The Food and Drug Administration has approved the biosimilar Ziextenzo (pegfilgrastim-bmez) to reduce the incidence of infection in patients with nonmyeloid cancer receiving suppressive anticancer drugs that are associated with febrile neutropenia.

Olivier Le Moal/Getty Images

More than 60,000 cancer patients are hospitalized in the United States each year with evidence of neutropenia, resulting in more than 4,000 deaths, according to Ziextenzo maker Sandoz, a Novartis division.

The FDA approval was based on analytical, preclinical, and clinical research, including data from a three-way pharmacokinetics and pharmacodynamics study that compared pegfilgrastim-bmez with the reference drug pegfilgrastim (Neulasta) from the United States and the European Union. Pharmacokinetic and pharmacodynamic similarity were shown between pegfilgrastim-bmez with the reference drugs, and there were no clinically significant differences in safety or immunogenicity.

The most common adverse events associated with pegfilgrastim-bmez are bone pain and pain in the extremities, according to the label.

lfranki@mdedge.com

The Food and Drug Administration has approved the biosimilar Ziextenzo (pegfilgrastim-bmez) to reduce the incidence of infection in patients with nonmyeloid cancer receiving suppressive anticancer drugs that are associated with febrile neutropenia.

Olivier Le Moal/Getty Images

More than 60,000 cancer patients are hospitalized in the United States each year with evidence of neutropenia, resulting in more than 4,000 deaths, according to Ziextenzo maker Sandoz, a Novartis division.

The FDA approval was based on analytical, preclinical, and clinical research, including data from a three-way pharmacokinetics and pharmacodynamics study that compared pegfilgrastim-bmez with the reference drug pegfilgrastim (Neulasta) from the United States and the European Union. Pharmacokinetic and pharmacodynamic similarity were shown between pegfilgrastim-bmez with the reference drugs, and there were no clinically significant differences in safety or immunogenicity.

The most common adverse events associated with pegfilgrastim-bmez are bone pain and pain in the extremities, according to the label.

lfranki@mdedge.com

The Food and Drug Administration has approved the biosimilar Ziextenzo (pegfilgrastim-bmez) to reduce the incidence of infection in patients with nonmyeloid cancer receiving suppressive anticancer drugs that are associated with febrile neutropenia.

Olivier Le Moal/Getty Images

More than 60,000 cancer patients are hospitalized in the United States each year with evidence of neutropenia, resulting in more than 4,000 deaths, according to Ziextenzo maker Sandoz, a Novartis division.

The FDA approval was based on analytical, preclinical, and clinical research, including data from a three-way pharmacokinetics and pharmacodynamics study that compared pegfilgrastim-bmez with the reference drug pegfilgrastim (Neulasta) from the United States and the European Union. Pharmacokinetic and pharmacodynamic similarity were shown between pegfilgrastim-bmez with the reference drugs, and there were no clinically significant differences in safety or immunogenicity.

The most common adverse events associated with pegfilgrastim-bmez are bone pain and pain in the extremities, according to the label.

lfranki@mdedge.com

The US Department of Veterans Affairs (VA) trains a large number of learners from across multiple health care professions— more than 122,000 in 2017.¹ The VA has affiliation agreements with almost all American medical schools (97%), and annually about one-third of all medical residents in the US train at VA academic medical centers (AMCs).^1,2 The VA also trains learners in more than 40 health care professions from >1,800 training programs.^1,3 This large commitment to training aides the recruitment of these learners as VA clinicians. In fact, a high percentage of current VA clinicians previously trained at the VA. For example, 60% of VA physicians and about 70% of both VA optometrists and psychologists trained at the VA.¹

Given the large scope of training experiences and the impact on future employment, it is critical that VA educators provide a highquality learning experience for trainees. To do this, VA educators need both initial and ongoing education and support to grow and develop as teachers and as supervisors.⁴ Few educators currently report receiving this type of training, which includes effectively providing feedback to trainees, assessing trainee learning, and teaching on interprofessional teams.⁵

Numerous benefits to the AMC may be realized when a structured approach to faculty development is implemented. Systematic literature reviews of such approaches found that faculty members were satisfied with programming and that the content of programing was useful and relevant to their teaching.^6,7 Faculty reported increased positive attitudes toward faculty development and toward teaching, increased knowledge of educational principles, greater establishment of faculty networks, and positive changes in teaching behavior (as identified by faculty and students).^6,7 Further, participating in faculty development programming increased teaching effectiveness.^6-8 Faculty development programs also provided direct and indirect financial benefits to the AMC and may lead to increased patient safety, increased patient satisfaction with care, and higher quality of care.^9,10 Faculty development programming can be delivered via an online system that is as effective as face-to-face trainings and is more cost-efficient than are face-to-face trainings, particularly for educators at rural sites.¹¹

Methods

The VA Boston Healthcare System (VABHS) is a large AMC with more than 350 academic affiliations, 500 faculty members, and 3200 trainees from a wide range of health care professions. Despite this robust presence of trainees, like many other AMCs, in 2014 VABHS lacked a structured approach to faculty development programming.^12,13

To realize the potential benefits of this programming, VABHS developed a framework to conceptualize multiple components of faculty development programming. The framework focused on faculty development activities in 5 areas: teaching, research, awards, interprofessional, networking (TRAIN).¹⁴ The TRAIN framework allowed VABHS to develop specific faculty development programs in a strategic and organized manner.

In this article, we describe the VABHS First Friday Faculty Development Presentation series, a faculty development program that was created to improve teaching and supervising skill. The presentation series began in 2014. Faculty members at all 3 VABHS campuses participated in the presentations either in-person or via videoconference. Over time, faculty members at other New England VA AMCs began to express interest in participating, and audio and videoconferences were used to allow participation from those sites.

The program soon developed a national audience. In January 2017, this program provided the opportunity for faculty members to earn continuing education (CE) credits for participation. This allowed faculty members a unique opportunity to earn CE for presentations specifically geared toward improving skills as an educator, which is not widely available—particularly at rural and remote VA sites.

Presentations were 1 hour and held on the first Friday of the month at 12 pm Eastern Standard time. Topics for the presentations were identified through formal and informal needs assessments of faculty and through faculty development needs identified in the literature. Presentation topics consistent with the components of the TRAIN framework were selected. The cost to develop the program was largely related to time spent by presentation organizers to arrange speakers, advertise the presentations, develop a protocol for the use of the technology, and apply for accreditation for participants to receive CE credits.

Presenters were educators from a range of health care professions, including physicians, psychologists, nurses, and other professions from VABHS and neighboring Boston-area AMCs. Topics included providing feedback to learners, using active learning strategies, teaching clinical thinking, reducing burnout among educators, managing work-life balance, and developing interprofessional learning curricula. Presentations are archived online.

