bluuebunny/crossref_metadata_2025 huggingface dataset:
Access to care in patients with pancreatic adenocarcinoma by race/ethnicity in an academic center in the Bronx, NY.
Authors: Brodsky Michael , Wei John X , Castagna Francesco , Jou Erin , Shusterman Michael , Goel Sanjay , Acuna-Villaorduna Ana
Published: June 2022

e16280

Background: Racial disparities in the overall survival (OS) of patients with pancreatic adenocarcinoma (PDAC) have been previously reported. Large population datasets suggest that Non-Hispanic Blacks (NHB) have decreased OS when compared to non-Hispanic Whites (NHW), and Hispanics. It is unclear whether this is related to biologic features or differences in access to care. This study was aimed to compare time to treatment in a racially-diverse cohort of patients with PDAC in an academic center in the Bronx, NY. Methods: Patients diagnosed with PDAC between 2015 and 2021, available race/ethnicity (NHW, NHB or Hispanic) who received treatment at Montefiore Medical Center were identified. Data including demographics (age, gender, BMI), clinical features (date of diagnosis, presentation [localized/metastatic], tumor location, grade), first-treatment received (surgery or chemotherapy) and outcomes (vital status, date of death) were collected manually. Time to first treatment was compared between racial/ethnic groups using the Kruskal-Wallis test. Results: Of 226 patients diagnosed with PDAC, there were 46 (20.4%), 77 (34.1%) and 103 (45.6%) NHW, NHB and Hispanics respectively. The frequency of metastatic disease was higher in Hispanics and NHB compared to NHW (42.7% vs. 46.7% vs. 22.2%, p = 0.02). Median time to first treatment did not differ significantly among racial/ethnic groups in the overall cohort and stratified by disease presentation. Conclusions: There were no differences in access to care among racial/ethnic groups in this cohort. A higher frequency of metastatic disease at presentation among NHB and Hispanics might be explained by more aggressive biology. Further evaluation of the molecular profile in this cohort is warranted.[Table: see text]
Impact of antibiotics on stage IV pancreatic ductal adenocarcinoma treated with gemcitabine or 5-fluorouracil.
Authors: Fulop Daniel Jeremy , Zylberberg Haley , Wu Linda , Aronson Anne , Labiner Arielle , Cohen Deirdre Jill , Sigel Keith Magnus , Lucas Aimee L.
Published: June 2022

e16292

Background: Recent studies have suggested a role for the tumor microbiome in conferring chemoresistance to gemcitabine (GEM) in patients with pancreatic ductal adenocarcinoma (PDAC). One proposed resistance mechanism is the presence of bacterial enzymes that metabolize GEM, but not 5-fluorouracil (5-FU). We therefore assessed the impact of antibiotic receipt in the month before and after initiation of either GEM- or 5-FU-based chemotherapy on PDAC overall survival (OS). Methods: We used the SEER-Medicare database to identify adults >66 years old with stage IV PDAC treated with either first-line GEM or 5-FU between 2007-2017. Antibiotic receipt was defined as a claim for >5 days of oral antibiotics or >1 intravenous antibiotic in the month before or after chemotherapy initiation. Demographic and clinical characteristics were compared using chi-squared and student t-tests, and univariable survival was assessed using Kaplan-Meier methods. Propensity scores (PS) were created to account for potential allocation bias in the receipt of antibiotics. We fit PS-adjusted Cox proportional-hazard models to evaluate the association between antibiotic receipt and OS. Results: We identified 3,990 stage IV PDAC patients treated with first-line GEM-based (n = 3,219) or 5-FU-based (n = 771) chemotherapy, of whom 2,318 (58.1%) received antibiotics. In univariable analyses, antibiotic receipt in the month surrounding chemotherapy initiation was associated with improved median OS in patients treated with GEM (214 days vs 199 days, p = 0.04) but not in patients treated with 5-FU (255 days vs 284 days, P = 0.14). In PS-adjusted multivariable analyses, the significant association between antibiotic receipt and improved OS in patients who received GEM remained (HR 0.89, 95% CI 0.83-0.96). However, no significant association between antibiotic receipt and OS was seen in patients treated with 5-FU (1.10, 95% CI 0.94-1.28). Conclusions: Antibiotic receipt in the month before or after chemotherapy initiation was associated with improved OS in stage IV PDAC patients who received GEM but not 5-FU. These findings support the concept that antibiotics may impact the activity of GEM-metabolizing bacteria proposed to confer chemoresistance. Further studies are needed to characterize the potential role for antibiotics in PDAC treatment.[Table: see text]
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.
Crosstalk among T-cell CX3CR1, immune checkpoints and toll-like receptor 4 signaling pathway in BCG-unresponsive nonmuscle invasive bladder cancer: Mechanism of action of OncoTherad Nano-Immunotherapy.
Authors: Alonso João Carlos Cardoso , Ribeiro de Souza Bianca , Leme Giovana , Brum Reis Ianny , Gonçalves Juliana Mattoso , Cintra Adriano Angelo , Freitas Leandro Luiz Lopes de , Pereira Fabio Gomes , Billis Athanase , Fávaro Wagner José
Published: June 2022

