bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gemcitabine response prediction in the adjuvant treatment of resected pancreatic ductal adenocarcinoma using an AI histopathology platform.
Authors: Krishna Viswesh , Nimgaonkar Vivek , Tiu Ekin , Krishna Vrishab , Bhambhvani Hriday , Cook Stephen , Miller Daniel , Vrabac Damir , Joshi Anirudh , Singhi Aatur D. , Hendifar Andrew Eugene , Rajpurkar Pranav , Collisson Eric Andrew 
Published: June 2022

e16295 Background: Adjuvant chemotherapy improves survival following resection of pancreatic ductal adenocarcinoma (PDAC). A modified fluorouracil/irinotecan/oxaliplatin regimen (mFOLFIRINOX) has demonstrated improved disease free survival and overall survival, though gemcitabine-based monotherapy and gemcitabine plus capecitabine are alternatives in less fit patients. Though there are several proposed biomarkers to guide treatment decisions (GATA6, hENT1, and GemPred), no biomarker is used to guide treatment selection in clinical practice. Consequently, we sought to develop an artificial intelligence-derived signature of features from digital images of routine histopathology specimens that could identify patients susceptible to routine chemotherapeutic agents. Methods: 139 whole-slide digitized histological slides corresponding to 102 resected PDAC tumors from TCGA-PAAD were used in this study. This dataset corresponded to patients that had received either gemcitabine-backbone or 5 FU-backbone chemotherapy as their first-line adjuvant treatment. We extracted nuclei images from tissue regions using segmentation models and computed geometric features of these nuclei which we then correlated with Disease Specific Survival (DSS) in order to construct a signature associated with treatment benefit. This signature was compared against two board certified pathologists using the grade of the digital slides images to classify patients into above or below average DSS buckets. Results: Among quantitative geometric features, a set of area and ellipse features describing nuclei geometry correlated most with response to gemcitabine (R̃0.4). The cox proportional hazards model using these geometric nuclei features was found to be predictive of response to gemcitabine and achieved a C-index (95% CI) of 0.69 (0.58, 0.79). The pathologist-based baseline model for above and below average DSS had a median DSS of 443 and 461 days respectively. Using the average expected lifetime as the threshold, the model divides patients receiving gemcitabine into two histological subtypes with median DSS of 586 and 394 days respectively (p < 0.05). The model appeared specific to gemcitabine. Among patients receiving 5-FU (n = 10) there was no statistical significance in median DSS between the subtypes and a c-index of 0.63 (0.27, 1.0). Conclusions: An artificial intelligence approach utilizing only routine histopathology can identify features that correlate with treatment outcomes in PDAC with classification performance (c-index:0.69) superior to the validated AJCC treatment prediction tool (0.59).
Racial and socioeconomic factors associated with palliative care utilization in pancreatic cancer: An analysis of National Inpatient Sample.
Authors: Hsieh Tien-Chan , Zou Guangchen , Yeo Yee Hui , Zheng Jiayi , Kloss Robert A. 
Published: June 2022

e16296 Background: Palliative care (PC) has been validated as a crucial component in end-of-life quality. Despite the higher PC utilization in cancer patients than other conditions, some studies have raised concern of systemic inequality in PC utilization. PC has a significant role in the care of pancreatic cancer, especially due to the poor prognosis. Here, we investigate the sociodemographic factors associated with the recent trend of PC utilization in pancreatic cancer. Methods: We used the Healthcare Cost and Utilization Project National Inpatient Sample database, all-payer inpatient care database in the United States, with data years 2016-2019. The end-of-life hospitalizations were defined as adult patients (age at least 18 years old) who were hospitalized at least three days and passed away. The cases were identified with International Classification of Diseases (ICD) 10th edition for pancreatic cancer (C25.0-25.9) within the top three diagnoses. Prevalence of PC consultation could be estimated with the billable code Z51.5. The factors that were statistically associated with PC utilization in univariable analysis would be included in the final multivariable logistic regression model. Charlson Comorbidity Index was used to adjust for comorbidities. Hospital factors such as size and base (rural, urban, urban teaching) were included in the analysis. Results: Among 339,318 adult patients who were hospitalized at least three days and passed away, 2,011 cases had pancreatic cancer within top three diagnosis codes. 1576 (78.4%) patients were at least age 60 or above. 1,275 (63.4%) of them had PC consult at their end-of-life. There was a significant yearly trend of increasing PC utilization (Cochran-Armitage test p-value < 0.05). Male, African American, lower income, and rural area were significantly associated with less PC consult in multivariable regression model. The adjusted odds ratio (aOR) of PC consult was 0.66 (p < 0.005) in African American. There was significantly more PC utilization in the top 25% income group (vs the bottom 25% counterpart, aOR 1.35; p < 0.05) and in urban hospitals (vs rural hospitals, aOR 1.80 in nonteaching; aOR 1.88 in teaching; p < 0.001). Conclusions: There was a trend of increasing PC utilization in pancreatic cancer. Nevertheless, racial and socioeconomic factors were still significantly associated with the PC utilization. Further study and systemic policy approach are required to investigate and address such disparities and promote the PC utilization.