Results

From January 2017 to June 2018, 869 CE credits were earned by faculty members at VA AMCs nationwide for participating in this faculty development program, including 359 credits for nurses (41.3%), 164 credits for pharmacists (18.9%), 128 credits for physicians (14.7%), 67 credits for social workers (7.7%), and 54 credits for psychologists (6.2%). Other CE credits were earned by dieticians (14), dentists (13), speech pathologists (3), and occupational therapists (2), and other health care professionals (65).

Participants completed satisfaction surveys, responding to 9 questions using a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree) (Table). Data collection practices were reviewed by the VABHS Internal Review Board, which determined that the data did not meet the definition of human subject research and did not require further review.

Participants were asked 2 additional questions to further assess the programming. Seven hundred forty-eight participants responded to the question “How much did you learn as a result of this CE program?” using Likert-scale responses (1 = very little to 5 = great deal): 56.6% responded with a 4, (fair amount), and 21.5% responded with a 5 (great deal). Participants also were asked whether the content of this CE program was useful for their practice or other professional development (1 = not useful to 5 = extremely useful). Seven hundred forty-nine participants responded with a 4 (useful), and 25.4% of participants responded with a 5 (extremely useful).

Discussion

Overall, participants reported that the presentations were effective in teaching content, they acquired new knowledge, and they can apply this knowledge in future teaching. Participants reported satisfaction with the training activities and that the content was presented in a fair and unbiased manner. Further, they reported the training environment was effective, and they would recommend the training to others.

Conclusion

VABHS will continue to identify mechanisms to further disseminate and enhance this programming, particularly in rural areas, where there is a shortage of faculty development programming.² We will continue to assess the impact of these presentations on many factors, including patient safety and veteran satisfaction with their health care. We will also seek to understand how many total participants attend each presentation, as we currently have data only from participants who completed the satisfaction survey.

We invite faculty members from all VA AMCs and training sites to attend future presentations. Information about upcoming presentations is disseminated across multiple VA listservs; you can also e-mail the authors to receive notification of future presentations.

The US Department of Veterans Affairs (VA) trains a large number of learners from across multiple health care professions— more than 122,000 in 2017.¹ The VA has affiliation agreements with almost all American medical schools (97%), and annually about one-third of all medical residents in the US train at VA academic medical centers (AMCs).^1,2 The VA also trains learners in more than 40 health care professions from >1,800 training programs.^1,3 This large commitment to training aides the recruitment of these learners as VA clinicians. In fact, a high percentage of current VA clinicians previously trained at the VA. For example, 60% of VA physicians and about 70% of both VA optometrists and psychologists trained at the VA.¹

Given the large scope of training experiences and the impact on future employment, it is critical that VA educators provide a highquality learning experience for trainees. To do this, VA educators need both initial and ongoing education and support to grow and develop as teachers and as supervisors.⁴ Few educators currently report receiving this type of training, which includes effectively providing feedback to trainees, assessing trainee learning, and teaching on interprofessional teams.⁵

Numerous benefits to the AMC may be realized when a structured approach to faculty development is implemented. Systematic literature reviews of such approaches found that faculty members were satisfied with programming and that the content of programing was useful and relevant to their teaching.^6,7 Faculty reported increased positive attitudes toward faculty development and toward teaching, increased knowledge of educational principles, greater establishment of faculty networks, and positive changes in teaching behavior (as identified by faculty and students).^6,7 Further, participating in faculty development programming increased teaching effectiveness.^6-8 Faculty development programs also provided direct and indirect financial benefits to the AMC and may lead to increased patient safety, increased patient satisfaction with care, and higher quality of care.^9,10 Faculty development programming can be delivered via an online system that is as effective as face-to-face trainings and is more cost-efficient than are face-to-face trainings, particularly for educators at rural sites.¹¹

Methods

The VA Boston Healthcare System (VABHS) is a large AMC with more than 350 academic affiliations, 500 faculty members, and 3200 trainees from a wide range of health care professions. Despite this robust presence of trainees, like many other AMCs, in 2014 VABHS lacked a structured approach to faculty development programming.^12,13

To realize the potential benefits of this programming, VABHS developed a framework to conceptualize multiple components of faculty development programming. The framework focused on faculty development activities in 5 areas: teaching, research, awards, interprofessional, networking (TRAIN).¹⁴ The TRAIN framework allowed VABHS to develop specific faculty development programs in a strategic and organized manner.

In this article, we describe the VABHS First Friday Faculty Development Presentation series, a faculty development program that was created to improve teaching and supervising skill. The presentation series began in 2014. Faculty members at all 3 VABHS campuses participated in the presentations either in-person or via videoconference. Over time, faculty members at other New England VA AMCs began to express interest in participating, and audio and videoconferences were used to allow participation from those sites.

The program soon developed a national audience. In January 2017, this program provided the opportunity for faculty members to earn continuing education (CE) credits for participation. This allowed faculty members a unique opportunity to earn CE for presentations specifically geared toward improving skills as an educator, which is not widely available—particularly at rural and remote VA sites.

Presentations were 1 hour and held on the first Friday of the month at 12 pm Eastern Standard time. Topics for the presentations were identified through formal and informal needs assessments of faculty and through faculty development needs identified in the literature. Presentation topics consistent with the components of the TRAIN framework were selected. The cost to develop the program was largely related to time spent by presentation organizers to arrange speakers, advertise the presentations, develop a protocol for the use of the technology, and apply for accreditation for participants to receive CE credits.

Presenters were educators from a range of health care professions, including physicians, psychologists, nurses, and other professions from VABHS and neighboring Boston-area AMCs. Topics included providing feedback to learners, using active learning strategies, teaching clinical thinking, reducing burnout among educators, managing work-life balance, and developing interprofessional learning curricula. Presentations are archived online.

Results

From January 2017 to June 2018, 869 CE credits were earned by faculty members at VA AMCs nationwide for participating in this faculty development program, including 359 credits for nurses (41.3%), 164 credits for pharmacists (18.9%), 128 credits for physicians (14.7%), 67 credits for social workers (7.7%), and 54 credits for psychologists (6.2%). Other CE credits were earned by dieticians (14), dentists (13), speech pathologists (3), and occupational therapists (2), and other health care professionals (65).

Participants completed satisfaction surveys, responding to 9 questions using a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree) (Table). Data collection practices were reviewed by the VABHS Internal Review Board, which determined that the data did not meet the definition of human subject research and did not require further review.

