bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab/ipilimumab primed immunotransplant in post-CAR-T and post-ASCT DLBCL.
Authors: Fitzgerald Bailey Gleason , Marron Thomas Urban , Ostrowski Dana , Shulman Jonah , Kalac Matko , Marshall Netonia , Brody Joshua 
Published: June 2021

2593 Background: Patients with refractory diffuse large b cell lymphoma (DLBCL) have poor outcomes with < 30% surviving for 12 months and especially poor outcomes for those who progress after chimeric antigen receptor T cells (CAR-T) or autologous stem cell transplant (ASCT). These therapies utilize lymphodepleting chemotherapy which induces homeostatic T cell proliferation. We have demonstrated these expanding T cells express high levels of PD1 and CTLA4. In pre-clinical models, addition of dual checkpoint blockade (DCB) with anti-PD1/anti-CTLA-4 to adoptive T cell transfer after lymphodepletion achieved a synergistic anti-tumor effect. Based on these studies, we developed a phase Ib/II study of Nivolumab/Ipilimumab primed “immunotransplant” for relapsed/refractory (R/R) DLBCL (NCT03305445). Methods: Phase Ib of the trial enrolled 6 patients with progressive disease following at least one line of standard therapy. Patients received two cycles of DCB with ipilimumab (1mg/kg) and nivolumab (3mg/kg) given at three-week intervals followed by immunotransplant (i.e. peripheral blood T cell harvest, lymphodepletion with fludarabine/cyclophosphamide, T cell reinfusion), followed by two further cycles of DCB and nivolumab maintenance. Results: Five patients received at least two cycles of DCB and the autologous T cell transfer, while one patient had progressive disease during initial DCB and required salvage chemotherapy. Treatment emergent AE (TEAE) occurred in 100% of patients. As expected with lymphodepleting chemotherapy, the most common TEAE were neutropenia (66.7% grade 1, 66.7% grade ≥ 3), fatigue (83.3%, 16.7%), fever (66.7%, 0%), and dyspnea (66.7%, 0.0%). One patient (16.7%) died during the intervention period (grade 5 TEAE), though relation to study drug is unclear. Three patients (50.0%) experienced clinical benefit with immunotransplant. One patient (a 58yo M with progression after seven lines of therapy including ASCT and CAR-T) is experiencing partial metabolic response after 4 months on protocol. One 77yo F with multiple prior lines of therapy including ASCT has experienced an extended complete metabolic response, currently 31 months post immunotransplant. A third (a 50yo F) experienced mixed radiographic response, and has not received subsequent therapy 30 months following immunotransplant. Conclusions: Nivolumab/Ipilimumab primed immunotransplant is well tolerated in patients with R/R DLBCL for whom there are few treatment options. Preliminary results demonstrate remissions in heavily pre-treated patients, including prior ASCT and CAR-T. Pre-clinical models in melanoma, non-small cell lung cancer, and T cell lymphoma all demonstrate synergy when DCB is administered with lymphodepletion and autologous T cell transfer. These data support further investigation of DCB-primed immunotransplant. Clinical trial information: NCT03305445.
MSIFinder: A python package for detecting MSI status using random forest classifier.
Authors: Zhou Tao , Chen Libin , Guo Jing , Zhang Mengmeng , Liu Huanhuan , Zhang Yanrui , Wang Huina , Cao Shanbo , Wang Haijun , Lou Feng 
Published: June 2021

2601 Background: Microsatellite instability (MSI) is a common genomic alteration in several tumors, such as colorectal cancer, endometrial carcinoma, and stomach, which is characterized as microsatellite instability-high (MSI-H) and microsatellite stable (MSS) based on a high degree of polymorphism in microsatellite lengths. MSI is a predictive biomarker for immunotherapy efficacy in advanced/metastatic solid tumors, especially in colorectal cancer (CRC) patients. Several computational approaches based on target panel sequencing data have been used to detect MSI; However, they are considerably affected by the sequencing depth and panel size. Methods: We developed MSIFinder, a python package for automatic MSI classification, using random forest classifier (RFC)-based genome sequencing, which is a machine learning technology. We included 19 MSI-H and 25 MSS samples as training sets. First, RFC model were built by 54 feature markers from the training sets. Second. The software was validated the classifier using a test set comprising 21 MSI-H and 379 MSS samples. Results: With this test set, MSIFinder achieved a sensitivity (recall) of 0.997, a specificity of 1, an accuracy of 0.998, a positive predictive value (PPV) of 0.954, an F1 score of 0.977, and an area under curve (AUC) of 0.999. We discovered that MSIFinder is less affected by low sequencing depth and can achieve a concordance of 0.993, while exhibiting a sequencing depth of 100×. Furthermore, we realized that MSIFinder is less affected by the panel size and can achieve a concordance of 0.99 when the panel size is 0.5 m (million base). Conclusions: These results indicated that MSIFinder is a robust MSI classification tool and not affected by the panel size and sequencing depth. Furthermore, MSIFinder can provide reliable MSI detection for scientific and clinical purposes.[Table: see text]
YAP1 mutation as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers.