A phase II study of KN046 monotherapy as 2nd line and above treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Gang Jin , Guo Shiwei , Zhang Yanqiao , Ma Yue , Guo Xiaodong , Zhou Xiaocui , Yu Qin 
Published: June 2022

e16305 Background: Pancreatic cancer is a malignancy with poor prognosis and high mortality ranking 7th worldwide and with a 5-year survival rate of 10.8%. More than 50% pts are diagnosed at the late stage. The monoclonal antibodies of immune checkpoint inhibitors are also being investigated but has very limit progression free survival (PFS) and overall survival (OS) benefit. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) in a phase 2 study arm 2 (NCT04324307) was reported before. Here, we report the efficacy and safety of KN046 as a monotherapy in the 2nd line and above setting (arm1). Methods: This ongoing phase 2 trial in China enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic PDAC who have ECOG PS of 0-1 and failed to at least one systemic anti-tumor treatment in arm 1. Single agent of KN046 (5mpk, Q2W) were administered until disease progression or intolerable toxicity. Tumor response was assessed according to RECIST 1.1 every 8 weeks. The primary endpoint is investigator-assessed objective response rate (ORR). Secondary endpoints including disease control rate (DCR), PFS, OS and safety, etc. Results: As of Jan 10, 2022, 21pts were enrolled, median (range) age was 57 (51-64) years, 14 (66.7%) pts ECOG 1, 16 (76.2%) pts had distant metastases, and 11 (52,4%) pts had received ≥2 lines systemic treatment. Median KN046 exposure time was 4.1(2.1,6,4) wks. 9 pts were included in the efficacy analysis with 1 PR and 3 SD. 21 pts in the safety analysis. Confirmed ORR was 11.1% (95% CI: 0.28,48.25), and DCR was 44.4% (95% CI: 13.7,78.8). Median PFS was 2.1 months (95% CI:1.61̃7.29), PFS rate in 6 and 9 months were 31.4% and 21%, respectively. Median OS was 7.5months (95% CI:3.02-NR), OS rate in 6 and 9 months were 61.3% and 49.5%, respectively. The incidence of KN046 related treatment-emergent adverse events (TRAE) was 71.4% (15/21), with 14.3% (3/21) ≥grade 3 TRAEs. Two pts experienced TRAE leading to discontinuation. The most common TRAEs (≥10%) were rash (n=6, 28.6%), alanine aminotransferase increased, chills, γ-glutamyl transferase increased and platelet count decreased (n = 3, 14.3%, respectively). No TRAE leading to death occurred. Conclusions: KN046, a bispecific antibody as 2nd line and above monotherapy for unresectable locally advanced or metastatic PDAC patients demonstrated a good PFS and OS benefit as well as acceptable safety profile, supporting KN046 in combination of chemotherapy as first line treatment. Clinical trial information: NCT04324307.
COVID-19 vaccine and incidence of severe immune-mediated adverse events in patients with renal cell carcinoma (RCC) on checkpoint inhibitor immunotherapy (CPI).
Authors: Gilbert Danielle , Hu Junxiao , Kessler Elizabeth R , Lam Elaine T. 