Participants were asked 2 additional questions to further assess the programming. Seven hundred forty-eight participants responded to the question “How much did you learn as a result of this CE program?” using Likert-scale responses (1 = very little to 5 = great deal): 56.6% responded with a 4, (fair amount), and 21.5% responded with a 5 (great deal). Participants also were asked whether the content of this CE program was useful for their practice or other professional development (1 = not useful to 5 = extremely useful). Seven hundred forty-nine participants responded with a 4 (useful), and 25.4% of participants responded with a 5 (extremely useful).

Discussion

Overall, participants reported that the presentations were effective in teaching content, they acquired new knowledge, and they can apply this knowledge in future teaching. Participants reported satisfaction with the training activities and that the content was presented in a fair and unbiased manner. Further, they reported the training environment was effective, and they would recommend the training to others.

Conclusion

VABHS will continue to identify mechanisms to further disseminate and enhance this programming, particularly in rural areas, where there is a shortage of faculty development programming.² We will continue to assess the impact of these presentations on many factors, including patient safety and veteran satisfaction with their health care. We will also seek to understand how many total participants attend each presentation, as we currently have data only from participants who completed the satisfaction survey.

We invite faculty members from all VA AMCs and training sites to attend future presentations. Information about upcoming presentations is disseminated across multiple VA listservs; you can also e-mail the authors to receive notification of future presentations.

The US Department of Veterans Affairs (VA) trains a large number of learners from across multiple health care professions— more than 122,000 in 2017.¹ The VA has affiliation agreements with almost all American medical schools (97%), and annually about one-third of all medical residents in the US train at VA academic medical centers (AMCs).^1,2 The VA also trains learners in more than 40 health care professions from >1,800 training programs.^1,3 This large commitment to training aides the recruitment of these learners as VA clinicians. In fact, a high percentage of current VA clinicians previously trained at the VA. For example, 60% of VA physicians and about 70% of both VA optometrists and psychologists trained at the VA.¹

Given the large scope of training experiences and the impact on future employment, it is critical that VA educators provide a highquality learning experience for trainees. To do this, VA educators need both initial and ongoing education and support to grow and develop as teachers and as supervisors.⁴ Few educators currently report receiving this type of training, which includes effectively providing feedback to trainees, assessing trainee learning, and teaching on interprofessional teams.⁵

Numerous benefits to the AMC may be realized when a structured approach to faculty development is implemented. Systematic literature reviews of such approaches found that faculty members were satisfied with programming and that the content of programing was useful and relevant to their teaching.^6,7 Faculty reported increased positive attitudes toward faculty development and toward teaching, increased knowledge of educational principles, greater establishment of faculty networks, and positive changes in teaching behavior (as identified by faculty and students).^6,7 Further, participating in faculty development programming increased teaching effectiveness.^6-8 Faculty development programs also provided direct and indirect financial benefits to the AMC and may lead to increased patient safety, increased patient satisfaction with care, and higher quality of care.^9,10 Faculty development programming can be delivered via an online system that is as effective as face-to-face trainings and is more cost-efficient than are face-to-face trainings, particularly for educators at rural sites.¹¹

Methods

The VA Boston Healthcare System (VABHS) is a large AMC with more than 350 academic affiliations, 500 faculty members, and 3200 trainees from a wide range of health care professions. Despite this robust presence of trainees, like many other AMCs, in 2014 VABHS lacked a structured approach to faculty development programming.^12,13

To realize the potential benefits of this programming, VABHS developed a framework to conceptualize multiple components of faculty development programming. The framework focused on faculty development activities in 5 areas: teaching, research, awards, interprofessional, networking (TRAIN).¹⁴ The TRAIN framework allowed VABHS to develop specific faculty development programs in a strategic and organized manner.

In this article, we describe the VABHS First Friday Faculty Development Presentation series, a faculty development program that was created to improve teaching and supervising skill. The presentation series began in 2014. Faculty members at all 3 VABHS campuses participated in the presentations either in-person or via videoconference. Over time, faculty members at other New England VA AMCs began to express interest in participating, and audio and videoconferences were used to allow participation from those sites.

The program soon developed a national audience. In January 2017, this program provided the opportunity for faculty members to earn continuing education (CE) credits for participation. This allowed faculty members a unique opportunity to earn CE for presentations specifically geared toward improving skills as an educator, which is not widely available—particularly at rural and remote VA sites.

Presentations were 1 hour and held on the first Friday of the month at 12 pm Eastern Standard time. Topics for the presentations were identified through formal and informal needs assessments of faculty and through faculty development needs identified in the literature. Presentation topics consistent with the components of the TRAIN framework were selected. The cost to develop the program was largely related to time spent by presentation organizers to arrange speakers, advertise the presentations, develop a protocol for the use of the technology, and apply for accreditation for participants to receive CE credits.

Presenters were educators from a range of health care professions, including physicians, psychologists, nurses, and other professions from VABHS and neighboring Boston-area AMCs. Topics included providing feedback to learners, using active learning strategies, teaching clinical thinking, reducing burnout among educators, managing work-life balance, and developing interprofessional learning curricula. Presentations are archived online.

Results

From January 2017 to June 2018, 869 CE credits were earned by faculty members at VA AMCs nationwide for participating in this faculty development program, including 359 credits for nurses (41.3%), 164 credits for pharmacists (18.9%), 128 credits for physicians (14.7%), 67 credits for social workers (7.7%), and 54 credits for psychologists (6.2%). Other CE credits were earned by dieticians (14), dentists (13), speech pathologists (3), and occupational therapists (2), and other health care professionals (65).

Participants completed satisfaction surveys, responding to 9 questions using a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree) (Table). Data collection practices were reviewed by the VABHS Internal Review Board, which determined that the data did not meet the definition of human subject research and did not require further review.

Participants were asked 2 additional questions to further assess the programming. Seven hundred forty-eight participants responded to the question “How much did you learn as a result of this CE program?” using Likert-scale responses (1 = very little to 5 = great deal): 56.6% responded with a 4, (fair amount), and 21.5% responded with a 5 (great deal). Participants also were asked whether the content of this CE program was useful for their practice or other professional development (1 = not useful to 5 = extremely useful). Seven hundred forty-nine participants responded with a 4 (useful), and 25.4% of participants responded with a 5 (extremely useful).

Discussion

Overall, participants reported that the presentations were effective in teaching content, they acquired new knowledge, and they can apply this knowledge in future teaching. Participants reported satisfaction with the training activities and that the content was presented in a fair and unbiased manner. Further, they reported the training environment was effective, and they would recommend the training to others.

Conclusion

VABHS will continue to identify mechanisms to further disseminate and enhance this programming, particularly in rural areas, where there is a shortage of faculty development programming.² We will continue to assess the impact of these presentations on many factors, including patient safety and veteran satisfaction with their health care. We will also seek to understand how many total participants attend each presentation, as we currently have data only from participants who completed the satisfaction survey.

