the primary care physician to identify whether a patient has secondary or primary PV.

We are lucky now that JAK2 has been identified. The JAK2-V617F and the other exon 12 mutations were identified back in 2006 by several groups and is a great test. With JAK2 along with an erythropoietin test, you can feel confident whether you have identified PV.

PV encompasses a wide variety of syndromes. Patients can come into the office with terrible symptoms, including aquagenic pruritus or erythromelalgia. I have seen young people in their 30s who happen to have a slightly elevated hematocrit and a positive JAK2 test. When this occurs, you try to understand how much the disease is affecting their life, whether they are going to be in a high-risk category or a low-risk category, whether they have had thrombosis, and how their age figures into all of it. To try to figure out this high-risk versus low-risk factor, we use a simple staging system to help determine whether they are going to need cytoreductive therapy or whether you can just start with phlebotomy and see how they do.

Oftentimes in the first visit, I recommend a bone marrow study. Is that going to be true 5 years from now? I am not sure. You know, next-generation sequencing (NGS) is turning into such an important part of determining prognosis in these patients. It helps if you have a great colleague down in hematopathology who can look at the bone marrow as it relates to megakaryocyte morphology, or whether there is early fibrosis.

Although these techniques may not be as prominent in practice today for determining diagnosis, they help us understand the prognosis. A bone marrow study or NGS is particularly useful when you have patients who you are convinced have PV, but it turns out they already have extensive fibrosis and are actually moving more toward the post-polycythemia phase a little faster than you think. While we do not use an allogeneic transplant often, in this scenario we may recommend it. Our primary goal at this point is to try to determine which patients would benefit from a transplant early on and to prepare the patient for this option.

What socioeconomic disparities have you observed in newly diagnosed patients?

Dr. Richard: There are definitely social disparities for people who have low income. I work in a veteran’s hospital where we take care of a lot of people who do not have health insurance, but who come to the VA because they do have benefits. If they are in our system, they get identified and their care is great. However, if they have been out in the regular system without health insurance, oftentimes they get diagnosed late. Identifying and treating patients from low socioeconomic backgrounds is an issue. I think everyone can agree with that.

We have a delicate situation with women veterans. Something that is incredibly painful that I think people should be aware of is the amount of military sexual trauma (MST) that has occurred over the years. These patients are in a unique place of trust with their care providers. They have spent a lot of time not being listened to in a variety of arenas. I see this in young military women who no one expects to have a stem cell disorder. We as health care providers do them a disservice if their complaints lead to referral to a psychotherapist or being prescribed a nonsteroidal anti-inflammatory drug or something like that. As health care providers, we are in a unique position to listen to and accurately evaluate these patients. We have a large population of veterans and, increasingly more women veterans, but I think we can all agree that they need better care, especially if they have suffered from MST. That is what I see in my patient population.

When I was a resident in Baltimore, it was Black people with lower income who did not trust doctors. We still have a lot of work to do.

rrichard_feb_2023.jpeg

Dr. Richard: The first thing we as physicians are worried about is patients with PV developing thrombosis. We start prophylaxis with aspirin, as aspirin remains the best treatment for reducing this risk. It is essential to make sure patients with PV understand the importance of taking an aspirin, even at a low dosage.

The second step is trying to control patients’ red blood cell counts. Phlebotomy has been used for this purpose for many decades and continues to be effective. You will find some experts in the field who consider phlebotomy to be the mainstay of treatment for patients with PV, and that it has benefits in and of itself.

However, despite the benefits, phlebotomy can be a little tough on patients. For instance, patients with PV cannot donate blood at a traditional blood center such as Red Cross, and therefore need to go to an actual infusion center. They also must stop their day and travel to a site to receive therapeutic phlebotomy treatment, which is most effective for patients with a blood disorder. I work in Seattle taking care of patients throughout the Northwest, and it is not always easy to find a close location to send patients for phlebotomy. Nevertheless, phlebotomy should be part of the treatment options for patients with PV, especially patients in the high-risk range who have high hemoglobin and hematocrit values.

The third step is controlling hemoglobin and hematocrit levels. Hydroxyurea is our standard of care with strong beneficial data for this purpose.

These are the 3 approaches to treatment we initially discuss with our patients during their first visit. These 3 strategies can improve a patient's life and reduce their risk for thrombosis.

Which treatment do you recommend depending on the patient’s symptoms?

Dr. Richard: The treatment that we offer can vary. The first thing I want to know is how their symptoms respond to aspirin. For instance, symptoms such as erythromelalgia oftentimes respond beautifully to aspirin. Most patients do not have massive splenomegaly—that would give me a high suspicion for myelofibrosis—but they can develop and present with some level of splenomegaly.

If the symptoms are bothersome to the patient, I will probably want to get them on some kind of cytoreduction to see if that is effective. Hydroxyurea, although not as effective as aspirin and associated with adverse effects in some patients, is a good medication to start cytoreductive therapy. The National Comprehensive Cancer Network® (NCCN®) Guidelines suggest that if a patient taking hydroxyurea experiences severe gastrointestinal (GI) toxicity, go ahead and move to a Janus kinase 2 (JAK2) inhibitor or try interferon. JAK2 inhibition with ruxolitinib, in this case, is effective, at least initially for treating splenomegaly. Unfortunately, symptoms sometimes get confused with effects from the medications. You have to use an individualized treatment approach and see what works for each patient.
 

What are some of the common adverse effects of treatment?

Dr. Richard: As you probably can tell, I never skip aspirin since it is such an important part of treatment for patients with PV. However, I do talk to patients about GI upset and the bleeding risks, such as the potential for GI bleed. Obviously, clotting is what causes an increase in morbidity and mortality, but bleeding can be an important adverse effect with platelets that do not function, or for other issues.

Hydroxyurea is generally well tolerated, but some patients can develop skin issues or ulcers due to GI toxicity. I have a lot of confidence in the use of hydroxyurea, and I use it without hesitation. However, you may have a patient who already has a relatively low neutrophil count or has some level of thrombocytopenia from either liver disease or some other issue, and they just cannot tolerate hydroxyurea. Some other bothersome symptoms include change of taste, skin changes, and brittle nails. It can be tricky. I will attempt hydroxyurea, if needed, but sometimes they just cannot tolerate it.

What happens when a patient cannot tolerate one or all the medications you mentioned?

Dr. Richard: Now that we have JAK2 inhibitors, ruxolitinib is generally my choice for patients who cannot tolerate hydroxyurea, which is more common than maybe we would like. Other problems with hydroxyurea include that it might not work, or phlebotomy combined with hydroxyurea results in cytopenias, or patients have a particularly aggressive form of PV.

There are numerous other JAK2 drug inhibitors on the market for myelofibrosis. The assumption is they probably work as well as ruxolitinib for PV, but right now ruxolitinib is what is approved by the US Food and Drug Administration for these patients.

The other drug that we do not use much is interferon, or now, pegylated interferon. It is a drug that has been around for a long time and worked well in chronic myelogenous leukemia before we had the tyrosine kinase inhibitors. Pegylated interferon is a well-tolerated drug that can be used for patients with PV who are pregnant or could get pregnant. It is not the interferon of our parents or grandparents. We now have options for controlling the disease and its complications, but the hardest thing is to tell patients that none of these treatments are going to cure them or reverse the overproduction of red blood cells in their bone marrow. There has always been discussion about whether there could be some effect of interferon on the actual tumor burden, but that remains to be proven.

Can you go a little bit more into your recommended approach to managing newly diagnosed patients with PV in your day-to-day practice?

Dr. Richard: Oftentimes these patients are identified through our consultation service. It can be hard on the primary care physician to identify whether a patient has secondary or primary PV.

We are lucky now that JAK2 has been identified. The JAK2-V617F and the other exon 12 mutations were identified back in 2006 by several groups and is a great test. With JAK2 along with an erythropoietin test, you can feel confident whether you have identified PV.

PV encompasses a wide variety of syndromes. Patients can come into the office with terrible symptoms, including aquagenic pruritus or erythromelalgia. I have seen young people in their 30s who happen to have a slightly elevated hematocrit and a positive JAK2 test. When this occurs, you try to understand how much the disease is affecting their life, whether they are going to be in a high-risk category or a low-risk category, whether they have had thrombosis, and how their age figures into all of it. To try to figure out this high-risk versus low-risk factor, we use a simple staging system to help determine whether they are going to need cytoreductive therapy or whether you can just start with phlebotomy and see how they do.

Oftentimes in the first visit, I recommend a bone marrow study. Is that going to be true 5 years from now? I am not sure. You know, next-generation sequencing (NGS) is turning into such an important part of determining prognosis in these patients. It helps if you have a great colleague down in hematopathology who can look at the bone marrow as it relates to megakaryocyte morphology, or whether there is early fibrosis.

Although these techniques may not be as prominent in practice today for determining diagnosis, they help us understand the prognosis. A bone marrow study or NGS is particularly useful when you have patients who you are convinced have PV, but it turns out they already have extensive fibrosis and are actually moving more toward the post-polycythemia phase a little faster than you think. While we do not use an allogeneic transplant often, in this scenario we may recommend it. Our primary goal at this point is to try to determine which patients would benefit from a transplant early on and to prepare the patient for this option.

What socioeconomic disparities have you observed in newly diagnosed patients?

Dr. Richard: There are definitely social disparities for people who have low income. I work in a veteran’s hospital where we take care of a lot of people who do not have health insurance, but who come to the VA because they do have benefits. If they are in our system, they get identified and their care is great. However, if they have been out in the regular system without health insurance, oftentimes they get diagnosed late. Identifying and treating patients from low socioeconomic backgrounds is an issue. I think everyone can agree with that.

We have a delicate situation with women veterans. Something that is incredibly painful that I think people should be aware of is the amount of military sexual trauma (MST) that has occurred over the years. These patients are in a unique place of trust with their care providers. They have spent a lot of time not being listened to in a variety of arenas. I see this in young military women who no one expects to have a stem cell disorder. We as health care providers do them a disservice if their complaints lead to referral to a psychotherapist or being prescribed a nonsteroidal anti-inflammatory drug or something like that. As health care providers, we are in a unique position to listen to and accurately evaluate these patients. We have a large population of veterans and, increasingly more women veterans, but I think we can all agree that they need better care, especially if they have suffered from MST. That is what I see in my patient population.

When I was a resident in Baltimore, it was Black people with lower income who did not trust doctors. We still have a lot of work to do.

rrichard_feb_2023.jpeg

Dr. Richard: The first thing we as physicians are worried about is patients with PV developing thrombosis. We start prophylaxis with aspirin, as aspirin remains the best treatment for reducing this risk. It is essential to make sure patients with PV understand the importance of taking an aspirin, even at a low dosage.

The second step is trying to control patients’ red blood cell counts. Phlebotomy has been used for this purpose for many decades and continues to be effective. You will find some experts in the field who consider phlebotomy to be the mainstay of treatment for patients with PV, and that it has benefits in and of itself.

However, despite the benefits, phlebotomy can be a little tough on patients. For instance, patients with PV cannot donate blood at a traditional blood center such as Red Cross, and therefore need to go to an actual infusion center. They also must stop their day and travel to a site to receive therapeutic phlebotomy treatment, which is most effective for patients with a blood disorder. I work in Seattle taking care of patients throughout the Northwest, and it is not always easy to find a close location to send patients for phlebotomy. Nevertheless, phlebotomy should be part of the treatment options for patients with PV, especially patients in the high-risk range who have high hemoglobin and hematocrit values.

The third step is controlling hemoglobin and hematocrit levels. Hydroxyurea is our standard of care with strong beneficial data for this purpose.

These are the 3 approaches to treatment we initially discuss with our patients during their first visit. These 3 strategies can improve a patient's life and reduce their risk for thrombosis.

Which treatment do you recommend depending on the patient’s symptoms?

Dr. Richard: The treatment that we offer can vary. The first thing I want to know is how their symptoms respond to aspirin. For instance, symptoms such as erythromelalgia oftentimes respond beautifully to aspirin. Most patients do not have massive splenomegaly—that would give me a high suspicion for myelofibrosis—but they can develop and present with some level of splenomegaly.

If the symptoms are bothersome to the patient, I will probably want to get them on some kind of cytoreduction to see if that is effective. Hydroxyurea, although not as effective as aspirin and associated with adverse effects in some patients, is a good medication to start cytoreductive therapy. The National Comprehensive Cancer Network® (NCCN®) Guidelines suggest that if a patient taking hydroxyurea experiences severe gastrointestinal (GI) toxicity, go ahead and move to a Janus kinase 2 (JAK2) inhibitor or try interferon. JAK2 inhibition with ruxolitinib, in this case, is effective, at least initially for treating splenomegaly. Unfortunately, symptoms sometimes get confused with effects from the medications. You have to use an individualized treatment approach and see what works for each patient.
 

What are some of the common adverse effects of treatment?

Dr. Richard: As you probably can tell, I never skip aspirin since it is such an important part of treatment for patients with PV. However, I do talk to patients about GI upset and the bleeding risks, such as the potential for GI bleed. Obviously, clotting is what causes an increase in morbidity and mortality, but bleeding can be an important adverse effect with platelets that do not function, or for other issues.

Hydroxyurea is generally well tolerated, but some patients can develop skin issues or ulcers due to GI toxicity. I have a lot of confidence in the use of hydroxyurea, and I use it without hesitation. However, you may have a patient who already has a relatively low neutrophil count or has some level of thrombocytopenia from either liver disease or some other issue, and they just cannot tolerate hydroxyurea. Some other bothersome symptoms include change of taste, skin changes, and brittle nails. It can be tricky. I will attempt hydroxyurea, if needed, but sometimes they just cannot tolerate it.

What happens when a patient cannot tolerate one or all the medications you mentioned?

Dr. Richard: Now that we have JAK2 inhibitors, ruxolitinib is generally my choice for patients who cannot tolerate hydroxyurea, which is more common than maybe we would like. Other problems with hydroxyurea include that it might not work, or phlebotomy combined with hydroxyurea results in cytopenias, or patients have a particularly aggressive form of PV.