e16551

Background: This study detailed and characterized the mechanisms of action of OncoTherad nano-immunotherapy based on modulation of Toll-like Receptor 4 (TLR4) signaling pathway, CX3C chemokine receptor 1 (CX3CR1, a marker of T-cell differentiation) and immune checkpoints in patients with Bacillus Calmette-Guérin (BCG)-unresponsive high-grade non-muscle invasive bladder cancer. Methods: A single-center open-label (Paulinia Municipal Hospital, Brazil) and single-arm phase 1/2 study (Clinical Trial: RBR-6swqd2) was applied in 44 patients (30 male and 14 female) with BCG-unresponsive NMIBC (≥ 1 prior course of BCG therapy) submitted to OncoTherad immunotherapy for 24 months. Patient follow-ups were performed with systematic mapping biopsies of the bladder every 3 months for the first year and every 6 months thereafter for up to 2 years. Bladder biopsies of each patient (n = 44) were divided into 2 groups: Group 1 (initial biopsy, before OncoTherad treatment); and Group 2 (bladder biopsy after OncoTherad treatment). Subsequently, the samples were submitted to immunohistochemistry analysis: TLR4-mediated IFN-γ production signaling pathway (TRIF, TBK1, IRF-3), CX3CR1+CD8+ T-cells, immune checkpoints (PD-1/PD-L1 CTLA-4) and Regulatory T cells (FOXP3). Results: After 24-months follow-up, pathological complete response rate was 72.7% (95% CI) and recurrence-free survival of 21.4 months. Bladder samples from patients submitted to OncoTherad treatment (Group 2) showed intensified TLR4, TRIF, TBK1, IRF-3 and IFN-γ immunoreactivities when compared (p < 0.01) to initial biopsies (Group 1). Furthermore, as result of interferon signaling pathway (TRIF-dependent pathway) induction by OncoTherad, intensified CX3CR1 immunoreactivities (p < 0.01) were found in the Group 2. In contrast, PD-1/PD-L1 immunoreactivities were decreased (p < 0.01) in the Group 2 when compared to Group 1. No statistical differences were found between the two groups for FOXP3 and CTLA4. Conclusions: OncoTherad nano-immunotherapy led to activation of TLR4-mediated innate immune system, resulting in increased interferon signaling pathway, which was fundamental in the activation of antitumor CD8+ T-cells and decrease of PD-1/PD-L1 expression in the bladder microenvironment. These important findings are relevant concerning the treatment of patients with NMIBC presenting high-risk of progression that are BCG-unresponsive.
Biomarker Exploration for neoadjuvant chemotherapy with gemcitabine combined with cisplatin in muscle-invasive bladder cancer.
Authors: Wang Kun , Chen Xusheng , Zhang Zhenting , Hu Hailong , Zhang Aili , Wang Xin , Chen Lijun , Liu Zhizhong , Yue Changjiu , Zhang Xueying , Zhang Menghuan , Yao Xin
Published: June 2022

