bluuebunny/crossref_metadata_2025_split huggingface dataset:
Camrelizumab in advanced or metastatic solid tumor patients with microsatellite instability–high/mismatch repair-deficient: Results from an open-label exploratory study.
Authors: Chen Jingde , Quan Ming , Chen Zhiqin , Zeng Tianmei , Li Yandong , Zhou Ying , Hai Yanan , Gao Yong 
Published: May 2020

e15140 Background: PD-1 checkpoint inhibitor has been shown a significant effect in patients (pts) with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumor. Herein, we assessed the efficacy and safety of camrelizumab, a PD-1 checkpoint inhibitor, in advanced or metastatic solid tumor pts with MSI-H/dMMR. Methods: Pts with MSI-H/dMMR solid tumor who had received at least one line of prior systemic chemotherapy were recruited in this single-arm exploratory study. Pts received camrelizumab (200mg, ivd, D1/2W) until disease progression or intolerable toxicity. Response was assessed every 8 weeks. The primary endpoint was objective response rate (ORR) according to RECIST v1.1 criteria. This study was registered at Chinese Clinical Trial Registry, ChiCTR-OIC-17013249. Results: From November 2017 to February 27, 2019, 12 eligible pts were recruited, which covered 9 cancer types. The median age was 58 (range 27-72) years; male/female was 58.3/41.7%. 11 pts were confirmed as MSI-H status, and 1 patient as d-MMR status. All pts were included in efficacy and safety analysis. 2 pts achieved complete response (CR), 6 pts partial response (PR), 4 pts stable disease (SD), yielding the ORR of 66.7% (95% CI: 34.9-90.1), and the disease control rate of 100% (95% CI 73.5-100) at best. What’s more, cancer types of CR pts covered rectal cancer and bladder cancer (1 patient each); PR pts included colon cancer, liver cancer, endometrial cancer, ureteric cancer, intrahepatic cholangiocarcinoma, and small intestine cancer (1 patient each); SD pts contained 3 colon cancer pts and 1 retroperitoneal leiomyosarcoma patient. The overall incidence of adverse incidences (AEs) was 100%. The incidence of Grade ≥3 AEs was 58.3%, which mainly included anemia (16.7%), increased γ-transglutaminase (16.7%), increased alkaline phosphatase (16.7%), increased blood bilirubin (16.7%). As of Oct 30, 2019, 11 pts were still on study medication. Conclusions: Camrelizumab resulted in encouraging objective response and tolerable toxicity in MSI-H/dMMR advanced or metastatic solid tumor. The survival benefits will be further observed. Clinical trial information: ChiCTR-OIC-17013249 .
Hyperprogression on immune checkpoint inhibitors: A single institution, real-world retrospective analysis.
Authors: Paydary Koosha , Moturi Krishna Rekha , Baral Binav , Farooq Muhammad Zain , Lad Thomas E. , Mangla Ankit 
Published: May 2020

e15143 Background: Hyper progressive disease (HPD) refers to the paradoxical acceleration of tumor growth following immune-checkpoint inhibitor (ICI) therapy. We aimed to evaluate the factors associated with HPD and its impact on overall survival (OS) in patients treated with ICI in our institution. Methods: We retrospectively reviewed the charts of 104 patients with solid tumors diagnosed from 04/01/2011 to 06/30/2018 who received ICI at John H. Stroger Jr. Hospital of Cook County, Chicago, IL. The OS, incidence of HPD and their demographic, clinical and laboratory correlates were recorded. HPD was defined as tumor growth ratio > = 2 on CT imaging after treatment with at least 2 cycles. The Log-rank method survival analysis was done to compare survival of patients with and without HPD. Results: Majority of patients were treated with either nivolumab (71.1%) or pembrolizumab (21.2%) in the second (50%) or third line (29.8%) setting. After excluding two patients without follow up scans, 14 out of 102 patients (13.7%) had HPD during the course of study. The patients with small cell lung cancer had higher incidence of HPD (4 out of 9). Patients who had evidence of HPD had significantly shorter OS (22.21±16.23 months versus 37.52±230.8 months, P value = 0.01). The variables associated with HPD were liver metastasis (Pearson Chi squared = 18.68, P value < 0.001) and persistently high LDH ( > 240 IU/L) during therapy (Pearson Chi squared = 16.85, P value < 0.001). Other variables that were significantly associated with HPD on univariate analysis, but not on multivariate analysis are as below. Conclusions: Although the etiopathogenesis of HPD is incompletely understood, the correlation of LDH to HPD is intriguing and warrants further studies as possible predictive marker of HPD. [Table: see text]
Hypocalcemia with immune checkpoint inhibitors: The disparity among various reports.
Authors: nalluru swarna sri , Piranavan Paramarajan , Ning Ying , Ackula Haritha , Siddiqui Ahmad Daniyal , Trivedi Nitin 
Published: May 2020