There are numerous other JAK2 drug inhibitors on the market for myelofibrosis. The assumption is they probably work as well as ruxolitinib for PV, but right now ruxolitinib is what is approved by the US Food and Drug Administration for these patients.

The other drug that we do not use much is interferon, or now, pegylated interferon. It is a drug that has been around for a long time and worked well in chronic myelogenous leukemia before we had the tyrosine kinase inhibitors. Pegylated interferon is a well-tolerated drug that can be used for patients with PV who are pregnant or could get pregnant. It is not the interferon of our parents or grandparents. We now have options for controlling the disease and its complications, but the hardest thing is to tell patients that none of these treatments are going to cure them or reverse the overproduction of red blood cells in their bone marrow. There has always been discussion about whether there could be some effect of interferon on the actual tumor burden, but that remains to be proven.

Can you go a little bit more into your recommended approach to managing newly diagnosed patients with PV in your day-to-day practice?

Dr. Richard: Oftentimes these patients are identified through our consultation service. It can be hard on the primary care physician to identify whether a patient has secondary or primary PV.

We are lucky now that JAK2 has been identified. The JAK2-V617F and the other exon 12 mutations were identified back in 2006 by several groups and is a great test. With JAK2 along with an erythropoietin test, you can feel confident whether you have identified PV.

PV encompasses a wide variety of syndromes. Patients can come into the office with terrible symptoms, including aquagenic pruritus or erythromelalgia. I have seen young people in their 30s who happen to have a slightly elevated hematocrit and a positive JAK2 test. When this occurs, you try to understand how much the disease is affecting their life, whether they are going to be in a high-risk category or a low-risk category, whether they have had thrombosis, and how their age figures into all of it. To try to figure out this high-risk versus low-risk factor, we use a simple staging system to help determine whether they are going to need cytoreductive therapy or whether you can just start with phlebotomy and see how they do.

Oftentimes in the first visit, I recommend a bone marrow study. Is that going to be true 5 years from now? I am not sure. You know, next-generation sequencing (NGS) is turning into such an important part of determining prognosis in these patients. It helps if you have a great colleague down in hematopathology who can look at the bone marrow as it relates to megakaryocyte morphology, or whether there is early fibrosis.

Although these techniques may not be as prominent in practice today for determining diagnosis, they help us understand the prognosis. A bone marrow study or NGS is particularly useful when you have patients who you are convinced have PV, but it turns out they already have extensive fibrosis and are actually moving more toward the post-polycythemia phase a little faster than you think. While we do not use an allogeneic transplant often, in this scenario we may recommend it. Our primary goal at this point is to try to determine which patients would benefit from a transplant early on and to prepare the patient for this option.

What socioeconomic disparities have you observed in newly diagnosed patients?

Dr. Richard: There are definitely social disparities for people who have low income. I work in a veteran’s hospital where we take care of a lot of people who do not have health insurance, but who come to the VA because they do have benefits. If they are in our system, they get identified and their care is great. However, if they have been out in the regular system without health insurance, oftentimes they get diagnosed late. Identifying and treating patients from low socioeconomic backgrounds is an issue. I think everyone can agree with that.

We have a delicate situation with women veterans. Something that is incredibly painful that I think people should be aware of is the amount of military sexual trauma (MST) that has occurred over the years. These patients are in a unique place of trust with their care providers. They have spent a lot of time not being listened to in a variety of arenas. I see this in young military women who no one expects to have a stem cell disorder. We as health care providers do them a disservice if their complaints lead to referral to a psychotherapist or being prescribed a nonsteroidal anti-inflammatory drug or something like that. As health care providers, we are in a unique position to listen to and accurately evaluate these patients. We have a large population of veterans and, increasingly more women veterans, but I think we can all agree that they need better care, especially if they have suffered from MST. That is what I see in my patient population.

When I was a resident in Baltimore, it was Black people with lower income who did not trust doctors. We still have a lot of work to do.

From Ayurveda to the teachings of Hippocrates, medicine’s earliest traditions advanced a belief that the gut was the foundation of all health and disease. It wasn’t until recently, however, that Western medicine has adopted the notion of gut-barrier dysfunction as a pathologic phenomenon critical to not only digestive health but also chronic allergic, inflammatory, and autoimmune disease.

To learn more, Medscape contributor Akash Goel, MD, interviewed Elena Ivanina, DO, MPH, an integrative gastroenterologist, on the role of the gut barrier. Dr. Ivanina is the founder of the Center for Integrative Gut Health and the former director of Neurogastroenterology and Motility at Lenox Hill Hospital in New York. She runs the educational platform for all things gut health, gutlove.com.

What is the role of the gut barrier in overall health and disease?

The gut contains the human body’s largest interface between a person and their external environment. The actual interface is at the gut barrier, where there needs to be an ideal homeostasis and selectivity mechanism to allow the absorption of healthy nutrients, but on the other hand prevent the penetration of harmful microbes, food antigens, and other proinflammatory factors and toxins.

The gut barrier is made up of the mucus layer, gut microbiome, epithelial cells, and immune cells in the lamina propria. When this apparatus is disrupted by factors such as infection, low-fiber diet, antibiotics, and alcohol, then it cannot function normally to selectively keep out the harmful intraluminal substances.

Gut-barrier disruption leads to translocation of dangerous intraluminal components, such as bacteria and their components, into the gut wall and, most importantly, exposes the immune system to them. This causes improper immune activation and dysregulation, which has been shown to lead to various diseases, including gastrointestinal inflammatory disorders such as inflammatory bowel disease (IBD) and celiac disease, systemic autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and metabolic diseases such as obesity and diabetes.



Is disruption of this barrier what is usually referred to as “leaky gut”?

Leaky gut is a colloquial term for increased intestinal permeability or intestinal hyperpermeability. In a 2019 review article, Dr. Michael Camilleri exposes leaky gut as a term that can be misleading and confusing to the general population. It calls upon clinicians to have an increased awareness of the potential of barrier dysfunction in diseases, and to consider the barrier as a target for treatment.



Is leaky gut more of a mechanism of underlying chronic disease or is it a disease of its own?

Intestinal permeability is a pathophysiologic process in the gut with certain risk factors that in some conditions has been shown to precede chronic disease. There has not been any convincing evidence that it can be diagnosed and treated as its own entity, but research is ongoing.

In IBD, the Crohn’s and Colitis Canada Genetic, Environmental, Microbial Project research consortium has been studying individuals at increased risk for Crohn’s disease because of a first-degree family member with Crohn’s disease. They found an increased abundance of Ruminococcus torques in the microbiomes of at-risk individuals who went on to develop the disease. R. torques are mucin degraders that induce an increase in other mucin-using bacteria, which can contribute to gut-barrier compromise.

In other studies, patients have been found to have asymptomatic intestinal hyperpermeability years before their diagnosis of Crohn’s disease. This supports understanding more about the potential of intestinal hyperpermeability as its own diagnosis that, if addressed, could possibly prevent disease development.
 

The many possible sources of gut-barrier disruption

What causes leaky gut, and when should physicians and patients be suspicious if they have it?

There are many risk factors that have been associated with leaky gut in both human studies and animal studies, including acrolein (food toxin), aging, alcohol, antacid drugs, antibiotics, burn injury, chemotherapy, circadian rhythm disruption, corticosteroids, emulsifiers (food additives), strenuous exercise (≥ 2 hours) at 60% VO₂ max, starvation, fructose, fructans, gliadin (wheat protein), high-fat diet, high-salt diet, high-sugar diet, hyperglycemia, low-fiber diet, nonsteroidal anti-inflammatory drugs, pesticide, proinflammatory cytokines, psychological stress, radiation, sleep deprivation, smoking, and sweeteners.

Patients may be completely asymptomatic with leaky gut. Physicians should be suspicious if there is a genetic predisposition to chronic disease or if any risk factors are unveiled after assessing diet and lifestyle exposures.



What is the role of the Western diet and processed food consumption in driving disruptions of the gut barrier?

The Western diet reduces gut-barrier mucus thickness, leading to increased gut permeability. People who consume a Western diet typically eat less than 15 grams of fiber per day, which is significantly less than many other cultures, including the hunter-gatherers of Tanzania (Hadza), who get 100 or more grams of fiber a day in their food.

With a fiber-depleted diet, gut microbiota that normally feed on fiber gradually disappear and other commensals shift their metabolism to degrade the gut-barrier mucus layer.

A low-fiber diet also decreases short-chain fatty acid production, which reduces production of mucus and affects tight junction regulation.
 

Emerging evidence on causality

New evidence is demonstrating that previous functional conditions of the gastrointestinal tract, like functional dyspepsia, are associated with abnormalities to the intestinal barrier. What is the association between conditions like functional dyspepsia and irritable bowel syndrome (IBS) with gut-barrier disruption?

Conditions such as functional dyspepsia and IBS are similar in that their pathophysiology is incompletely understood and likely attributable to contributions from many different underlying mechanisms. This makes it difficult for clinicians to explain the condition to patients and often to treat without specific therapeutic targets.

Emerging evidence with new diagnostic tools, such as confocal laser endomicroscopy, has demonstrated altered mucosal barrier function in both conditions.

In patients with IBS who have a suspected food intolerance, studies looking at exposure to the food antigens found that the food caused immediate breaks, increased intervillous spaces, and increased inflammatory cells in the gut mucosa. These changes were associated with patient responses to exclusion diets.

In functional dyspepsia, another study, using confocal laser endomicroscopy, has shown that affected patients have significantly greater epithelial gap density in the duodenum, compared with healthy controls. There was also impaired duodenal-epithelial barrier integrity and evidence of increased cellular pyroptosis in the duodenal mucosa.

These findings suggest that while IBS and functional dyspepsia are still likely multifactorial, there may be a common preclinical state that can be further investigated as far as preventing its development and using it as a therapeutic target.



What diagnostic testing are you using to determine whether patients have disruptions to the gut barrier? Are they validated or more experimental?

There are various testing strategies that have been used in research to diagnose intestinal hyperpermeability. In a 2021 analysis, Dr. Michael Camilleri found that the optimal probes for measuring small intestinal and colonic permeability are the mass excreted of 13C-mannitol at 0-2 hours and lactulose during 2-8 hours or sucralose during 8-24 hours. Studies looking at postinfectious IBS have incorporated elevated urinary lactulose/mannitol ratios. Dr. Alessio Fasano and others have looked at using zonulin as a biomarker of impaired gut-barrier function. These tests are still considered experimental.



Is there an association between alterations in the gut microbiome and gut-barrier disruption?

There is an integral relationship between the gut microbiome and gut-barrier function, and dysbiosis can disrupt gut-barrier functionality.

The microbiota produce a variety of metabolites in close proximity to the gut epithelium, impacting gut-barrier function and immune response. For example, short-chain fatty acids produced by Bifidobacterium, Bacteroides, Enterobacter, Faecalibacterium, and Roseburia species impact host immune cell differentiation and metabolism as well as influence susceptibility to pathogens.

Studies have shown that sodium butyrate significantly improves epithelial-barrier function. Other experiments have used transplantation of the intestinal microbiota to show that introduction of certain microbial phenotypes can significantly increase gut permeability.
 

Practical advice for clinicians and patients

How do you advise patients to avoid gut-barrier disruption?

It is important to educate and counsel patients about the long list of risk factors, many of which are closely related to a Western diet and lifestyle, which can increase their risk for leaky gut.

Once one has it, can it be repaired? Can you share a bit about your protocols in general terms?

Many interventions have been shown to improve intestinal permeability. They include berberine, butyrate, caloric restriction and fasting, curcumin, dietary fiber (prebiotics), moderate exercise, fermented food, fish oil, glutamine, quercetin, probiotics, vagus nerve stimulation, vitamin D, and zinc.

Protocols have to be tailored to patients and their risk factors, diet, and lifestyle.

What are some tips from a nutrition and lifestyle standpoint that patients can follow to ensure a robust gut barrier?

It is important to emphasize a high-fiber diet with naturally fermented food, incorporating time-restricted eating, such as eating an early dinner and nothing else before bedtime, a moderate exercise routine, and gut-brain modulation with techniques such as acupuncture that can incorporate vagus nerve stimulation. Limited safe precision supplementation can be discussed on an individual basis based on the patient’s interest, additional testing, and other existing health conditions.
 

Dr. Akash Goel is a clinical assistant professor of medicine at Weill Cornell in gastroenterology and hepatology. He has disclosed no relevant financial relationships. His work has appeared on networks and publications such as CNN, The New York Times, Time Magazine, and Financial Times. He has a deep interest in nutrition, food as medicine, and the intersection between the gut microbiome and human health.

A version of this article appeared on Medscape.com.

From Ayurveda to the teachings of Hippocrates, medicine’s earliest traditions advanced a belief that the gut was the foundation of all health and disease. It wasn’t until recently, however, that Western medicine has adopted the notion of gut-barrier dysfunction as a pathologic phenomenon critical to not only digestive health but also chronic allergic, inflammatory, and autoimmune disease.

To learn more, Medscape contributor Akash Goel, MD, interviewed Elena Ivanina, DO, MPH, an integrative gastroenterologist, on the role of the gut barrier. Dr. Ivanina is the founder of the Center for Integrative Gut Health and the former director of Neurogastroenterology and Motility at Lenox Hill Hospital in New York. She runs the educational platform for all things gut health, gutlove.com.

What is the role of the gut barrier in overall health and disease?

The gut contains the human body’s largest interface between a person and their external environment. The actual interface is at the gut barrier, where there needs to be an ideal homeostasis and selectivity mechanism to allow the absorption of healthy nutrients, but on the other hand prevent the penetration of harmful microbes, food antigens, and other proinflammatory factors and toxins.

The gut barrier is made up of the mucus layer, gut microbiome, epithelial cells, and immune cells in the lamina propria. When this apparatus is disrupted by factors such as infection, low-fiber diet, antibiotics, and alcohol, then it cannot function normally to selectively keep out the harmful intraluminal substances.

Gut-barrier disruption leads to translocation of dangerous intraluminal components, such as bacteria and their components, into the gut wall and, most importantly, exposes the immune system to them. This causes improper immune activation and dysregulation, which has been shown to lead to various diseases, including gastrointestinal inflammatory disorders such as inflammatory bowel disease (IBD) and celiac disease, systemic autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and metabolic diseases such as obesity and diabetes.



