Evaluation of prognostic factors in patients with high-risk classical Hodgkin lymphoma undergoing autologous transplantation.

ABSTRACT: There are limited data assessing the risk scores for primary treatment failure (PTF) in patients with classical Hodgkin lymphoma (cHL; PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE (Evaluation of Classical Hodgkin Lymphoma patients wIth Primary treatment failure and analySis of outcomEs) is a multicenter retrospective cohort of patients with PTF-cHL (aged ≥15 years) diagnosed on or after 1 January 2005, at 15 US medical centers. PTF was defined as 1 of the following patterns of failure: (1) progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); (2) partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); (3) progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR; early relapse [ER]). A total of 478 patients were included in the analysis. Among these, 217 (45%) were PP, 86 (18%) were PR/SD, and 175 (37%) were ER. The 6-month and 1-year cumulative incidence of nonrelapse mortality after auto-HCT were 0.9% and 1.1%, respectively. The median progression-free survival (PFS) and overall survival (OS) after auto-HCT were 4.33 and 10.09 years, respectively. Although those not in CR at the time of auto-HCT were associated with inferior PFS and OS, advanced age and diagnosis before 2011 were associated with inferior OS. This study showcases the safety and long-term efficacy of auto-HCT, even in patients with high-risk disease who are traditionally considered chemotherapy refractory, and will serve as a benchmark for the ongoing transplant vs no transplant trials.

Survival of patients with transformed follicular lymphoma in the United States: a multiple cohort study.

Population-based data comparing the outcomes of patients with transformed follicular lymphoma (t-FL) and de novo diffuse large B-cell lymphoma (DLBCL) are lacking. The objective of this study was to compare the survival of patients with t-FL and de novo DLBCL diagnosed in the United States between 2010-2018. We hypothesized that patients with t-FL would have an inferior survival compared to patients with de novo DLBCL. The study outcomes were relative survival (RS), overall survival (OS), and lymphoma-specific survival (LSS) compared between t-FL and de novo DLBCL. Flexible parametric survival models were used to estimate the study outcomes. There were 569 cases of t-FL and 44,706 cases of de novo DLBCL. Patients with t-FL had an estimated 5-year RS of 54% [95% confidence interval (CI), 49-59%) compared to 67% (95% CI, 66-67%) for those with de novo DLBCL (adjusted hazard ratio, 1.29; 95% CI, 1.11-1.50; P = 0.001). The corresponding 5-year OS estimates were 49% (95% CI, 44-53%) and 57% (95% CI, 57-58%), respectively (adjusted hazard ratio, 1.23; 95% CI, 1.07-1.42; P = 0.004). The corresponding 5-year LSS estimates were 54% (95% CI, 50-59%) and 66% (95% CI, 65-66%), respectively (adjusted hazard ratio, 1.34; 95% CI, 1.15-1.56; P < 0.001). This population-based registry analysis shows that patients with t-FL continue to have an inferior survival in the modern era and should be prioritized for enrollment in clinical trials.

Racial and ethnic differences in the utilization of autologous transplantation for lymphoma in the United States.

BACKGROUND: Racial/ethnic disparities in the utilization of hematopoietic cell transplantation (HCT) have been reported for patients with hematologic malignancies, but population-based data are lacking for lymphoma patients. The objective of this study was to determine whether racial and ethnic disparities exist in the utilization of autologous HCT for lymphoma in the United States. METHOD: We used Surveillance, Epidemiology, and End Results data linked to Medicare fee-for-service claims. We included Medicare beneficiaries aged 66+ years with Hodgkin or Non-Hodgkin lymphomas diagnosed between 2008 and 2015. The primary outcome was time-to-autologous HCT. We used Cox proportional hazards models to estimate racial/ethnic differences in utilization. Missing data were handled using multiple imputation with chained equations. RESULTS: We included 40,605 individuals with lymphoma. A total of 452 autologous transplants were performed. In the unadjusted model, Non-Hispanic Black patients were 51% less likely to receive a transplant than Non-Hispanic White patients (95% CI, 0.26-0.96; p = 0.04). After adjusting for age at diagnosis and sex, Non-Hispanic Black patients were 61% less likely to receive a transplant (95% CI, 0.20-0.76; p = 0.01). However, observed differences attenuated and became non-significant after adjustment for socioeconomic factors (adjusted hazard ratio [aHR], 0.62; 95% CI, 0.32-1.21; p = 0.16) and disease-specific factors (aHR, 0.58; 95% CI, 0.30-1.12; p = 0.11), separately. In the fully adjusted model, we also did not observe a statistically significant association between Non-Hispanic Black race/ethnicity and receipt of transplant (aHR, 0.54; 95% CI, 0.28-1.05; p = 0.07). CONCLUSION: In this population-based cohort study of lymphoma patients, Non-Hispanic Black patients were less likely to receive autologous HCT compared to Non-Hispanic White patients, but this difference was partially explained by socioeconomic and disease-specific factors.

