المؤلفون: Gitelman, Stephen E, Bundy, Brian N, Ferrannini, Ele, Lim, Noha, Blanchfield, J Lori, DiMeglio, Linda A, Felner, Eric I, Gaglia, Jason L, Gottlieb, Peter A, Long, S Alice, Mari, Andrea, Mirmira, Raghavendra G, Raskin, Philip, Sanda, Srinath, Tsalikian, Eva, Wentworth, John M, Willi, Steven M, Krischer, Jeffrey P, Bluestone, Jeffrey A, Group, Gleevec Trial Study, Barr, Mayalin, Buchanan, Jeanne, Cabbage, Joanne, Coleman, Peter, De La Vega, Monica, Evans-Molina, Carmella, Ferrara, Christine, Healy, Felicity, Higgins, Laurie, Hildinger, Megan, Jenkins, Margaret, Bryant, Nora Kayton, Kinderman, Amanda, Koshy, Nisha, Kost, Brianne, Krishfield, Suzanne, Kucheruk, Olena, Lindsley, Karen, Mantravadi, Manasa, Mesfin, Shelley, Michels, Aaron, Migre, Mary Ellen, Minnock, Pantea, Mohammed-Nur, Elham, Nelson, Jennifer, Nursing, Ashvin, O'Donnell, Ryan, Olivos, Diana, Parker, Melissa, Redl, Leanne, Reed, Nicole, Resnick, Brittany, Sayre, Peter, Serti, Elisavet, Sims, Emily, Smith, Karen, Soppe, Carol, Stuart, Fiona, Szubowicz, Sarah, Tansey, Michel, Terrell, Jennifer, Tersey, Sarah, Torok, Christine, Watson, Kelly, Wesch, Rebecca, Willi, Steven, Woerner, Stephanie

المصدر: The Lancet Diabetes & Endocrinology. 9(8)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Prevention, Autoimmune Disease, Clinical Research, Diabetes, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Adolescent, Adult, Biomarkers, Blood Glucose, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Follow-Up Studies, Humans, Imatinib Mesylate, Male, Middle Aged, Prognosis, Protein Kinase Inhibitors, Young Adult, Gleevec Trial Study Group, Medical Biochemistry and Metabolomics, Public Health and Health Services, Clinical sciences, Medical biochemistry and metabolomics

الوصف: BackgroundType 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes.MethodsWe did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (

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المؤلفون: Yuan, Tze-An, Yourk, Vandy, Farhat, Ali, Guo, Katherine L, Garcia, Angela, Meyskens, Frank L, Liu-Smith, Feng

المصدر: International journal of molecular sciences. 21(5)

مصطلحات موضوعية: Humans, Melanoma, Receptor, IGF Type 1, Insulin-Like Growth Factor I, Estrogen Receptor alpha, Estrogen Receptor beta, Prognosis, Risk Factors, Case-Control Studies, Follow-Up Studies, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Middle Aged, Child, Child, Preschool, Infant, Infant, Newborn, Female, Male, Young Adult, Biomarkers, Tumor, cutaneous melanoma, estrogen receptors, gender disparities, genetic variants, insulin-like growth factor 1, insulin-like growth factor 1 receptor, Estrogen, Clinical Research, Cancer, Genetics, 2.1 Biological and endogenous factors, Chemical Physics, Other Chemical Sciences, Other Biological Sciences

الوصف: The mechanism of gender disparity in cutaneous melanoma incidence remains unclear. Steroid hormones including estrogens have long been implicated in the course of melanoma, but the conclusion is controversial. Estrogen receptors (ERs) and insulin-like growth factor 1 receptor (IGF1R) show extensive crosstalk in cancer development, but how the ER/IGF1R network impacts melanoma is currently unclear. Here we studied the melanoma associations of selected SNPs from the ER/IGF1R network. Part of the International Genes, Environment, and Melanoma (GEM) cohort was used as a discovery set, and the Gene Environment Association Studies Initiative (GENEVA) dataset served as a validation set. Based on the associations with other malignant disease conditions, thirteen single nucleotide polymorphism (SNP) variants in ESR1, ESR2, IGF1, and IGF1R were selected for candidate gene association analyses. The rs1520220 in IGF1 and rs2229765 in IGF1R variants were significantly associated with melanoma risk in the GEM dataset after Benjamini-Hochberg multiple comparison correction, although they were not validated in the GENEVA set. The discrepancy may be caused by the multiple melanoma characteristics in the GEM patients. Further analysis of gender disparity was carried out for IGF1 and IGF1R SNPs in the GEM dataset. The GG phenotype in IGF1 rs1520220 (recessive model) presented an increased risk of melanoma (OR = 8.11, 95% CI: 2.20, 52.5, p = 0.006) in men but a significant opposite effect in women (OR = 0.15, 95% CI: 0.018, 0.86, p = 0.045). The AA genotype in IGF1R rs2229765 (recessive model) showed a significant protective effect in men (OR = 0.24, 95% CI: 0.07, 0.64, p = 0.008) and no effect in women. Results from the current study are warranted for further validation.