Is disruption of this barrier what is usually referred to as “leaky gut”?

Leaky gut is a colloquial term for increased intestinal permeability or intestinal hyperpermeability. In a 2019 review article, Dr. Michael Camilleri exposes leaky gut as a term that can be misleading and confusing to the general population. It calls upon clinicians to have an increased awareness of the potential of barrier dysfunction in diseases, and to consider the barrier as a target for treatment.



Is leaky gut more of a mechanism of underlying chronic disease or is it a disease of its own?

Intestinal permeability is a pathophysiologic process in the gut with certain risk factors that in some conditions has been shown to precede chronic disease. There has not been any convincing evidence that it can be diagnosed and treated as its own entity, but research is ongoing.

In IBD, the Crohn’s and Colitis Canada Genetic, Environmental, Microbial Project research consortium has been studying individuals at increased risk for Crohn’s disease because of a first-degree family member with Crohn’s disease. They found an increased abundance of Ruminococcus torques in the microbiomes of at-risk individuals who went on to develop the disease. R. torques are mucin degraders that induce an increase in other mucin-using bacteria, which can contribute to gut-barrier compromise.

In other studies, patients have been found to have asymptomatic intestinal hyperpermeability years before their diagnosis of Crohn’s disease. This supports understanding more about the potential of intestinal hyperpermeability as its own diagnosis that, if addressed, could possibly prevent disease development.
 

The many possible sources of gut-barrier disruption

What causes leaky gut, and when should physicians and patients be suspicious if they have it?

There are many risk factors that have been associated with leaky gut in both human studies and animal studies, including acrolein (food toxin), aging, alcohol, antacid drugs, antibiotics, burn injury, chemotherapy, circadian rhythm disruption, corticosteroids, emulsifiers (food additives), strenuous exercise (≥ 2 hours) at 60% VO₂ max, starvation, fructose, fructans, gliadin (wheat protein), high-fat diet, high-salt diet, high-sugar diet, hyperglycemia, low-fiber diet, nonsteroidal anti-inflammatory drugs, pesticide, proinflammatory cytokines, psychological stress, radiation, sleep deprivation, smoking, and sweeteners.

Patients may be completely asymptomatic with leaky gut. Physicians should be suspicious if there is a genetic predisposition to chronic disease or if any risk factors are unveiled after assessing diet and lifestyle exposures.



What is the role of the Western diet and processed food consumption in driving disruptions of the gut barrier?

The Western diet reduces gut-barrier mucus thickness, leading to increased gut permeability. People who consume a Western diet typically eat less than 15 grams of fiber per day, which is significantly less than many other cultures, including the hunter-gatherers of Tanzania (Hadza), who get 100 or more grams of fiber a day in their food.

With a fiber-depleted diet, gut microbiota that normally feed on fiber gradually disappear and other commensals shift their metabolism to degrade the gut-barrier mucus layer.

A low-fiber diet also decreases short-chain fatty acid production, which reduces production of mucus and affects tight junction regulation.
 

Emerging evidence on causality

New evidence is demonstrating that previous functional conditions of the gastrointestinal tract, like functional dyspepsia, are associated with abnormalities to the intestinal barrier. What is the association between conditions like functional dyspepsia and irritable bowel syndrome (IBS) with gut-barrier disruption?

Conditions such as functional dyspepsia and IBS are similar in that their pathophysiology is incompletely understood and likely attributable to contributions from many different underlying mechanisms. This makes it difficult for clinicians to explain the condition to patients and often to treat without specific therapeutic targets.

Emerging evidence with new diagnostic tools, such as confocal laser endomicroscopy, has demonstrated altered mucosal barrier function in both conditions.

In patients with IBS who have a suspected food intolerance, studies looking at exposure to the food antigens found that the food caused immediate breaks, increased intervillous spaces, and increased inflammatory cells in the gut mucosa. These changes were associated with patient responses to exclusion diets.

In functional dyspepsia, another study, using confocal laser endomicroscopy, has shown that affected patients have significantly greater epithelial gap density in the duodenum, compared with healthy controls. There was also impaired duodenal-epithelial barrier integrity and evidence of increased cellular pyroptosis in the duodenal mucosa.

These findings suggest that while IBS and functional dyspepsia are still likely multifactorial, there may be a common preclinical state that can be further investigated as far as preventing its development and using it as a therapeutic target.



What diagnostic testing are you using to determine whether patients have disruptions to the gut barrier? Are they validated or more experimental?

There are various testing strategies that have been used in research to diagnose intestinal hyperpermeability. In a 2021 analysis, Dr. Michael Camilleri found that the optimal probes for measuring small intestinal and colonic permeability are the mass excreted of 13C-mannitol at 0-2 hours and lactulose during 2-8 hours or sucralose during 8-24 hours. Studies looking at postinfectious IBS have incorporated elevated urinary lactulose/mannitol ratios. Dr. Alessio Fasano and others have looked at using zonulin as a biomarker of impaired gut-barrier function. These tests are still considered experimental.



Is there an association between alterations in the gut microbiome and gut-barrier disruption?

There is an integral relationship between the gut microbiome and gut-barrier function, and dysbiosis can disrupt gut-barrier functionality.

The microbiota produce a variety of metabolites in close proximity to the gut epithelium, impacting gut-barrier function and immune response. For example, short-chain fatty acids produced by Bifidobacterium, Bacteroides, Enterobacter, Faecalibacterium, and Roseburia species impact host immune cell differentiation and metabolism as well as influence susceptibility to pathogens.

Studies have shown that sodium butyrate significantly improves epithelial-barrier function. Other experiments have used transplantation of the intestinal microbiota to show that introduction of certain microbial phenotypes can significantly increase gut permeability.
 

Practical advice for clinicians and patients

How do you advise patients to avoid gut-barrier disruption?

It is important to educate and counsel patients about the long list of risk factors, many of which are closely related to a Western diet and lifestyle, which can increase their risk for leaky gut.

Once one has it, can it be repaired? Can you share a bit about your protocols in general terms?

Many interventions have been shown to improve intestinal permeability. They include berberine, butyrate, caloric restriction and fasting, curcumin, dietary fiber (prebiotics), moderate exercise, fermented food, fish oil, glutamine, quercetin, probiotics, vagus nerve stimulation, vitamin D, and zinc.

Protocols have to be tailored to patients and their risk factors, diet, and lifestyle.

What are some tips from a nutrition and lifestyle standpoint that patients can follow to ensure a robust gut barrier?

It is important to emphasize a high-fiber diet with naturally fermented food, incorporating time-restricted eating, such as eating an early dinner and nothing else before bedtime, a moderate exercise routine, and gut-brain modulation with techniques such as acupuncture that can incorporate vagus nerve stimulation. Limited safe precision supplementation can be discussed on an individual basis based on the patient’s interest, additional testing, and other existing health conditions.
 

Dr. Akash Goel is a clinical assistant professor of medicine at Weill Cornell in gastroenterology and hepatology. He has disclosed no relevant financial relationships. His work has appeared on networks and publications such as CNN, The New York Times, Time Magazine, and Financial Times. He has a deep interest in nutrition, food as medicine, and the intersection between the gut microbiome and human health.

A version of this article appeared on Medscape.com.

From Ayurveda to the teachings of Hippocrates, medicine’s earliest traditions advanced a belief that the gut was the foundation of all health and disease. It wasn’t until recently, however, that Western medicine has adopted the notion of gut-barrier dysfunction as a pathologic phenomenon critical to not only digestive health but also chronic allergic, inflammatory, and autoimmune disease.

To learn more, Medscape contributor Akash Goel, MD, interviewed Elena Ivanina, DO, MPH, an integrative gastroenterologist, on the role of the gut barrier. Dr. Ivanina is the founder of the Center for Integrative Gut Health and the former director of Neurogastroenterology and Motility at Lenox Hill Hospital in New York. She runs the educational platform for all things gut health, gutlove.com.

What is the role of the gut barrier in overall health and disease?

The gut contains the human body’s largest interface between a person and their external environment. The actual interface is at the gut barrier, where there needs to be an ideal homeostasis and selectivity mechanism to allow the absorption of healthy nutrients, but on the other hand prevent the penetration of harmful microbes, food antigens, and other proinflammatory factors and toxins.

The gut barrier is made up of the mucus layer, gut microbiome, epithelial cells, and immune cells in the lamina propria. When this apparatus is disrupted by factors such as infection, low-fiber diet, antibiotics, and alcohol, then it cannot function normally to selectively keep out the harmful intraluminal substances.

Gut-barrier disruption leads to translocation of dangerous intraluminal components, such as bacteria and their components, into the gut wall and, most importantly, exposes the immune system to them. This causes improper immune activation and dysregulation, which has been shown to lead to various diseases, including gastrointestinal inflammatory disorders such as inflammatory bowel disease (IBD) and celiac disease, systemic autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and metabolic diseases such as obesity and diabetes.



Is disruption of this barrier what is usually referred to as “leaky gut”?

Leaky gut is a colloquial term for increased intestinal permeability or intestinal hyperpermeability. In a 2019 review article, Dr. Michael Camilleri exposes leaky gut as a term that can be misleading and confusing to the general population. It calls upon clinicians to have an increased awareness of the potential of barrier dysfunction in diseases, and to consider the barrier as a target for treatment.



Is leaky gut more of a mechanism of underlying chronic disease or is it a disease of its own?

Intestinal permeability is a pathophysiologic process in the gut with certain risk factors that in some conditions has been shown to precede chronic disease. There has not been any convincing evidence that it can be diagnosed and treated as its own entity, but research is ongoing.

In IBD, the Crohn’s and Colitis Canada Genetic, Environmental, Microbial Project research consortium has been studying individuals at increased risk for Crohn’s disease because of a first-degree family member with Crohn’s disease. They found an increased abundance of Ruminococcus torques in the microbiomes of at-risk individuals who went on to develop the disease. R. torques are mucin degraders that induce an increase in other mucin-using bacteria, which can contribute to gut-barrier compromise.

In other studies, patients have been found to have asymptomatic intestinal hyperpermeability years before their diagnosis of Crohn’s disease. This supports understanding more about the potential of intestinal hyperpermeability as its own diagnosis that, if addressed, could possibly prevent disease development.
 

The many possible sources of gut-barrier disruption

What causes leaky gut, and when should physicians and patients be suspicious if they have it?

There are many risk factors that have been associated with leaky gut in both human studies and animal studies, including acrolein (food toxin), aging, alcohol, antacid drugs, antibiotics, burn injury, chemotherapy, circadian rhythm disruption, corticosteroids, emulsifiers (food additives), strenuous exercise (≥ 2 hours) at 60% VO₂ max, starvation, fructose, fructans, gliadin (wheat protein), high-fat diet, high-salt diet, high-sugar diet, hyperglycemia, low-fiber diet, nonsteroidal anti-inflammatory drugs, pesticide, proinflammatory cytokines, psychological stress, radiation, sleep deprivation, smoking, and sweeteners.

Patients may be completely asymptomatic with leaky gut. Physicians should be suspicious if there is a genetic predisposition to chronic disease or if any risk factors are unveiled after assessing diet and lifestyle exposures.



What is the role of the Western diet and processed food consumption in driving disruptions of the gut barrier?

The Western diet reduces gut-barrier mucus thickness, leading to increased gut permeability. People who consume a Western diet typically eat less than 15 grams of fiber per day, which is significantly less than many other cultures, including the hunter-gatherers of Tanzania (Hadza), who get 100 or more grams of fiber a day in their food.

With a fiber-depleted diet, gut microbiota that normally feed on fiber gradually disappear and other commensals shift their metabolism to degrade the gut-barrier mucus layer.

A low-fiber diet also decreases short-chain fatty acid production, which reduces production of mucus and affects tight junction regulation.
 

Emerging evidence on causality

New evidence is demonstrating that previous functional conditions of the gastrointestinal tract, like functional dyspepsia, are associated with abnormalities to the intestinal barrier. What is the association between conditions like functional dyspepsia and irritable bowel syndrome (IBS) with gut-barrier disruption?

Conditions such as functional dyspepsia and IBS are similar in that their pathophysiology is incompletely understood and likely attributable to contributions from many different underlying mechanisms. This makes it difficult for clinicians to explain the condition to patients and often to treat without specific therapeutic targets.

Emerging evidence with new diagnostic tools, such as confocal laser endomicroscopy, has demonstrated altered mucosal barrier function in both conditions.

In patients with IBS who have a suspected food intolerance, studies looking at exposure to the food antigens found that the food caused immediate breaks, increased intervillous spaces, and increased inflammatory cells in the gut mucosa. These changes were associated with patient responses to exclusion diets.

In functional dyspepsia, another study, using confocal laser endomicroscopy, has shown that affected patients have significantly greater epithelial gap density in the duodenum, compared with healthy controls. There was also impaired duodenal-epithelial barrier integrity and evidence of increased cellular pyroptosis in the duodenal mucosa.

These findings suggest that while IBS and functional dyspepsia are still likely multifactorial, there may be a common preclinical state that can be further investigated as far as preventing its development and using it as a therapeutic target.



What diagnostic testing are you using to determine whether patients have disruptions to the gut barrier? Are they validated or more experimental?

There are various testing strategies that have been used in research to diagnose intestinal hyperpermeability. In a 2021 analysis, Dr. Michael Camilleri found that the optimal probes for measuring small intestinal and colonic permeability are the mass excreted of 13C-mannitol at 0-2 hours and lactulose during 2-8 hours or sucralose during 8-24 hours. Studies looking at postinfectious IBS have incorporated elevated urinary lactulose/mannitol ratios. Dr. Alessio Fasano and others have looked at using zonulin as a biomarker of impaired gut-barrier function. These tests are still considered experimental.



Is there an association between alterations in the gut microbiome and gut-barrier disruption?

There is an integral relationship between the gut microbiome and gut-barrier function, and dysbiosis can disrupt gut-barrier functionality.

The microbiota produce a variety of metabolites in close proximity to the gut epithelium, impacting gut-barrier function and immune response. For example, short-chain fatty acids produced by Bifidobacterium, Bacteroides, Enterobacter, Faecalibacterium, and Roseburia species impact host immune cell differentiation and metabolism as well as influence susceptibility to pathogens.

