Ryan A. Williams, MD

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is curable in most patients, however this high cure rate is mostly reserved for those who achieve a complete remission with first line treatment. In patients who have relapsed/refractory disease the cure rate is significantly lower. There are limited studies that have previously investigated the rate of clinical trial discussion and enrollment among DLBCL patients. Our aim, as part of a larger study, was to determine the rate of clinical trial enrollment for patients diagnosed with DLBCL at the Veterans Health Administration system (VHA), a population that traditionally experiences poorer outcomes when compared to the community and academic centers.

METHODS: We performed a retrospective chart review of patients diagnosed with DLBCL in the VHA nationwide from 01/01/2011 to 12/31/2017. Patients treated outside of the VHA and patients with primary DLBCL of the CNS were excluded. During our inclusion period, we randomly selected patients and evaluated the number of patients that engaged in discussions with their providers about clinical trials and the number of patients that eventually enrolled in trials.

RESULTS: In total, 721 patients met our inclusion criteria. Median age was 67 and the majority of patients were white (74.5%), male (96.8%), had an ECOG of 2 (83.7%) and presented with advanced stage disease (stage IV: 40.3% and stage III: 26.5%). Of all the patients included in our study 3.7% engaged in discussion about clinical trials and amongst relapsed/ refractory patients (N=182), 12.6% engaged in discussion. The rate of clinical trial enrollment was 1.8% in all patients and 6% in relapsed/refractory patients.

CONCLUSION: Our results show a low rate of 1.8% of DLBCL patients enrolling in clinical trials. These rates are improved but remain low at 6% in relapsed/ refractory patients with only 12.6 % of all relapsed/refractory patients engaging in discussions with their provider about clinical trials, despite NCCN’s recommendation for clinical trial consideration in this subset of DLBCL patients. These results are concerning and show a need to identify and understand the barriers to enrollment in this population in addition to the implementation of mitigation practices.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is curable in most patients, however this high cure rate is mostly reserved for those who achieve a complete remission with first line treatment. In patients who have relapsed/refractory disease the cure rate is significantly lower. There are limited studies that have previously investigated the rate of clinical trial discussion and enrollment among DLBCL patients. Our aim, as part of a larger study, was to determine the rate of clinical trial enrollment for patients diagnosed with DLBCL at the Veterans Health Administration system (VHA), a population that traditionally experiences poorer outcomes when compared to the community and academic centers.

METHODS: We performed a retrospective chart review of patients diagnosed with DLBCL in the VHA nationwide from 01/01/2011 to 12/31/2017. Patients treated outside of the VHA and patients with primary DLBCL of the CNS were excluded. During our inclusion period, we randomly selected patients and evaluated the number of patients that engaged in discussions with their providers about clinical trials and the number of patients that eventually enrolled in trials.

RESULTS: In total, 721 patients met our inclusion criteria. Median age was 67 and the majority of patients were white (74.5%), male (96.8%), had an ECOG of 2 (83.7%) and presented with advanced stage disease (stage IV: 40.3% and stage III: 26.5%). Of all the patients included in our study 3.7% engaged in discussion about clinical trials and amongst relapsed/ refractory patients (N=182), 12.6% engaged in discussion. The rate of clinical trial enrollment was 1.8% in all patients and 6% in relapsed/refractory patients.

CONCLUSION: Our results show a low rate of 1.8% of DLBCL patients enrolling in clinical trials. These rates are improved but remain low at 6% in relapsed/ refractory patients with only 12.6 % of all relapsed/refractory patients engaging in discussions with their provider about clinical trials, despite NCCN’s recommendation for clinical trial consideration in this subset of DLBCL patients. These results are concerning and show a need to identify and understand the barriers to enrollment in this population in addition to the implementation of mitigation practices.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is curable in most patients, however this high cure rate is mostly reserved for those who achieve a complete remission with first line treatment. In patients who have relapsed/refractory disease the cure rate is significantly lower. There are limited studies that have previously investigated the rate of clinical trial discussion and enrollment among DLBCL patients. Our aim, as part of a larger study, was to determine the rate of clinical trial enrollment for patients diagnosed with DLBCL at the Veterans Health Administration system (VHA), a population that traditionally experiences poorer outcomes when compared to the community and academic centers.