Published: June 2022

e16509 Background: Immune-mediated adverse events (irAEs) can be seen in patients (pts) receiving checkpoint inhibitors (CPI). It is unknown whether the immune response to vaccines against Sars-CoV-2 interacts with the immune activation from CPI therapy. In this retrospective study, we examined the incidence of severe irAEs in pts with renal cell carcinoma (RCC) who received vaccines against Sars-CoV-2 during the course of their CPI therapy. Methods: Following IRB approval, RCC pts who received any CPI treatment since FDA authorization of the first COVID-19 vaccine in March 2021 were identified via institutional electronic health record. Pts who received one or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (defined as one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation. Data was analyzed using descriptive statistics. Results: Sixty-five pts were included in our analysis with a median age of 66 years (IQR: 58.0, 73.0); 80% pts were male. At the time of vaccination, 26 pts (40.0%) received CPI monotherapy, 12 pts (18.4%) received combination (combo) CPI therapy, and 27 pts (41.6%) received combo therapy with a tyrosine kinase inhibitor (TKI) and CPI. The type of vaccine received was Pfizer Bio-N-Tech in 30 pts (46.2%), Moderna in 33 pts (50.7%), and Johnson and Johnson in 2 pts (3.1%). Six pts received only one vaccination (9.2%), 18 pts received two vaccinations (27.7%), and 40 pts received 3 or more vaccinations (61.5%). Eleven pts (16.9%) experienced severe irAEs following vaccination. Rates of severe irAEs was 3.8% (1/26) with CPI monotherapy, 25% (3/12) with combo CPI, and 25.9% (7/27) with combo CPI and TKI. Severe irAEs occurred after the first vaccine dose in 4 pts (36.4%), second dose in 3 pts (27.3%), and third dose in 4 pts (36.4%) pts. The median time between CPI treatment and vaccination in this group was 11.0 days (IQR: 7.5-15.5). Hospitalization was required for 6 patients (54.5%). Ten pts (90.9%) required immunosuppressive therapy with a median steroid duration of 85.5 days (IQR 36.8, 176.0). Six pts (54.5%) discontinued CPI therapy following severe irAEs. Conclusions: In this retrospective study, the observed rate of severe irAEs in RCC patients who received CPI and COVID-19 vaccine concomitantly was similar to historical controls, suggesting that there is no definite increase in the incidence of severe irAEs in pts undergoing CPI therapy and receiving COVID-19 vaccination. Future confirmatory studies are warranted. Supported by the Health Data Compass Data Warehouse project (healthdatacompass.org)
Does timing of Immune checkpoint inhibitors (ICIs) administration in first line Metastatic Renal Cell Carcinoma (mRCC) have impact in survival outcomes?
Authors: Molina-Cerrillo Javier , Ortego Ignacio , Pinto Alvaro , Alonso-Gordoa Teresa , Massari Francesco , Aurilio Gaetano , Buti Sebastiano , Santoni Matteo , Grande Enrique 
Published: June 2022

e16512 Background: Recent data in metastatic melanoma patients shows that time-of-day infusion of ICIs may directly impact on the efficacy based on the dependence of the adaptive immune system on circadian rhythm. ICIs either as single agents or in combinations, are now considered the backbone systemic treatment of mRCC pts. There is a strong biological rational showing that “Clock genes”, particularly PER2, TIMELESS and TIPIN have an altered expression in RCC compared with normal tissue. We conducted a retrospective analysis in pts with mRCC receiving ICIs-based therapies in order to determinate whether timing of ICIs administration has an impact on survival outcomes. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 3 in Italy to describe the outcome of all pts who received ICIs-ICIs or ICIs-TKI treatment for the first line setting of mRCC in daily standarc practice related to the timing of administration. We selected 16.30h as the time-limit and identified the pts receiving more than 20% of the treatment infusion after that time. Pts were treated and evaluated according to institutional local guidelines. Pts characteristics, efficacy and treatment-related toxicities were gathered. A Cox regression analysis was conducted to explore the association of baseline variables. Results: From 2019, 61 pts received either Nivolumab/Ipilimumab (N = 46, 75.4%) or pembrolizumab/axitinib (N = 15, 24,6%) for the upfront mRCC treatment. 52 (85.2%) pts (17 ICI+TKI and 25 ICI+ICI) received less than 20% of the ICIs combination treatment infusion after 16.30h compared with 9 (14.8%) pts (3 ICI+TKI and 6 ICI+ICI) who received more than 20% of the treatment infusion after 16.30h. Median follow up was 14.6 months (m). Pts who received most treatment before 16.30h had a significantly longer median PFS compared with those pts with the latest administration (12.3 vs 5.6m; HR 2.28: 95%CI 1.1-5.15; p = 0.048). Overall Survival (OS) data were immature but showed a tend to a better survival for those patients with earlier infusion administration (HR 2.33 p = 0.16). Corticosteroids concomitant administration or immune-related adverse events did not seem to have an impact on these results. Conclusions: Consistently to the melanoma findings, we also identified a potential survival impact from timing of IO administration in mRCC pts receiving ICIs-based combinations in first line treatment. Despite these promising results, there are study limitations such as number of patients and heterogeneous treatment groups. Larger prospective and randomized data are needed to assess the robustness of this hypothesis in the clinic.
