bluuebunny/crossref_metadata_2025 huggingface dataset:
Pancreatic cancer germline mutation report: An in-depth analysis of demographics, mutation profile, and patient survival.
Authors: Zou Xianghui , Sidiqi Baho , Patruni Sunita , Hollweg Christopher , Kauff Noah D. , King Daniel
Published: June 2022

e16233

Background: Germline genetic testing is now recommended for patients with pancreatic ductal adenocarcinoma (PDAC). We explored whether attributes of testing, such as uptake fraction and rate, were associated with various clinical features. Here we examined germline mutations found in our database, identified barriers to germline testing, and explored a relationship between mutations and survival in our cohort of patients from New York’s largest healthcare system. Methods: Patients with PDAC were identified using billing records across our institution with an IRB-approved protocol. Germline mutation data were assessed through chart review. Median income was annotated using zip codes and www.census.gov. Date of diagnosis (DOD) was recorded as the date of biopsy or, if no biopsy was performed, the date of earliest lesion-found CT scan. Lag of testing was calculated as the difference between DOD and the date of germline sample collection. Overall survival (OS) was calculated by mutational status. Results: Between Mar 2016 and Feb 2022, 305 patients with PDAC were identified, with 103 (36.3%) having reports found (F), and 202 (63.7%) not having reports found (NF). Availability of germline testing did not vary by median income (F: 95954 dollars vs NF: 94368 dollars, t = 0.414, p = 0.68). The geographic distribution of patients among F and NF is listed below in Table. Pearson analysis between median income and lag of testing showed a negative correlation (y = -0.0027x+315.6, R = -0.241, p = 0.014). Level of income (cutoff: 100k) also affected the mean days in lag of testing (below: 111.8d, above: -44.0d, t = 2.190, p = 0.031). There was no difference in the median survival between F and NF (median: F: 573d, NF: 717d, HR 0.459-1.155, p = 0.17). For mutational analysis, 103 patients with PDAC were identified: 59 without germline mutations (GMs) (12 deaths), and 44 with GMs (16 deaths). We identified 7 patients with pathogenic GMs (APC, ATM, BRCA2, CHEK2, CDKN2A, and PALB2) and 41 patients with variants of unknown significance (VUS), including ATM (6), BRCA2 (4), MSH6 (3) and CHEK2 (2). OS was not statistically different between GM and no GM (Median OS: no GM 1520d; GM 573d, HR 0.394-1.871, p = 0.702). Conclusions: Analysis of germline and clinical data from our 305-patient cohort identified a striking and concerning negative correlation between patient median income and lag between DOD and germline testing. These results compel further investigation into the operational processes that prompt germline testing at our institution. [Table: see text]
Repurposing HDAC and mTOR inhibitors for pancreatic cancer.
Authors: Biermann Mitch , Quintero Cynthia , Ferguson Paige , Rajbhandari Nirakar , Park Donglim Esther , Patel Hitendra , Reya Tannishtha
Published: June 2022