Authors: Xu Wei-guo , Zhu Jing , Li Lin , Chen Dongsheng , Zhang Qin , Duan Qianqian , Li Si , Xiao Mingzhe 
Published: June 2021

2604 Background: YAP1 is the main downstream target of the Hippo pathway and acts as a transcriptional coactivator to regulate development processes. YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored in nonsurgical esophageal squamous cell carcinoma (ESCC). YAP1 overexpression has been identified in multiple solid cancers, which consistently correlated with unfavorable clinical outcomes. Previous work suggested that YAP1 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of these findings in needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients, and the public database of TACG was also compared. Data from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of YAP1 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 0.62 % (22 in 3547). Meanwhile, the frequency of YAP1 mutation in TCGA cohort was 0.90 % (99 in 10953). We further analyzed Kaplan-Meier curves from MSK-IMPACT study (n = 1661, anti-PD-(L)1/CTLA-4 mono/ combined therapy). In MSK-IMPACT cohort, mutation of YAP1 was associated with higher TMB (P = 0.022) and higher mutation count (P = 0.017) in pan-cancers. YAP1 mutation was associated with prolonged overall survival (OS) trend compared with YAP1 wt in pan-cancers (P = 0.15; HR, 2.209, 95% CI, 0.7109-6.8639). Conclusions: In our study, the frequency of YAP1 mutation was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. YAP1 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in pan-cancers via upregulating TMB and mutation count.
Investigating the various predictive values of POLE/POLD1 mutations for response to immune checkpoint inhibitors (ICIs) in different solid tumors.
Authors: Niu Yanling , Ma Tonghui , Niu Yanling , Li Tao 
Published: June 2021

2606 Background: Both POLE and POLD1 encode the catalytic subunit of polymerase enzyme complexes involved in DNA replication and repair. The mutations of POLE and POLD1 have been shown to be oncogenic and lead to DNA repair defects and elevated tumor mutation burden (TMB). And patients with POLE/POLD1 mutations are more likely to benefit from ICIs therapy. Previous studies have shown that TMB has divergent predictive value for response to ICIs therapy in different cancer types. We hypothesized that the associations between POLE/POLD1 mutations and ICIs efficacy are also varied in different solid tumors. Therefore, we explored the prediction values of POLE/POLD1 mutations in some cancer types. Methods: The ICIs treatment cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of POLE/POLD1 mutations with ICIs efficacy. TCGA cohort was enrolled for characterizing tumor infiltrating lymphocytes (TILs) with CIBERSORT. The patients were classified into two groups: POLE/POLD1 mutations (Mut) and wildtype (WT). Overall survival (OS) after ICIs therapy was estimated with Kaplan-Meier method. Results: In MSKCC pan-cancer dataset, patients with POLE/ POLD1 mutations had significantly longer median OS after ICIs therapy (34.00 vs 19.00 months, P = 0.0143), indicating that POLE/POLD1 mutations were associated with better immunotherapy outcomes. Then we analyzed the predictive roles in each cancer type. Notably, we found the associations of POLE/POLD1 mutations with longer median OS in NSCLC (Undefined vs 12.00 months, P = 0.05) and esophagogastric cancer (27.00 vs 15.00 months, P = 0.05). However, the associations between POLE/POLD1 mutations and ICIs efficacy were not observed in bladder cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, and colorectal cancer. Furthermore, our data showed that the median TMB was significantly higher in the Mut group for NSCLC (20.2 vs 6.9 muts/Mb, P < 0.0001) and esophagogastric cancer (21.4 vs 5.6 muts/Mb, P < 0.0001). In TCGA esophagogastric cancer cohort, POLE/POLD1 mutations were correlated with decreased naive B cells (P = 0.0306) and increased activated memory CD4+ T cells (P = 0.0224). In TCGA NSCLC cohort, POLE/POLD1 mutations were correlated with elevated gamma delta T cells (P = 0.0219). These data suggested that POLE/POLD1 mutations were also involved in the infiltration of some immune cells. Conclusions: Although POLE/POLD1 mutations were associated with better ICIs efficacy for all the enrolled patients, the prolonged OS was only found in the Mut group for NSCLC and esophagogastric. These data suggested that POLE/POLD1 mutations may be a useful predictor for ICIs efficacy in these two types of cancer. Moreover, POLE/POLD1 mutations were correlated with the level of TILs in NSCLC and esophagogastric. The finding was consistent with the efficacy of immunotherapy.