Body composition in patients with metastatic renal cell carcinoma receiving ipilimumab plus nivolumab.
Authors: Dzimitrowicz Hannah Elizabeth , Schwartz Fides , Infield Jordan , Zhang Dylan , Ho Ethan , Wu Yuan , Gupta Rajan T. , Harrison Michael Roger 
Published: June 2022

e16517 Background: Body composition (comp) is an increasingly recognized prognostic indicator in patients with cancer, but there are limited data regarding body comp measurements in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors. The goal of this study was to assess baseline body comp measurements and rates of sarcopenia in patients with mRCC receiving ipilimumab + nivolumab (ipi/nivo) as first-line systemic therapy and examine potential associations with overall survival (OS). Methods: We conducted a retrospective analysis of all patients with mRCC treated with first line ipi/nivo at Duke Cancer Center prior to June 1, 2021, who had a CT scan within 6 weeks of ipi/nivo initiation. CT images were segmented and measured with Automatic Body composition Analyser using Computed tomography image Segmentation (ABACS) software (Voronoi Health Analytics). Areas of skeletal muscle (SM), subcutaneous fat (SF), and visceral fat (VF) at the level of the 3rd lumbar vertebra were measured and converted to indices by dividing by height (m2) (Area SMI, SFI, VFI). Volumes of SM, SF, and VF between the 1st and 5th lumbar vertebrae were measured and converted to indices by dividing by the height of the measured slab (Volume SMI, SFI, VFI). Sarcopenia was defined as SMI < 55cm2/m2 in men and < 39cm2/m2 in women based on prior studies. Medical records were retrospectively reviewed to identify demographic and oncologic details. Effects of body comp measures on overall survival were assessed using Cox proportional hazard models, which were adjusted for IMDC risk, age, and sex. Results: 104 patients met study criteria and had an analyzable baseline CT scan. Median age was 62 (range 37 – 81). 71% of patients were male. Median body mass index (BMI) was 27.2 (range 17.8 – 43.6). IMDC risk score was 12% favorable, 63% intermediate, 20% poor, and 5% unknown. Median follow up time was 19.98 months. Median survival was 39.79 months (95% CI 27.01, NA). 1-year survival rate was 0.81 [95% CI 0.73, 0.89] and 2-year survival rate was 0.68 [95% CI 0.59, 0.79]. 77 of 104 patients (74%) met the definition of sarcopenia prior to treatment. No body comp measurements were associated with OS. Effects of body comp measurements on overall survival are shown in table 1. Conclusions: Baseline body comp measures were not associated with OS in a population of patients with mRCC receiving ipi/nivo as first-line systemic therapy. Changes in body comp over time may instead be of interest as potential biomarkers for OS in patients with mRCC receiving ipi/nivo. [Table: see text]
Predictors for metastatic renal cell carcinoma in IMDC favorable risk group treated with a single agent first line systemic therapy.