Racial disparities in the survival of patients with indolent non-Hodgkin lymphomas in the United States.

There is a paucity of data regarding racial disparities in the survival of patients with indolent non-Hodgkin lymphomas (iNHL) in the contemporary time-period. Hence, we sought to determine whether racial disparities exist in the survival of patients with iNHLs in the US. We included 68 059 adult patients with follicular lymphoma (FL, n = 41 943), marginal zone lymphoma (MZL, n = 22 485), and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM, n = 3631) who were diagnosed in the US between 2000 and 2017. Race was categorized as White, Black, Asian/Pacific Islander, or American Indian/Alaska Native (API/AI). The primary outcome was relative survival (RS), which was estimated using flexible parametric survival models. The RS estimates varied according to race and disease histology but were consistently lower for racial minorities, including those diagnosed during the most recent 5-year time-period of 2012-2017. On multivariable analysis for RS, Black patients with FL had a 32% higher excess mortality rate compared to White patients [adjusted excess hazard ratio (aEHR), 1.32; 95% CI, 1.15-1.51; p < .001], corresponding to a difference of 55 (95% CI, 24-86) excess deaths per 10 000 person-years. For MZL, Black patients had a 40% higher excess mortality rate compared to White patients (aEHR 1.40; 95% CI, 1.18-1.66; p < .001), corresponding to a difference of 62 (95% CI, 26-98) excess deaths per 10 000 person-years. No significant racial differences were detected for patients with WM. The greatest disparity was seen for younger Black patients with FL. Our findings highlight the need for interventions to improve the outcomes of Black patients with iNHLs, particularly younger Black patients with FL.

Recent survival trends in diffuse large B-cell lymphoma--Have we made any progress beyond rituximab?

BACKGROUND: Population-based studies previously showed an improvement in overall survival (OS) for patients with diffuse large B-cell lymphoma (DLBCL) who received chemoimmunotherapy with rituximab. However, there is limited data (especially at the population level) that show a similar trend in OS improvement, in the most recent time period. We hypothesized that survival for DLBCL patients diagnosed in the United States has continued to improve in recent years and intended to measure outcome improvements. METHODS: Using the SEER-18 registries, we compared the incidence and relative survival rates (RSRs) of DLBCL patients between 2002-2007 and 2008-2013 (availability of novel agents, broader use of autologous hematopoietic cell transplantation and improvement in supportive care). Multivariable Cox regression models were used to assess associations between the year of diagnosis and OS while controlling for age, gender, stage, and ethnicity. RESULTS: There were a total of 53 439 patients with DLBCL who were diagnosed between 2002 and 2013. Of these, 25 810 were diagnosed during time period-1 and 27 629 diagnosed during time period-2. There was a slight decline in incidence of DLBCL (time period-1 vs time period-2), 7.75 (95% CI = 7.66-7.84) vs 7.43 (95% CI = 7.34-7.52) cases per 100 000 persons, respectively (P < .0001). Overall, there was a modest improvement in DLBCL RSRs, with 5-year RSR improving from 61% (time period-1) to 64% (time period-2) and the improvement was noted across all subsets of patients. On multivariable analysis, patients diagnosed in time period-2 had lower mortality relative to time period-1 (HR = 0.87, 95% CI = 0.85-0.89). CONCLUSIONS: Our study shows an improvement in the outcomes of DLBCL patients beyond the introduction of rituximab, although the magnitude of improvement is small. It will be interesting to see the impact of chimeric antigen receptor-T cell therapy translating to population-level survival in the next 5 years.

Multicenter Analysis of Advanced Stage Grade 3A Follicular Lymphoma Outcomes by Frontline Treatment Regimen.