Studies have shown that sodium butyrate significantly improves epithelial-barrier function. Other experiments have used transplantation of the intestinal microbiota to show that introduction of certain microbial phenotypes can significantly increase gut permeability.
 

Practical advice for clinicians and patients

How do you advise patients to avoid gut-barrier disruption?

It is important to educate and counsel patients about the long list of risk factors, many of which are closely related to a Western diet and lifestyle, which can increase their risk for leaky gut.

Once one has it, can it be repaired? Can you share a bit about your protocols in general terms?

Many interventions have been shown to improve intestinal permeability. They include berberine, butyrate, caloric restriction and fasting, curcumin, dietary fiber (prebiotics), moderate exercise, fermented food, fish oil, glutamine, quercetin, probiotics, vagus nerve stimulation, vitamin D, and zinc.

Protocols have to be tailored to patients and their risk factors, diet, and lifestyle.

What are some tips from a nutrition and lifestyle standpoint that patients can follow to ensure a robust gut barrier?

It is important to emphasize a high-fiber diet with naturally fermented food, incorporating time-restricted eating, such as eating an early dinner and nothing else before bedtime, a moderate exercise routine, and gut-brain modulation with techniques such as acupuncture that can incorporate vagus nerve stimulation. Limited safe precision supplementation can be discussed on an individual basis based on the patient’s interest, additional testing, and other existing health conditions.
 

Dr. Akash Goel is a clinical assistant professor of medicine at Weill Cornell in gastroenterology and hepatology. He has disclosed no relevant financial relationships. His work has appeared on networks and publications such as CNN, The New York Times, Time Magazine, and Financial Times. He has a deep interest in nutrition, food as medicine, and the intersection between the gut microbiome and human health.

A version of this article appeared on Medscape.com.

More than 1 in 10 Americans over age 60 years will be diagnosed with cancer, according to the National Cancer Institute, making screening for the disease in older patients imperative. Much of the burden of cancer screening falls on primary care physicians. This news organization spoke recently with William L. Dahut, MD, chief scientific officer of the American Cancer Society, about the particular challenges of screening in older patients.

Question: How much does cancer screening change with age? What are the considerations for clinicians – what risks and comorbidities are important to consider in older populations?

Answer: We at the American Cancer Society are giving a lot of thought to how to help primary care practices keep up with screening, particularly with respect to guidelines, but also best practices where judgment is required, such as cancer screening in their older patients.

We’ve had a lot of conversations recently about cancer risk in the young, largely because data show rates are going up for colorectal and breast cancer in this population. But it’s not one size fits all. Screening for young women who have a BRCA gene, if they have dense breasts, or if they have a strong family history of breast cancer should be different from those who are at average risk of the disease.

But statistically, there are about 15 per 100,000 breast cancer diagnoses in women under the age of 40 while over the age of 65 it’s 443 per 100,000. So, the risk significantly increases with age but we should not have an arbitrary cut-off. The life expectancy of a woman at age 75 is about 13.5 years. If you’re over the age of 70 or 75, then it’s going to be comorbidities that you look at, as well as individual patient decisions. Patients may say, “I don’t want to ever go through a mammogram again, because I don’t want to have a biopsy again, and I’m not going to get treated.” Or they may say, “My mom died of metastatic breast cancer when she was 82 and I want to know.”
 

Q: How should primary care physicians interpret conflicting guidance from the major medical groups? For example, the American College of Gastroenterology and your own organization recommend colorectal cancer screening start at age 45 now. But the American College of Physicians recently came out and said 50. What is a well-meaning primary care physician supposed to do?

A: We make more of guideline differences than we should. Sometimes guideline differences aren’t a reflection of different judgments, but rather what data were available when the most recent update took place. For colorectal cancer screening, the ACS dropped the age to begin screening to 45 in 2018 based on a very careful consideration of disease burden data and within several years most other guideline developers reached the same conclusion.

However, I think it’s good for family practice and internal medicine doctors to know that significant GI symptoms in a young patient could be colorectal cancer. It’s not as if nobody sees a 34-year-old or 27-year-old with colorectal cancer. They should be aware that if something goes away in a day or two, that’s fine, but persistent GI symptoms need a cancer workup – colonoscopy or referral to a gastroenterologist. So that’s why I think age 45 is the time when folks should begin screening.
 

Q: What are the medical-legal issues for a physician who is trying to follow guideline-based care when there are different guidelines?

A: Any physician can say, “We follow the guidelines of this particular organization.” I don’t think anyone can say that an organization’s guidelines are malpractice. For individual physicians, following a set of office-based guidelines will hopefully keep them out of legal difficulty.

Q: What are the risks of overscreening, especially in breast cancer where false positives may result in invasive testing?

A: What people think of as overscreening takes a number of different forms. What one guideline would imply is overscreening is recommended screening by another guideline. I think we would all agree that in an average-risk population, beginning screening before it is recommended would be overscreening, and continuing screening when a patient has life-limiting comorbidities would constitute overscreening. Screening too frequently can constitute overscreening.

For example, many women report that their doctors still are advising a baseline mammogram at age 35. Most guideline-developing organizations would regard this as overscreening in an average-risk population.

I think we are also getting better, certainly in prostate cancer, about knowing who needs to be treated and not treated. There are a lot of cancers that would have been treated 20-30 years ago but now are being safely followed with PSA and MRI. We may be able to get to that point with breast cancer over time, too.
 

Q: Are you saying that there may be breast cancers for which active surveillance is appropriate? Is that already the case?

A: We’re not there yet. I think some of the DCIS breast cancers are part of the discussion on whether hormonal treatment or surgeries are done. I think people do have those discussions in the context of morbidity and life expectancy. Over time, we’re likely to have more cancers for which we won’t need surgical treatments.
 

Q: Why did the American Cancer Society change the upper limit for lung cancer screening from 75 to 80 years of age?

 A: For an individual older than 65, screening will now continue until the patient is 80, assuming the patient is in good health. According to the previous guideline, if a patient was 65 and more than 15 years beyond smoking cessation, then screening would end. This is exactly the time when we see lung cancers increase in the population and so a curable lung cancer would not previously have been detected by a screening CT scan. *  

Q: What role do the multicancer blood and DNA tests play in screening now?

A: As you know, the Exact Sciences Cologuard test is already included in major guidelines for colorectal cancer screening and covered by insurance. Our philosophy on multicancer early detection tests is that we’re supportive of Medicare reimbursement when two things occur: 1. When we know there’s clinical benefit, and 2. When the test has been approved by the FDA.

The multicancer early detection tests in development and undergoing prospective research would not now replace screening for the cancers with established screening programs, but if they are shown to have clinical utility for the cancers in their panel, we would be able to reduce deaths from cancers that mostly are diagnosed at late stages and have poor prognoses.

There’s going to be a need for expertise in primary care practices to help interpret the tests. These are new questions, which are well beyond what even the typical oncologist is trained in, much less primary care physicians. We and other organizations are working on providing those answers.
 

Q: While we’re on the subject of the future, how do you envision AI helping or hindering cancer screening specifically in primary care?

A: I think AI is going to help things for a couple of reasons. The ability of AI is to get through data quickly and get you information that’s personalized and useful. If AI tools could let a patient know their individual risk of a cancer in the near and long term, that would help the primary care doctor screen in an individualized way. I think AI is going to be able to improve both diagnostic radiology and pathology, and could make a very big difference in settings outside of large cancer centers that operate at high volume every day. The data look very promising for AI to contribute to risk estimation by operating like a second reader in imaging and pathology.
 

Q: Anything else you’d like to say on this subject that clinicians should know?

A: The questions about whether or not patients should be screened is being pushed on family practice doctors and internists and these questions require a relationship with the patient. A hard stopping point at age 70 when lots of people will live 20 years or more doesn’t make sense.

There’s very little data from randomized clinical trials of screening people over the age of 70. We know that cancer risk does obviously increase with age, particularly prostate and breast cancer. And these are the cancers that are going to be the most common in your practices. If someone has a known mutation, I think you’re going to look differently at screening them. And first-degree family members, particularly for the more aggressive cancers, should be considered for screening.

My philosophy on cancer screening in the elderly is that I think the guidelines are guidelines. If patients have very limited life expectancy, then they shouldn’t be screened. There are calculators that estimate life expectancy in the context of current age and current health status, and these can be useful for decision making and counseling. Patients never think their life expectancy is shorter than 10 years. If their life expectancy is longer than 10 years, then I think, all things being equal, they should continue screening, but the question of ongoing screening needs to be periodically revisited.

*This story was updated on Nov. 1, 2023.
 

More than 1 in 10 Americans over age 60 years will be diagnosed with cancer, according to the National Cancer Institute, making screening for the disease in older patients imperative. Much of the burden of cancer screening falls on primary care physicians. This news organization spoke recently with William L. Dahut, MD, chief scientific officer of the American Cancer Society, about the particular challenges of screening in older patients.

Question: How much does cancer screening change with age? What are the considerations for clinicians – what risks and comorbidities are important to consider in older populations?

Answer: We at the American Cancer Society are giving a lot of thought to how to help primary care practices keep up with screening, particularly with respect to guidelines, but also best practices where judgment is required, such as cancer screening in their older patients.

We’ve had a lot of conversations recently about cancer risk in the young, largely because data show rates are going up for colorectal and breast cancer in this population. But it’s not one size fits all. Screening for young women who have a BRCA gene, if they have dense breasts, or if they have a strong family history of breast cancer should be different from those who are at average risk of the disease.

But statistically, there are about 15 per 100,000 breast cancer diagnoses in women under the age of 40 while over the age of 65 it’s 443 per 100,000. So, the risk significantly increases with age but we should not have an arbitrary cut-off. The life expectancy of a woman at age 75 is about 13.5 years. If you’re over the age of 70 or 75, then it’s going to be comorbidities that you look at, as well as individual patient decisions. Patients may say, “I don’t want to ever go through a mammogram again, because I don’t want to have a biopsy again, and I’m not going to get treated.” Or they may say, “My mom died of metastatic breast cancer when she was 82 and I want to know.”
 

Q: How should primary care physicians interpret conflicting guidance from the major medical groups? For example, the American College of Gastroenterology and your own organization recommend colorectal cancer screening start at age 45 now. But the American College of Physicians recently came out and said 50. What is a well-meaning primary care physician supposed to do?

A: We make more of guideline differences than we should. Sometimes guideline differences aren’t a reflection of different judgments, but rather what data were available when the most recent update took place. For colorectal cancer screening, the ACS dropped the age to begin screening to 45 in 2018 based on a very careful consideration of disease burden data and within several years most other guideline developers reached the same conclusion.

However, I think it’s good for family practice and internal medicine doctors to know that significant GI symptoms in a young patient could be colorectal cancer. It’s not as if nobody sees a 34-year-old or 27-year-old with colorectal cancer. They should be aware that if something goes away in a day or two, that’s fine, but persistent GI symptoms need a cancer workup – colonoscopy or referral to a gastroenterologist. So that’s why I think age 45 is the time when folks should begin screening.
 

Q: What are the medical-legal issues for a physician who is trying to follow guideline-based care when there are different guidelines?

A: Any physician can say, “We follow the guidelines of this particular organization.” I don’t think anyone can say that an organization’s guidelines are malpractice. For individual physicians, following a set of office-based guidelines will hopefully keep them out of legal difficulty.

Q: What are the risks of overscreening, especially in breast cancer where false positives may result in invasive testing?

A: What people think of as overscreening takes a number of different forms. What one guideline would imply is overscreening is recommended screening by another guideline. I think we would all agree that in an average-risk population, beginning screening before it is recommended would be overscreening, and continuing screening when a patient has life-limiting comorbidities would constitute overscreening. Screening too frequently can constitute overscreening.

For example, many women report that their doctors still are advising a baseline mammogram at age 35. Most guideline-developing organizations would regard this as overscreening in an average-risk population.

I think we are also getting better, certainly in prostate cancer, about knowing who needs to be treated and not treated. There are a lot of cancers that would have been treated 20-30 years ago but now are being safely followed with PSA and MRI. We may be able to get to that point with breast cancer over time, too.
 

Q: Are you saying that there may be breast cancers for which active surveillance is appropriate? Is that already the case?

A: We’re not there yet. I think some of the DCIS breast cancers are part of the discussion on whether hormonal treatment or surgeries are done. I think people do have those discussions in the context of morbidity and life expectancy. Over time, we’re likely to have more cancers for which we won’t need surgical treatments.
 

Q: Why did the American Cancer Society change the upper limit for lung cancer screening from 75 to 80 years of age?

 A: For an individual older than 65, screening will now continue until the patient is 80, assuming the patient is in good health. According to the previous guideline, if a patient was 65 and more than 15 years beyond smoking cessation, then screening would end. This is exactly the time when we see lung cancers increase in the population and so a curable lung cancer would not previously have been detected by a screening CT scan. *  

Q: What role do the multicancer blood and DNA tests play in screening now?

A: As you know, the Exact Sciences Cologuard test is already included in major guidelines for colorectal cancer screening and covered by insurance. Our philosophy on multicancer early detection tests is that we’re supportive of Medicare reimbursement when two things occur: 1. When we know there’s clinical benefit, and 2. When the test has been approved by the FDA.

The multicancer early detection tests in development and undergoing prospective research would not now replace screening for the cancers with established screening programs, but if they are shown to have clinical utility for the cancers in their panel, we would be able to reduce deaths from cancers that mostly are diagnosed at late stages and have poor prognoses.

There’s going to be a need for expertise in primary care practices to help interpret the tests. These are new questions, which are well beyond what even the typical oncologist is trained in, much less primary care physicians. We and other organizations are working on providing those answers.
 

Q: While we’re on the subject of the future, how do you envision AI helping or hindering cancer screening specifically in primary care?

A: I think AI is going to help things for a couple of reasons. The ability of AI is to get through data quickly and get you information that’s personalized and useful. If AI tools could let a patient know their individual risk of a cancer in the near and long term, that would help the primary care doctor screen in an individualized way. I think AI is going to be able to improve both diagnostic radiology and pathology, and could make a very big difference in settings outside of large cancer centers that operate at high volume every day. The data look very promising for AI to contribute to risk estimation by operating like a second reader in imaging and pathology.
 