e15153 Background: Immune-related adverse events affecting parathyroid function are rarely reported with immune checkpoint inhibitors (ICPI). Activating calcium-sensing receptor antibodies causing autoimmune hypoparathyroidism with nivolumab was recently published by Piranavan et al. KEYNOTE-189 and CHECKMATE-067 trials reported a 21-29% hypocalcemia event rate. The purpose of our study is to identify the hypocalcemia incidence in patients receiving ICPI at a single institution with multiple sites. Also, we aimed to investigate hypoparathyroidism as the etiology in these patients, if hypocalcemia was detected. Methods: A chart review to study patients receiving ICPI from 2015 to 2018 at multiple sites affiliated with Saint Vincent Hospital. The study population was divided into two groups based on the presence or absence of calcium altering conditions or medications. True hypocalcemia incidence was calculated after correcting calcium for albumin from the initiation of ICPI to their last follow-up. Results: Group 1 (N = 83) includes patients with no calcium altering conditions or medications. Group 2 (N = 98) includes patients on calcium supplements (N = 17), vitamin D (N = 44), bisphosphonates (N = 24), > stage IIIB CKD (N = 5), and bone metastasis (N = 38). Hypocalcemia events in Group 1 vs. Group 2 were 8.4% and 19.3%, respectively. Our entire study demonstrated 26.8% vs. 1.1% of Grade I vs. II hypocalcemia events. However, after correcting the calcium for albumin, hypocalcemia incidence was 0.56% (N = 1). No further workup was done to investigate the etiology as that patient passed away. Conclusions: Our data suggest that the true hypocalcemia incidence after using albumin-corrected calcium values is very low in patients receiving IPCI, even in the presence of calcium altering factors. The percentage of patients with hypocalcemia is much higher and similar to the KEYNOTE-189 and CHECKMATE-067 trials when serum calcium values without albumin correction are used. Thus, the higher reported incidence of hypocalcemia in these trials is likely due to the reporting of serum calcium without albumin correction.
Awareness of immune-related adverse events among medical residents in a community hospital.
Authors: Kulkarni Ajinkya , Kulkarni Mrunal , Edlukudige Keshava Vinay , Ellangovan Rithikaa , Thirumaran Rajesh 
Published: May 2020

e15154 Background: Immunotherapy has paved the way for new frontiers in the management of certain advanced cancers. Immune checkpoint inhibitors (ICI) have substantially improved prognosis in patients with advanced malignancy. Primary targets for ICIs include programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1) and Cytotoxic T-lymphocyte-associated antigen 4(CTLA-4). These treatments have a wide range of adverse effects distinct from traditional chemotherapy regimens. We conducted a survey to assess the awareness of immune-related adverse events (IRAE) among medical residents in a community hospital. Methods: Internal medicine residents in a community hospital were given a survey of 10 questions related to IRAEs. A total of 40 responses were collected and analyzed. Results: 22.50% respondents were aware that nephrotoxicity is not a common side effect of immunotherapy. 35% were aware that cutaneous toxicities are the most common IRAEs. 42.50% were aware that hair loss is not a common side effect of ICIs. 42.50% were aware that patients do not need pretreatment with anti-emetics before immunotherapy. 45% were aware that the onset of hepatotoxicity is usually not seen within the first week of starting immunotherapy. 50% were aware that immunotherapy is associated with the development of pneumonitis. 62.5% were aware that steroids formed mainstay of treatment in IRAEs. 65% were aware that immunotherapy is associated with thyroid-related side effects. 67.5% were aware that patients with pre-existing autoimmune conditions are at greater risk for immune-related adverse effects. 70% were aware that immune related colitis was not treated with antibiotics. Conclusions: With the rapid advancement and use of immunotherapy the incidence of IRAEs is increasing. Involvement of single or multiple organ systems as well as flare of previously well controlled autoimmune disease can add to the challenge. As we gain more experience, long term data will emerge to help predict at-risk patients. This is a dynamic area of research and new treatments are under development. 6/10 questions were answered correctly by less than 50% respondents and 4/10 were answered correctly by 50-70% respondents. At present no data is available to gauge awareness regarding IRAEs among internists. Our survey suggests a lack of awareness among medical residents on many fronts. Lack of awareness leads to inappropriate treatment and prolonged hospital stay. Active efforts need to be taken to educate residents regarding immunotherapy and IRAEs to achieve better patient outcomes.
Predictors of immune-related adverse events associated with checkpoint inhibitors.
Authors: Alsayed Alhareth , Manne Ashish , Escobar Daisy E , Sharma Gaurav , Prodduturvar Pranitha , Alkharabsheh Omar 
Published: May 2020