e16556

Background: Neoadjuvant chemotherapy (NCT) is a standard treatment for muscle-invasive bladder cancer (MIBC). However, there is still a considerable proportion of patients who respond suboptimally to available treatments or experience adverse effects. Thus, identifying novel biomarkers to predict response to NCT of MIBC is urgently needed. Methods: A total of 23 patients were enrolled in this study, all of whom were cT2-T4aNxM0 MIBC and received 2̃4 cycles CG (gemcitabine and cisplatin) NCT. Radiographic assessment was performed at the end of each cycle or at the time of progression. Tumor tissue were collected from all patients before NCT. Whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed for tissue samples. In addition, peripheral blood was collected as a control for WES. Treatment responses were assessed by comparing the imaging data before and after treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients with CR and PR were regarded as the responder group, and those with SD and PD were regarded as the non-responder group. Results: Number of patients received 2̃4 cycles NCT were 16 for the responder group and 7 for the non-responder group. Of 19 patients completed WES, 13 patients achieved response and 6 patients did not respond. In the responder group, 6 patients (46%) had variant in any of RB1, ERCC2 and ATM, which were previously reported to predict better response to NCT. Only a patient (16.7%) in the non-responder group had any of those variants. Additionally, our results showed that 3 patients in the non-responder group had MAST4 gene mutations, but not in the responder group, and there was a significant difference between the two groups (p < 0.05). There were no differences in Tumor Mutational Burden (TMB) and Microsatellite instability (MSI) between the two groups. RNA-seq was also completed in 18 patients, of which 14 patients achieved response and 4 patients did not respond. Significant differences in gene expression (eg. UPK3A, CD8B2, TUBB2B) between the two groups were found. The KEGG pathway enrichment analysis revealed that down-regulated DEGs were enriched in the Cytokine-cytokine receptor interaction pathway and up-regulated DEGs were enriched in the Steroid hormone biosynthesis. The infiltration of immune cells in the non-responder group was higher, and the CD4 cells, B cells, Th17 cells, and NK cells in the non-response group were significantly higher than those in the responder group (p < 0.05). Conclusions: Patients with MAST4 mutations may be insensitive to GC NCT. The non-response group had higher levels of immune cell infiltration and may be more sensitive to immunotherapy. These results require further validation in additional sample sets.
Treatment patterns and outcomes in prostate cancer patients tested with Decipher in SEER.
Authors: Zaorsky Nicholas George , Proudfoot James Alexander , Vince Randy , Liu Yang , Liu Vinnie YT , Zuhour Raed , Jia Angela Y , Sun Yilun , Hu Jim C. , Shoag Jonathan Evan , Schaeffer Edward M. , Davicioni Elai , Petkov Valentina I. , Spratt Daniel Eidelberg
Published: June 2022

e17006

Background: In 2021, national data between the Decipher 22-gene prognostic gene expression classifier (GC) for men with prostate cancer and the Surveillance, Epidemiology, and End Results (SEER) cancer registries were linked. The purpose of the work is to report on the linkage by characterizing national GC usage and its association with treatment decisions for men with prostate cancer. Methods: Patients in the SEER registries with primary prostate cancer diagnosis from 2010 to 2018 were included and linked to data from GC testing conducted between 2014 to 2020 (Veracyte, San Diego, CA). GC scores (range 0-1) and GC risk groups (low, intermediate, and high) were used for continuous and categorical analyses. Multivariable logistic regression was used to quantify the association between GC and active surveillance and watchful waiting (AS/WW) use and adverse pathology at radical prostatectomy (RP). Adverse pathology was defined as pathological grade group ≥3, pathological stage ≥pT3b, or lymph node invasion. Results: A total of 575,363 patients were eligible for analysis, of which 10,528 patients underwent GC testing (5,015 GC biopsy test, and 5,513 GC RP test). The median age was 67 for both tested and untested, but more white patients underwent testing (82% vs 76%, p < 0.001). For GC biopsy tested patients, AS/WW was highest for those with GC low risk results (41%) as compared to those with intermediate (32%) or high (17%) GC risk (p < 0.001). RP rates were lower in the tested compared to untested (25% vs. 36%, p < 0.001), and among the tested patients, RP use increased by GC risk group (19% of low, 25% of intermediate, and 34% of high GC risk, p < 0.001). A similar trend by GC risk group in management for radiation therapy was observed (13% of low, 19% of intermediate, and 29% of high GC risk, p < 0.001). In a multivariable logistic regression adjusted for age, race, NCCN risk group, and year of diagnosis, GC tested patients were more likely to undergo AS/WW compared to untested (OR 2.9 [95% CI, 2.8-3.1], p < 0.001). Within the subset of patients classified as NCCN low/favorable intermediate risk at biopsy and who were subsequently treated with RP (n = 594), GC high risk (> 0.6) was associated with more than 3 times the odds of harboring adverse pathology (OR 3.2 [95% CI 1.6-6.4], p < 0.001). Conclusions: Using the first ever linked SEER-Decipher data, we demonstrate that population-based treatment patterns are independently associated with GC test results. Patients with lower GC scores are independently more likely to undergo AS/WW; those with higher scores are more likely to have adverse pathology at time of RP.
Outcomes of second-line therapies in patients with metastatic de novo small cell prostate cancer (SCPC) and treatment-emergent neuroendocrine prostate cancer (tNEPC).
Authors: Eule Corbin , Hu Junxiao , Al-Saadi Sulaiman , Collier Katharine , Boland Patrick James , McKay Rana R. , Narayan Vivek , Bosse Dominick , Mortazavi Amir , Rose Tracy L , Lam Elaine T.
Published: June 2022