Q: Anything else you’d like to say on this subject that clinicians should know?

A: The questions about whether or not patients should be screened is being pushed on family practice doctors and internists and these questions require a relationship with the patient. A hard stopping point at age 70 when lots of people will live 20 years or more doesn’t make sense.

There’s very little data from randomized clinical trials of screening people over the age of 70. We know that cancer risk does obviously increase with age, particularly prostate and breast cancer. And these are the cancers that are going to be the most common in your practices. If someone has a known mutation, I think you’re going to look differently at screening them. And first-degree family members, particularly for the more aggressive cancers, should be considered for screening.

My philosophy on cancer screening in the elderly is that I think the guidelines are guidelines. If patients have very limited life expectancy, then they shouldn’t be screened. There are calculators that estimate life expectancy in the context of current age and current health status, and these can be useful for decision making and counseling. Patients never think their life expectancy is shorter than 10 years. If their life expectancy is longer than 10 years, then I think, all things being equal, they should continue screening, but the question of ongoing screening needs to be periodically revisited.

*This story was updated on Nov. 1, 2023.
 

More than 1 in 10 Americans over age 60 years will be diagnosed with cancer, according to the National Cancer Institute, making screening for the disease in older patients imperative. Much of the burden of cancer screening falls on primary care physicians. This news organization spoke recently with William L. Dahut, MD, chief scientific officer of the American Cancer Society, about the particular challenges of screening in older patients.

Question: How much does cancer screening change with age? What are the considerations for clinicians – what risks and comorbidities are important to consider in older populations?

Answer: We at the American Cancer Society are giving a lot of thought to how to help primary care practices keep up with screening, particularly with respect to guidelines, but also best practices where judgment is required, such as cancer screening in their older patients.

We’ve had a lot of conversations recently about cancer risk in the young, largely because data show rates are going up for colorectal and breast cancer in this population. But it’s not one size fits all. Screening for young women who have a BRCA gene, if they have dense breasts, or if they have a strong family history of breast cancer should be different from those who are at average risk of the disease.

But statistically, there are about 15 per 100,000 breast cancer diagnoses in women under the age of 40 while over the age of 65 it’s 443 per 100,000. So, the risk significantly increases with age but we should not have an arbitrary cut-off. The life expectancy of a woman at age 75 is about 13.5 years. If you’re over the age of 70 or 75, then it’s going to be comorbidities that you look at, as well as individual patient decisions. Patients may say, “I don’t want to ever go through a mammogram again, because I don’t want to have a biopsy again, and I’m not going to get treated.” Or they may say, “My mom died of metastatic breast cancer when she was 82 and I want to know.”
 

Q: How should primary care physicians interpret conflicting guidance from the major medical groups? For example, the American College of Gastroenterology and your own organization recommend colorectal cancer screening start at age 45 now. But the American College of Physicians recently came out and said 50. What is a well-meaning primary care physician supposed to do?

A: We make more of guideline differences than we should. Sometimes guideline differences aren’t a reflection of different judgments, but rather what data were available when the most recent update took place. For colorectal cancer screening, the ACS dropped the age to begin screening to 45 in 2018 based on a very careful consideration of disease burden data and within several years most other guideline developers reached the same conclusion.

However, I think it’s good for family practice and internal medicine doctors to know that significant GI symptoms in a young patient could be colorectal cancer. It’s not as if nobody sees a 34-year-old or 27-year-old with colorectal cancer. They should be aware that if something goes away in a day or two, that’s fine, but persistent GI symptoms need a cancer workup – colonoscopy or referral to a gastroenterologist. So that’s why I think age 45 is the time when folks should begin screening.
 

Q: What are the medical-legal issues for a physician who is trying to follow guideline-based care when there are different guidelines?

A: Any physician can say, “We follow the guidelines of this particular organization.” I don’t think anyone can say that an organization’s guidelines are malpractice. For individual physicians, following a set of office-based guidelines will hopefully keep them out of legal difficulty.

Q: What are the risks of overscreening, especially in breast cancer where false positives may result in invasive testing?

A: What people think of as overscreening takes a number of different forms. What one guideline would imply is overscreening is recommended screening by another guideline. I think we would all agree that in an average-risk population, beginning screening before it is recommended would be overscreening, and continuing screening when a patient has life-limiting comorbidities would constitute overscreening. Screening too frequently can constitute overscreening.

For example, many women report that their doctors still are advising a baseline mammogram at age 35. Most guideline-developing organizations would regard this as overscreening in an average-risk population.

I think we are also getting better, certainly in prostate cancer, about knowing who needs to be treated and not treated. There are a lot of cancers that would have been treated 20-30 years ago but now are being safely followed with PSA and MRI. We may be able to get to that point with breast cancer over time, too.
 

Q: Are you saying that there may be breast cancers for which active surveillance is appropriate? Is that already the case?

A: We’re not there yet. I think some of the DCIS breast cancers are part of the discussion on whether hormonal treatment or surgeries are done. I think people do have those discussions in the context of morbidity and life expectancy. Over time, we’re likely to have more cancers for which we won’t need surgical treatments.
 

Q: Why did the American Cancer Society change the upper limit for lung cancer screening from 75 to 80 years of age?

 A: For an individual older than 65, screening will now continue until the patient is 80, assuming the patient is in good health. According to the previous guideline, if a patient was 65 and more than 15 years beyond smoking cessation, then screening would end. This is exactly the time when we see lung cancers increase in the population and so a curable lung cancer would not previously have been detected by a screening CT scan. *  

Q: What role do the multicancer blood and DNA tests play in screening now?

A: As you know, the Exact Sciences Cologuard test is already included in major guidelines for colorectal cancer screening and covered by insurance. Our philosophy on multicancer early detection tests is that we’re supportive of Medicare reimbursement when two things occur: 1. When we know there’s clinical benefit, and 2. When the test has been approved by the FDA.

The multicancer early detection tests in development and undergoing prospective research would not now replace screening for the cancers with established screening programs, but if they are shown to have clinical utility for the cancers in their panel, we would be able to reduce deaths from cancers that mostly are diagnosed at late stages and have poor prognoses.

There’s going to be a need for expertise in primary care practices to help interpret the tests. These are new questions, which are well beyond what even the typical oncologist is trained in, much less primary care physicians. We and other organizations are working on providing those answers.
 

Q: While we’re on the subject of the future, how do you envision AI helping or hindering cancer screening specifically in primary care?

A: I think AI is going to help things for a couple of reasons. The ability of AI is to get through data quickly and get you information that’s personalized and useful. If AI tools could let a patient know their individual risk of a cancer in the near and long term, that would help the primary care doctor screen in an individualized way. I think AI is going to be able to improve both diagnostic radiology and pathology, and could make a very big difference in settings outside of large cancer centers that operate at high volume every day. The data look very promising for AI to contribute to risk estimation by operating like a second reader in imaging and pathology.
 

Q: Anything else you’d like to say on this subject that clinicians should know?

A: The questions about whether or not patients should be screened is being pushed on family practice doctors and internists and these questions require a relationship with the patient. A hard stopping point at age 70 when lots of people will live 20 years or more doesn’t make sense.

There’s very little data from randomized clinical trials of screening people over the age of 70. We know that cancer risk does obviously increase with age, particularly prostate and breast cancer. And these are the cancers that are going to be the most common in your practices. If someone has a known mutation, I think you’re going to look differently at screening them. And first-degree family members, particularly for the more aggressive cancers, should be considered for screening.

My philosophy on cancer screening in the elderly is that I think the guidelines are guidelines. If patients have very limited life expectancy, then they shouldn’t be screened. There are calculators that estimate life expectancy in the context of current age and current health status, and these can be useful for decision making and counseling. Patients never think their life expectancy is shorter than 10 years. If their life expectancy is longer than 10 years, then I think, all things being equal, they should continue screening, but the question of ongoing screening needs to be periodically revisited.

*This story was updated on Nov. 1, 2023.
 

In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.

Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.

Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview. His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.

Cummings_Jeffrey_Las Vegas 1_web.jpg

Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.

Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.

Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
 

How did all this begin?

Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.

How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?

We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.

We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
 

Are you able to capture every Alzheimer’s drug in development globally?

If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.

Who are the report’s main readers?

Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.

It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
 

What about patients and families? Are they able to use the report as well?

One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.

Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?

My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.

What other approaches are interesting to you?

We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.

Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?

That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.

What about other therapy classes?

We aim to be more serious about devices.

What will you call the database?

The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.

The annual pipeline report is very much associated with you. Is the database going to be different?

Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.

Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.

We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.

Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.

In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.

Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.

Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview. His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.

Cummings_Jeffrey_Las Vegas 1_web.jpg

Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.

Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.

Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
 

How did all this begin?

Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.

How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?

We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.

We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
 

Are you able to capture every Alzheimer’s drug in development globally?

If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.

Who are the report’s main readers?

Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.

It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
 

What about patients and families? Are they able to use the report as well?

One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.

Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?

My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.

What other approaches are interesting to you?

We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.

Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?

That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.

What about other therapy classes?

We aim to be more serious about devices.

What will you call the database?

The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.

The annual pipeline report is very much associated with you. Is the database going to be different?

Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.

Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.

We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.

Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.

In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.

Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.

Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview. His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.

Cummings_Jeffrey_Las Vegas 1_web.jpg

Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.

Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.

Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
 

How did all this begin?

Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.

How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?

We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.

We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
 

Are you able to capture every Alzheimer’s drug in development globally?

If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.

Who are the report’s main readers?

Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.

It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
 

What about patients and families? Are they able to use the report as well?

One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.

Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?

My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.

What other approaches are interesting to you?

We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.

Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?

That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.

What about other therapy classes?

We aim to be more serious about devices.

What will you call the database?

The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.

The annual pipeline report is very much associated with you. Is the database going to be different?

Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.

Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.

We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.

Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

A version of this article first appeared on WebMD.com.

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

A version of this article first appeared on WebMD.com.

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

A version of this article first appeared on WebMD.com.

v_flores_headshot.jpg

What is the value of considering noninvasive methods for the diagnosis of endometriosis?

Dr. Flores: There is great value in noninvasive diagnostics for endometriosis. This is because while surgical diagnosis is the “gold standard,” surgery is invasive, and waiting until a surgical diagnosis can be made further contributes to delays in diagnosis. However, more recently there has been a shift toward utilizing noninvasive approaches to the diagnosis of endometriosis, with the primary one focusing on clinically diagnosing endometriosis. 

One of the first things to remember is the importance of gathering a patient history and conducting a physical exam. We've all learned this in medical school, and it comes into play even more so with a condition such as endometriosis. Endometriosis is defined as a benign gynecologic disease characterized by endometrial-like tissue outside of the uterus, but this definition does not reflect the true scope and manifestations of endometriosis. Research over the years has demonstrated that endometriosis has systemic effects—affecting regions of the brain associated with anxiety/depression, altering pain sensitization, and having inflammatory effects that can not only affect the reproductive organs but also other organ systems. As such, our questions when evaluating patients for endometriosis need to focus on these various aspects of the disease. 

Endometriosis usually leads to cyclic pain. This is because just as the lining of the uterus (the endometrium) grows and sheds every month in response to hormones, endometriotic lesions—which are endometrial-like tissue outside of the uterus—also grow and shed each month. However, there is no outflow for this shed tissue and, as a result, there is an inflammatory response as well as pain. Depending on where those lesions implant, symptoms can include not only cyclic pelvic pain but also cyclic bowel/bladder pain. I’ve also had patients complain of cyclic sharp/shooting leg pain. 

Many times, patients present to us after having seen several different types of providers and having been diagnosed with conditions such as irritable bowel syndrome or painful bladder syndrome. However, if you talk to patients and ask them to tell you a little bit more about this bowel or bladder pain, they will frequently endorse that their symptoms are cyclic/most severe during their menses. With respect to pelvic pain, endometriosis-related pelvic pain is usually progressive—becoming progressively more painful over the years. These symptoms are strong indicators that endometriosis is the cause. A pelvic exam is also helpful as findings of nodularity or a fixed uterus may lend further support for endometriosis; a normal exam, however, does not rule out endometriosis. 

What are the primary imaging techniques used to diagnose endometriosis?

Dr. Flores: While history and physical exam are the primary components of the clinical diagnosis, imaging can also be helpful. The 2 techniques most often used are pelvic ultrasound and magnetic resonance imaging (MRI). 

While transvaginal ultrasound is sensitive and specific for diagnosing endometriomas (ovarian cysts of endometriotic tissue) and may also be able to accurately identify deep-infiltrating endometriosis, it is limited in its ability to visualize peritoneal disease. MRI can improve diagnosis of endometriosis and better estimate the depth of invasion of deep-infiltrating disease, as well as confirm diagnosis of an endometrioma. While MRI is an option for peritoneal endometriosis, superficial disease is usually not detected. Lastly, computed tomography imaging of the chest can be used when thoracic endometriosis is suspected but is otherwise not routinely recommended. Imaging is also helpful in ruling in/out other potential etiologies of pelvic pain such as fibroids and adenomyosis. It is important to recognize, however, that the absence of any findings of endometriosis on imaging does not rule out the disease. 

What other best practices do you implement in your day-to-day to aid in diagnosis?

Dr. Flores: Take the time to listen to your patient. Often, they’ve seen several providers before ultimately seeing a provider who can diagnosis their endometriosis without the need for surgical evaluation. We have to ask questions related to their pain and when the pain occurs, and we can’t forget to also ask about pain during intercourse, as well as non-menstrual pelvic pain. Additionally, it is important to recognize that, for patients who may have been suffering from endometriosis for several years before reaching a diagnosis, they may present with chronic pelvic pain. In this case, it is important to ask what their menstrual cycles were like before the pelvic pain became chronic, and usually patients note cyclic pelvic pain that became progressive. We also know that patients who have a first-degree relative with endometriosis are 7 times more likely to be affected by the disease, so asking about a family history of endometriosis is important. 