e15159 Background: Immune-related adverse events (irAE) remain a significant challenge with the expansion of checkpoint inhibitors (ICI) indications. Unlike previous studies published, we investigated risk factors for irAE development, including lymphocytes and neutrophils counts in lung cancer and melanoma treated with all available ICIs in current clinical practice. Methods: This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute. Between 2015-2019. A total of 160 patients with a diagnosis of melanoma (N = 54) or lung cancer (N = 106) who received at least two doses of ICI including ipilimumab (15%), nivolumab (32%), pembrolizumab (35%), dual nivolumab/ipilimumab (5%), durvalumab (9%) and atezolizumab (4%). The patient's baseline characteristics were extracted with irAE (grade 3/4) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, and Wilcoxon rank sum test for continuous variables using JMP software. Results: The median age at diagnosis was 64 years (range 17-93), with 51% females. Race distribution with 76% Caucasians and 26% African Americans. Around 30% of the cohort was treated for recurrence, and 39% did receive prior systemic chemotherapy. Median overall survival (OS) was 13.5 months (m) for melanoma and 16 m for lung cancer with CI 95% [16-24] and [15-23], respectively. Twenty-nine (29%) percent of the cohort (N = 46) had grade 3/4 irAEs. Median of baseline hematological parameters including total white blood count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC ratio, and platelet to ALC ratio of these patients were not statistically different from the cohort without grade 3/4 irAEs. Interestingly, if a patient has baseline ALC < 1K/μL, the risk of irAE recurrence is low when ICI is re-initiated, p = .0143 (after symptomatic recovery from irAEs). Conclusions: Irrespective of ICI used, baseline lymphocyte count, and its relation to other blood counts have no clear impact on irAE. Larger cohorts or prospective studies are needed to make stronger conclusions about the relationship between the immune system and the occurrence of irAEs
PD-1 inhibitor combined with radiotherapy and GM-CSF as salvage therapy in patients with chemotherapy-refractory metastatic solid tumors.
Authors: Kong Yuehong , Zhao Xiangrong , Zou Li , Xing Pengfei , Ma Yifu , Tian Ye , Zhang Liyuan 
Published: May 2020

e15173 Background: Patients with refractory metastatic solid tumors have poor prognoses and few therapeutic options. The application of PD-1 inhibitor has led to a paradigm shift in the treatment of advanced cancer, but its efficacy as a monotherapy is limited. Previous evidence has shown that the anti-tumor effects might be reinforced when PD-1 inhibitor combines with radiotherapy or granulocyte macrophage-colony stimulating factor (GM-CSF). An exploratory study was conducted to assess the clinical efficacy and safety of PD-1 inhibitor combined with radiotherapy and GM-CSF (PRaG regimen) for the treatment of refractory patients. Methods: Participants had multimetastatic solid tumors progressing beyond at least first-line chemotherapy.They were treated with hyperfractionated radiotherapy (3 doses of 8Gy or 5 doses of 5Gy) for each metastatic site. On the second day after radiotherapy, PD-1 inhibitor 200 mg once was intravenously administered and GM-CSF 200 µg daily was subcutaneously injected for 2 weeks. This course was repeated every 3 weeks, targeting a second metastatic site. Triple-combination therapy. (PRaG regimen) was given for at least 2 cycles. After combination therapy, maintenance with PD-1 inhibitor was administered until disease progression or unacceptable toxicity. The main outcome measures included safety, toxicity, progression-free survival (PFS) and objective response rate (ORR) after three cycles of treatment. Results: A total of 16 patients were enrolled.The median number of metastatic lesions was 7.5(95%CI, 5.3 to 19.5) and the median sum of the longest diameter of all measurable lesions was 161.7mm (95%CI, 104.1 to 279.3mm).All patients completed two cycles or more of triple-combination therapy. The ORR was 20% and the median PFS was 3.3 months (95%CI, 2.3to 7.2months) at the time of evaluation. Treatment-related adverse events of any grade occurred in 13 (81%) patients, and grade 3 and higher adverse event like pneumonitis occurred in 2 (11.0%) patients. Conclusions: The PRaG regimen is well tolerated with acceptable toxicity. For patients with resistant metastatic solid tumors, low efficacy and high cytotoxicity are commonly observed in conventional therapy. With the new chemo-free PRaG regimen, myelosuppression was not observed and gastrointestinal side effects remained low. So, PRaG regimen is considered as a promising salvage treatment for patients with chemotherapy-refractory metastatic solid tumor. The suggested mechanism might involve radiosensitization of immunotherapy. Clinical trial information: ChiCTR1900020175 .
Robust prediction of immune checkpoint inhibition therapy for non-small cell lung cancer.
Authors: Zhang Yiqun , Zhao Guodong , He Ning , Wang Lingyu , Wang Jianfei , Jin Ge , Lin Rongbo , Yang Yadong 
Published: May 2020