e17022

Background: De novo SCPC and tNEPC in metastatic castrate resistant prostate cancer (mCRPC) are rare, aggressive cancers with a poor prognosis. After first-line (1L) platinum chemotherapy (PLT), there is no consensus on 2L treatments. This multi-institutional, retrospective study examines practice patterns among clinicians and evaluates the outcomes of patients (pts) with SCPC or tNEPC in the 2L setting. Methods: After IRB approval, pts with a pathologic diagnosis of SCPC or tNEPC (any % of SC or NE histology defined by institutional review) were identified. Pts diagnosed between 2000-2020 who received 1L PLT and any 2L systemic therapy (tx) for SCPC or tNEPC were included. Standardized data collection templates containing demographic, clinical, and pathologic variables were collected. The primary endpoint was objective response rate (ORR) to 2L tx. Secondary endpoints included PSA response, time on 2L treatment, and overall survival (OS) from time of 2L tx. Data was analyzed using descriptive statistics. Results: Forty-two pts (21 SCPC, 21 tNEPC) from 6 institutions were included. At SCPC/tNEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 60.5, 68.0) and median PSA of 3.0 ng/dL (IQR 0.5, 21.8). The most common sites of metastasis included lymph node (78.6%), bone (54.8%), and liver (52.4%). For 1L tx, 37 pts (88.1%) received PLT and 5 (11.9%) had PLT + immunotherapy (IMM). For treatment to the prostate, 21 (51.2%) had none, 7 (17.1%) radiation (RT), 9 (22.0%) surgery, 3 (7.3%) RT + surgery, and 1 (2.4%) brachytherapy alone. Concurrent ADT was given to 32 pts (76.2%) in the 1L and 2L. At last follow-up, 34 pts (81.0%) were dead, 4 (9.5%) were alive, and 4 (9.5%) were lost to follow-up/censored. For 2L tx, 10 pts (23.8%) received PLT, 8 (19.0%) taxane monotherapy (TAX), 10 (23.8%) IMM, 8 (19.0%) other chemotherapy (CHX), and 6 (14.3%) other tx. Among 38 pts evaluable for response, the ORR was 15.8% (6 pts with PR: 4 PLT, 1 IMM, 1 CHX). PSA response ≥ 50% to 2L tx was seen in 5 of 29 pts with PSA data (17.2%). Other outcomes data are reported in Table. Conclusions: In this retrospective study, pts with SCPC or tNEPC who reached 2L tx received a wide variety of treatment regimens, reflecting the lack of consensus in this tx setting. ORR was low and overall prognosis was poor in the 2L regardless of tx choice. Pts on 2L immunotherapy seemed to have the shortest mOS. [Table: see text]
Clinical markers of successful liquid biopsy-based genomic profiling in veterans with prostate cancer.
Authors: Guo Aixia , Ahmed Sara , Rowe Kerry , Pritchard Colin C. , Montgomery Robert B. , Kelley Michael J. , Rettig Matthew
Published: June 2022