METHODS: We performed a retrospective chart review of patients diagnosed with DLBCL in the VHA nationwide from 01/01/2011 to 12/31/2017. Patients treated outside of the VHA and patients with primary DLBCL of the CNS were excluded. During our inclusion period, we randomly selected patients and evaluated the number of patients that engaged in discussions with their providers about clinical trials and the number of patients that eventually enrolled in trials.

RESULTS: In total, 721 patients met our inclusion criteria. Median age was 67 and the majority of patients were white (74.5%), male (96.8%), had an ECOG of 2 (83.7%) and presented with advanced stage disease (stage IV: 40.3% and stage III: 26.5%). Of all the patients included in our study 3.7% engaged in discussion about clinical trials and amongst relapsed/ refractory patients (N=182), 12.6% engaged in discussion. The rate of clinical trial enrollment was 1.8% in all patients and 6% in relapsed/refractory patients.

CONCLUSION: Our results show a low rate of 1.8% of DLBCL patients enrolling in clinical trials. These rates are improved but remain low at 6% in relapsed/ refractory patients with only 12.6 % of all relapsed/refractory patients engaging in discussions with their provider about clinical trials, despite NCCN’s recommendation for clinical trial consideration in this subset of DLBCL patients. These results are concerning and show a need to identify and understand the barriers to enrollment in this population in addition to the implementation of mitigation practices.

INTRODUCTION: In diffuse large B-cell lymphoma (DLBCL), approximately 5-10% of patients develop secondary central nervous system (CNS) involvement. CNS disease is associated with very poor outcomes. Therefore, it is important to identify patients at risk, via the CNS International Prognostic Index (IPI), in order to initiate appropriate interventions. Additional independent risk factors for CNS involvement include HIV-related lymphoma and high-grade B-cell lymphomas. The purpose of this study was to assess for appropriate CNS evaluation and prophylaxis in DLBCL patients within the Veterans Health Administration (VHA).

METHODS: We performed a retrospective chart review of 1,605 randomly selected patients seen in the VHA nationwide who were diagnosed with lymphoma between January 1, 2011 and December 31, 2017. We included patients diagnosed with DLBCL and excluded patients diagnosed or treated outside the VHA. We evaluated CNS IPI score, HIV status, pathology reports to identify high-grade lymphomas, performance of lumbar puncture (LP), and administration of CNS prophylaxis.

RESULTS: A total of 725 patients met our inclusion criteria. Patients were predominantly male (96.8%), white (74.5%), had a median age of 67, and presented with advanced disease (stage III 26.5%, stage IV 40.3%). From the included population, 190 (26.2%) had a highrisk CNS IPI score. Of those with high-risk CNS IPI scores, 64 (33.7%) underwent LP and 46 (24.2%) were treated with CNS prophylaxis. 23 (3.2%) were HIV positive; of those, 14 (60.8%) underwent LP and 4 (17.4%) were treated with CNS prophylaxis. FISH results were available in only 242 (33.4%) of patients and of these, 25 (10.3%) met criteria for high-grade lymphoma. Of those with high-grade lymphoma, 9 (36%) underwent LP and 7 (28%) were treated with CNS prophylaxis.

CONCLUSIONS: The National Comprehensive Cancer Network guidelines recommend that patients at high risk for CNS involvement undergo LP and treatment with CNS prophylaxis. This study found that within the VHA, patients with DLBCL at high risk for CNS involvement are not being evaluated with LPs or treated with CNS prophylaxis as often as indicated, based on CNS IPI, HIV status, and high-grade pathology. We demonstrate a need for improvement in the evaluation and treatment of these patients in order to improve outcomes.

INTRODUCTION: In diffuse large B-cell lymphoma (DLBCL), approximately 5-10% of patients develop secondary central nervous system (CNS) involvement. CNS disease is associated with very poor outcomes. Therefore, it is important to identify patients at risk, via the CNS International Prognostic Index (IPI), in order to initiate appropriate interventions. Additional independent risk factors for CNS involvement include HIV-related lymphoma and high-grade B-cell lymphomas. The purpose of this study was to assess for appropriate CNS evaluation and prophylaxis in DLBCL patients within the Veterans Health Administration (VHA).