الوصول الحر: https://escholarship.org/uc/item/8xw1f78mTest

المؤلفون: Basu, Arpita, Bebu, Ionut, Jenkins, Alicia J, Stoner, Julie A, Zhang, Ying, Klein, Richard L, Lopes-Virella, Maria F, Garvey, W Timothy, Budoff, Matthew J, Alaupovic, Petar, Lyons, Timothy J, Group, the Diabetes Control Complications Trial Epidemiology of Diabetes Interventions Complications Research

المصدر: Journal of Lipid Research. 60(8)

مصطلحات موضوعية: Medical Biochemistry and Metabolomics, Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Cardiovascular, Atherosclerosis, Prevention, Heart Disease, Heart Disease - Coronary Heart Disease, Good Health and Well Being, Adult, Apolipoproteins, Cardiovascular Diseases, Diabetes Complications, Diabetes Mellitus, Type 1, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prospective Studies, apolipoprotein C3, major adverse cardiac event, type 1 diabetes, Diabetes Control Complications Trial/Epidemiology of Diabetes Interventions Complications Research Group, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics

الوصف: APOB, APOC3, and APOE and apolipoprotein-defined lipoprotein subclasses (ADLSs; based on qualitative apolipoprotein complement) have been associated with dyslipidemia and CVD. Our main objective was to define associations of serum apolipoproteins and ADLSs with "any CVD" and "major atherosclerotic cardiovascular events" (MACEs) in a prospective study of T1D. Serum apolipoproteins and ADLSs (14 biomarkers in total) were measured in sera (obtained between 1997 and 2000) from a subset (n = 465) of the Epidemiology of Diabetes Interventions and Complications cohort. Prospective associations of "any CVD" (myocardial infarction, stroke, confirmed angina, silent myocardial infarction, revascularization, or congestive heart failure) and MACEs (fatal or nonfatal myocardial infarction or stroke), over 5,943 and 6,180 patient-years follow-up, respectively, were investigated using Cox proportional hazards models that were unadjusted and adjusted for risk factors. During 15 years of follow-up, 50 "any CVD" events and 24 MACEs occurred. Nominally significant positive univariate associations with "any CVD" were APOB, APOC3 and its subfractions [heparin precipitate, heparin-soluble (HS)], and ADLS-defined Lp-B. In adjusted analyses, APOC3-HS remained nominally significant. Nominally significant positive univariate associations with MACEs were APOC3 and its subfractions and Lp-B:C; those with total APOC3 and APOC3-HS persisted in adjusted analyses. However, these associations did not reach significance after adjusting for multiple testing. There were no significant associations of APOA1, APOA2, APOE, or other ADLSs with either "any CVD" or MACEs. These hypothesis-generating data suggest that total serum APOC3 and APOC3 in HDL are potentially important predictive biomarkers for any CVD and MACEs in adults with T1D.

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المؤلفون: Algazi, Alain P, Twitty, Christopher G, Tsai, Katy K, Le, Mai, Pierce, Robert, Browning, Erica, Hermiz, Reneta, Canton, David A, Bannavong, Donna, Oglesby, Arielle, Francisco, Murray, Fong, Lawrence, Pittet, Mikael J, Arlauckas, Sean P, Garris, Christopher, Levine, Lauren P, Bifulco, Carlos, Ballesteros-Merino, Carmen, Bhatia, Shailender, Gargosky, Sharron, Andtbacka, Robert HI, Fox, Bernard A, Rosenblum, Michael D, Daud, Adil I

المصدر: Clinical Cancer Research. 26(12)

مصطلحات موضوعية: Clinical Research, Cancer, Clinical Trials and Supportive Activities, Adult, Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Case-Control Studies, Female, Follow-Up Studies, Humans, Interleukin-12, Male, Melanoma, Middle Aged, Prognosis, Programmed Cell Death 1 Receptor, Prospective Studies, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.