We invite faculty members from all VA AMCs and training sites to attend future presentations. Information about upcoming presentations is disseminated across multiple VA listservs; you can also e-mail the authors to receive notification of future presentations.

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Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

SAN ANTONIO – Clinicians don’t appear to mind too much when their red blood cell orders are flagged for review by a best practice alert system, and alert fatigue doesn’t seem to hamper patient blood management efforts, investigators in a single-center study reported.

Neil Osterweil/MDedge News

At the Medical University of South Carolina, Charleston (MUSC), if clinicians order RBC transfusions for patients with hemoglobin levels over 7.0 g/dL or for patients who did not have a hemoglobin determination over the past 24 hours, they receive a best practice alert. They must acknowledge it and cancel the order, or override it and document a reason in the medical record.

Although approximately 70% of alerts were overridden, the reasons for the overrides “were consistent over time and appropriate,” reported Jerry E. Squires, MD, PhD, and colleagues from MUSC in a poster presentation at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The goal of the study was to find out if the effectiveness of the alert was wearing out after months of active use by clinicians. “Is it true that they’re clicking too much and they’re inundated with other [best practice alerts], and are they even paying attention?” said coauthor Heather Toeppner, RN, also from MUSC, in an interview. “All in all, we found that the alert is making a lasting impression in our institution,” she said.

Transfusion clinical decision support systems that produce automated alerts for clinicians can improve usage and reduce waste of RBCs, but whether the effect is sustained over time was unknown, Ms. Toeppner said, prompting the investigators to study the effect of the RBC best practice alert over 10 months.

As noted, the alert is triggered when providers order RBCs for patients with hemoglobin levels over 7.0 g/dL or when there is no record of a hemoglobin test in the chart within the past 24 hours. Before the alert is triggered, however, the system reviews the record and excludes alerts for patients with specific conditions, such as concurrent surgery or sickle cell disease.

The authors found that the alert was triggered an average of 195 times per month over the 10 months studied. On average, 16% of the alerts resulted in a cancellation of the RBC order, and 71% of alerts were overridden.

“Most importantly, there was no trend suggesting that either cancellation of the RBC order or overriding the alert became more frequent over time,” the investigators wrote. “Similarly, reasons for overriding the alert were consistent over time, with ‘preparation for an invasive procedure’ and ‘active bleeding’ being the most common reasons for overriding the alert (32% and 23% of all overrides, respectively).”

Other common reasons for overrides included tachycardia, shortness of breath, hypotension, onset of chest pain, and acute coronary syndrome.

Interestingly, but perhaps not surprisingly, they found that overrides dropped sharply and changed orders rose by the same magnitude in July, when new residents started their rotations.

The investigators wrote that the relatively small number of alerts may be attributable to their institution’s robust patient blood management program and the intentional exclusion of orders for patients with specific diagnostic codes, including intraoperative patients, those with sickle cell disease, and all patients aged younger than 18 years.

The study was internally funded. The authors reported having no conflicts of interest.

SAN ANTONIO – Clinicians don’t appear to mind too much when their red blood cell orders are flagged for review by a best practice alert system, and alert fatigue doesn’t seem to hamper patient blood management efforts, investigators in a single-center study reported.

Neil Osterweil/MDedge News

At the Medical University of South Carolina, Charleston (MUSC), if clinicians order RBC transfusions for patients with hemoglobin levels over 7.0 g/dL or for patients who did not have a hemoglobin determination over the past 24 hours, they receive a best practice alert. They must acknowledge it and cancel the order, or override it and document a reason in the medical record.

Although approximately 70% of alerts were overridden, the reasons for the overrides “were consistent over time and appropriate,” reported Jerry E. Squires, MD, PhD, and colleagues from MUSC in a poster presentation at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The goal of the study was to find out if the effectiveness of the alert was wearing out after months of active use by clinicians. “Is it true that they’re clicking too much and they’re inundated with other [best practice alerts], and are they even paying attention?” said coauthor Heather Toeppner, RN, also from MUSC, in an interview. “All in all, we found that the alert is making a lasting impression in our institution,” she said.

Transfusion clinical decision support systems that produce automated alerts for clinicians can improve usage and reduce waste of RBCs, but whether the effect is sustained over time was unknown, Ms. Toeppner said, prompting the investigators to study the effect of the RBC best practice alert over 10 months.

As noted, the alert is triggered when providers order RBCs for patients with hemoglobin levels over 7.0 g/dL or when there is no record of a hemoglobin test in the chart within the past 24 hours. Before the alert is triggered, however, the system reviews the record and excludes alerts for patients with specific conditions, such as concurrent surgery or sickle cell disease.

The authors found that the alert was triggered an average of 195 times per month over the 10 months studied. On average, 16% of the alerts resulted in a cancellation of the RBC order, and 71% of alerts were overridden.

“Most importantly, there was no trend suggesting that either cancellation of the RBC order or overriding the alert became more frequent over time,” the investigators wrote. “Similarly, reasons for overriding the alert were consistent over time, with ‘preparation for an invasive procedure’ and ‘active bleeding’ being the most common reasons for overriding the alert (32% and 23% of all overrides, respectively).”

Other common reasons for overrides included tachycardia, shortness of breath, hypotension, onset of chest pain, and acute coronary syndrome.

Interestingly, but perhaps not surprisingly, they found that overrides dropped sharply and changed orders rose by the same magnitude in July, when new residents started their rotations.

The investigators wrote that the relatively small number of alerts may be attributable to their institution’s robust patient blood management program and the intentional exclusion of orders for patients with specific diagnostic codes, including intraoperative patients, those with sickle cell disease, and all patients aged younger than 18 years.

The study was internally funded. The authors reported having no conflicts of interest.

SAN ANTONIO – Clinicians don’t appear to mind too much when their red blood cell orders are flagged for review by a best practice alert system, and alert fatigue doesn’t seem to hamper patient blood management efforts, investigators in a single-center study reported.

Neil Osterweil/MDedge News

At the Medical University of South Carolina, Charleston (MUSC), if clinicians order RBC transfusions for patients with hemoglobin levels over 7.0 g/dL or for patients who did not have a hemoglobin determination over the past 24 hours, they receive a best practice alert. They must acknowledge it and cancel the order, or override it and document a reason in the medical record.

Although approximately 70% of alerts were overridden, the reasons for the overrides “were consistent over time and appropriate,” reported Jerry E. Squires, MD, PhD, and colleagues from MUSC in a poster presentation at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The goal of the study was to find out if the effectiveness of the alert was wearing out after months of active use by clinicians. “Is it true that they’re clicking too much and they’re inundated with other [best practice alerts], and are they even paying attention?” said coauthor Heather Toeppner, RN, also from MUSC, in an interview. “All in all, we found that the alert is making a lasting impression in our institution,” she said.

