Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance.

Introduction: The microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure. Methods: Two complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways. Results: Both models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation. Discussion: These studies clarify Mitf's role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity.

Hypertension Treatment in Patients Receiving Ibrutinib: A Multicenter Retrospective Study.

Although Bruton's tyrosine kinase inhibitors (BTKis) are generally well-tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and anti-hypertensive drug(s) and with at least 3 months of follow up data were sorted into two groups: those diagnosed with HTN prior to BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of the 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took beta blockers (BBs) with hydrochlorothiazide (HCTZ), (-5.05 mmHg; 95% CI -10.0 to -0.0596; p = 0.047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (-5.47 mmHg; 95% CI -10.9 to -0.001; p = 0.05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple anti-hypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

Patterns of Care and Outcomes of Low-Lying Adenocarcinoma and Squamous Cell Carcinoma of the Rectum.

PURPOSE: Squamous cell carcinoma (SCC) of the rectum is a unique entity that lacks definitive guidelines regarding prognosis and treatment. This study aimed to analyze patterns of care and survival for SCC and adenocarcinoma (AC) of the rectum. METHODS: This was a retrospective analysis of patients with stage I-III SCC or AC of the rectum treated from 2004 to 2016 from the National Cancer Database. The treatment groups analyzed were surgery alone (S), chemoradiation followed by surgery (CRT + S), surgery followed by chemoradiation (S + CRT), and definitive chemoradiation (CRT). Patient- and clinical-related factors were compared. Overall survival was assessed with the Kaplan-Meier method and Cox proportional regression models. RESULTS: Of the patients studied, 21,587 (97.1%) were AC and 640 (2.9%) were SCC. Among patients with AC, most (n = 8549, 59.4%) received chemoradiation followed by surgery; those with SCC (n = 305, 66.4%) received definitive chemoradiation. Among patients who received surgery, the majority (69.2%) with AC histology had a low anterior resection while the majority (52.1%) of SCC had an abdominoperineal resection. Five-year overall survival of AC versus SCC in the entire cohort was 61.6% versus 56.1%, respectively (p < 0.001). On multivariable analysis for AC, CRT + S (HR 0.61, p < 0.001), or S + CRT (HR 0.67, p < 0.001) had improved survival compared to S alone while those who had definitive CRT (HR 1.55, p < 0.001) had worse survival. CONCLUSIONS: SCC of the rectum tends to be treated like anal cancers with definitive chemoradiation, with similar survival to historical reports of anal cancer. AC of the rectum is most commonly treated under the rectal cancer paradigm.

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.

Patterns of Care and Outcomes of Adjuvant Chemoradiation for Node-Positive Pancreatic Adenocarcinoma.

PURPOSE: The literature has been conflicting on the superiority of adjuvant chemoradiation over chemotherapy for node-positive adenocarcinoma of the pancreas following definitive surgery. We aimed to evaluate the patterns of care and outcomes of these two treatment options using the National Cancer Database (NCDB). METHODS: Patients diagnosed with non-metastatic, node-positive adenocarcinoma of the pancreas from 2006 to 2014 who received oncologic resection with negative margins were identified in the NCDB. Patient- and clinical-related factors were compared between those who received adjuvant chemotherapy alone (aC) versus adjuvant chemoradiation (aCRT). Univariable and multivariable logistic regression was performed to assess for predictors of adjuvant chemoradiation use. The Kaplan-Meier method was used to assess overall survival (OS) and Cox regression analysis was used to assess impact of covariables on OS. RESULTS: There were 3609 patients who met the study criteria, of which 2988 (82.8%) received chemotherapy alone and 621 (17.2%) who received chemoradiation. Median follow up for living patients was 33.8 months (IQR 22-51). On multivariable logistic regression, those who received treatment in more recent years of diagnoses (OR 0.21-0.37, p < 0.001) were less likely to receive aCRT over aC. Two-year OS for those who received chemo alone was 44.9% and for chemoradiation was 42.6% (p = 0.169). This finding was sustained on multivariable survival analysis (HR 0.99, p = 0.867). CONCLUSIONS: Adjuvant chemotherapy alone for adenocarcinoma of the pancreas is the predominant treatment of choice among US hospitals. There was no overall survival benefit noted in those who were treated with adjuvant chemoradiation.