Proton pump inhibitor use (PPI) in patients treated with immune checkpoint inhibitors (ICI) for advanced cancer: Survival and prior therapy.
Authors: Husain Marium , Xu Menglin , Patel Sandipkumar , Johns Andrew , Grogan Madison , Li Mingjia , Lopez Gabrielle , Miah Abdul , Hoyd Rebecca , Liu YunZhou , Muniak Mitchell , Haddad Tyler , Tinoco Gabriel , Kendra Kari Lynn , Otterson Gregory Alan , Presley Carolyn J , Spakowicz Daniel , Owen Dwight Hall 
Published: June 2021

2633 Background: Emerging data suggest that concomitant medications (CM) influence response to ICI. CM impact the host microbiome which may mitigate tumor-immune responsiveness. PPI use in patients treated with ICI has been associated with worse survival. Few data exist regarding the effects of PPI use in terms of prior chemotherapy or in risk for immune related adverse events (irAE) (e.g., colitis). Methods: This retrospective study of patients with advanced cancer treated with ICI between 2011 and 2019 was conducted at The Ohio State University. Patients who received ICI as either single agent or combination were included. Clinical data was abstracted from chart review, including CM, toxicity, and survival. Overall survival (OS) was evaluated to date of death or last contact. Associations between OS and proton pump inhibitor (PPI) use were studied using log-rank tests and Cox regression analyses overall and by the groups of whether prior chemotherapy was administered and timing from chemotherapy to ICI. The associations between PPI and incidence of irAE (overall and colitis) were assessed by chi-square tests. Results: We identified 1,091 patients treated with ICI, of whom 415 (38%) received PPI at time of ICI. Most common cancers were NSCLC and melanoma; most common therapy was PD1/L1 (Table). PPI use was associated with shorter OS in patients treated as first line therapy (HR = 1.46, 95% CI = [1.11, 1.91], p=0.006) and in second line and beyond (HR = 1.30, 95% CI = [1.10, 1.53], p=0.002). PPI use was associated with shorter OS in patients treated with ICI for those without prior chemotherapy (HR = 1.47, 95% CI = [1.17, 1.86], p=0.001). When evaluated by timing from chemotherapy to ICI, PPI use was associated with shorter OS only in patients where last chemotherapy was > 1 year from ICI (HR = 1.99, 95% CI [1.15, 3.45], p=0.014) but not for patients with chemotherapy within 1 year of ICI (HR = 1.01, 95% CI = [0.79, 1.29], p=0.960). The use of PPI was not associated with incidence of irAE (p=0.317) or colitis in particular (p=0.781). Conclusions: PPI use was associated with shorter survival in patients treated with ICI across a broad variety of cancers and in first line of therapy or beyond. In patients with recent chemotherapy (<1 year), PPI use was not associated with survival, which may be due to disruption of the microbiome by chemotherapy. Further study is needed to determine the impact of CM (e.g, PPI), on outcomes of patients treated with ICI.[Table: see text]
Cardiovascular toxicity incidence following immune checkpoint inhibitors in randomized clinical trials: A systematic review and meta-analysis.