Transfusion clinical decision support systems that produce automated alerts for clinicians can improve usage and reduce waste of RBCs, but whether the effect is sustained over time was unknown, Ms. Toeppner said, prompting the investigators to study the effect of the RBC best practice alert over 10 months.

As noted, the alert is triggered when providers order RBCs for patients with hemoglobin levels over 7.0 g/dL or when there is no record of a hemoglobin test in the chart within the past 24 hours. Before the alert is triggered, however, the system reviews the record and excludes alerts for patients with specific conditions, such as concurrent surgery or sickle cell disease.

The authors found that the alert was triggered an average of 195 times per month over the 10 months studied. On average, 16% of the alerts resulted in a cancellation of the RBC order, and 71% of alerts were overridden.

“Most importantly, there was no trend suggesting that either cancellation of the RBC order or overriding the alert became more frequent over time,” the investigators wrote. “Similarly, reasons for overriding the alert were consistent over time, with ‘preparation for an invasive procedure’ and ‘active bleeding’ being the most common reasons for overriding the alert (32% and 23% of all overrides, respectively).”

Other common reasons for overrides included tachycardia, shortness of breath, hypotension, onset of chest pain, and acute coronary syndrome.

Interestingly, but perhaps not surprisingly, they found that overrides dropped sharply and changed orders rose by the same magnitude in July, when new residents started their rotations.

The investigators wrote that the relatively small number of alerts may be attributable to their institution’s robust patient blood management program and the intentional exclusion of orders for patients with specific diagnostic codes, including intraoperative patients, those with sickle cell disease, and all patients aged younger than 18 years.

The study was internally funded. The authors reported having no conflicts of interest.

WASHINGTON – Although severe, community-acquired sepsis in previously healthy U.S. adults is relatively uncommon, it occurs often enough to strike about 40,000 people annually, and when previously healthy people are hospitalized for severe sepsis, their rate of in-hospital mortality was double the rate in people with one or more comorbidities who have severe, community-acquired sepsis, based on a review of almost 7 million Americans hospitalized for sepsis.

The findings “underscore the importance of improving public awareness of sepsis and emphasizing early sepsis recognition and treatment in all patients,” including those without comorbidities, Chanu Rhee, MD, said at an annual scientific meeting on infectious diseases. He hypothesized that the increased sepsis mortality among previously healthy patients may have stemmed from factors such as delayed sepsis recognition resulting in hospitalization at a more advanced stage and less aggressive management.

In addition, “the findings provide context for high-profile reports about sepsis death in previously healthy people,” said Dr. Rhee, an infectious diseases and critical care physician at Brigham and Women’s Hospital in Boston. Dr. Rhee and associates found that, among patients hospitalized with what the researchers defined as “community-acquired” sepsis, 3% were judged previously healthy by having no identified major or minor comorbidity or pregnancy at the time of hospitalization, a percentage that – while small – still translates into roughly 40,000 such cases annually in the United States. That helps explain why every so often a headline appears about a famous person who died suddenly and unexpectedly from sepsis, he noted.

The study used data collected on hospitalized U.S. patients in the Cerner Health Facts, HCA Healthcare, and Institute for Health Metrics and Evaluation databases, which included about 6.7 million people total including 337,983 identified as having community-acquired sepsis, defined as patients who met the criteria for adult sepsis advanced by the Centers for Disease Control and Prevention within 2 days of their hospital admission. The researchers looked further into the hospital records of these patients and divided them into patients with one or more major comorbidities (96% of the cohort), patients who were pregnant or had a “minor” comorbidity such as a lipid disorder, benign neoplasm, or obesity (1% of the study group), or those with no chronic comorbidity (3%; the subgroup the researchers deemed previously healthy).

In a multivariate analysis that adjusted for patients’ age, sex, race, infection site, and illness severity at the time of hospital admission the researchers found that the rate of in-hospital death among the previously healthy patients was exactly twice the rate of those who had at least one major chronic comorbidity, Dr. Rhee reported. Differences in the treatment received by the previously-healthy patients or in their medical status compared with patients with a major comorbidity suggested that the previously health patients were sicker. They had a higher rate of mechanical ventilation, 30%, compared with about 18% for those with a comorbidity; a higher rate of acute kidney injury, about 43% in those previously healthy and 28% in those with a comorbidity; and a higher percentage had an elevated lactate level, about 41% among the previously healthy patients and about 22% among those with a comorbidity.

mzoler@mdedge.com

SOURCE: Alrawashdeh M et al. Open Forum Infect Dis. 2019 Oct 23;6. Abstract 891.

WASHINGTON – Although severe, community-acquired sepsis in previously healthy U.S. adults is relatively uncommon, it occurs often enough to strike about 40,000 people annually, and when previously healthy people are hospitalized for severe sepsis, their rate of in-hospital mortality was double the rate in people with one or more comorbidities who have severe, community-acquired sepsis, based on a review of almost 7 million Americans hospitalized for sepsis.

The findings “underscore the importance of improving public awareness of sepsis and emphasizing early sepsis recognition and treatment in all patients,” including those without comorbidities, Chanu Rhee, MD, said at an annual scientific meeting on infectious diseases. He hypothesized that the increased sepsis mortality among previously healthy patients may have stemmed from factors such as delayed sepsis recognition resulting in hospitalization at a more advanced stage and less aggressive management.

In addition, “the findings provide context for high-profile reports about sepsis death in previously healthy people,” said Dr. Rhee, an infectious diseases and critical care physician at Brigham and Women’s Hospital in Boston. Dr. Rhee and associates found that, among patients hospitalized with what the researchers defined as “community-acquired” sepsis, 3% were judged previously healthy by having no identified major or minor comorbidity or pregnancy at the time of hospitalization, a percentage that – while small – still translates into roughly 40,000 such cases annually in the United States. That helps explain why every so often a headline appears about a famous person who died suddenly and unexpectedly from sepsis, he noted.

The study used data collected on hospitalized U.S. patients in the Cerner Health Facts, HCA Healthcare, and Institute for Health Metrics and Evaluation databases, which included about 6.7 million people total including 337,983 identified as having community-acquired sepsis, defined as patients who met the criteria for adult sepsis advanced by the Centers for Disease Control and Prevention within 2 days of their hospital admission. The researchers looked further into the hospital records of these patients and divided them into patients with one or more major comorbidities (96% of the cohort), patients who were pregnant or had a “minor” comorbidity such as a lipid disorder, benign neoplasm, or obesity (1% of the study group), or those with no chronic comorbidity (3%; the subgroup the researchers deemed previously healthy).