e15192 Background: Immune checkpoint inhibition (ICI) has been validated and applied in advanced lung cancer patients. However Oonly part of patients response to ICI, thus optimizing ICI would be emergent. Based on public non-small cell lung cancer (NSCLC) cohorts’ data, we expected to build a multivariable model which would improve the efficacy of predicting ICIs response. Methods: 2 NSCLC and 1 pan-cancer cohorts treated with ICIs were collected from cBioPortal (luad_mskcc_2015, n = 203; nsclc_pd1_msk_2018, n = 33; tmb_mskcc_2018, n = 1661, pan-cancer). Another NSCLC cohort (cancer_cell_2018) was collected from MD. Hellmann’s study (Cancer Cell, 2018, n = 75). We incorporated features including tumor mutation burden (TMB), PD-L1 expression, Mutant-Allele Tumor Heterogeneity (MATH), and mutational status of cancer-related pathways. And we used Bayesian Regularization for Feed-Forward Neural Networks ( brnn) method to fit models of predicting clinical response. Results: The correlation analysis showed that MATH was independent of TMB (R = 0.141, p = 0.01252) and PD-L1 expression (p = 0.432, ANOVA test among high, median and low PD-L1 expression group) in 3 merged NSCLC cohorts. We randomly selected 70% of cancer_cell_2018 cohort as training set, and the AUC improved from 0.5702/0.5191/0.6728 to 0.6893/0.527/0.8554 (in cancer_cell_2018 validation set, luad_mskcc_2015, and nsclc_pd1_msk_2018 cohort, respectively) after incorporating MATH to TMB + PD-L1 model. Additionally, we identified that mutational status of DDR, HRR, MAPK, Wnt, JAK, PI3K, and NFKB pathway was significantly associated with overall survival in tmb_mskcc_2018 cohort. After incorporating the mutation status of these pathways, the model exhibited further improvement in prediction efficacy (AUC reached 0.8595/0.5634/0.7831). When using luad_mskcc_2015 cohort as training set, the model performance improvement was also observed after joining pathway mutation information into TMB + PD-L1 + MATH model (AUC improved from 0.5742/0.6339 to 0.7305/0.7 in predicting luad_mskcc_2015 and cancer_cell_2018 cohort). Conclusions: We built a multivariable model with robust performance in predicting ICI response in independent NSCLC cohorts. With the accumulation of larger datasets, further studies are warranted to refine the predictive performance of the approach.
CD8A and HAPLN3 expression profiling to reveal an immunologic subtype of bladder cancer with favorable survival.
Authors: Ma Jingjiao , He Ning , Wang Jianfei , Wang Lingyu , Jin Ge , Lin Rongbo , Yang Yadong 
Published: May 2020

