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Introduction Peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) is a rare, highly heterogeneous group of mature T‐cell neoplasms that historically has been associated with poor outcomes. We sought to investigate the influence of primary disease site on PTCL‐NOS outcomes using a large national cancer registry. Methods Baseline clinical and demographic data including primary organ of involvement and Ann Arbor disease stage were extracted from the SEER database. Patients were grouped into nine organ system groups and compared to nodal disease acting as a control. Cox regression models were utilized for adjusted survival analyses. Results A total of 3095 patients were identified in the SEER database and included in the final analysis. The median age was 61 and a majority of patients were male (60%) and identified as non‐Hispanic white (68%). A plurality of patients had stage IV disease (32%). Lymph nodes and spleen were the most common primary disease sites (67%), while central nervous system was the least common (1%). Patients with early‐stage PTCL‐NOS of the gastrointestinal/genitourinary systems had worse overall survival [HR = 1.97 (1.50–2.59); p < 0.001] and lymphoma‐specific survival [HR = 1.74 (1.26–2.40); p < 0.001] which was statistically significant even after adjusting for other variables. Early‐stage PTCL‐NOS of the central nervous system also had worse overall survival [HR = 1.90 (1.11–3.27); p = 0.020] and lymphoma‐specific survival [HR = 2.11 (1.17–3.80); p = 0.013]. Early‐stage PTCL‐NOS of the skin had better overall survival [HR = 0.54 (0.42–0.68); p < 0.001] and lymphoma‐specific survival [HR = 0.388 (0.28–0.53); p < 0.001] which was statistically significant even after adjustments. Conclusion Our findings suggest an association between primary organ involved by PTCL‐NOS and both overall and lymphoma‐specific survival even after adjusting for common variables. These results warrant validation in future prospective studies.

Signal regulatory protein alpha (SIRPα) is the receptor for cluster of differentiation (CD)47, a potent “don't eat me” signal for macrophages. Disruption of CD47‐SIRPα signaling in the presence of prophagocytic signals can lead to enhanced phagocytosis of tumor cells, resulting in a direct antitumor effect; agents targeting this pathway have shown efficacy in non‐Hodgkin lymphoma (NHL) and other tumor types. GS‐0189 is a novel anti‐SIRPα humanized monoclonal antibody. Here we report: (1) clinical safety, preliminary activity, and pharmacokinetics of GS‐0189 as monotherapy and in combination with rituximab from a phase 1 clinical trial in patients with relapsed/refractory NHL (NCT04502706, SRP001); (2) in vitro characterization of GS‐0189 binding to SIRPα; and (3) in vitro phagocytic activity. Clinically, GS‐0189 was well tolerated in patients with relapsed/refractory NHL with evidence of clinical activity in combination with rituximab. Receptor occupancy (RO) of GS‐0189 was highly variable in NHL patients; binding affinity studies showed significantly higher affinity for SIRPα variant 1 than variant 2, consistent with RO in patient and healthy donor samples. In vitro phagocytosis induced by GS‐0189 was also SIRPα variant–dependent. Although clinical development of GS‐0189 was discontinued, the CD47‐SIRPα signaling pathway remains a promising therapeutic target and should continue to be explored.

Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL. TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18–75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET–positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 106 CAR+ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously—R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1–3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)—followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing. Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4–11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months [95% CI 6·1–not reached]) compared with the standard-of-care group (2·3 months [2·2–4·3]; stratified hazard ratio 0·35; 95% CI 0·23–0·53; stratified Cox proportional hazards model one-sided p<0·0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group. These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL. Celgene, a Bristol-Myers Squibb Company.

The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a primary intestinal T-cell lymphoma, previously known as enteropathy-associated T-cell lymphoma (EATL) type II. Its clinical, morphologic, and immunophenotypic features distinguishing it from the more common EATL (previously EATL type I) made it a separate entity. Unlike EATL, MEITL typically is noted in Asian, Hispanic, and indigenous populations; it is rarer in native European and Caucasian populations. Due to its poor prognosis, it needs to be distinguished from inflammatory diseases and less aggressive T-cell lymphomas. We present an unusual case of MEITL in a Caucasian patient who developed nonspecific GI symptoms and was diagnosed with MEITL of the jejunum, mesenteric lymph nodes, and multiple extraintestinal sites based on histology, immunophenotype, molecular testing, and imaging. Despite aggressive treatment, he expired about seven months after the definitive diagnosis.Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a primary intestinal T-cell lymphoma, previously known as enteropathy-associated T-cell lymphoma (EATL) type II. Its clinical, morphologic, and immunophenotypic features distinguishing it from the more common EATL (previously EATL type I) made it a separate entity. Unlike EATL, MEITL typically is noted in Asian, Hispanic, and indigenous populations; it is rarer in native European and Caucasian populations. Due to its poor prognosis, it needs to be distinguished from inflammatory diseases and less aggressive T-cell lymphomas. We present an unusual case of MEITL in a Caucasian patient who developed nonspecific GI symptoms and was diagnosed with MEITL of the jejunum, mesenteric lymph nodes, and multiple extraintestinal sites based on histology, immunophenotype, molecular testing, and imaging. Despite aggressive treatment, he expired about seven months after the definitive diagnosis.

The association between mediastinal germ cell tumors (MGCT) and acute megakaryoblastic (M7) leukemia has been known for many years. We hereby present this review to better characterize the coexistence of these entities as well as the salient features, the treatment options, and the overall prognosis. A search of PUBMED, Medline, and EMBASE databases via OVID engine for primary articles and case reports under keywords “germ cell tumors” and “acute myeloid leukemia” revealed a total of 26 cases in English that reported MGCT and M7 leukemia. The median age at diagnosis of MGCT was 24 (13–36) years. All cases were stage III. All cases of MGCT were of non-seminomatous origin and one case was unclassified. MGCT occurred prior to the diagnosis of leukemia in 46% of cases and concomitantly in 31% of cases. M7 leukemia was never reported prior to the appearance of MGCT. Complex cytogenetics and hyperdiploidy were the most commonly reported cytogenetic abnormalities. In the 23 cases where the treatment regimen was available, platinum-based chemotherapy directed towards management of the germ cell tumors was used initially in 21 cases and leukemia-directed treatment was used initially in 2 cases only. The median time from diagnosis of MGCT to development of M7 leukemia was 5 (2.25–39) months. Median time to death from the initial diagnosis of MGCT was 6 (0.5–60) months. Patients with a history of MGCT are at higher risk of developing M7 leukemia. They need long-term follow-up with a particular attention to the development of hematological malignancies. The overall prognosis remains poor.

The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.