In a multivariate analysis that adjusted for patients’ age, sex, race, infection site, and illness severity at the time of hospital admission the researchers found that the rate of in-hospital death among the previously healthy patients was exactly twice the rate of those who had at least one major chronic comorbidity, Dr. Rhee reported. Differences in the treatment received by the previously-healthy patients or in their medical status compared with patients with a major comorbidity suggested that the previously health patients were sicker. They had a higher rate of mechanical ventilation, 30%, compared with about 18% for those with a comorbidity; a higher rate of acute kidney injury, about 43% in those previously healthy and 28% in those with a comorbidity; and a higher percentage had an elevated lactate level, about 41% among the previously healthy patients and about 22% among those with a comorbidity.

mzoler@mdedge.com

SOURCE: Alrawashdeh M et al. Open Forum Infect Dis. 2019 Oct 23;6. Abstract 891.

WASHINGTON – Although severe, community-acquired sepsis in previously healthy U.S. adults is relatively uncommon, it occurs often enough to strike about 40,000 people annually, and when previously healthy people are hospitalized for severe sepsis, their rate of in-hospital mortality was double the rate in people with one or more comorbidities who have severe, community-acquired sepsis, based on a review of almost 7 million Americans hospitalized for sepsis.

The findings “underscore the importance of improving public awareness of sepsis and emphasizing early sepsis recognition and treatment in all patients,” including those without comorbidities, Chanu Rhee, MD, said at an annual scientific meeting on infectious diseases. He hypothesized that the increased sepsis mortality among previously healthy patients may have stemmed from factors such as delayed sepsis recognition resulting in hospitalization at a more advanced stage and less aggressive management.

In addition, “the findings provide context for high-profile reports about sepsis death in previously healthy people,” said Dr. Rhee, an infectious diseases and critical care physician at Brigham and Women’s Hospital in Boston. Dr. Rhee and associates found that, among patients hospitalized with what the researchers defined as “community-acquired” sepsis, 3% were judged previously healthy by having no identified major or minor comorbidity or pregnancy at the time of hospitalization, a percentage that – while small – still translates into roughly 40,000 such cases annually in the United States. That helps explain why every so often a headline appears about a famous person who died suddenly and unexpectedly from sepsis, he noted.

The study used data collected on hospitalized U.S. patients in the Cerner Health Facts, HCA Healthcare, and Institute for Health Metrics and Evaluation databases, which included about 6.7 million people total including 337,983 identified as having community-acquired sepsis, defined as patients who met the criteria for adult sepsis advanced by the Centers for Disease Control and Prevention within 2 days of their hospital admission. The researchers looked further into the hospital records of these patients and divided them into patients with one or more major comorbidities (96% of the cohort), patients who were pregnant or had a “minor” comorbidity such as a lipid disorder, benign neoplasm, or obesity (1% of the study group), or those with no chronic comorbidity (3%; the subgroup the researchers deemed previously healthy).

In a multivariate analysis that adjusted for patients’ age, sex, race, infection site, and illness severity at the time of hospital admission the researchers found that the rate of in-hospital death among the previously healthy patients was exactly twice the rate of those who had at least one major chronic comorbidity, Dr. Rhee reported. Differences in the treatment received by the previously-healthy patients or in their medical status compared with patients with a major comorbidity suggested that the previously health patients were sicker. They had a higher rate of mechanical ventilation, 30%, compared with about 18% for those with a comorbidity; a higher rate of acute kidney injury, about 43% in those previously healthy and 28% in those with a comorbidity; and a higher percentage had an elevated lactate level, about 41% among the previously healthy patients and about 22% among those with a comorbidity.

mzoler@mdedge.com

SOURCE: Alrawashdeh M et al. Open Forum Infect Dis. 2019 Oct 23;6. Abstract 891.

The annual Skin Disease Education Foundation’s Las Vegas Dermatology Seminar gets underway Thursday and will feature presentations on topics ranging from updates on acne, hyperhidrosis, and rosacea, to pigmentation disorders and connective tissue disease. The annual Psoriasis Forum at the meeting will feature talks on tumor necrosis factor inhibitors and interleukin-17 inhibitors, as well as presentations on phototherapy, emerging treatments, and IL-12/23 and IL-23 inhibitors. The Atopic Dermatology Forum will address new horizons in treatment, pediatric inflammatory disease, and the pathophysiology of atopic dermatitis.

The meeting wraps up on Saturday, with a slate of aesthetic dermatology presentations, kicking off with “Assessment of the Aging Face” and ending with “An Overview of Tissue-Tightening Devices.”

New this year is the Cutaneous Malignancies Forum, which is being held today, one day before the regular Las Vegas Dermatology Seminar program begins. With a focus on contemporary issues in effective diagnosis and treatment of cutaneous malignancies, the forum is cochaired by Sancy Leachman, MD, PhD, professor and chair of the department of dermatology, and the John D. Gray endowed chair in melanoma research, at Oregon Health & Science Center, Portland, and Mohammed Kashani-Sabet, MD, director of the Center for Melanoma Research and Treatment, at the California Pacific Medical Research Institute, San Francisco. The forum will feature four sessions: melanoma, keratinocyte carcinomas, cutaneous T-cell lymphoma, and Merkel cell carcinoma.

SDEF and this news organization are owned by the same parent company. For full coverage, go to www.mdedge.com/dermatology.
 

emechcatie@mdedge.com

The annual Skin Disease Education Foundation’s Las Vegas Dermatology Seminar gets underway Thursday and will feature presentations on topics ranging from updates on acne, hyperhidrosis, and rosacea, to pigmentation disorders and connective tissue disease. The annual Psoriasis Forum at the meeting will feature talks on tumor necrosis factor inhibitors and interleukin-17 inhibitors, as well as presentations on phototherapy, emerging treatments, and IL-12/23 and IL-23 inhibitors. The Atopic Dermatology Forum will address new horizons in treatment, pediatric inflammatory disease, and the pathophysiology of atopic dermatitis.

The meeting wraps up on Saturday, with a slate of aesthetic dermatology presentations, kicking off with “Assessment of the Aging Face” and ending with “An Overview of Tissue-Tightening Devices.”

New this year is the Cutaneous Malignancies Forum, which is being held today, one day before the regular Las Vegas Dermatology Seminar program begins. With a focus on contemporary issues in effective diagnosis and treatment of cutaneous malignancies, the forum is cochaired by Sancy Leachman, MD, PhD, professor and chair of the department of dermatology, and the John D. Gray endowed chair in melanoma research, at Oregon Health & Science Center, Portland, and Mohammed Kashani-Sabet, MD, director of the Center for Melanoma Research and Treatment, at the California Pacific Medical Research Institute, San Francisco. The forum will feature four sessions: melanoma, keratinocyte carcinomas, cutaneous T-cell lymphoma, and Merkel cell carcinoma.