Patterns of Care and Comparison of Outcomes Between Primary Anal Squamous Cell Carcinoma and Anal Adenocarcinoma.

BACKGROUND: The management of adenocarcinoma of the anus can be challenging because there are few data on outcomes and trends in its treatment to date. OBJECTIVE: This study aimed to compare and analyze the patterns of care and survival outcomes of patients with anal squamous cell carcinoma and anal adenocarcinoma. DESIGN: This was a retrospective study. SETTING: This study was performed by utilizing the National Cancer Database. PATIENTS: We selected a total of 19,539 patients between 2004 and 2014 with stage II to III squamous cell carcinoma or adenocarcinoma of the anus. INTERVENTION: The treatment groups analyzed were surgery alone, neoadjuvant chemoradiation followed by surgery, surgery followed by adjuvant chemoradiation, or definitive chemoradiation. MAIN OUTCOME MEASURES: Patient- and clinical-related factors were compared between the 2 groups. Kaplan-Meier and Cox proportional hazards regression models were used to assess overall survival. RESULTS: Of the patients studied, 18,346 (93.9%) had primary squamous cell carcinoma and 1193 (6.1%) had primary adenocarcinoma of the anus. The 5-year overall survival for stage II squamous cell carcinoma was 69.2%, and, for stage II adenocarcinoma, 5-year overall survival was 54.2% (p < 0.001). The 5-year overall survival for stage III squamous cell carcinoma was 55.2%, and, for stage III adenocarcinoma, 5-year overall survival was 32.9% (p < 0.001). On multivariable Cox regression, treatment with chemoradiation alone (HR, 0.67; p = 0.008) was associated with improved survival in squamous cell carcinoma. For the adenocarcinoma group, stage III disease (HR, 2.26; p < 0.001) and high tumor grade (HR, 1.59; p < 0.011) had a negative impact on survival, but there were no differences in survival based on the type of treatment received. LIMITATIONS: The National Cancer Database does not include information on specific chemotherapeutic or immunotherapy agents given to patients, nor does it provide the exact cause of death. CONCLUSIONS: Anal adenocarcinoma in comparison to anal squamous cell carcinoma had a lower 5-year overall survival stage for stage. Anal adenocarcinoma appears to be treated similarly to the rectal cancer paradigm, with frequent use of neoadjuvant chemoradiation. See Video Abstract at http://links.lww.com/DCR/B50. PATRONES DE EL CUIDADO Y COMPARACIÓN DE RESULTADOS ENTRE EL CARCINOMA DE CÉLULAS ESCAMOSAS ANAL PRIMARIO Y EL ADENOCARCINOMA ANAL: El tratamiento del adenocarcinoma del ano puede ser un desafío ya que hasta la fecha, hay pocos datos sobre los resultados y las tendencias en su tratamiento.Comparar y analizar los patrones de el cuidado y resultados de supervivencia de pacientes con carcinoma anal de células escamosas y adenocarcinoma anal.Este fue un estudio retrospectivo.Este estudio se realizó utilizando la Base de Datos Nacional de Cancer (National Cancer Database, NCB).Seleccionamos un total de 19,539 pacientes entre el 2004-2014 con carcinoma de células escamosas en estadio II-III o adenocarcinoma del ano.Los grupos de tratamiento analizados fueron solo cirugía, quimiorradiación neoadyuvante seguida por cirugía, cirugía seguida por quimiorradiación adyuvante o quimiorradiación definitiva.Se compararon los factores clínicos y de pacientes entre los dos grupos. Se utilizaron modelos de regresión de riesgos proporcionales de Kaplan-Meier y Cox para evaluar la supervivencia general.18,346 (93.9%) tenían carcinoma primario de células escamosas y 1,193 (6.1%) tenían adenocarcinoma primario del ano. La supervivencia global a 5 años para el carcinoma de células escamosas en estadio II fue del 69.2% y para el adenocarcinoma en estadio II fue del 54.2% (p < 0.001). La supervivencia global a cinco años para el carcinoma de células escamosas en estadio III fue del 55.2% y para el adenocarcinoma en estadio III fue del 32.9% (p < 0.001). En la regresión de Cox multivariable, el tratamiento con quimiorradiación sola (proporción de riesgo 0.67, p = 0.008) se asoció con una mejor supervivencia en el carcinoma de células escamosas. Para el grupo de adenocarcinoma, la enfermedad en estadio III (proporción de riesgo 2.26, p < 0.001) y el alto grado tumoral (proporción de riesgo 1.59, p < 0.011) tuvieron un impacto negativo en la supervivencia, pero no hubo diferencias en la supervivencia según el tipo de tratamiento recibido.La Base de Datos Nacional de Cancer no incluye información sobre agentes quimioterapéuticos o de inmunoterapia específicos que se administran a los pacientes, ni proporciona la causa exacta de la muerte.El adenocarcinoma anal en comparación con el carcinoma anal de células escamosas tuvo una supervivencia general inferior a 5 años, etapa por etapa. El adenocarcinoma anal parece tratarse de manera similar al paradigma del cáncer rectal, con el uso frecuente de quimiorradiación neoadyuvante. Vea el video del resumen en http://links.lww.com/DCR/B50.