METHODS: We performed a retrospective chart review of 1,605 randomly selected patients seen in the VHA nationwide who were diagnosed with lymphoma between January 1, 2011 and December 31, 2017. We included patients diagnosed with DLBCL and excluded patients diagnosed or treated outside the VHA. We evaluated CNS IPI score, HIV status, pathology reports to identify high-grade lymphomas, performance of lumbar puncture (LP), and administration of CNS prophylaxis.

RESULTS: A total of 725 patients met our inclusion criteria. Patients were predominantly male (96.8%), white (74.5%), had a median age of 67, and presented with advanced disease (stage III 26.5%, stage IV 40.3%). From the included population, 190 (26.2%) had a highrisk CNS IPI score. Of those with high-risk CNS IPI scores, 64 (33.7%) underwent LP and 46 (24.2%) were treated with CNS prophylaxis. 23 (3.2%) were HIV positive; of those, 14 (60.8%) underwent LP and 4 (17.4%) were treated with CNS prophylaxis. FISH results were available in only 242 (33.4%) of patients and of these, 25 (10.3%) met criteria for high-grade lymphoma. Of those with high-grade lymphoma, 9 (36%) underwent LP and 7 (28%) were treated with CNS prophylaxis.

CONCLUSIONS: The National Comprehensive Cancer Network guidelines recommend that patients at high risk for CNS involvement undergo LP and treatment with CNS prophylaxis. This study found that within the VHA, patients with DLBCL at high risk for CNS involvement are not being evaluated with LPs or treated with CNS prophylaxis as often as indicated, based on CNS IPI, HIV status, and high-grade pathology. We demonstrate a need for improvement in the evaluation and treatment of these patients in order to improve outcomes.

INTRODUCTION: In diffuse large B-cell lymphoma (DLBCL), approximately 5-10% of patients develop secondary central nervous system (CNS) involvement. CNS disease is associated with very poor outcomes. Therefore, it is important to identify patients at risk, via the CNS International Prognostic Index (IPI), in order to initiate appropriate interventions. Additional independent risk factors for CNS involvement include HIV-related lymphoma and high-grade B-cell lymphomas. The purpose of this study was to assess for appropriate CNS evaluation and prophylaxis in DLBCL patients within the Veterans Health Administration (VHA).

METHODS: We performed a retrospective chart review of 1,605 randomly selected patients seen in the VHA nationwide who were diagnosed with lymphoma between January 1, 2011 and December 31, 2017. We included patients diagnosed with DLBCL and excluded patients diagnosed or treated outside the VHA. We evaluated CNS IPI score, HIV status, pathology reports to identify high-grade lymphomas, performance of lumbar puncture (LP), and administration of CNS prophylaxis.

RESULTS: A total of 725 patients met our inclusion criteria. Patients were predominantly male (96.8%), white (74.5%), had a median age of 67, and presented with advanced disease (stage III 26.5%, stage IV 40.3%). From the included population, 190 (26.2%) had a highrisk CNS IPI score. Of those with high-risk CNS IPI scores, 64 (33.7%) underwent LP and 46 (24.2%) were treated with CNS prophylaxis. 23 (3.2%) were HIV positive; of those, 14 (60.8%) underwent LP and 4 (17.4%) were treated with CNS prophylaxis. FISH results were available in only 242 (33.4%) of patients and of these, 25 (10.3%) met criteria for high-grade lymphoma. Of those with high-grade lymphoma, 9 (36%) underwent LP and 7 (28%) were treated with CNS prophylaxis.

CONCLUSIONS: The National Comprehensive Cancer Network guidelines recommend that patients at high risk for CNS involvement undergo LP and treatment with CNS prophylaxis. This study found that within the VHA, patients with DLBCL at high risk for CNS involvement are not being evaluated with LPs or treated with CNS prophylaxis as often as indicated, based on CNS IPI, HIV status, and high-grade pathology. We demonstrate a need for improvement in the evaluation and treatment of these patients in order to improve outcomes.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Patients with DLBCL refractory to initial treatment or who experience relapse have low rates of prolonged disease-free survival. Fluorescence in situ hybridization (FISH) revealing rearrangements in the MYC gene along with either the BCL2 or BCL6 genes (double- and triple-hit lymphomas) demonstrate inferior outcomes when treated with standard front-line chemoimmunotherapy. Immunohistochemistry (IHC) testing for MUM1, CD10, BCL6, and MYC also provides important prognostic information and is used in the Hans algorithm to determine the cell of origin. We assessed how frequently these crucial tests were performed on DLBCL patients within the Veterans Health Administration (VHA).

