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INTRODUCTION: Follicular lymphoma is a common non-Hodgkin lymphoma that can start in a diverse array of tissues throughout the body. While the majority of patients may be able to live many years with this disease, cure remains very difficult to achieve. OBJECTIVE: We sought to investigate the impact of follicular lymphoma primary disease site in early-stage disease on patient outcomes using a large national database. METHODS: Baseline demographic and disease data for patients diagnosed with follicular lymphoma from 2000-2015 was identified and extracted from the NCI Surveillance, Epidemiology, and End Results (SEER) database. Primary disease sites were grouped into one of two cohorts: nodal disease (lymph nodes and spleen) and extranodal disease (everything else). Analysis was performed using summary statistics, Kaplan-Meier method, and Cox-proportional hazards models for univariate and multivariate analysis. RESULTS: A total of 13,400 patients were included in the final analysis and the majority were non-Hispanic white (81%), with stage I (63%), and nodal FL (79%). Median overall survival for nodal disease was 15.1 years [95% CI (14.6-15.6)] while median overall survival for extranodal disease was 15.8 years [95% CI (14.9-16.3)]. Overall survival was slightly better for patients with extranodal disease [HR = 0.89, 95% CI (0.84-0.96); p-value = 0.00012]. This finding remained consistent after controlling for age and race [HR = 0.84, 95% CI (0.79-0.90); p-value <0.0001]. CONCLUSIONS: The primary site of involvement by early-stage follicular lymphoma may have an impact on patient outcomes and warrants further investigation.
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What is this summary about? People diagnosed with a disease called large B-cell lymphoma (LBCL) may experience return, or early relapse, of their disease within the first year after receiving and responding to their first (first-line) treatment regimen. Others may have primary refractory disease, meaning that the disease either did not respond to first-line treatment at all or only responded for a very brief period. Second (second-line) treatment includes immunotherapy followed by high-dose chemotherapy and ASCT, which has the potential to cure LBCL. However, if the disease does not respond to immunotherapy, people cannot receive ASCT, and less than 30% of people are cured.Therefore, new second-line treatment options are required, such as CAR T cell therapy, which uses a person's own genetically engineered lymphocytes, also called T cells, to fight their lymphoma. In this article, we summarize the key results of the phase 3 TRANSFORM clinical study that tested if liso-cel, a CAR T cell treatment, can safely and effectively be used as a second-line treatment for people with early relapsed or primary refractory (relapsed/refractory) LBCL.A total of 184 adults with relapsed/refractory LBCL who were able to receive ASCT were randomly treated with either liso-cel or standard of care (SOC) as second-line treatment. SOC included immunochemotherapy followed by high-dose chemotherapy and ASCT.What were the key takeaways? Almost all (97%) people in the liso-cel group completed treatment, whereas 53% of people in the SOC group did not complete treatment, mostly due to their disease not responding or relapsing, and therefore they were not able to receive ASCT. People who received liso-cel as a second-line treatment lived longer without the occurrence of an unfavorable medical event or worsening of the disease and had a better response to treatment than those who received SOC as second-line treatment. People who received liso-cel reported side effects that researchers considered to be manageable, and that were known to occur with CAR T cell treatment.What were the main conclusions reported by the researchers? Results from the TRANSFORM study support the use of liso-cel as a more effective second-line treatment compared with SOC that is safe for people with relapsed/refractory LBCL.Clinical Trial Registration: NCT03575351 (TRANSFORM study) (ClinicalTrials.gov).
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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.
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Linfoma de Células T Periférico , Humanos , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Ganglios Linfáticos/patología , Estudios ProspectivosRESUMEN
BACKGROUND: Hereditary thrombotic thrombocytopenia purpura (hTTP) is an ultra-rare disorder resulting from an inherited deficiency of ADAMTS13, a von Willebrand factor (VWF)-cleaving metalloprotease. The plasma-derived factor VIII/VWF Koate (FVIII/VWFKoate ) has been shown to contain ADAMTS13, allowing for its use to treat hTTP at home by the patient/caregiver. AIM: Based on prior demonstration of safe and effective use of FVIII/VWFKoate in eight patients with hTTP, we conducted a retrospective study to gather additional data regarding the use of FVIII/VWFKoate for hTTP. METHODS: This was a multicentre, retrospective, noninterventional chart review of patients who had received FVIII/VWFKoate for the management of hTTP. Data collected included demographics, medical history, relevant family history, past use and tolerability of fresh frozen plasma, and details regarding FVIII/VWFKoate therapy. RESULTS: The cohort included 11 patients (seven males, four females) with hTTP, ranging in age at study entry from 2 to 28 years. The average duration of FVIII/VWFKoate therapy was 4.8 years (range, 0.5-6.5 years). Among nine patients using FVIII/VWFKoate as prophylaxis, the normalized annual rate of breakthrough TTP episodes ranged from 0.2 to 1.1 episodes/year. All nine patients who received FVIII/VWFKoate prophylaxis had thrombocytopenia recorded at baseline, while eight (88.9%) did not have thrombocytopenia after using FVIII/VWFKoate . There was one AE (unspecified) attributed to FVIII/VWFKoate . CONCLUSION: These data suggest that FVIII/VWFKoate is a safe and well-tolerated source of the missing ADAMTS13 enzyme in patients with hTTP, producing a marked reduction in thrombocytopenia prevalence, low frequency of TTP episodes, and with the added benefit of self- or caregiver-administration.