Authors: Xavier Camila Bragança , Lopes Carlos Diego Holanda , Harada Guilherme , Katz Artur , Fontes Jardim Denis Leonardo 
Published: June 2021

2636 Background: Immune checkpoint inhibitors (ICIs) are widely used in oncology and may be associated with a variety of immune-related toxicities. Cardiovascular (CV) adverse effects (AEs) are underreported in randomized clinical trials (RCTs), and the real risk associated with ICIs use has yet to be defined. Therefore, we aimed to investigate the incidence and risk of cardiovascular toxicities in patients receiving ICIs, using an up-to-date meta-analysis of prospective RCTs. Methods: We conducted a systematic search of the literature from January 1st, 2010 until July 1st, 2020 to identify RCTs testing ICIs for solid tumors, either in monotherapy or in combination between them. Our initial search yielded a total of 21,249 relevant publications. For CV AEs incidence estimation, we included phase III RCTs testing PD-1, PD-L1, CTLA-4 inhibitors or any combination of these agents. For relative risk (RR) assessment, we included phase II or phase III RCTs testing the same agents and with placebo or best supportive care (BSC) as the comparator. Data were extracted by independent reviewers following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. CV AEs were categorized based on the Common Toxicity Criteria (CTCAE) and stratified by ICIs type. Analyses were conducted using random effects model. Results: After screening and eligibility assessment, a total of 21,118 patients (67 cohorts from 57 trials) were available for this meta-analysis. We categorized the cohorts by ICIs regimen as monotherapy with a PD-1 inhibitor (35 cohorts; 10,241 patients), PD-L1 inhibitor (12 cohorts; 3,755 patients), CTLA-4 inhibitor (11 cohorts; 4,135 patients), and combination therapy (9 cohorts; 2,987 patients). Incidence measures are described in the table. Deaths from any CV cause occurred in 0.20% of the patients (95%CI 0.10%; 0.20%). For RR analysis, we included 12 cohorts from 11 RCTs. Risk of experiencing all grade AEs was numerically higher among patients who received ICIs than placebo or BSC (RR 1.16; 95%CI 0.98; 1.37; p=0.09). When only grade 3-5 CV AEs were considered, ICIs were associated with increased risk (RR 1.36; 95%CI 1.06; 1.73; p= 0.01). Additional analyses were conducted to estimate the RR of individual CV AEs including arrhythmia, cardiac arrest, heart failure, stroke, hypertension, myocardial infarction, myocarditis, pericardial events, and thromboembolic events. None of the analysis identified a significant additional risk. Conclusions: This meta-analysis corroborates the preclinical rationale of worsen CV risk related to ICIs use.[Table: see text]
Pan-Canadian cohort of immune checkpoint inhibitor-induced insulin-dependent diabetes mellitus (CANDIED).
Authors: Pimentel Muniz Thiago , Araujo Daniel Vilarim , Savage Kerry J. , Cheng Tina , Saha Moumita , Song Xinni , Gill Sabrina , Monzon Jose Gerard , Grenier Debjani , Genta Sofia , Spreafico Anna , Hogg David 
Published: June 2021

2640 Background: Endocrine immune-related adverse events (irAEs) are frequent with immune checkpoint inhibitors (ICIs); however, ICI-related insulin-dependent diabetes mellitus (IDDM) is a rare but serious endocrine irAE. We describe the characteristics of patients who developed ICI-related IDDM across five academic Canadian cancer centres. Methods: In this multicentre, retrospective study, we included both patients who developed IDDM and patients with non-IDDM (NIDDM) or pre-DM who became insulin-dependent while on treatment with ICI. We collected data on primary tumor type, ICI regimen (single agent or combination), time to development of IDDM from ICI initiation, comorbidities, laboratory parameters at the time of IDDM diagnosis, tumor response and survival. A p value < 0.05 was considered statistically significant. Results: We identified 27 patients between July 2016 and August 2019. Median age was 60 (39-79) years, 20 (74%) were male, 15 (55%) had melanoma and 4 each (15%) non-small cell lung cancer (NSCLC) and renal cell carcinoma. Seven (26%) patients had prior NIDDM or pre-DM; 5 (18%) had an auto-immune disease (2 psoriasis, 2 inflammatory bowel disease, and 1 systemic lupus erythematosus). Laboratory parameters at presentation and management of IDDM are presented in the Table. Mean A1c was not statistically different between patients with or without prior NIDDM or pre-DM (8.4% vs. 