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المؤلفون: Patel, Sandip P, Othus, Megan, Chae, Young Kwang, Giles, Francis J, Hansel, Donna E, Singh, Preet Paul, Fontaine, Annette, Shah, Manisha H, Kasi, Anup, Al Baghdadi, Tareq, Matrana, Marc, Gatalica, Zoran, Korn, W Michael, Hayward, Jourdain, McLeod, Christine, Chen, Helen X, Sharon, Elad, Mayerson, Edward, Ryan, Christopher W, Plets, Melissa, Blanke, Charles D, Kurzrock, Razelle

المصدر: Clinical Cancer Research. 26(10)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Immunology, Rare Diseases, Cancer, Clinical Research, Orphan Drug, Health Disparities, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, CTLA-4 Antigen, Female, Follow-Up Studies, Humans, Ipilimumab, Male, Middle Aged, Neuroendocrine Tumors, Nivolumab, Prognosis, Programmed Cell Death 1 Receptor, Prospective Studies, Survival Rate, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis

الوصف: PurposeImmune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).Patients and methodsWe performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.ResultsThirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.ConclusionsIpilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease.

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https://escholarship.org/content/qt9dd0221w/qt9dd0221w.pdfTest

المؤلفون: Tolcher, Anthony W, Kurzrock, Razelle, Valero, Vincente, Gonzalez, Rene, Heist, Rebecca S, Tan, Antoinette R, Means-Powell, Julie, Werner, Theresa L, Becerra, Carlos, Wang, Chenxi, Leonowens, Cathrine, Kalyana-Sundaram, Shanker, Kleha, Joseph F, Gauvin, Jennifer, D’Amelio, Anthony M, Ellis, Catherine, Ibrahim, Nageatte, Yan, Li

المصدر: Cancer Chemotherapy and Pharmacology. 85(4)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Trials and Supportive Activities, Clinical Research, Cancer, Evaluation of treatments and therapeutic interventions, 6.2 Cellular and gene therapies, 6.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cohort Studies, Diamines, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Male, Maximum Tolerated Dose, Melanoma, Middle Aged, Prognosis, Proto-Oncogene Proteins c-akt, Pyrazoles, Pyridones, Pyrimidinones, Tissue Distribution, Triple Negative Breast Neoplasms, Young Adult, AKT inhibitor, BRAF-wild type melanoma, MEK inhibitor, Trametinib, Triple-negative breast cancer, Uprosertib, Oncology & Carcinogenesis, Oncology and carcinogenesis, Pharmacology and pharmaceutical sciences

الوصف: PurposeThis study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.MethodsThis was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.ResultsAdverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was

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المؤلفون: Berg, Cynthia A, Wiebe, Deborah J, Lee Tracy, Eunjin, Kelly, Caitlin S, Mello, Daniel, Turner, Sara L, Butner, Jonathan E, Munion, Ascher K, Mansfield, Jessica H, White, Perrin C, Murray, Mary, Suchy, Yana

المصدر: Journal of Pediatric Psychology. 44(8)

مصطلحات موضوعية: Prevention, Diabetes, Metabolic and endocrine, Adolescent, Adult, Cognitive Dysfunction, Diabetes Mellitus, Type 1, Executive Function, Female, Follow-Up Studies, Humans, Male, Parenting, Parents, Patient Compliance, Young Adult, diabetes, family functioning, longitudinal research, neuropsychology, parents, Psychology, Developmental & Child Psychology