We have to think about endometriosis as a systemic disease. Previously, endometriosis was incorrectly thought of as solely a pelvic disease, but we've been learning more and more through research that it truly is a chronic, systemic disease with multifactorial effects throughout the body. For example, we have found that endometriosis affects regions of the brain associated with anxiety and depression, as well as causing changes in metabolism. For example, a common misconception is that women with a low body mass index (BMI) were at risk for endometriosis, when in fact it's just the opposite—it is the endometriosis that is causing changes in metabolism that lead to a decreased BMI. Patients with endometriosis also frequently struggle with mood disorders; therefore, we cannot dismiss this aspect of the disease process. It is imperative that we help patients feel heard and let them know that some of the mood symptoms they are experiencing may be related to their endometriosis. Expanding our view of endometriosis as a disease that extends beyond the pelvis and thinking about the systemic effects of endometriosis is key.

We have also identified small molecules (microRNAs) that are predictive of endometriosis. They are continuing to be investigated as a noninvasive biomarker of endometriosis.  

Can you talk a little more about these biomarkers?

Dr. Flores: In terms of biomarkers, this is actually some exciting work I was fortunate to be involved in with Dr. Hugh Taylor at Yale. We studied circulating molecules known as microRNAs—these are small, noncoding RNAs that can modify gene expression. In endometriosis, we've identified several that, when combined, have a high sensitivity and specificity for diagnosing endometriosis. These specific microRNAs are undergoing continued studies to ensure that they are reliable in predicting endometriosis. Hopefully they will be available soon for clinical use, as this would be of great value to help shorten the time to diagnosis of endometriosis and ultimately avoid delays in endometriosis treatment.

v_flores_headshot.jpg

What is the value of considering noninvasive methods for the diagnosis of endometriosis?

Dr. Flores: There is great value in noninvasive diagnostics for endometriosis. This is because while surgical diagnosis is the “gold standard,” surgery is invasive, and waiting until a surgical diagnosis can be made further contributes to delays in diagnosis. However, more recently there has been a shift toward utilizing noninvasive approaches to the diagnosis of endometriosis, with the primary one focusing on clinically diagnosing endometriosis. 

One of the first things to remember is the importance of gathering a patient history and conducting a physical exam. We've all learned this in medical school, and it comes into play even more so with a condition such as endometriosis. Endometriosis is defined as a benign gynecologic disease characterized by endometrial-like tissue outside of the uterus, but this definition does not reflect the true scope and manifestations of endometriosis. Research over the years has demonstrated that endometriosis has systemic effects—affecting regions of the brain associated with anxiety/depression, altering pain sensitization, and having inflammatory effects that can not only affect the reproductive organs but also other organ systems. As such, our questions when evaluating patients for endometriosis need to focus on these various aspects of the disease. 

Endometriosis usually leads to cyclic pain. This is because just as the lining of the uterus (the endometrium) grows and sheds every month in response to hormones, endometriotic lesions—which are endometrial-like tissue outside of the uterus—also grow and shed each month. However, there is no outflow for this shed tissue and, as a result, there is an inflammatory response as well as pain. Depending on where those lesions implant, symptoms can include not only cyclic pelvic pain but also cyclic bowel/bladder pain. I’ve also had patients complain of cyclic sharp/shooting leg pain. 

Many times, patients present to us after having seen several different types of providers and having been diagnosed with conditions such as irritable bowel syndrome or painful bladder syndrome. However, if you talk to patients and ask them to tell you a little bit more about this bowel or bladder pain, they will frequently endorse that their symptoms are cyclic/most severe during their menses. With respect to pelvic pain, endometriosis-related pelvic pain is usually progressive—becoming progressively more painful over the years. These symptoms are strong indicators that endometriosis is the cause. A pelvic exam is also helpful as findings of nodularity or a fixed uterus may lend further support for endometriosis; a normal exam, however, does not rule out endometriosis. 

What are the primary imaging techniques used to diagnose endometriosis?

Dr. Flores: While history and physical exam are the primary components of the clinical diagnosis, imaging can also be helpful. The 2 techniques most often used are pelvic ultrasound and magnetic resonance imaging (MRI). 

While transvaginal ultrasound is sensitive and specific for diagnosing endometriomas (ovarian cysts of endometriotic tissue) and may also be able to accurately identify deep-infiltrating endometriosis, it is limited in its ability to visualize peritoneal disease. MRI can improve diagnosis of endometriosis and better estimate the depth of invasion of deep-infiltrating disease, as well as confirm diagnosis of an endometrioma. While MRI is an option for peritoneal endometriosis, superficial disease is usually not detected. Lastly, computed tomography imaging of the chest can be used when thoracic endometriosis is suspected but is otherwise not routinely recommended. Imaging is also helpful in ruling in/out other potential etiologies of pelvic pain such as fibroids and adenomyosis. It is important to recognize, however, that the absence of any findings of endometriosis on imaging does not rule out the disease. 

What other best practices do you implement in your day-to-day to aid in diagnosis?

Dr. Flores: Take the time to listen to your patient. Often, they’ve seen several providers before ultimately seeing a provider who can diagnosis their endometriosis without the need for surgical evaluation. We have to ask questions related to their pain and when the pain occurs, and we can’t forget to also ask about pain during intercourse, as well as non-menstrual pelvic pain. Additionally, it is important to recognize that, for patients who may have been suffering from endometriosis for several years before reaching a diagnosis, they may present with chronic pelvic pain. In this case, it is important to ask what their menstrual cycles were like before the pelvic pain became chronic, and usually patients note cyclic pelvic pain that became progressive. We also know that patients who have a first-degree relative with endometriosis are 7 times more likely to be affected by the disease, so asking about a family history of endometriosis is important. 

We have to think about endometriosis as a systemic disease. Previously, endometriosis was incorrectly thought of as solely a pelvic disease, but we've been learning more and more through research that it truly is a chronic, systemic disease with multifactorial effects throughout the body. For example, we have found that endometriosis affects regions of the brain associated with anxiety and depression, as well as causing changes in metabolism. For example, a common misconception is that women with a low body mass index (BMI) were at risk for endometriosis, when in fact it's just the opposite—it is the endometriosis that is causing changes in metabolism that lead to a decreased BMI. Patients with endometriosis also frequently struggle with mood disorders; therefore, we cannot dismiss this aspect of the disease process. It is imperative that we help patients feel heard and let them know that some of the mood symptoms they are experiencing may be related to their endometriosis. Expanding our view of endometriosis as a disease that extends beyond the pelvis and thinking about the systemic effects of endometriosis is key.

We have also identified small molecules (microRNAs) that are predictive of endometriosis. They are continuing to be investigated as a noninvasive biomarker of endometriosis.  

Can you talk a little more about these biomarkers?

Dr. Flores: In terms of biomarkers, this is actually some exciting work I was fortunate to be involved in with Dr. Hugh Taylor at Yale. We studied circulating molecules known as microRNAs—these are small, noncoding RNAs that can modify gene expression. In endometriosis, we've identified several that, when combined, have a high sensitivity and specificity for diagnosing endometriosis. These specific microRNAs are undergoing continued studies to ensure that they are reliable in predicting endometriosis. Hopefully they will be available soon for clinical use, as this would be of great value to help shorten the time to diagnosis of endometriosis and ultimately avoid delays in endometriosis treatment.

v_flores_headshot.jpg

What is the value of considering noninvasive methods for the diagnosis of endometriosis?

Dr. Flores: There is great value in noninvasive diagnostics for endometriosis. This is because while surgical diagnosis is the “gold standard,” surgery is invasive, and waiting until a surgical diagnosis can be made further contributes to delays in diagnosis. However, more recently there has been a shift toward utilizing noninvasive approaches to the diagnosis of endometriosis, with the primary one focusing on clinically diagnosing endometriosis. 

One of the first things to remember is the importance of gathering a patient history and conducting a physical exam. We've all learned this in medical school, and it comes into play even more so with a condition such as endometriosis. Endometriosis is defined as a benign gynecologic disease characterized by endometrial-like tissue outside of the uterus, but this definition does not reflect the true scope and manifestations of endometriosis. Research over the years has demonstrated that endometriosis has systemic effects—affecting regions of the brain associated with anxiety/depression, altering pain sensitization, and having inflammatory effects that can not only affect the reproductive organs but also other organ systems. As such, our questions when evaluating patients for endometriosis need to focus on these various aspects of the disease. 

Endometriosis usually leads to cyclic pain. This is because just as the lining of the uterus (the endometrium) grows and sheds every month in response to hormones, endometriotic lesions—which are endometrial-like tissue outside of the uterus—also grow and shed each month. However, there is no outflow for this shed tissue and, as a result, there is an inflammatory response as well as pain. Depending on where those lesions implant, symptoms can include not only cyclic pelvic pain but also cyclic bowel/bladder pain. I’ve also had patients complain of cyclic sharp/shooting leg pain. 

Many times, patients present to us after having seen several different types of providers and having been diagnosed with conditions such as irritable bowel syndrome or painful bladder syndrome. However, if you talk to patients and ask them to tell you a little bit more about this bowel or bladder pain, they will frequently endorse that their symptoms are cyclic/most severe during their menses. With respect to pelvic pain, endometriosis-related pelvic pain is usually progressive—becoming progressively more painful over the years. These symptoms are strong indicators that endometriosis is the cause. A pelvic exam is also helpful as findings of nodularity or a fixed uterus may lend further support for endometriosis; a normal exam, however, does not rule out endometriosis. 

What are the primary imaging techniques used to diagnose endometriosis?

Dr. Flores: While history and physical exam are the primary components of the clinical diagnosis, imaging can also be helpful. The 2 techniques most often used are pelvic ultrasound and magnetic resonance imaging (MRI). 

While transvaginal ultrasound is sensitive and specific for diagnosing endometriomas (ovarian cysts of endometriotic tissue) and may also be able to accurately identify deep-infiltrating endometriosis, it is limited in its ability to visualize peritoneal disease. MRI can improve diagnosis of endometriosis and better estimate the depth of invasion of deep-infiltrating disease, as well as confirm diagnosis of an endometrioma. While MRI is an option for peritoneal endometriosis, superficial disease is usually not detected. Lastly, computed tomography imaging of the chest can be used when thoracic endometriosis is suspected but is otherwise not routinely recommended. Imaging is also helpful in ruling in/out other potential etiologies of pelvic pain such as fibroids and adenomyosis. It is important to recognize, however, that the absence of any findings of endometriosis on imaging does not rule out the disease. 

What other best practices do you implement in your day-to-day to aid in diagnosis?

Dr. Flores: Take the time to listen to your patient. Often, they’ve seen several providers before ultimately seeing a provider who can diagnosis their endometriosis without the need for surgical evaluation. We have to ask questions related to their pain and when the pain occurs, and we can’t forget to also ask about pain during intercourse, as well as non-menstrual pelvic pain. Additionally, it is important to recognize that, for patients who may have been suffering from endometriosis for several years before reaching a diagnosis, they may present with chronic pelvic pain. In this case, it is important to ask what their menstrual cycles were like before the pelvic pain became chronic, and usually patients note cyclic pelvic pain that became progressive. We also know that patients who have a first-degree relative with endometriosis are 7 times more likely to be affected by the disease, so asking about a family history of endometriosis is important. 

We have to think about endometriosis as a systemic disease. Previously, endometriosis was incorrectly thought of as solely a pelvic disease, but we've been learning more and more through research that it truly is a chronic, systemic disease with multifactorial effects throughout the body. For example, we have found that endometriosis affects regions of the brain associated with anxiety and depression, as well as causing changes in metabolism. For example, a common misconception is that women with a low body mass index (BMI) were at risk for endometriosis, when in fact it's just the opposite—it is the endometriosis that is causing changes in metabolism that lead to a decreased BMI. Patients with endometriosis also frequently struggle with mood disorders; therefore, we cannot dismiss this aspect of the disease process. It is imperative that we help patients feel heard and let them know that some of the mood symptoms they are experiencing may be related to their endometriosis. Expanding our view of endometriosis as a disease that extends beyond the pelvis and thinking about the systemic effects of endometriosis is key.

We have also identified small molecules (microRNAs) that are predictive of endometriosis. They are continuing to be investigated as a noninvasive biomarker of endometriosis.  

Can you talk a little more about these biomarkers?

Dr. Flores: In terms of biomarkers, this is actually some exciting work I was fortunate to be involved in with Dr. Hugh Taylor at Yale. We studied circulating molecules known as microRNAs—these are small, noncoding RNAs that can modify gene expression. In endometriosis, we've identified several that, when combined, have a high sensitivity and specificity for diagnosing endometriosis. These specific microRNAs are undergoing continued studies to ensure that they are reliable in predicting endometriosis. Hopefully they will be available soon for clinical use, as this would be of great value to help shorten the time to diagnosis of endometriosis and ultimately avoid delays in endometriosis treatment.

ann_lacasce-pf_ann_lacasce_sog_9902_11.jpg

What is the significance of the recent TRIANGLE study on mantle cell lymphoma (MCL)?

Dr. LaCasce: The TRIANGLE study is extremely important in previously untreated, transplant-eligible patients with MCL. The cutoff age for transplants varies by center and is between 60 and 75 years. In the absence of a TP53 mutation, we have typically used induction chemotherapy followed by autologous stem-cell transplant (ASCT), followed by 3 years of maintenance rituximab. Obviously, this is a lot of therapy.

The TRIANGLE study was a 3-arm study in which ibrutinib-containing therapy was compared with standard RCHOP/RDHAP followed by ASCT. Maintenance rituximab became standard of care midway through the trial and was added. In the first experimental arm, ibrutinib was combined with RCHOP and then given as maintenance for 2 years following ASCT. The second experimental arm included the same schedule of ibrutinib and omitted the ASCT.

The results are early, but what has been presented thus far, ibrutinib induction and maintenance with ASCT is clearly superior to the standard arm with ASCT. Although the data are not statistically mature, the failure-free survival of the 2 ibrutinib arms was similar, suggesting that transplant may not be necessary. Longer follow-up is necessary to confirm this conclusion and assess overall survival in all 3 arms.