BACKGROUND: Follicular lymphoma (FL) is a common form of non-Hodgkin lymphoma with a wide spectrum of presentation. While grade 1/2 FL is considered low grade and grade 3B FL is approached as an aggressive lymphoma, the management of grade 3A FL remains controversial. PATIENTS AND METHODS: We performed a retrospective, multicenter analysis of patients aged ≥ 18 years with advanced stage 3/4 grade 3A FL diagnosed between January 2006 and July 2016. Patients were stratified by frontline chemotherapy regimen: anthracycline based (ATC), bendamustine (BD), and cyclophosphamide, vincristine, and prednisone (CVP). A total of 103 patients were identified from 6 contributing centers: 65 patients received ATC chemotherapy, 30 BD, and 8 CVP. The primary outcome was time to progression (TTP). Secondary outcomes included progression-free survival, overall survival, complete response rates, large cell transformation, and impact of standardized maximum uptake value on positron emission tomography/computed tomography with outcomes. Patient characteristics were similar among the 3 treatment groups. RESULTS: For TTP at 24 months from initiation of treatment, 72% of ATC, 79% of BD, and 50% of CVP patients had not experienced disease progression (P = .01). Multivariate analysis demonstrated a TTP benefit for ATC compared to CVP (hazard ratio 3.22; 95% confidence interval, 1.26-8.25; P = .01) but no difference when compared to BD. Similar findings were seen with progression-free survival. While overall survival was similar among the 3 arms, there was a higher risk of large cell transformation following BD and CVP. Last, standardized maximum uptake value on positron emission tomography/computed tomography did not affect TTP when comparing BD- and ATC-treated patients. CONCLUSION: Although ATC was superior to CVP, clinical outcomes (TTP, progression-free survival, and overall survival) were similar compared to BD chemotherapy for patients with grade 3A FL.

Detection of toxigenic Clostridium difficile colonization in patients admitted to the hospital for chemotherapy or haematopoietic cell transplantation.

Increasing evidence suggests that asymptomatic carriers are an important source of healthcare-associated Clostridium difficile infection. However, it is not known which test for the detection of C. difficile colonization is most sensitive in patients with haematological malignancies. We performed a prospective cohort study of 101 patients with haematological malignancies who had been admitted to the hospital for scheduled chemotherapy or haematopoietic cell transplantation. Each patient provided a formed stool sample. We compared the performance of five different commercially available assays, using toxigenic culture as the reference method. The prevalence of toxigenic C. difficile colonization as determined by toxigenic culture was 14/101 (14 %). The Cepheid Xpert PCR C. difficile/Epi was the most sensitive test for the detection of toxigenic C. difficile colonization, with 93 % sensitivity and 99 % negative predictive value. Our findings suggest that the Xpert PCR C. difficile/Epi could be used to rule out toxigenic C. difficile colonization in this population.

BRAF V600E expression in histiocytic sarcoma associated with splenic marginal zone lymphoma: a case report.

BACKGROUND: Histiocytic sarcoma is a rare histiocytic neoplasm of unknown etiology that constitutes less than 1% of hematologic malignancies. A few cases of histiocytic sarcoma harboring the BRAF V600E mutation have been reported, but this finding has not been confirmed in all studies. CASE PRESENTATION: We report the case of a 63-year-old white woman with a history of splenic marginal zone lymphoma who presented with 2 weeks of right-sided neck swelling. Positron emission tomography revealed an intensely hypermetabolic and destructive soft tissue mass in her right skull base. A bone marrow biopsy was performed, which revealed an infiltrate of malignant cells characterized as large pleomorphic cells with frequent folded/irregular nuclei, variably prominent nucleoli, fine chromatin, and abundant amounts of eosinophilic cytoplasm. The malignant cells were positive for CD163, CD68 (granular), lysozyme (granular), CD4, and CD45 (partial). Based on the biopsy findings, she was diagnosed as having histiocytic sarcoma. The malignant cells tested positive for the BRAFV600E protein using immunohistochemistry. Before treatment of her histiocytic sarcoma could be initiated, she developed disseminated intravascular coagulation and acute hypoxemic respiratory failure secondary to non-cardiogenic pulmonary edema. She decided to pursue comfort care and died in our hospital 2 weeks following admission. CONCLUSIONS: Our case illustrates the aggressive nature of histiocytic sarcoma, and provides rare evidence that histiocytic sarcoma associated with indolent lymphomas may harbor the BRAF V600E mutation. Further research is needed to clarify the role of targeted therapies such as vemurafenib in the treatment of patients with this disorder.

Acute Systolic Heart Failure Associated with Complement-Mediated Hemolytic Uremic Syndrome.

Complement-mediated hemolytic uremic syndrome (otherwise known as atypical HUS) is a rare disorder of uncontrolled complement activation that may be associated with heart failure. We report the case of a 49-year-old female with no history of heart disease who presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Given her normal ADAMSTS13 activity, evidence of increased complement activation, and renal biopsy showing evidence of thrombotic microangiopathy, she was diagnosed with complement-mediated HUS. She subsequently developed acute hypoxemic respiratory failure secondary to pulmonary edema requiring intubation and mechanical ventilation. A transthoracic echocardiogram showed evidence of a Takotsubo cardiomyopathy with an estimated left ventricular ejection fraction of 20%, though ischemic cardiomyopathy could not be ruled out. Treatment was initiated with eculizumab. After several failed attempts at extubation, she eventually underwent tracheotomy. She also required hemodialysis to improve her uremia and hypervolemia. After seven weeks of hospitalization and five doses of eculizumab, her renal function and respiratory status improved, and she was discharged in stable condition on room air and independent of hemodialysis. Our case illustrates a rare association between acute systolic heart failure and complement-mediated HUS and highlights the potential of eculizumab in stabilizing even the most critically-ill patients with complement-mediated disease.