METHODS: We performed a retrospective chart review of 1,605 randomly selected records of patients diagnosed with lymphoma seen within the VHA nationwide between 1/1/2011 and 12/31/2017. We included patients diagnosed with DLBCL. We excluded patients whose workup and treatment were outside of the VHA system, and patients with primary CNS lymphoma. We analyzed pathology reports. The proportion of patients who had IHC and FISH testing for each marker was assessed.

RESULTS: 725 patients were included in the study. Our patients were predominantly male (96.8%), with a median age of 67 years. Out of the patients analyzed, IHC to determine cell of origin was performed in 481 (66.3%). Out of those tested, 316 (65.7%) were of germinal center B-cell (GCB) origin, and 165 (34.3%) were non-GCB origin. FISH testing was performed in only 242 patients (33.4%). Out of the population tested, 25 (10.3%) were double- or triple-hit.

CONCLUSION: Pathological characterization is key to the diagnosis, prognosis, and treatment of DLBCL. It is recommended by the National Comprehensive Cancer Network (NCCN) to obtain IHC testing for MUM1, BCL6, CD10, and MYC, and FISH testing for MYC (with BCL2 and BCL6 if MYC is positive) in all patients with DLBCL. Our study shows that more than one half of patients did not have FISH testing, and that cell of origin was not determined in about one third of patients, indicating a need for improved testing of these protein expressions and gene rearrangements within the VHA.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Patients with DLBCL refractory to initial treatment or who experience relapse have low rates of prolonged disease-free survival. Fluorescence in situ hybridization (FISH) revealing rearrangements in the MYC gene along with either the BCL2 or BCL6 genes (double- and triple-hit lymphomas) demonstrate inferior outcomes when treated with standard front-line chemoimmunotherapy. Immunohistochemistry (IHC) testing for MUM1, CD10, BCL6, and MYC also provides important prognostic information and is used in the Hans algorithm to determine the cell of origin. We assessed how frequently these crucial tests were performed on DLBCL patients within the Veterans Health Administration (VHA).

METHODS: We performed a retrospective chart review of 1,605 randomly selected records of patients diagnosed with lymphoma seen within the VHA nationwide between 1/1/2011 and 12/31/2017. We included patients diagnosed with DLBCL. We excluded patients whose workup and treatment were outside of the VHA system, and patients with primary CNS lymphoma. We analyzed pathology reports. The proportion of patients who had IHC and FISH testing for each marker was assessed.

RESULTS: 725 patients were included in the study. Our patients were predominantly male (96.8%), with a median age of 67 years. Out of the patients analyzed, IHC to determine cell of origin was performed in 481 (66.3%). Out of those tested, 316 (65.7%) were of germinal center B-cell (GCB) origin, and 165 (34.3%) were non-GCB origin. FISH testing was performed in only 242 patients (33.4%). Out of the population tested, 25 (10.3%) were double- or triple-hit.

CONCLUSION: Pathological characterization is key to the diagnosis, prognosis, and treatment of DLBCL. It is recommended by the National Comprehensive Cancer Network (NCCN) to obtain IHC testing for MUM1, BCL6, CD10, and MYC, and FISH testing for MYC (with BCL2 and BCL6 if MYC is positive) in all patients with DLBCL. Our study shows that more than one half of patients did not have FISH testing, and that cell of origin was not determined in about one third of patients, indicating a need for improved testing of these protein expressions and gene rearrangements within the VHA.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Patients with DLBCL refractory to initial treatment or who experience relapse have low rates of prolonged disease-free survival. Fluorescence in situ hybridization (FISH) revealing rearrangements in the MYC gene along with either the BCL2 or BCL6 genes (double- and triple-hit lymphomas) demonstrate inferior outcomes when treated with standard front-line chemoimmunotherapy. Immunohistochemistry (IHC) testing for MUM1, CD10, BCL6, and MYC also provides important prognostic information and is used in the Hans algorithm to determine the cell of origin. We assessed how frequently these crucial tests were performed on DLBCL patients within the Veterans Health Administration (VHA).