8.6%; p = 0.9). All IDDM events were irreversible; 1 (4%) patient died of diabetic ketoacidosis. At time of IDDM diagnosis, 17 (63%) patients were receiving single agent anti-PD1 and 10 (37%) anti-PD1-based combinations (7 anti-CTLA-4, and 3 other compounds). Median time for development of IDDM from ICI initiation was 2.7 months (95% CI 0.2-5.3). Patients receiving combination ICI developed IDDM earlier than those treated with single agent (1.4 vs 4.8 months; p = 0.05). Amongst patients with metastatic disease (n = 24), 9 (38%) had a complete response and 7 (29%) had a partial response. Two patients (8%) were treated in the adjuvant setting; 1 (4%) received consolidation ICI. IDDM led to ICI discontinuation in 12 (44%) patients. After a median follow up of 21 months from ICI initiation, median survival was 30 months (95% CI NE) and was not reached in patients with melanoma and NSCLC. Conclusions: ICI-related IDDM is a rare and typically irreversible irAE that occurs early in the course of treatment and develops earlier with combination ICI. In this cohort, patients who developed ICI-related IDDM had a high tumor response rate and prolonged survival, especially melanoma and NSCLC patients. Prospective evaluation of autoantibodies to predict development of IDDM is ongoing.[Table: see text]
Pancreatic volumes in immune checkpoint inhibitor-induced diabetes.
Authors: Jeun Rebecca , Yedururi Sireesha , Lavis Victor , Best Conor , Varghese Jeena , Dadu Ramona , Glitza Isabella Claudia , Thosani Sonali 
Published: June 2021

2644 Background: Immune checkpoint inhibitor-mediated insulin dependent diabetes (ICI-DM) is a rare and irreversible adverse event often presenting with life-threatening diabetic ketoacidosis (DKA). Pancreatic volume changes have been studied in classic Type 1 and Type 2 diabetes as a surrogate for functional β-cell mass. In this study, we investigate longitudinal changes in pancreatic volumes in patients who develop ICI-DM. Methods: Among patients with ICI-DM seen at our institution between 2014 and 2020, 20 patients who had serial CT scans of the abdomen and pelvis before and after ICI DM diagnosis were identified for inclusion in this study. Demographic data and clinical variables were obtained from the electronic medical record. Weight-adjusted pancreatic volumes were calculated from CT scans at three time points. The most recent CT scan prior to ICI initiation was used as baseline, the CT scan immediately prior to ICI DM diagnosis was used as a midpoint, and the most recent CT scan prior to the end of the study period was used as the final time point for comparison. Results: Median age was 63 years old (range 35 to 83). Renal cell carcinoma and melanoma were the most common cancer types. Male gender predominated (80%). 18/20 patients were on a PD-1 inhibitor with the remaining two on a PD-L1 inhibitor. After initiation of ICI therapy there was a variable response in pancreatic volumes prior to the diagnosis of ICI-DM with 20% patients experiencing a volume loss of > 10% and 25% experiencing a volume gain of > 10%. Volume loss nor volume gain prior to diabetes diagnosis was associated with presentation with DKA. 9/13 (69%) of patients who had pancreatic enzymes checked at diagnosis of ICI-DM had elevated levels. Pancreatic atrophy with a median volume loss of 41% was seen in all patients at a median of 14.9 months (range 3-77 months) after ICI-DM diagnosis. Most had more than 20% volume loss from baseline to most recent scan with no correlation in degree of volume loss with the time interval. There was no evidence of pancreatic ductal dilation, increased pancreatic fat nor any changes consistent with chronic pancreatitis. Conclusions: This study shows a variable response in pancreatic volumes after initiation of ICI in patients who progress to developing ICI-DM, though most had a significant decline in volume after the diagnosis of ICI-DM with long-term pancreatic atrophy. As β-cell mass is thought to comprise 1-2% of the pancreas, these findings may suggest both endocrine and exocrine compartment changes because of ICI-DM, though exocrine dysfunction has not been clinically described in this patient population. As these patients receive frequent imaging during treatment, fluctuations in pancreatic volumes with new or worsening hyperglycemia may portend the onset of ICI-DM and clinicians should have a low threshold to screen for this diagnosis as many will present with life-threatening DKA.