If the results hold, ASCT could become a thing of the past or perhaps used in the second line. With the favorable activity of chimeric antigen receptor (CAR) T-cell therapy, however, it is unclear whether ASCT would be used in second line. Avoiding the sequential use of ASCT and CAR T-cell therapy is appealing given the stem-cell damage that can result. It is appealing to think about not using ASCT upfront, because ASCT increases the risk of myelodysplastic syndrome.

The TRIANGLE data are likely to change the frontline management of MCL. Although ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved in MCL and has obviously changed the field dramatically, it is significantly less well-tolerated than the next generation of drugs—acalabrutinib and zanubrutinib. I suspect these will be substituted for ibrutinib and we will see even more tolerable upfront regimens for patients with newly diagnosed MCL.

Have there been any disparities that you found in patients newly diagnosed with MCL regarding age, sex, or ethnicity?

Dr. LaCasce: MCL typically affects patients in their 60s. It is rare in young patients, and approximately 75% of the cases are male. If you look at the demographics, it is more common in White patients and less common in Hispanic and African American patients. In addition, there is an association with farming, which likely contribute to the demographics of patients with MCL.

What is your recommended approach to managing patients newly diagnosed with MCL in your day-to-day practice?

Dr. LaCasce: Management is a bit tricky right now because the TRIANGLE study is not part of any guidelines thus far. Therefore, most would argue the standard treatment continues to include ASCT upfront. There is an important, large randomized  study (NCT03267433) going on in the United States that is assessing the role of ASCT in patients who are in MRD-negative complete remission at the end of induction therapy. These patients are randomized to ASCT plus maintenance rituximab versus maintenance rituximab alone.

We are still enrolling patients to participate in this study, which is addressing a different question than TRIANGLE. I think we will learn a lot from this study. For patients who are not interested in participating in this study, we talk about the risks and benefits of ASCT.

One or 2 years ago, I would have strongly encouraged patients who were appropriate candidates to consider transplant in first remission. With the TRIANGLE data, however, and now that we have CAR T-cell therapy, I think it is more important to tailor the recommendation to the individual patient. If a patient is reluctant about ASCT and the associated risks, I do not push it.

If patients want the most aggressive approach associated with the longest remissions, at this moment, before TRIANGLE findings have been adopted into guidelines, I continue to recommend ASCT. For patients who have TP53 mutation, however, we treat with typically less aggressive therapy, as this patient population does not benefit from ASCT. We look forward to more data incorporating BTK inhibitors upfront, particularly for this group of patients, who tend to have a more adverse prognosis.

Do you feel MCL data and clinical trials are important areas of focus for your colleagues?

Dr. LaCasce: Yes. I think it is a rapidly evolving field, which is really exciting. We are seeing data now from the bispecific antibodies in the relapsed/refractory setting. We also need more data using pirtobrutinib for patients who have had BTK inhibitors and compare pirtobrutinib (a non-covalent BTK inhibitor) with the covalent BTK inhibitors.

I would strongly encourage patients to participate in clinical trials so that we can better answer these important questions. When patients go online and read about MCL, they often see a median survival of 3 to 4 years, which is completely outdated. The overall prognosis of MCL has changed dramatically since I have been in the field. Hopefully, survival will continue to improve, and therapies will become more tolerable, as well.

ann_lacasce-pf_ann_lacasce_sog_9902_11.jpg

What is the significance of the recent TRIANGLE study on mantle cell lymphoma (MCL)?

Dr. LaCasce: The TRIANGLE study is extremely important in previously untreated, transplant-eligible patients with MCL. The cutoff age for transplants varies by center and is between 60 and 75 years. In the absence of a TP53 mutation, we have typically used induction chemotherapy followed by autologous stem-cell transplant (ASCT), followed by 3 years of maintenance rituximab. Obviously, this is a lot of therapy.

The TRIANGLE study was a 3-arm study in which ibrutinib-containing therapy was compared with standard RCHOP/RDHAP followed by ASCT. Maintenance rituximab became standard of care midway through the trial and was added. In the first experimental arm, ibrutinib was combined with RCHOP and then given as maintenance for 2 years following ASCT. The second experimental arm included the same schedule of ibrutinib and omitted the ASCT.

The results are early, but what has been presented thus far, ibrutinib induction and maintenance with ASCT is clearly superior to the standard arm with ASCT. Although the data are not statistically mature, the failure-free survival of the 2 ibrutinib arms was similar, suggesting that transplant may not be necessary. Longer follow-up is necessary to confirm this conclusion and assess overall survival in all 3 arms.

If the results hold, ASCT could become a thing of the past or perhaps used in the second line. With the favorable activity of chimeric antigen receptor (CAR) T-cell therapy, however, it is unclear whether ASCT would be used in second line. Avoiding the sequential use of ASCT and CAR T-cell therapy is appealing given the stem-cell damage that can result. It is appealing to think about not using ASCT upfront, because ASCT increases the risk of myelodysplastic syndrome.

The TRIANGLE data are likely to change the frontline management of MCL. Although ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved in MCL and has obviously changed the field dramatically, it is significantly less well-tolerated than the next generation of drugs—acalabrutinib and zanubrutinib. I suspect these will be substituted for ibrutinib and we will see even more tolerable upfront regimens for patients with newly diagnosed MCL.

Have there been any disparities that you found in patients newly diagnosed with MCL regarding age, sex, or ethnicity?

Dr. LaCasce: MCL typically affects patients in their 60s. It is rare in young patients, and approximately 75% of the cases are male. If you look at the demographics, it is more common in White patients and less common in Hispanic and African American patients. In addition, there is an association with farming, which likely contribute to the demographics of patients with MCL.

What is your recommended approach to managing patients newly diagnosed with MCL in your day-to-day practice?

Dr. LaCasce: Management is a bit tricky right now because the TRIANGLE study is not part of any guidelines thus far. Therefore, most would argue the standard treatment continues to include ASCT upfront. There is an important, large randomized  study (NCT03267433) going on in the United States that is assessing the role of ASCT in patients who are in MRD-negative complete remission at the end of induction therapy. These patients are randomized to ASCT plus maintenance rituximab versus maintenance rituximab alone.

We are still enrolling patients to participate in this study, which is addressing a different question than TRIANGLE. I think we will learn a lot from this study. For patients who are not interested in participating in this study, we talk about the risks and benefits of ASCT.

One or 2 years ago, I would have strongly encouraged patients who were appropriate candidates to consider transplant in first remission. With the TRIANGLE data, however, and now that we have CAR T-cell therapy, I think it is more important to tailor the recommendation to the individual patient. If a patient is reluctant about ASCT and the associated risks, I do not push it.

If patients want the most aggressive approach associated with the longest remissions, at this moment, before TRIANGLE findings have been adopted into guidelines, I continue to recommend ASCT. For patients who have TP53 mutation, however, we treat with typically less aggressive therapy, as this patient population does not benefit from ASCT. We look forward to more data incorporating BTK inhibitors upfront, particularly for this group of patients, who tend to have a more adverse prognosis.

Do you feel MCL data and clinical trials are important areas of focus for your colleagues?

Dr. LaCasce: Yes. I think it is a rapidly evolving field, which is really exciting. We are seeing data now from the bispecific antibodies in the relapsed/refractory setting. We also need more data using pirtobrutinib for patients who have had BTK inhibitors and compare pirtobrutinib (a non-covalent BTK inhibitor) with the covalent BTK inhibitors.

I would strongly encourage patients to participate in clinical trials so that we can better answer these important questions. When patients go online and read about MCL, they often see a median survival of 3 to 4 years, which is completely outdated. The overall prognosis of MCL has changed dramatically since I have been in the field. Hopefully, survival will continue to improve, and therapies will become more tolerable, as well.

ann_lacasce-pf_ann_lacasce_sog_9902_11.jpg

What is the significance of the recent TRIANGLE study on mantle cell lymphoma (MCL)?

Dr. LaCasce: The TRIANGLE study is extremely important in previously untreated, transplant-eligible patients with MCL. The cutoff age for transplants varies by center and is between 60 and 75 years. In the absence of a TP53 mutation, we have typically used induction chemotherapy followed by autologous stem-cell transplant (ASCT), followed by 3 years of maintenance rituximab. Obviously, this is a lot of therapy.

The TRIANGLE study was a 3-arm study in which ibrutinib-containing therapy was compared with standard RCHOP/RDHAP followed by ASCT. Maintenance rituximab became standard of care midway through the trial and was added. In the first experimental arm, ibrutinib was combined with RCHOP and then given as maintenance for 2 years following ASCT. The second experimental arm included the same schedule of ibrutinib and omitted the ASCT.

The results are early, but what has been presented thus far, ibrutinib induction and maintenance with ASCT is clearly superior to the standard arm with ASCT. Although the data are not statistically mature, the failure-free survival of the 2 ibrutinib arms was similar, suggesting that transplant may not be necessary. Longer follow-up is necessary to confirm this conclusion and assess overall survival in all 3 arms.

If the results hold, ASCT could become a thing of the past or perhaps used in the second line. With the favorable activity of chimeric antigen receptor (CAR) T-cell therapy, however, it is unclear whether ASCT would be used in second line. Avoiding the sequential use of ASCT and CAR T-cell therapy is appealing given the stem-cell damage that can result. It is appealing to think about not using ASCT upfront, because ASCT increases the risk of myelodysplastic syndrome.

The TRIANGLE data are likely to change the frontline management of MCL. Although ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved in MCL and has obviously changed the field dramatically, it is significantly less well-tolerated than the next generation of drugs—acalabrutinib and zanubrutinib. I suspect these will be substituted for ibrutinib and we will see even more tolerable upfront regimens for patients with newly diagnosed MCL.

Have there been any disparities that you found in patients newly diagnosed with MCL regarding age, sex, or ethnicity?

Dr. LaCasce: MCL typically affects patients in their 60s. It is rare in young patients, and approximately 75% of the cases are male. If you look at the demographics, it is more common in White patients and less common in Hispanic and African American patients. In addition, there is an association with farming, which likely contribute to the demographics of patients with MCL.

What is your recommended approach to managing patients newly diagnosed with MCL in your day-to-day practice?

Dr. LaCasce: Management is a bit tricky right now because the TRIANGLE study is not part of any guidelines thus far. Therefore, most would argue the standard treatment continues to include ASCT upfront. There is an important, large randomized  study (NCT03267433) going on in the United States that is assessing the role of ASCT in patients who are in MRD-negative complete remission at the end of induction therapy. These patients are randomized to ASCT plus maintenance rituximab versus maintenance rituximab alone.

We are still enrolling patients to participate in this study, which is addressing a different question than TRIANGLE. I think we will learn a lot from this study. For patients who are not interested in participating in this study, we talk about the risks and benefits of ASCT.

One or 2 years ago, I would have strongly encouraged patients who were appropriate candidates to consider transplant in first remission. With the TRIANGLE data, however, and now that we have CAR T-cell therapy, I think it is more important to tailor the recommendation to the individual patient. If a patient is reluctant about ASCT and the associated risks, I do not push it.

If patients want the most aggressive approach associated with the longest remissions, at this moment, before TRIANGLE findings have been adopted into guidelines, I continue to recommend ASCT. For patients who have TP53 mutation, however, we treat with typically less aggressive therapy, as this patient population does not benefit from ASCT. We look forward to more data incorporating BTK inhibitors upfront, particularly for this group of patients, who tend to have a more adverse prognosis.

Do you feel MCL data and clinical trials are important areas of focus for your colleagues?

Dr. LaCasce: Yes. I think it is a rapidly evolving field, which is really exciting. We are seeing data now from the bispecific antibodies in the relapsed/refractory setting. We also need more data using pirtobrutinib for patients who have had BTK inhibitors and compare pirtobrutinib (a non-covalent BTK inhibitor) with the covalent BTK inhibitors.

I would strongly encourage patients to participate in clinical trials so that we can better answer these important questions. When patients go online and read about MCL, they often see a median survival of 3 to 4 years, which is completely outdated. The overall prognosis of MCL has changed dramatically since I have been in the field. Hopefully, survival will continue to improve, and therapies will become more tolerable, as well.

jeannettelagermdmph.jpg

What is the link between endometriosis and abnormal uterine bleeding?

Dr. Lager: This is an important question because when people first learn about endometriosis, common symptoms include pain with periods, pelvic pain, but not necessarily abnormal uterine bleeding. However, many patients do complain of abnormal uterine bleeding when presenting with endometriosis.

There are a couple of reasons why abnormal uterine bleeding is important to consider. Within the spectrum of endometriosis, vaginal endometriosis can contribute to abnormal vaginal bleeding, most commonly cyclic or postcoital. The bleeding could be rectal due to deeply infiltrative endometriosis, although gastrointestinal etiologies should be included in the differential. Another link is coexisting diagnoses such as fibroids, adenomyosis, and endometrial polyps. In fact, the rates for coexisting conditions with endometriosis can be high and vary from study to study.

As an example, some studies show rates between 7% and 11%, where adenomyosis coexists with endometriosis. Other studies look at magnetic resonance imaging for adenomyosis and deep infiltrative endometriosis and find that women younger than 36 years have rates as high as 90% for coexisting diagnoses, and 79% for all women, regardless of the diagnosis.

The overlap is high. When I think particularly about adenomyosis and endometriosis, in some ways, the conditions are along a spectrum where adenomyosis involves ectopic endometrial glands in the myometrium, whereas endometriosis involves ectopic tissue outside of the uterus, predominantly in reproductive organs, but can be anywhere outside of the endometrium. So, when I think about abnormal uterine bleeding particularly associated with dysmenorrhea or pelvic pain, this can often be included in the constellation of symptoms for endometriosis.

Furthermore, it is important to rule out other causes of abnormal uterine bleeding because they would potentially change the treatment.

What are the current treatment options for endometriosis and abnormal uterine bleeding?

Dr. Lager: Treatments for endometriosis are inclusive of any overlapping conditions and we use a multidisciplinary approach to address symptoms. Medical treatments include hormonal management, including birth control pills, etonogestrel implants (Nexplanon), levonorgestrel-releasing intrauterine devices, progestin-only pills, gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and combination medications. Some medications do overlap and work for both, such as combined GnRH antagonists, estradiol, and progesterone.