METHODS: We performed a retrospective chart review of 1,605 randomly selected records of patients diagnosed with lymphoma seen within the VHA nationwide between 1/1/2011 and 12/31/2017. We included patients diagnosed with DLBCL. We excluded patients whose workup and treatment were outside of the VHA system, and patients with primary CNS lymphoma. We analyzed pathology reports. The proportion of patients who had IHC and FISH testing for each marker was assessed.

RESULTS: 725 patients were included in the study. Our patients were predominantly male (96.8%), with a median age of 67 years. Out of the patients analyzed, IHC to determine cell of origin was performed in 481 (66.3%). Out of those tested, 316 (65.7%) were of germinal center B-cell (GCB) origin, and 165 (34.3%) were non-GCB origin. FISH testing was performed in only 242 patients (33.4%). Out of the population tested, 25 (10.3%) were double- or triple-hit.

CONCLUSION: Pathological characterization is key to the diagnosis, prognosis, and treatment of DLBCL. It is recommended by the National Comprehensive Cancer Network (NCCN) to obtain IHC testing for MUM1, BCL6, CD10, and MYC, and FISH testing for MYC (with BCL2 and BCL6 if MYC is positive) in all patients with DLBCL. Our study shows that more than one half of patients did not have FISH testing, and that cell of origin was not determined in about one third of patients, indicating a need for improved testing of these protein expressions and gene rearrangements within the VHA.

BACKGROUND: Neutropenic fever poses a significant risk to cancer patients, with a major complication rate of 30% and mortality rate as high as 11%. Prompt evaluation with labs, imaging, and appropriate antibiotics are crucial to improving outcomes. In an attempt to reduce morbidity and mortality, the Infectious Disease Society of America (IDSA) and American Society of Clinical Oncology (ASCO) have set guidelines for the evaluation and treatment of neutropenic fever. The purpose of this project was to assess the management of neutropenic fever within our institution, and to identify potential areas for improvement in the care of these patients.

METHODS: We included patients seen at Audie L. Murphy VA Medical Center between September 1, 2018 and January 31, 2020 for neutropenic fever. We excluded patients without a diagnosis of malignancy and who had not received chemotherapy within the prior 4 weeks. We recorded the times of patient presentation, labs, imaging, and antibiotic administration. These were compared to the standards set forth by IDSA/ASCO. We also calculated average times to lab collection and to antibiotic administration. The proportion of patients who received unwarranted dose reductions of antibiotics also was assessed.

RESULTS: There were 35 unique encounters that met our inclusion criteria. All patients included in the study underwent all recommended diagnostic testing. 3 of 35 (8.6%) patients had CBC/CMP, 2 of 35 (5.7%) had urinalysis, 6 of 35 (17.1%) had blood cultures, and 3 of 35 (8.6%) had a chest x-ray (CXR) within the recommended 15 minutes from time of presentation. Only 3 of 35 (8.6%) patients received antibiotics within the recommended 1 hour from presentation. The average times to obtain CBC/CMP, urinalysis, blood cultures, CXR, and administration of antibiotics were 52.1 minutes, 162.4 minutes, 49.5 minutes, 96.1 minutes, and 308.4 minutes, respectively. 9 of 35 (25.7%) patients received unnecessary dose reductions of antibiotics.

CONCLUSIONS: Although patients received the appropriate evaluation according to IDSA/ASCO guidelines, the times to obtain appropriate diagnostic tests and administer recommend antibiotics were significantly prolonged. Establishing a standardized neutropenic fever protocol, prompt triaging, educational interventions, and identifying patients at risk for neutropenic fever may expedite care and improve outcomes for these high-risk patients.