Patterns of care and outcomes of chemoradiation versus radiation alone for MGMT promoter unmethylated glioblastoma.

OBJECTIVE: The recommended treatment for O6-methylguanine-DNA methyltransferase (MGMT) promoter unmethylated glioblastoma (GBM) is radiation therapy with concurrent/adjuvant temozolomide (TMZ). However, it is well known that the clinical benefit from TMZ is lower in these patients. We sought to analyze patterns of care and outcomes of chemoradiation versus radiation alone in this cohort using a large, hospital database. PATIENTS AND METHODS: Patients diagnosed with MGMT promoter unmethylated GBM from 2010 to 2012 who received radiation (RT) or chemoradiation (CRT) were identified in the National Cancer Database. Logistic regression was performed to assess for predictors of receiving chemoradiation. The Kaplan-Meier method was used to assess overall survival (OS) by treatment group and Cox regression analysis was used to assess impact of covariates on OS. RESULTS: There were 738 patients who met the study criteria, of which 107 (14.5%) received RT alone and 631 (85.5%) received CRT with median RT dose 6000cGy for both groups. Median follow up for living patients was 21.9 months. Ninety-two (12.5%) patients did not undergo any resection, 330 (44.7%) underwent a subtotal resection and 316 (42.8%) had a gross total resection. The median and 2-year OS was 16.8 months and 24.7% for RT alone compared to 15.6 months and 25.9% for the CRT group (p = 0.250). On multivariable analysis, the addition of chemotherapy had no impact on survival (HR 1.12, 95% CI 0.86-1.46, p = 0.396). CONCLUSION: Despite the routine use of chemoradiation among patients with MGMT promoter unmethylated GBM, there does not appear to be a survival benefit compared to radiation alone.

Patterns of care and outcomes for glioblastoma in patients with poor performance status.

PURPOSE/OBJECTIVES: While treatment with tumor resection followed by chemoradiation is generally the accepted standard of care for glioblastoma (GBM), the treatment for patients with poor performance status remains uncertain. Therefore we sought to examine patterns of care and survival outcomes among patients with poor performance status utilizing a large hospital database. METHODS/MATERIALS: We queried the National Cancer Database (NCDB) for patients with GBM and Karnofsky performance status (KPS) <60 between 2010 and 2013. Data was collected regarding surgery, radiation therapy and chemotherapy. Logistic regression was used to analyze predictors for utilization of chemoradiation. The Kaplan-Meier method was used to compare survival between those who received chemoradiation to radiation alone and Cox regression was performed to assess covariates associated with survival. RESULTS: There were 488 patients included in the analysis of which 51.2% received chemoradiation and 46.1% underwent subtotal or gross total resection. None of the factors analyzed were significantly associated with increased likelihood of receiving chemoradiation over radiation alone. Survival data was available for 236 patients that received radiation therapy with and without combination chemotherapy. The median overall survival for those receiving radiation alone was 3.6 months and 8.7 months in those who received chemoradiation (p < 0.001). On multivariable Cox regression, increasing age (HR 1.80-2.10, p = 0.001) was associated with worse survival while subtotal/gross total resection (HR 0.60, p = 0.003) and chemoradiation (HR 0.57, CI 0.40-0.83, p = 0.003) were associated with improved survival. CONCLUSION: Even patients with poor performance status had better survival outcomes when they received treatment with chemoradiation over radiation alone.