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Hemostáticos , Púrpura Trombocitopénica Trombótica , Masculino , Femenino , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Factor VIII/uso terapéutico , Factor de von Willebrand/uso terapéutico , Estudios Retrospectivos , Estudios de Seguimiento , Proteínas ADAM , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Plasma , Proteína ADAMTS13RESUMEN
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.
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Adenocarcinoma , Neoplasias Gastrointestinales , Masculino , Femenino , Humanos , Quinurenina , Triptófano , Leucocitos Mononucleares , Obesidad/genética , Neoplasias Gastrointestinales/genéticaRESUMEN
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.
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BACKGROUND: Advances in treatment for patients with Diffuse Large B-Cell Lymphoma (DLBCL) have led to improved patient outcomes but the magnitude of these disparities remains understudied with regards to improved survival outcomes. We sought to describe changes in DLBCL survival trends over time and explore potential differential survival patterns by patients' race/ethnicity and age. METHODS: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with DLBCL from 1980 to 009 and determined 5-year survival outcomes for all patients, categorizing patients by year of diagnosis. We used descriptive statistics and logistic regression, adjusting for stage and year of diagnosis, to describe changes in 5-year survival rates over time by race/ethnicity and age. RESULTS: We identified 43,564 patients with DLBCL eligible for this study. Median age was 67 years (ages: 18-64 = 44.2%, 65-79 = 37.1%, 80 + = 18.7%). Most patients were male (53.4%) and had advanced stage III/IV disease (40.0%). Most patients were White race (81.4%), followed by Asian/Pacific Islander (API) (6.3%), Black (6.3%), Hispanic (5.4%), and American Indian/Alaska Native (AIAN) (0.05%). Overall, the 5-year survival rate improved from 35.1% in 1980 to 52.4% in 2009 across all races and age groups (odds ratio [OR] for 5-year survival with increasing year of diagnosis = 1.05, P < .001). Patients in racial/ethnic minority groups (API: OR = 0.86, P < .0001; Black: OR = 0.57, P < .0001; AIAN: OR = 0.51, P = .008; Hispanic: 0.76, P = 0.291) and older adults (ages 65-79: OR = 0.43, P < .0001; ages 80+: OR = 0.13, P < .0001) had lower 5-year survival rates after adjusting for race, age, stage, and diagnosis year. We found consistent improvement in the odds of 5-year survival for year of diagnosis across all race and ethnicity groups (White: OR = 1.05, P < .001; API: OR = 1.04, P < .001; Black: OR = 1.06, p<.001; AIAN: OR = 1.05, P < .001; Hispanic: OR = 1.05, P < .005) and age groups (ages 18-64: OR = 1.06, P < .001; ages 65-79: OR = 1.04, P < .001; ages 80+: OR = 1.04, P < .001). CONCLUSION: Patients with DLBCL experienced improvements in 5-year survival rates from 1980 to 2009, despite persistently lower survival among patients in racial/ethnic minority groups and older adults.
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Etnicidad , Disparidades en el Estado de Salud , Linfoma de Células B Grandes Difuso , Grupos Minoritarios , Grupos Raciales , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Factores de Edad , Etnicidad/estadística & datos numéricos , Linfoma de Células B Grandes Difuso/etnología , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Grupos Minoritarios/estadística & datos numéricos , Factores Raciales , Grupos Raciales/estadística & datos numéricos , Programa de VERF , Tasa de Supervivencia/tendenciasRESUMEN
This global phase 3 study compared lisocabtagene maraleucel (liso-cel) with a standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (ASCT; N = 184) were randomly assigned in a 1:1 ratio to liso-cel (100 × 106 chimeric antigen receptor-positive T cells) or SOC (3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and ASCT in responders). The primary end point was event-free survival (EFS). In this primary analysis with a 17.5-month median follow-up, median EFS was not reached (NR) for liso-cel vs 2.4 months for SOC. Complete response (CR) rate was 74% for liso-cel vs 43% for SOC (P < .0001) and median progression-free survival (PFS) was NR for liso-cel vs 6.2 months for SOC (hazard ratio [HR] = 0.400; P < .0001). Median overall survival (OS) was NR for liso-cel vs 29.9 months for SOC (HR = 0.724; P = .0987). When adjusted for crossover from SOC to liso-cel, 18-month OS rates were 73% for liso-cel and 54% for SOC (HR = 0.415). Grade 3 cytokine release syndrome and neurological events occurred in 1% and 4% of patients in the liso-cel arm, respectively (no grade 4 or 5 events). These data show significant improvements in EFS, CR rate, and PFS for liso-cel compared with SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03575351.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Trasplante Autólogo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Modelos de Riesgos Proporcionales , Inmunoterapia Adoptiva/efectos adversos , Antígenos CD19/uso terapéuticoRESUMEN