BACKGROUND: Neutropenic fever poses a significant risk to cancer patients, with a major complication rate of 30% and mortality rate as high as 11%. Prompt evaluation with labs, imaging, and appropriate antibiotics are crucial to improving outcomes. In an attempt to reduce morbidity and mortality, the Infectious Disease Society of America (IDSA) and American Society of Clinical Oncology (ASCO) have set guidelines for the evaluation and treatment of neutropenic fever. The purpose of this project was to assess the management of neutropenic fever within our institution, and to identify potential areas for improvement in the care of these patients.

METHODS: We included patients seen at Audie L. Murphy VA Medical Center between September 1, 2018 and January 31, 2020 for neutropenic fever. We excluded patients without a diagnosis of malignancy and who had not received chemotherapy within the prior 4 weeks. We recorded the times of patient presentation, labs, imaging, and antibiotic administration. These were compared to the standards set forth by IDSA/ASCO. We also calculated average times to lab collection and to antibiotic administration. The proportion of patients who received unwarranted dose reductions of antibiotics also was assessed.

RESULTS: There were 35 unique encounters that met our inclusion criteria. All patients included in the study underwent all recommended diagnostic testing. 3 of 35 (8.6%) patients had CBC/CMP, 2 of 35 (5.7%) had urinalysis, 6 of 35 (17.1%) had blood cultures, and 3 of 35 (8.6%) had a chest x-ray (CXR) within the recommended 15 minutes from time of presentation. Only 3 of 35 (8.6%) patients received antibiotics within the recommended 1 hour from presentation. The average times to obtain CBC/CMP, urinalysis, blood cultures, CXR, and administration of antibiotics were 52.1 minutes, 162.4 minutes, 49.5 minutes, 96.1 minutes, and 308.4 minutes, respectively. 9 of 35 (25.7%) patients received unnecessary dose reductions of antibiotics.

CONCLUSIONS: Although patients received the appropriate evaluation according to IDSA/ASCO guidelines, the times to obtain appropriate diagnostic tests and administer recommend antibiotics were significantly prolonged. Establishing a standardized neutropenic fever protocol, prompt triaging, educational interventions, and identifying patients at risk for neutropenic fever may expedite care and improve outcomes for these high-risk patients.

BACKGROUND: Neutropenic fever poses a significant risk to cancer patients, with a major complication rate of 30% and mortality rate as high as 11%. Prompt evaluation with labs, imaging, and appropriate antibiotics are crucial to improving outcomes. In an attempt to reduce morbidity and mortality, the Infectious Disease Society of America (IDSA) and American Society of Clinical Oncology (ASCO) have set guidelines for the evaluation and treatment of neutropenic fever. The purpose of this project was to assess the management of neutropenic fever within our institution, and to identify potential areas for improvement in the care of these patients.

METHODS: We included patients seen at Audie L. Murphy VA Medical Center between September 1, 2018 and January 31, 2020 for neutropenic fever. We excluded patients without a diagnosis of malignancy and who had not received chemotherapy within the prior 4 weeks. We recorded the times of patient presentation, labs, imaging, and antibiotic administration. These were compared to the standards set forth by IDSA/ASCO. We also calculated average times to lab collection and to antibiotic administration. The proportion of patients who received unwarranted dose reductions of antibiotics also was assessed.

RESULTS: There were 35 unique encounters that met our inclusion criteria. All patients included in the study underwent all recommended diagnostic testing. 3 of 35 (8.6%) patients had CBC/CMP, 2 of 35 (5.7%) had urinalysis, 6 of 35 (17.1%) had blood cultures, and 3 of 35 (8.6%) had a chest x-ray (CXR) within the recommended 15 minutes from time of presentation. Only 3 of 35 (8.6%) patients received antibiotics within the recommended 1 hour from presentation. The average times to obtain CBC/CMP, urinalysis, blood cultures, CXR, and administration of antibiotics were 52.1 minutes, 162.4 minutes, 49.5 minutes, 96.1 minutes, and 308.4 minutes, respectively. 9 of 35 (25.7%) patients received unnecessary dose reductions of antibiotics.

CONCLUSIONS: Although patients received the appropriate evaluation according to IDSA/ASCO guidelines, the times to obtain appropriate diagnostic tests and administer recommend antibiotics were significantly prolonged. Establishing a standardized neutropenic fever protocol, prompt triaging, educational interventions, and identifying patients at risk for neutropenic fever may expedite care and improve outcomes for these high-risk patients.