SDEF and this news organization are owned by the same parent company. For full coverage, go to www.mdedge.com/dermatology.
 

emechcatie@mdedge.com

The annual Skin Disease Education Foundation’s Las Vegas Dermatology Seminar gets underway Thursday and will feature presentations on topics ranging from updates on acne, hyperhidrosis, and rosacea, to pigmentation disorders and connective tissue disease. The annual Psoriasis Forum at the meeting will feature talks on tumor necrosis factor inhibitors and interleukin-17 inhibitors, as well as presentations on phototherapy, emerging treatments, and IL-12/23 and IL-23 inhibitors. The Atopic Dermatology Forum will address new horizons in treatment, pediatric inflammatory disease, and the pathophysiology of atopic dermatitis.

The meeting wraps up on Saturday, with a slate of aesthetic dermatology presentations, kicking off with “Assessment of the Aging Face” and ending with “An Overview of Tissue-Tightening Devices.”

New this year is the Cutaneous Malignancies Forum, which is being held today, one day before the regular Las Vegas Dermatology Seminar program begins. With a focus on contemporary issues in effective diagnosis and treatment of cutaneous malignancies, the forum is cochaired by Sancy Leachman, MD, PhD, professor and chair of the department of dermatology, and the John D. Gray endowed chair in melanoma research, at Oregon Health & Science Center, Portland, and Mohammed Kashani-Sabet, MD, director of the Center for Melanoma Research and Treatment, at the California Pacific Medical Research Institute, San Francisco. The forum will feature four sessions: melanoma, keratinocyte carcinomas, cutaneous T-cell lymphoma, and Merkel cell carcinoma.

SDEF and this news organization are owned by the same parent company. For full coverage, go to www.mdedge.com/dermatology.
 

emechcatie@mdedge.com

WASHINGTON– Gene therapy for the treatment of rare diseases continues to develop and new products are entering the pipeline; however, more work is needed to make the gene therapy experience easier on patients and their families, according to members of a panel at the NORD Rare Diseases & Orphan Product Breakthrough Summit, held by the National Organization for Rare Disorders.

Companies developing gene therapy cite their main challenges as identifying patients, developing clinical trials, coordinating treatment and supporting families, managing reimbursement, and manufacturing the treatment, said Mark Rothera, president and CEO of Orchard Therapeutics, developer of ex vivo autologous hematopoietic stem cell gene therapy.

For families of patients with rare diseases who are undergoing gene therapy, challenges include struggles such as language barriers, lack of wifi, and separation from other family members for extended periods, according to Amy Price, mother of a gene therapy recipient, as well as principal consultant to Rarallel and an advocate for metachromatic leukodystrophy.

Ms. Price cited a survey she conducted of families with children who underwent gene therapy. She collected data from 16 families about their initial visit as part of a gene therapy trial; the trials included 14 families in Milan; 1 in Bethesda, Md.; and 1 in Paris. The average age of the patients at the start of the trial was 3 years, with a range of 8 months to 11 years. The trials were conducted between 1990 and 2018.

Families participating in the trials spent an average of 5.5 months in the city where the trial was conducted, and an average of 48 days in an isolation ward with their child at the start of the study.

The five biggest challenges were financial well-being (cited by 60% of survey respondents), social isolation/being away from support system (60%), fear of the unknown/long-term treatment diagnosis (73%), family separation (67%), and caring for other children simultaneous during the trial period (60%).

In addition, patients averaged 12 follow-up visits, and the most common secondary challenges cited in the survey included time spent at the hospital, emotional and physical stress on the patient, fear of test results and outcomes, exhaustion, time away from work and school, and travel logistics.

Other stressors include language barriers and not being in children’s hospital, Ms. Price said.

Ms. Price proposed patient-focused solutions such as addressing cultural challenges, connecting families to local resources, and providing clinical follow-up locally to reduce the burden of travel to the trial site.

WASHINGTON– Gene therapy for the treatment of rare diseases continues to develop and new products are entering the pipeline; however, more work is needed to make the gene therapy experience easier on patients and their families, according to members of a panel at the NORD Rare Diseases & Orphan Product Breakthrough Summit, held by the National Organization for Rare Disorders.

Companies developing gene therapy cite their main challenges as identifying patients, developing clinical trials, coordinating treatment and supporting families, managing reimbursement, and manufacturing the treatment, said Mark Rothera, president and CEO of Orchard Therapeutics, developer of ex vivo autologous hematopoietic stem cell gene therapy.

For families of patients with rare diseases who are undergoing gene therapy, challenges include struggles such as language barriers, lack of wifi, and separation from other family members for extended periods, according to Amy Price, mother of a gene therapy recipient, as well as principal consultant to Rarallel and an advocate for metachromatic leukodystrophy.

Ms. Price cited a survey she conducted of families with children who underwent gene therapy. She collected data from 16 families about their initial visit as part of a gene therapy trial; the trials included 14 families in Milan; 1 in Bethesda, Md.; and 1 in Paris. The average age of the patients at the start of the trial was 3 years, with a range of 8 months to 11 years. The trials were conducted between 1990 and 2018.

Families participating in the trials spent an average of 5.5 months in the city where the trial was conducted, and an average of 48 days in an isolation ward with their child at the start of the study.

The five biggest challenges were financial well-being (cited by 60% of survey respondents), social isolation/being away from support system (60%), fear of the unknown/long-term treatment diagnosis (73%), family separation (67%), and caring for other children simultaneous during the trial period (60%).

In addition, patients averaged 12 follow-up visits, and the most common secondary challenges cited in the survey included time spent at the hospital, emotional and physical stress on the patient, fear of test results and outcomes, exhaustion, time away from work and school, and travel logistics.

Other stressors include language barriers and not being in children’s hospital, Ms. Price said.

Ms. Price proposed patient-focused solutions such as addressing cultural challenges, connecting families to local resources, and providing clinical follow-up locally to reduce the burden of travel to the trial site.

WASHINGTON– Gene therapy for the treatment of rare diseases continues to develop and new products are entering the pipeline; however, more work is needed to make the gene therapy experience easier on patients and their families, according to members of a panel at the NORD Rare Diseases & Orphan Product Breakthrough Summit, held by the National Organization for Rare Disorders.

Companies developing gene therapy cite their main challenges as identifying patients, developing clinical trials, coordinating treatment and supporting families, managing reimbursement, and manufacturing the treatment, said Mark Rothera, president and CEO of Orchard Therapeutics, developer of ex vivo autologous hematopoietic stem cell gene therapy.