Surgical management includes diagnostic laparoscopy with excision of endometriosis. If there is another coexisting diagnosis that is structural in nature, such as endometrial polyps, adenomyosis, or fibroids, surgical management may include hysteroscopy, myomectomy, or hysterectomy as indicated. When we consider surgical and nonsurgical approaches, it is important to be clear on the etiology of abnormal uterine bleeding to appropriately counsel patients for what the surgery could entail.

Have you found there to be any age or racial disparities in endometriosis treatment?

Dr. Lager: One of the things that is important about endometriosis, and in medicine in general, is to really think about how we approach race as a social construct. In the past, medicine has included race as a risk factor for certain medical conditions. And physicians in training were taught to use these risk factors to determine a differential diagnosis. However, this strategy has limited us in understanding how historical and structural racism affected patient diagnosis and treatment.

If we think back to literature that was published in the 1950s or the 1970s, Dr. Meeks was one of the physicians who described a set of characteristics of patients with endometriosis. He commented that typical patients were women who were goal-oriented, had private insurance, and experienced delayed marriage, among other traits.

The problem with this characterization was that patients would then present with symptoms of endometriosis who did not fit the original phenotype as historically described and they would be misdiagnosed and thus treated incorrectly. This incorrect treatment further reinforced incorrect stereotypes of patient presentations. These misdiagnoses could lead to unfortunate consequences in their activities of daily living as well as reproductive outcomes. We do not have data on how many patients may have been misdiagnosed and treated for pelvic inflammatory disease because they were not White, did not have private insurance, or had children early. This is an example of areas where we need to recognize systemic racism and classism and work hard to simply do better for our patients.

Although misdiagnosing based on stereotypes has decreased over time, I still think that original thinking can certainly affect patient referrals. When we look at the data of patients who are diagnosed with endometriosis, we find a higher rate of White patients (17%) compared to Black (10.1%), Asian (11.3%), and Hispanic patients (7.4%). Ensuring that all of our patients are getting appropriate referrals and diagnosis should be a priority.

When we think about the timing to initial diagnosis, globally, we know that there is a delay in diagnosis anywhere from 7 to 12 years, and then on top of that, those social constructs decrease the rate of diagnosis for certain patient populations. Misdiagnosis based on social constructs is unacceptable and one aspect that I think is very important to point out.

In a more recent study of 12,000 patients in 2022, the rate of surgical complications associated with endometriosis surgery was higher in women who were Black, Asian and Pacific Islander, and Native American/American Indian than in women who were White. These groups have a much higher rate of complications and higher rates of laparotomy—an open procedure—versus laparoscopy. In younger women, there is a higher rate of oophorectomy at the time of surgery for endometriosis than in older women.

Are there any best practices you would like to share with your peers?

Dr. Lager: For patients with abnormal uterine bleeding, it is important to consider other diagnoses and not assume that abnormal bleeding is solely related to endometriosis, while considering deeply infiltrative endometriosis in the differential.

When patients do present with cyclical bleeding, especially, for example, after hysterectomy, it is important to examine for either vaginal or vaginal cuff endometriosis because there can be other reasons that patients will have abnormal uterine bleeding related to atypical endometriosis.

It is important to know the patient’s history and focus on each patient’s level of pain, how it affects their day-to-day activities, and how they are experiencing that pain.

We all should be working to improve our understanding of social history and systemic racism as best as we can and make sure all patients are getting the right care that they deserve.

jeannettelagermdmph.jpg

What is the link between endometriosis and abnormal uterine bleeding?

Dr. Lager: This is an important question because when people first learn about endometriosis, common symptoms include pain with periods, pelvic pain, but not necessarily abnormal uterine bleeding. However, many patients do complain of abnormal uterine bleeding when presenting with endometriosis.

There are a couple of reasons why abnormal uterine bleeding is important to consider. Within the spectrum of endometriosis, vaginal endometriosis can contribute to abnormal vaginal bleeding, most commonly cyclic or postcoital. The bleeding could be rectal due to deeply infiltrative endometriosis, although gastrointestinal etiologies should be included in the differential. Another link is coexisting diagnoses such as fibroids, adenomyosis, and endometrial polyps. In fact, the rates for coexisting conditions with endometriosis can be high and vary from study to study.

As an example, some studies show rates between 7% and 11%, where adenomyosis coexists with endometriosis. Other studies look at magnetic resonance imaging for adenomyosis and deep infiltrative endometriosis and find that women younger than 36 years have rates as high as 90% for coexisting diagnoses, and 79% for all women, regardless of the diagnosis.

The overlap is high. When I think particularly about adenomyosis and endometriosis, in some ways, the conditions are along a spectrum where adenomyosis involves ectopic endometrial glands in the myometrium, whereas endometriosis involves ectopic tissue outside of the uterus, predominantly in reproductive organs, but can be anywhere outside of the endometrium. So, when I think about abnormal uterine bleeding particularly associated with dysmenorrhea or pelvic pain, this can often be included in the constellation of symptoms for endometriosis.

Furthermore, it is important to rule out other causes of abnormal uterine bleeding because they would potentially change the treatment.

What are the current treatment options for endometriosis and abnormal uterine bleeding?

Dr. Lager: Treatments for endometriosis are inclusive of any overlapping conditions and we use a multidisciplinary approach to address symptoms. Medical treatments include hormonal management, including birth control pills, etonogestrel implants (Nexplanon), levonorgestrel-releasing intrauterine devices, progestin-only pills, gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and combination medications. Some medications do overlap and work for both, such as combined GnRH antagonists, estradiol, and progesterone.

Surgical management includes diagnostic laparoscopy with excision of endometriosis. If there is another coexisting diagnosis that is structural in nature, such as endometrial polyps, adenomyosis, or fibroids, surgical management may include hysteroscopy, myomectomy, or hysterectomy as indicated. When we consider surgical and nonsurgical approaches, it is important to be clear on the etiology of abnormal uterine bleeding to appropriately counsel patients for what the surgery could entail.

Have you found there to be any age or racial disparities in endometriosis treatment?

Dr. Lager: One of the things that is important about endometriosis, and in medicine in general, is to really think about how we approach race as a social construct. In the past, medicine has included race as a risk factor for certain medical conditions. And physicians in training were taught to use these risk factors to determine a differential diagnosis. However, this strategy has limited us in understanding how historical and structural racism affected patient diagnosis and treatment.

If we think back to literature that was published in the 1950s or the 1970s, Dr. Meeks was one of the physicians who described a set of characteristics of patients with endometriosis. He commented that typical patients were women who were goal-oriented, had private insurance, and experienced delayed marriage, among other traits.

The problem with this characterization was that patients would then present with symptoms of endometriosis who did not fit the original phenotype as historically described and they would be misdiagnosed and thus treated incorrectly. This incorrect treatment further reinforced incorrect stereotypes of patient presentations. These misdiagnoses could lead to unfortunate consequences in their activities of daily living as well as reproductive outcomes. We do not have data on how many patients may have been misdiagnosed and treated for pelvic inflammatory disease because they were not White, did not have private insurance, or had children early. This is an example of areas where we need to recognize systemic racism and classism and work hard to simply do better for our patients.

Although misdiagnosing based on stereotypes has decreased over time, I still think that original thinking can certainly affect patient referrals. When we look at the data of patients who are diagnosed with endometriosis, we find a higher rate of White patients (17%) compared to Black (10.1%), Asian (11.3%), and Hispanic patients (7.4%). Ensuring that all of our patients are getting appropriate referrals and diagnosis should be a priority.

When we think about the timing to initial diagnosis, globally, we know that there is a delay in diagnosis anywhere from 7 to 12 years, and then on top of that, those social constructs decrease the rate of diagnosis for certain patient populations. Misdiagnosis based on social constructs is unacceptable and one aspect that I think is very important to point out.

In a more recent study of 12,000 patients in 2022, the rate of surgical complications associated with endometriosis surgery was higher in women who were Black, Asian and Pacific Islander, and Native American/American Indian than in women who were White. These groups have a much higher rate of complications and higher rates of laparotomy—an open procedure—versus laparoscopy. In younger women, there is a higher rate of oophorectomy at the time of surgery for endometriosis than in older women.

Are there any best practices you would like to share with your peers?

Dr. Lager: For patients with abnormal uterine bleeding, it is important to consider other diagnoses and not assume that abnormal bleeding is solely related to endometriosis, while considering deeply infiltrative endometriosis in the differential.

When patients do present with cyclical bleeding, especially, for example, after hysterectomy, it is important to examine for either vaginal or vaginal cuff endometriosis because there can be other reasons that patients will have abnormal uterine bleeding related to atypical endometriosis.

It is important to know the patient’s history and focus on each patient’s level of pain, how it affects their day-to-day activities, and how they are experiencing that pain.

We all should be working to improve our understanding of social history and systemic racism as best as we can and make sure all patients are getting the right care that they deserve.

jeannettelagermdmph.jpg

What is the link between endometriosis and abnormal uterine bleeding?

Dr. Lager: This is an important question because when people first learn about endometriosis, common symptoms include pain with periods, pelvic pain, but not necessarily abnormal uterine bleeding. However, many patients do complain of abnormal uterine bleeding when presenting with endometriosis.

There are a couple of reasons why abnormal uterine bleeding is important to consider. Within the spectrum of endometriosis, vaginal endometriosis can contribute to abnormal vaginal bleeding, most commonly cyclic or postcoital. The bleeding could be rectal due to deeply infiltrative endometriosis, although gastrointestinal etiologies should be included in the differential. Another link is coexisting diagnoses such as fibroids, adenomyosis, and endometrial polyps. In fact, the rates for coexisting conditions with endometriosis can be high and vary from study to study.

As an example, some studies show rates between 7% and 11%, where adenomyosis coexists with endometriosis. Other studies look at magnetic resonance imaging for adenomyosis and deep infiltrative endometriosis and find that women younger than 36 years have rates as high as 90% for coexisting diagnoses, and 79% for all women, regardless of the diagnosis.

The overlap is high. When I think particularly about adenomyosis and endometriosis, in some ways, the conditions are along a spectrum where adenomyosis involves ectopic endometrial glands in the myometrium, whereas endometriosis involves ectopic tissue outside of the uterus, predominantly in reproductive organs, but can be anywhere outside of the endometrium. So, when I think about abnormal uterine bleeding particularly associated with dysmenorrhea or pelvic pain, this can often be included in the constellation of symptoms for endometriosis.

Furthermore, it is important to rule out other causes of abnormal uterine bleeding because they would potentially change the treatment.

What are the current treatment options for endometriosis and abnormal uterine bleeding?

Dr. Lager: Treatments for endometriosis are inclusive of any overlapping conditions and we use a multidisciplinary approach to address symptoms. Medical treatments include hormonal management, including birth control pills, etonogestrel implants (Nexplanon), levonorgestrel-releasing intrauterine devices, progestin-only pills, gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and combination medications. Some medications do overlap and work for both, such as combined GnRH antagonists, estradiol, and progesterone.

Surgical management includes diagnostic laparoscopy with excision of endometriosis. If there is another coexisting diagnosis that is structural in nature, such as endometrial polyps, adenomyosis, or fibroids, surgical management may include hysteroscopy, myomectomy, or hysterectomy as indicated. When we consider surgical and nonsurgical approaches, it is important to be clear on the etiology of abnormal uterine bleeding to appropriately counsel patients for what the surgery could entail.

Have you found there to be any age or racial disparities in endometriosis treatment?

Dr. Lager: One of the things that is important about endometriosis, and in medicine in general, is to really think about how we approach race as a social construct. In the past, medicine has included race as a risk factor for certain medical conditions. And physicians in training were taught to use these risk factors to determine a differential diagnosis. However, this strategy has limited us in understanding how historical and structural racism affected patient diagnosis and treatment.

If we think back to literature that was published in the 1950s or the 1970s, Dr. Meeks was one of the physicians who described a set of characteristics of patients with endometriosis. He commented that typical patients were women who were goal-oriented, had private insurance, and experienced delayed marriage, among other traits.

The problem with this characterization was that patients would then present with symptoms of endometriosis who did not fit the original phenotype as historically described and they would be misdiagnosed and thus treated incorrectly. This incorrect treatment further reinforced incorrect stereotypes of patient presentations. These misdiagnoses could lead to unfortunate consequences in their activities of daily living as well as reproductive outcomes. We do not have data on how many patients may have been misdiagnosed and treated for pelvic inflammatory disease because they were not White, did not have private insurance, or had children early. This is an example of areas where we need to recognize systemic racism and classism and work hard to simply do better for our patients.

Although misdiagnosing based on stereotypes has decreased over time, I still think that original thinking can certainly affect patient referrals. When we look at the data of patients who are diagnosed with endometriosis, we find a higher rate of White patients (17%) compared to Black (10.1%), Asian (11.3%), and Hispanic patients (7.4%). Ensuring that all of our patients are getting appropriate referrals and diagnosis should be a priority.

When we think about the timing to initial diagnosis, globally, we know that there is a delay in diagnosis anywhere from 7 to 12 years, and then on top of that, those social constructs decrease the rate of diagnosis for certain patient populations. Misdiagnosis based on social constructs is unacceptable and one aspect that I think is very important to point out.

In a more recent study of 12,000 patients in 2022, the rate of surgical complications associated with endometriosis surgery was higher in women who were Black, Asian and Pacific Islander, and Native American/American Indian than in women who were White. These groups have a much higher rate of complications and higher rates of laparotomy—an open procedure—versus laparoscopy. In younger women, there is a higher rate of oophorectomy at the time of surgery for endometriosis than in older women.

Are there any best practices you would like to share with your peers?

Dr. Lager: For patients with abnormal uterine bleeding, it is important to consider other diagnoses and not assume that abnormal bleeding is solely related to endometriosis, while considering deeply infiltrative endometriosis in the differential.

When patients do present with cyclical bleeding, especially, for example, after hysterectomy, it is important to examine for either vaginal or vaginal cuff endometriosis because there can be other reasons that patients will have abnormal uterine bleeding related to atypical endometriosis.

It is important to know the patient’s history and focus on each patient’s level of pain, how it affects their day-to-day activities, and how they are experiencing that pain.

We all should be working to improve our understanding of social history and systemic racism as best as we can and make sure all patients are getting the right care that they deserve.