e17031

Background: Liquid biopsy with plasma circulating tumor DNA (ctDNA) is a noninvasive alternative to tissue genomic profiling. The yield of ctDNA is largely dependent upon the total amount and proportion of ctDNA in the total circulating DNA pool. Factors that predict successful genomic profiling via liquid biopsy amongst Veterans with prostate cancer are unknown. Methods: 764 veterans with prostate cancer who received liquid biopsy testing between February 2019-2021 were selected from the VA National Precision Oncology Program (NPOP) database. Baseline patient variables including age at specimen collection date, race, PSA, PSA doubling time (PSADT), sites of metastatic involvement (i.e., bone, brain, liver, lung, and lymph nodes), number of metastatic sites, Gleason score, and Gleason grade group were extracted from the VA Corporate Data Warehouse (CDW). Two independent approaches were used to define a successful liquid biopsy: Approach 1: Liquid biopsies with an alteration detected in one or more prostate cancer related genes ( AR, CDK12, SPOP, MED12, CCND1, BRAF, AKT1, TMPRSS2) (n = 337); Approach 2: Liquid biopsies with alterations detected in any gene detected by the Foundation One Liquid CDx assay (n = 670). We performed univariate and multivariate logistic regression analysis for Odds Ratio (OR), 95% confidence interval (CI), and conducted statistical significance tests to investigate associations between clinical factors and liquid biopsy test outcome. P-value < 0.05 was considered significant. Results: In Approach 1, the OR by univariate analysis was 4.80 (P < 0.001; 95% CI [3.09, 7.47]) for 4th PSA quantile group versus 1st PSA quantile group. The OR was 3.61 (P < 0.001; 95% CI [2.0, 6.5]) for PSADT less than 3 months versus PSADT more than 60 months; brain metastasis had the highest OR value among metastatic sites of 2.47 (P = 0.008; 95% CI [1.27. 4.8]). In multivariate analysis, PSA, PSADT and sites of metastasis remained significant risk factors. Statistical significance tests indicated PSA, PSADT, and sites of metastasis were significantly different between the success and failure groups. In Approach 2, no statistically significant associations were observed between the studied variables and any outcome. Conclusions: Factors such as PSA, PSADT, and metastatic site were significantly associated with a successful liquid biopsy of detecting prostate cancer related gene mutations, while the outcome of detecting any gene mutations was not statistically significant associated with studied variables in this study population. Given the likelihood that a significant number of non-prostate cancer mutations are likely due to clonal hematopoiesis, this finding is expected. Our findings may facilitate clinical decisions around genomic profiling by liquid biopsies in the absence of tumor tissue, thereby increasing the success rate of sequencing efforts for treatment selection.
Profiling of clinically relevant subgroups of asymptomatic or mild-symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients using PSA and testosterone levels and deep learning.
Authors: Dominguez Correa Juan Manuel , Gomez del Campo Pablo , Galmarini Carlos Maria
Published: June 2022

e17032

Background: The optimal time to begin therapy in mCRPC patients who have either no, or minimal symptoms is not defined yet. Estimating prognosis of these patients can avoid undertreatment or overtreatment and guide the follow-up intensity. This study has investigated the ability of a deep learning framework (DLF) to identify asymptomatic or mildly symptomatic mCRPC patients with high risk of disease progression and mortality using PSA and testosterone levels. Methods: Data from the control arm of the NCT00554229 trial was obtained from www.projectdatasphere.org . These mCRPC patients were treated with placebo alone. The dataset consisted of more than 150 clinical variables. We generated synthetic fingerprints (SF) for each patient through the integration of PSA values collected at baseline and during the first 90 days of follow-up and testosterone levels at baseline. These SF were then input into a DLF to identify subgroup of patients based on their similarities. The resultant subgroups were correlated with progression-free survival (PFS) and overall survival (OS). Feature contribution analysis identified the significant predictive clinical variables in each subgroup. Results: After discarding missing data, 189 patients were eligible for this exploratory study. Median PFS and OS for the total population were 8.7 months and 24.5 months, respectively. DLF identified two different subpopulations, SPA (n = 89) and SPB (n = 100), with significantly different survival outcome. Patients in SPA had a lower risk of progression (median PFS 12.2 months vs. 7.2 months; hazard ratio 0.54, 95% CI 0.41-0.71; p < .0001) and death (median OS not reached vs. 20.3 months; hazard ratio 0.33, 95% CI 0.21-0.52; p < .0001) compared to patients in SPB. SPA signature was significantly correlated to leuprolide treatment. These patients also had higher levels of haemoglobin, red blood cells, haematocrit, total bilirubin, Ca, phosphate, and K. Instead, SPB signature was significantly correlated with presence of > 3 bone metastasis, lack of energy or forced time to bed in the FACT-P and moderate problems in selfcare in the EQ-5D, and treatment with goserelin, tamsulosin, opioids and contact laxatives. In addition, these patients had higher levels of platelets, basophils, monocytes, ALP, AST, LDH, PSA, free PSA, Mg, Na, and specific gravity. Conclusions: DLF identifies mCRPC subtypes that correlate with higher risk of progression and death according to PSA and testosterone levels. Model predictions also suggest complex interactions among many clinical features that might be important modulators of key clinical traits and outcome. Further work is required to validate this approach to anticipate the clinical course of asymptomatic or mildly symptomatic mCRPC patients and help to better decide when to start appropriate therapy.