e15193 Background: At present, immune checkpoint inhibitors (ICI) have demonstrated robust anti-tumor activity with a favorable safety in bladder cancer (BLCA). However, less than half of BLCA patients respond to immunotherapy. We aimed to further delineate the immunologic subtype of BLCA to pick patients who might benefit from ICI treatment. Methods: The RNA-seq and clinical data were collected from The Cancer Genome Atlas (TCGA) data portal (n = 408) and Gene Expression Omnibus (GEO) (GSE48075, n = 142; GSE32894, n = 308). TCGA and GSE48075 cohort are the discovery datasets, and GSE32894 cohort is used for validation. According to the expression of every specific gene ( Gi), patients were divided into two groups using median FPKM as cutpoint value, namely Gi_high and Gi_low, respectively. Combined with CD8A expression, all the patients were divided to four groups as follows: CD8A_high/ Gi_high, CD8A_high/ Gi_low, CD8A_low/ Gi_high, and CD8A_low/ Gi_low. Then we calculated the pearson correlation coefficients between Gi and 13 immune checkpoint genes ( CD274, IDO1, CTLA4, LAG3, CD276, VTCN1, CD70, HAVCR2, CD40, CD47, TNFRSF18, TIGIT, and TNFSF14). Overall or disease free survival of the four groups were compared using the survfit function from the survival R package and P values from log-rank tests were reported. Results: In the discovery cohort, we found CD8A_high/ HAPLN3_low group showed the best overall survival, whereas the CD8A_low/ HAPLN3_high showed the worst (TCGA, p = 0.013; GSE48075, p = 0.012). Additionally, HAPLN3 was positively correlated with 5/13 immune-checkpoint genes: CD274, IDO1, CTLA4, LAG3, HAVCR2 (r > 0.6, p < 0.01). And the same observations were extended in the validation cohort (GSE32894): CD8A_high/ HAPLN3_low group exhibited a favorable survival (p = 0.00059), and HAPLN3 had a strong correlation with the same 5 immune-checkpoint genes (r > 0.6, p < 0.01). Conclusions: The combination of high CD8A and low HAPLN3 expression identified a subtype of BLCA patients with favorable survival and these findings may further help refining the selection of BLCA patients for immunotherapy.
RNA pathway enrichment in serum-based mass spectroscopy prognostic analyses.
Authors: German Benjamin D , Borgia Jeffrey Allen , Naqib Ankur D , Bonomi Philip D. , Batus Marta , Basu Sanjib , Fidler Mary J. 
Published: May 2020

e15197 Background: Veristrat(VS) good and poor labels were found to be prognostic in the front-line NSCLC setting with or without immune checkpoint inhibitors. Little is known about RNA expression data corresponding to these good and poor prognostic labels. Methods: Raw RNA seq expression data was obtained from TEMPUS XP RNA analysis. Sequences were filtered for allowing only genes that had an overall count of at least 20 across all samples. Samples were then processed through the EdgeR analysis in the R programming environment. Along with a Z-scored heatmap, PCA plot was also generated. Differential abundance analysis was done further filter out the genes. Benjamini-Hochberg correction was done and only genes with corrected p-value of < 0.05 were selected for further pathway analysis. 242 genes with corrected p-value < 0.05 were used. Pathway analysis was performed using the Broad Institute GSEA (Gene Set Enrichment Analysis) and DAVID (Database for Annotation, Visualization and Integrated Discovery). The gene list was ran using KEGG database in GSEA and using KEGG, BioCarta and Reactome pathway databases. Functional analyses against the KEGG and REACTOME database were reported out to determine the enriched pathways in the VS poor and VS good groups. Kaplan-Meier and Logrank were used to compare overall survival in the poor vs. good label cohorts of patients. Results: 26 patients had VS label and RNA expression data available. Nine patients had VS poor label and 17 had veristrat good label. 6(66%) VS poor 13(76%) VS good patients received anti PD1 agents during the course of their therapy. Overall survival was not significantly different between good and poor label groups in this small series. 242 genes had significantly different abundance in the VS poor vs good patients with the majority (211) over expressed in the poor label patients. Significant pathways enriched in the VS poor group included the intrinsic pathway of fibrin clot formation, platelet degranulation (DAVID), steroid hormone biosynthesis and dilated cardiomyopathy (KEGG). Systemic lupus erythematous pathway was enriched in the VS good group (KEGG). Conclusions: In this small set of front-line patients with RNA pathway analyses and known VS poor or good labels, differential expression of acute phase reactants was found in VS poor patients. DAVID and KEGG pathways were differentially enriched and may reveal potential targets to mitigate prognosis in poor risk NSCLC.