الوصف: ObjectiveTo examine (a) changes in parental involvement across early emerging adulthood, (b) whether yearly fluctuations in parental involvement were associated with adherence and glycated hemoglobin (HbA1c) over time, and (c) whether higher involvement was more beneficial for those with poorer executive function (EF).MethodsA total of 228 high school seniors (M age = 17.76) with type 1 diabetes reported on mothers' and fathers' acceptance, knowledge of diabetes activities, disclosure to mothers and fathers regarding diabetes, and adherence at four yearly time points. At baseline, participants completed performance-based measures of EF. HbA1c was collected from assay kits.ResultsGrowth curve models revealed significant declines in disclosure to fathers and mothers' and fathers' knowledge of diabetes activities; no changes were found in mothers' or fathers' acceptance nor disclosure to mothers. Multilevel models indicated significant between-person effects for nearly all aspects of parental involvement with more acceptance, knowledge, and disclosure associated with better HbA1c and adherence. Within-person effects for disclosure to fathers, and mothers' and fathers' knowledge indicated that in years when emerging adults perceived higher amounts of these types of involvement (compared with their own average), HbA1c was lower. Within-person effects were found for acceptance to mothers, disclosure to mothers and fathers, and mothers' diabetes knowledge for adherence. Disclosure to fathers and mothers' knowledge of diabetes activities were especially beneficial for HbA1c for those with poorer EF performance.ConclusionsParental involvement in diabetes management remains important during the high-risk time of emerging adulthood, especially for those with poorer EF.

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المؤلفون: Wisel, SA, Gardner, JM, Roll, GR, Harbell, J, Freise, CE, Feng, S, Kang, SM, Hirose, R, Kaufman, DB, Posselt, AM, Stock, PG

المصدر: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 17(9)

مصطلحات موضوعية: Humans, Diabetes Mellitus, Type 1, Insulin, Immunosuppressive Agents, Prognosis, Pancreas Transplantation, Islets of Langerhans Transplantation, Risk Factors, Follow-Up Studies, Graft Rejection, Graft Survival, Adult, Middle Aged, Female, Male, Young Adult, clinical research/practice, diabetes: type 1, immunosuppressive regimens, islet transplantation, pancreas/simultaneous pancreas-kidney transplantation, patient characteristics, protocol biopsy, Kidney Disease, Diabetes, Organ Transplantation, Transplantation, Autoimmune Disease, Development of treatments and therapeutic interventions, 5.4 Surgery, Renal and urogenital, Metabolic and endocrine, Medical and Health Sciences, Surgery

الوصف: Islet transplantation offers a minimally invasive approach for β cell replacement in diabetic patients with hypoglycemic unawareness. Attempts at insulin independence may require multiple islet reinfusions from distinct donors, increasing the risk of allogeneic sensitization. Currently, solid organ pancreas transplant is the only remaining surgical option following failed islet transplantation in the United States; however, the immunologic impact of repeated exposure to donor antigens on subsequent pancreas transplantation is unclear. We describe a case series of seven patients undergoing solid organ pancreas transplant following islet graft failure with long-term follow-up of pancreatic graft survival and renal function. Despite highly variable panel reactive antibody levels prior to pancreas transplant (mean 27 ± 35%), all seven patients achieved stable and durable insulin independence with a mean follow-up of 6.7 years. Mean hemoglobin A1c values improved significantly from postislet, prepancreas levels (mean 8.1 ± 1.5%) to postpancreas levels (mean 5.3 ± 0.1%; p = 0.0022). Three patients experienced acute rejection episodes that were successfully managed with thymoglobulin and methylprednisolone, and none of these preuremic type 1 diabetic recipients developed stage 4 or 5 chronic kidney disease postoperatively. These results support pancreas-after-islet transplantation with aggressive immunosuppression and protocol biopsies as a viable strategy to restore insulin independence after islet graft failure.

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المؤلفون: Bair, Steven M, Strelec, Lauren E, Feldman, Tatyana A, Ahmed, Gulrayz, Armand, Philippe, Shah, Nirav N, Singavi, Arun N, Reddy, Nishitha, Khan, Nadia, Andreadis, Charalambos, Vu, Khoan, Huntington, Scott F, Giri, Smith, Ujjani, Chaitra, Howlett, Christina, Faheem, Malik, Youngman, Matthew R, Nasta, Sunita D, Landsburg, Daniel J, Schuster, Stephen J, Svoboda, Jakub

المصدر: The Oncologist. 24(7)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Hematology, Rare Diseases, Clinical Research, Cancer, Lymphoma, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Adrenal Cortex Hormones, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, Drug-Related Side Effects and Adverse Reactions, Female, Follow-Up Studies, Hodgkin Disease, Humans, Male, Middle Aged, Nivolumab, Prognosis, Programmed Cell Death 1 Receptor, Retrospective Studies, Survival Rate, Young Adult, Hodgkin lymphoma, Immunotherapy, PD-1 inhibitor, Real-world, Checkpoint inhibitor, PD‐1 inhibitor, Real‐world, Oncology & Carcinogenesis, Oncology and carcinogenesis