Patients' Attitudes Toward Medical Student Participation Across Specialties: A Systematic Review.

UNLABELLED: Phenomenon: Medical students commonly participate in patient care in a variety of different settings. However, a systematic review of patients' attitudes toward medical student participation across specialties has not been performed. APPROACH: The authors searched 7 databases (CINAHL, Cochrane Library, ERIC, MEDLINE, PsycINFO, Scopus, and Web of Science) between January 1, 1999, and August 5, 2014. Two authors independently screened the results and selected articles that were written in English, were published in a peer-reviewed journal, and used a structured or semistructured survey or interview to determine patients' attitudes toward medical student participation in their care. Study quality was assessed using the Medical Education Research Study Quality Instrument. FINDINGS: Fifty-nine studies were included. Average study quality was low. Sixty-one unique evaluation instruments were used, and 34 instruments (56%) lacked validity data. Patient satisfaction was not significantly affected by medical student participation. However, patients' acceptance of medical student participation varied widely between studies and depended on the type of participation. The most common reason for acceptance was a desire to contribute to the education of others, and the most common reason for refusal was concerns about privacy. Minorities were more likely to refuse medical student participation. Patients preferred to be informed before medical students participated in their care. Insights: Patient satisfaction is not significantly affected by medical student participation. However, patient satisfaction may be a poor surrogate marker of patients' acceptance of medical students. Future research should employ validated evaluation instruments to further explore patients' attitudes toward medical student participation.

Acute kidney injury, hyperbilirubinemia, and ischemic skin necrosis due to massive sulindac overdose.

Sulindac is a long-acting nonsteroidal anti-inflammatory drug (NSAID) widely used for the management of osteoarthritis, rheumatoid arthritis, ankylosing sponydlitis, and acute gouty arthritis. Reports of sulindac toxicity in the literature are rare. We report the case of a 22-year old male with a history of bipolar disorder who was brought to the emergency department after ingesting approximately 15 g of sulindac in a suicide attempt. He was found to have acute kidney injury and hyperbilirubinemia. Despite aggressive fluid resuscitation, his renal function progressively worsened requiring the initiation of hemodialysis. Ten days following ingestion of sulindac, he began to develop ischemic skin changes with a gangrenous appearance in his hands and feet. He continued to receive supportive treatment, and his acute kidney injury, hyperbillirubinemia, and ischemic skin necrosis eventually resolved. Clinicians should be aware of this long-acting NSAID and its ability to cause prolonged multisystem organ dysfunction.

Contribution of amino acid region 659-663 of Factor Va heavy chain to the activity of factor Xa within prothrombinase .

Factor Va, the cofactor of prothrombinase, is composed of heavy and light chains associated noncovalently in the presence of divalent metal ions. The COOH-terminal region of the heavy chain contains acidic amino acid clusters that are important for cofactor activity. In this work, we have investigated the role of amino acid region 659-663, which contains five consecutive acidic amino acid residues, by site-directed mutagenesis. We have generated factor V molecules in which all residues were mutated to either lysine (factor V(5K)) or alanine (factor V(5A)). We have also constructed a mutant molecule with this region deleted (factor V(Δ659-663)). The recombinant molecules along with wild-type factor V (factor V(WT)) were transiently expressed in mammalian cells, purified, and assessed for cofactor activity. Two-stage clotting assays revealed that the mutant molecules had reduced clotting activities compared to that of factor Va(WT). Kinetic analyses of prothrombinase assembled with the mutant molecules demonstrated diminished k(cat) values, while the affinity of all mutant molecules for factor Xa was similar to that for factor Va(WT). Gel electrophoresis analyses of plasma-derived and recombinant mutant prothrombin activation demonstrated delayed cleavage of prothrombin at both Arg(320) and Arg(271) by prothrombinase assembled with the mutant molecules, resulting in meizothrombin lingering throughout the activation process. These results were confirmed after analysis of the cleavage of FPR-meizothrombin. Our findings provide new insights into the structural contribution of the acidic COOH-terminal region of factor Va heavy chain to factor Xa activity within prothrombinase and demonstrate that amino acid region 659-663 from the heavy chain of the cofactor contributes to the regulation of the rate of cleavage of prothrombin by prothrombinase.