Lisocabtagene maraleucel (liso-cel) has shown promising efficacy in clinical trials for patients with relapsed/refractory large B-cell lymphoma (LBCL). We present health-related quality of life (HRQOL) results from the TRANSFORM study, the first comparative analysis of liso-cel vs standard of care (SOC) as second-line therapy in this population. Adults with LBCL refractory or relapsed ≤12 months after first-line therapy and eligible for autologous stem cell transplantation were randomized 1:1 to the liso-cel or SOC arms (3 cycles of immunochemotherapy in which responders proceeded to high-dose chemotherapy and autologous stem cell transplantation). HRQOL was assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - 30 items and the Functional Assessment of Cancer Therapy-Lymphoma subscale. Patients with baseline and ≥1 postbaseline assessment were analyzed (liso-cel, n = 47; SOC, n = 43). The proportion of patients with meaningful improvement in global health status/quality of life (QOL) was higher, whereas deterioration was lower in the liso-cel arm vs SOC arm from day 126 to month 6. Mean change scores showed meaningful worsening in global health status/QOL at month 6, fatigue at day 29 and month 6, and pain at month 6 with SOC; mean scores for other domains were maintained or improved in both arms. Time to confirmed deterioration favored the liso-cel arm vs SOC arm in global health status/QOL (median: not reached vs 19.0 weeks, respectively; hazard ratio, 0.47; 95% confidence interval, 0.24-0.94). HRQOL was either improved or maintained from baseline in patients with relapsed/refractory LBCL in the liso-cel arm vs SOC arm as second-line treatment. This study is registered at clinicaltrials.gov as #NCT0357531.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Adulto , Humanos , Calidad de Vida , Nivel de Atención , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante AutólogoRESUMEN
BACKGROUND: 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. METHODS: 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 (100â×â106 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. FINDINGS: 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. INTERPRETATION: These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL. FUNDING: Celgene, a Bristol-Myers Squibb Company.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Trombocitopenia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Dexametasona , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Rituximab/uso terapéutico , Nivel de Atención , Trombocitopenia/tratamiento farmacológico , Trasplante AutólogoAsunto(s)
Receptores Quiméricos de Antígenos , Tratamiento Basado en Trasplante de Células y Tejidos , Estudios de Factibilidad , Humanos , Inmunoterapia Adoptiva/efectos adversos , Pacientes Ambulatorios , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores Quiméricos de Antígenos/uso terapéutico , Centros de Atención TerciariaRESUMEN
Hodgkin's lymphoma is a rare yet highly curable disease in the majority of patients treated with modern chemotherapy regimens. For patients who fail to respond to or relapse after initial systemic therapies, treatment with high-dose chemotherapy and autologous hematopoietic stem cell transplantation can provide a cure for many with chemotherapy-responsive lymphoma. Patients who relapse after autologous transplant or those with chemorefractory disease have poor prognosis and represent a high unmet need. Allogeneic hematopoietic stem cell transplantation provides a proven curative therapy for these patients and should be considered, especially in young and medically fit patients. The use of newer agents in this disease such as brentuximab vedotin and immune checkpoint inhibitors can help bring more patients to transplantation and should be considered as well.
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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.
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BACKGROUND: Immune-related adverse events are associated with efficacy of immune checkpoint inhibitors (ICIs). We hypothesize that immune-mediated thrombocytopenia could be a biomarker for response to ICIs. MATERIALS & METHODS: This retrospective study included 215 patients with metastatic malignancies treated with ICIs. Patients were stratified by nadir platelet count. Outcomes of interest were progression-free survival and overall survival. RESULTS: On multivariate analysis, grade 1 thrombocytopenia was positively associated with overall survival compared with patients who did not develop thrombocytopenia (hazard ratio [HR]= 0.28 [95% CI: 0.13-0.60]; p = 0.001), while grade 2-4 thrombocytopenia was not (HR= 0.36 [95% CI: 0.13-1.04]; p = 0.060). There was no association between degree of thrombocytopenia and progression-free survival. CONCLUSION: Follow-up studies are warranted to substantiate the predictive significance of thrombocytopenia in patients receiving ICIs.
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Regresión Neoplásica Espontánea , Neoplasias Pancreáticas/inmunología , Pancreatitis/inmunología , Enfermedad Aguda , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Pancreatitis/complicaciones , RecurrenciaAsunto(s)
Neoplasias del Mediastino , Neoplasias de Células Germinales y Embrionarias , Sarcoma Mieloide , Adulto , Humanos , Masculino , Neoplasias del Mediastino/diagnóstico por imagen , Neoplasias del Mediastino/metabolismo , Neoplasias del Mediastino/patología , Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Neoplasias de Células Germinales y Embrionarias/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Sarcoma Mieloide/diagnóstico por imagen , Sarcoma Mieloide/metabolismo , Sarcoma Mieloide/patologíaRESUMEN
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.