For families of patients with rare diseases who are undergoing gene therapy, challenges include struggles such as language barriers, lack of wifi, and separation from other family members for extended periods, according to Amy Price, mother of a gene therapy recipient, as well as principal consultant to Rarallel and an advocate for metachromatic leukodystrophy.

Ms. Price cited a survey she conducted of families with children who underwent gene therapy. She collected data from 16 families about their initial visit as part of a gene therapy trial; the trials included 14 families in Milan; 1 in Bethesda, Md.; and 1 in Paris. The average age of the patients at the start of the trial was 3 years, with a range of 8 months to 11 years. The trials were conducted between 1990 and 2018.

Families participating in the trials spent an average of 5.5 months in the city where the trial was conducted, and an average of 48 days in an isolation ward with their child at the start of the study.

The five biggest challenges were financial well-being (cited by 60% of survey respondents), social isolation/being away from support system (60%), fear of the unknown/long-term treatment diagnosis (73%), family separation (67%), and caring for other children simultaneous during the trial period (60%).

In addition, patients averaged 12 follow-up visits, and the most common secondary challenges cited in the survey included time spent at the hospital, emotional and physical stress on the patient, fear of test results and outcomes, exhaustion, time away from work and school, and travel logistics.

Other stressors include language barriers and not being in children’s hospital, Ms. Price said.

Ms. Price proposed patient-focused solutions such as addressing cultural challenges, connecting families to local resources, and providing clinical follow-up locally to reduce the burden of travel to the trial site.

Mint is the most popular flavor among school students who use Juul e-cigarettes, according to data from the 2019 Monitoring the Future study.

Almost half (47.1%) of the 12th graders who had used Juul e-cigarettes in the past 30 days reported that mint was the flavor they most often used, compared with 23.8% for mango and 8.6% for fruit, which is a combination of flavors, Adam M. Leventhal, PhD, of the University of Southern California, Los Angeles, and associates wrote in JAMA.

Mint was also the flavor most often used by 10th graders (43.5%), with mango again second at 27.3%, and fruit third at 10.8%. Eighth-grade students switched mango (33.5%) and mint (29.2%) but had fruit third again at 16.0%, the investigators reported, based on data for 1,739 respondents to the Monitoring the Future survey who had used a vaping product within the past 30 days.

Juul has suspended sales of four – mango, fruit, creme, and cucumber – of its original eight flavors, Dr. Leventhal and associates noted, and e-cigarette flavors other than tobacco, menthol, and mint have been prohibited by some local municipalities.

“The current findings raise uncertainty whether regulations or sales suspensions that exempt mint flavors are optimal strategies for reducing youth e-cigarette use,” they wrote.

As this article was being written, the Wall Street Journal had just reported that the Food and Drug Administration will ban mint and all other e-cigarette flavors except tobacco and menthol.

rfranki@mdedge.com

SOURCE: Leventhal AM et al. JAMA. 2019 Nov 5. doi: 10.1001/jama.2019.17968.

Mint is the most popular flavor among school students who use Juul e-cigarettes, according to data from the 2019 Monitoring the Future study.

Almost half (47.1%) of the 12th graders who had used Juul e-cigarettes in the past 30 days reported that mint was the flavor they most often used, compared with 23.8% for mango and 8.6% for fruit, which is a combination of flavors, Adam M. Leventhal, PhD, of the University of Southern California, Los Angeles, and associates wrote in JAMA.

Mint was also the flavor most often used by 10th graders (43.5%), with mango again second at 27.3%, and fruit third at 10.8%. Eighth-grade students switched mango (33.5%) and mint (29.2%) but had fruit third again at 16.0%, the investigators reported, based on data for 1,739 respondents to the Monitoring the Future survey who had used a vaping product within the past 30 days.

Juul has suspended sales of four – mango, fruit, creme, and cucumber – of its original eight flavors, Dr. Leventhal and associates noted, and e-cigarette flavors other than tobacco, menthol, and mint have been prohibited by some local municipalities.

“The current findings raise uncertainty whether regulations or sales suspensions that exempt mint flavors are optimal strategies for reducing youth e-cigarette use,” they wrote.

As this article was being written, the Wall Street Journal had just reported that the Food and Drug Administration will ban mint and all other e-cigarette flavors except tobacco and menthol.

rfranki@mdedge.com

SOURCE: Leventhal AM et al. JAMA. 2019 Nov 5. doi: 10.1001/jama.2019.17968.

Mint is the most popular flavor among school students who use Juul e-cigarettes, according to data from the 2019 Monitoring the Future study.

Almost half (47.1%) of the 12th graders who had used Juul e-cigarettes in the past 30 days reported that mint was the flavor they most often used, compared with 23.8% for mango and 8.6% for fruit, which is a combination of flavors, Adam M. Leventhal, PhD, of the University of Southern California, Los Angeles, and associates wrote in JAMA.

Mint was also the flavor most often used by 10th graders (43.5%), with mango again second at 27.3%, and fruit third at 10.8%. Eighth-grade students switched mango (33.5%) and mint (29.2%) but had fruit third again at 16.0%, the investigators reported, based on data for 1,739 respondents to the Monitoring the Future survey who had used a vaping product within the past 30 days.

Juul has suspended sales of four – mango, fruit, creme, and cucumber – of its original eight flavors, Dr. Leventhal and associates noted, and e-cigarette flavors other than tobacco, menthol, and mint have been prohibited by some local municipalities.

“The current findings raise uncertainty whether regulations or sales suspensions that exempt mint flavors are optimal strategies for reducing youth e-cigarette use,” they wrote.

As this article was being written, the Wall Street Journal had just reported that the Food and Drug Administration will ban mint and all other e-cigarette flavors except tobacco and menthol.

rfranki@mdedge.com

SOURCE: Leventhal AM et al. JAMA. 2019 Nov 5. doi: 10.1001/jama.2019.17968.

Background: Identifying paroxysmal atrial fibrillation (AFib) as the etiology of a transient ischemic attack (TIA) or stroke has implications for treatment as well as secondary prevention. Currently, there is not a universal, practical way to help determine which patients would benefit from prolonged cardiac monitoring to establish the diagnosis of AFib.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Background: Identifying paroxysmal atrial fibrillation (AFib) as the etiology of a transient ischemic attack (TIA) or stroke has implications for treatment as well as secondary prevention. Currently, there is not a universal, practical way to help determine which patients would benefit from prolonged cardiac monitoring to establish the diagnosis of AFib.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Background: Identifying paroxysmal atrial fibrillation (AFib) as the etiology of a transient ischemic attack (TIA) or stroke has implications for treatment as well as secondary prevention. Currently, there is not a universal, practical way to help determine which patients would benefit from prolonged cardiac monitoring to establish the diagnosis of AFib.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.