Authors: Mizuno Ryuichi , Tanaka Nobuyuki , Matsumoto Kazuhiro , Oya Mototsugu 
Published: June 2022

e16518 Background: With the induction of molecular targeted agents, which interfere with proteins that play critical roles in tumor growth and progression, and immune checkpoint inhibitors, the scenario of systemic treatment of metastatic renal cell carcinoma (mRCC) have dramatically been changed with improved survival. Prognostic risk assessment is essential for choosing the most appropriate first line treatment option, with selection based on International Metastatic RCC Database Consortium (IMDC) Risk Category. This study was designed to evaluate the actual efficacy of a single agent systemic therapy in the IMDC favorable risk group patients with mRCC. Methods: A total of 240 patients with mRCC who received systemic therapy were retrospectively reviewed (Institutional review board approval No 2013-0425). Among them, 55 patients were classified as favorable risk group based on the IMDC Risk Category and received a single agent systemic therapy. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each marker on overall survival (OS) was investigated with univariate and multivariate Cox’s proportional hazards regression models. Results: After a median follow-up of 46 months after first-line treatment initiation, the median progression free survival (PFS) for first line treatment and OS of patients in favorable risk group were 29 months (95% CI 21–34)) and not reached, respectively. The estimated percentage of patients who were alive at 12 and 24 months were 96 and 94%, respectively. Multivariate analysis revealed that the long-term duration of first-line treatment (hazard ratio [HR]: 0.97, 95% confidence interval [CI]: 0.94–0.99, p = 0.0299) and the metastases limited to lung (HR: 3.85, 95% CI: 1.08–24.50, p = 0.0361) were independent predictors for longer OS in favorable risk mRCC patients. Conclusions: First-line systemic therapy for favorable risk mRCC patients with a single agent resulted in relatively longer PFS and OS. A longer duration of first-line treatment and lung only metastases are correlated with longer OS.
Investigation of CREBBP mutation and correlation with immunotherapy biomarker in Chinese bladder cancer patients.
Authors: Chen Junyong , Hu Xue , Zheng Yating , Huang Mengli 
Published: June 2022

e16537 Background: The CREBBP gene provides instructions for making CREB binding protein, is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. Previous research on CREBBP gene revealed that CREBBP is correlated with tumor occurrence and the efficacy of immune checkpoint inhibitors (ICIs) through directly regulate DNA damage response (DDR) pathway. However, the CREBBP characteristics, its correlation with immunogenic marker, and the predictive value of immunotherapy in bladder cancer was unknown. Methods: An independent cohorts (the MSKCC study cohort) with next generation sequencing (NGS) data from 211 patients with bladder cancer of pan-cancer, which were used to analyze the prognostic effect of CREBBP on immunotherapy. Tumor tissue samples from Chinese bladder cancer were analyzed using NGS (panel on 381/733-gene). TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Estimation of immune filtration cells scores were conducted via TIMER2.0. Results: In MSKCC cohort, there were 30 (14.2%) patients harbored CREBBP mutation ( CREBBPmut), and it (median, 15.71 Muts/Mb) was associated with higher TMB (P ＜0.0001) than the wild-type ( CREBBPwt) (median, 7.81 Muts/Mb). In terms of prognostic effect with ICIs therapy, there was significant difference on overall survival (OS) (HR = 0.43; 95% CI, 0.21–0.90; P = 0.02) between CREBBPmut (median, 12 months) and CREBBPwt (median, 8 months). In Chinese patients, genetic mutation of 184 bladder cancer patients were analyzed with NGS and 24 (13.0%) harbored CREBBPmut, similar to western patients of the MSKCC cohort. In bladder cancer patients with CREBBPmut, the most frequently co-mutated genes were TP53 (71%), followed by ATM (46%), BLM (42%), and BRCA1 (29%). CREBBPmut (median, 15.10 Muts/Mb) was associated with higher TMB (P = 0.0008) than CREBBPwt (median, 9.50 Muts/Mb), which was significant difference. Similarly, there was significant difference in MSI between CREBBPmut and CREBBPwt (P = 0.0095). However, there was no difference in PD-L1 expression between the two groups (P = 0.53). In the immune microenvironment of TCGA-SKCM cohort, only CD4+ T cell (P = 0.022) and activated NK cell (P = 0.042) were significantly higher in CREBBPmut patients. Conclusions: The results showed that the CREBBP gene had a high correlation with TMB and MSI in bladder cancer, and might a potential biomarker for ICIs therapy.