الوصف: BACKGROUND:Although classical Hodgkin lymphoma (cHL) is highly curable, 20%-30% of patients will not be cured with conventional treatments. The programmed death-1 (PD-1) inhibitors (PD-1i) nivolumab and pembrolizumab have been Food and Drug Administration-approved for relapsed/refractory (R/R) cHL. There is limited data on the real-world experience with PD-1i in cHL and it is unknown whether fewer selected patients treated with PD-1i derive benefits similar to those observed in published trials. MATERIALS AND METHODS:We performed a multicenter, retrospective analysis of R/R cHL patients treated with PD-1i in the nontrial setting. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) in this population. Secondary objectives were to characterize response rates, toxicities, discontinuation patterns, and post-PD-1i therapies. RESULTS:The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses. CONCLUSION:To our knowledge, this analysis is the first describing real-world experience with PD-1i in cHL patients in the U.S. Here, we demonstrate similar response rates compared to prior studies. The toxicity profile of PD-1i was similar to that seen in previous studies; we further describe toxicity patterns in those with prior autoimmune disease or allogeneic transplant. Post-PD-1i systemic therapies appear active. These results support the effectiveness and tolerability of PD-1i therapy in R/R cHL in a real-world setting. IMPLICATIONS FOR PRACTICE:Two PD-1 inhibitors have recently been approved for patients with relapsed/refractory classical Hodgkin lymphoma based on results from nonrandomized clinical trials. However, to date, there have been no studies evaluating the effectiveness and toxicity profile of these drugs in the real-world setting in the U.S. The present study demonstrates that patients treated in a real-world context experience similar rates of overall effectiveness compared with published clinical trials. Patients who discontinue PD-1 inhibitors may experience clinical responses to subsequent treatment with systemic chemotherapy or targeted therapy. This study provides clinicians with further insight into the effectiveness and tolerability of PD-1 inhibitors and suggests that when patients progress while on these drugs, conventional systemic chemotherapy may be an effective treatment option.

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المؤلفون: Moin, Abu Saleh Md, Butler, Peter C, Butler, Alexandra E

المصدر: The Journal of clinical endocrinology and metabolism. 102(1)

مصطلحات موضوعية: Islets of Langerhans, Pancreas, Exocrine, Pancreatic Ducts, Stem Cells, Humans, Diabetes Mellitus, Type 1, Prognosis, Case-Control Studies, Follow-Up Studies, Regeneration, Cell Proliferation, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Child, Child, Preschool, Female, Male, Young Adult, Biomarkers, Pancreas, Exocrine, Diabetes Mellitus, Type 1, and over, Preschool, Endocrinology & Metabolism, Clinical Sciences, Paediatrics and Reproductive Medicine

الوصف: ContextPancreatic duct glands (PDGs) have been proposed as a source of regeneration in response to exocrine pancreas injury, and thus may serve as an organ stem cell niche. There is evidence to suggest ongoing β-cell formation in longstanding type 1 diabetes (T1D), but the source is unknown.ObjectiveTo investigate the PDG compartment of the pancreas in humans with T1D for evidence of an active regenerative signature (presence of progenitor cells and increased proliferation) and, in particular, as a potential source of β-cells.Design, setting, and participantsPancreases from 46 brain dead organ donors (22 with T1D, 24 nondiabetic controls) were investigated for activation (increased proliferation) and markers of pancreatic exocrine and endocrine progenitors.ResultsPDG cell replication was increased in T1D (6.3% ± 1.6% vs 0.6% ± 0.1%, P < 0.001, T1D vs nondiabetic), most prominently in association with pancreatic inflammation. There were increased progenitor-like cells in PDGs of T1D, but predominantly with an exocrine fate.ConclusionThe PDG compartment is activated in T1D consistent with a response to ongoing inflammation, and via resulting ductal hyperplasia may contribute to local obstructive pancreatitis and eventual pancreatic atrophy characteristic of T1D. However, there is no evidence of effective endocrine cell formation from PDGs.

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