e16234

Background: Pancreatic ductal adenocarcinoma (PDAC) will be the second leading cause of cancer death by 2030 through early onset dedifferentiation and metastasis that results in limited treatments. FDA-approved targeted therapies–including proteasome, mitogen-activated protein kinase (MEK), histone deacetylase (HDAC), and mammalian target of rapamycin (mTOR) inhibitors–have shown preclinical benefit but failed in clinic. However, combination targeted therapy has been largely unexplored in clinical trials. We hypothesized based on prior drug screening efforts in the lab on aggressive subtypes of pancreatic cancer that combinations of these targeted therapies could be synergistically active in preclinical PDAC models. Methods: We optimized combinations of proteasome, MEK, mTOR, and HDAC inhibitors by performing cell viability experiments in human PDAC lines in 2D and 3D cell culture conditions in vitro. Optimized drug combinations from these experiments were then trialed in two different in vivo animal models–human FG xenografts in immunocompromised mice (NSG) and spontaneous primary PDAC tumors from transgenic pancreatic-specific Kras-overexpressing, P53-deficient mice (KPC). RNA-sequencing and Seahorse metabolic assays were utilized to analyze molecular mechanisms of drug synergy. Dedifferentiation was assessed by histology of KPC tumors. Results: The HDAC inhibitor Panobinostat and mTOR inhibitor Everolimus synergistically killed human pancreatic cancer cell lines grown in 2D and 3D cell culture in vitro. Synergy was highest at low concentrations of Panobinostat. In vivo, low-dose Panobinostat and Everolimus synergistically blocked growth of human FG xenografts in NSG mice. In vivo synergy of low-dose Panobinostat and Everolimus was highest in the KPC mouse model, where only combination therapy could significantly reduce tumor growth, stall dedifferentiation, and improve survival. Mechanistically, RNA-sequencing of Panobinostat/Everolimus-treated FG cells revealed that Panobinostat increased tumor suppressor genes opposing dedifferentiation such as p21, EGR1, and CCN2. Everolimus complemented Panobinostat by decreasing expression of enzymes metabolizing acetyl groups such as fatty acid synthase, stearoyl-CoA desaturase, and sterol response element binding factors. Functionally, Everolimus’ activity to reduce oxidative consumption increased histone acetylation specifically in the presence of Panobinostat. Conclusions: A combination of FDA-approved, targeted oral therapies (low-dose Panobinostat/Everolimus) is synergistically active in preclinical models of pancreatic cancer in vitro and in vivo. mTOR inhibitors create drug synergy by specifically increasing histone acetylation in HDAC inhibitor-treated cells by reversing HDAC inhibitor de-repression of acetyl/oxidative metabolism, illustrating a novel connection between cancer epigenetics and metabolism.
Outcomes of pulmonary embolism in patients with pancreatic cancer: A nationwide inpatient sample study.
Authors: Obeidat Khaldun , Turk Ekrem , Deenadayalan Vaishali , Weir Catherine , Vakil Jay , Rodriguez Alarcon Pierre Alexander , Batra Kunnal
Published: June 2022

e16235

Background: Pancreatic cancer is considered one of the most aggressive cancers with five-year relative survival of 10.8% as per the national institute of health (NIH); Thromboembolism is a well-known complication of pancreatic cancer which contributes to increased morbidity, mortality and burden on the health care system. We attempted to evaluate the outcomes of pulmonary embolism in patients with pancreatic cancer. Methods: Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS) was queried to identify Pulmonary embolism admissions between 2016-2018 In Adult patients with diagnosis of pancreatic cancer using International Classification of Disease 10th Revision (ICD-10) codes. We evaluated mortality, Need for ventilation, Tissue plasminogen activator (TPA) administration, Embolectomy, Inferior vena cava (IVC) filter insertion and Acute kidney injury. Secondary outcomes included mean length of stay (LOS) and the mean cost of hospitalization. Results: A total 5335 admissions with PE and Pancreatic cancer were identified; in the baseline characteristics mean age was 67.4 at time of diagnosis with 51% being females and the white race constituted 73% of the total admissions. 385 patients (7%) died during hospitalization,165 patients (3%) required ventilation, 140 patients (2.6%) had TPA administration,560 patient (10.4%) had IVC inserted, 640 patients (12%) developed Acute kidney injury, and none had embolectomy. Mean length of stay was around 5 days and the mean cost of hospitalization was $12405. Conclusions: Pulmonary embolism increases mortality among patients with Pancreatic cancer; in addition to its effect on morbidity and burden on health care system; Efforts should be made to identify those with pancreatic cancer and considered high risk for Venous thromboembolism who may benefit from primary prophylaxis.
Value-based care outcomes in pancreatic cancer patients with and without access to registered dietitians: A retrospective cohort study of patients enrolled in the Oncology Care Model.
Authors: Smith Karen , Hodac Nicole , Jensen Terry Lynn , Torres Vanessa , Ortega Lance , Broussard Stephanie Broadnax , Books Holly , Hudson Kathryn Elizabeth , Hoverman John Russell , Wilfong Lalan S.
Published: June 2022

e16249

Background: Patients with pancreatic cancer face many nutrition-related concerns, although few guidelines exist to direct clinical nutrition services in this population. Examining quality outcomes for patients in clinics with and without access to a Registered Dietitians (RD’s) can help examine the contributions of RD’s in this area. Methods: A retrospective cohort design was used to compare Total Cost of Care (TCOC), hospital admissions and Length of Stay (LOS), and Emergency Department (ED) and Observation visits for patients with pancreatic cancer who were enrolled in the Oncology Care Model (OCM) during Performance Periods (PP) 1-6 (July 1, 2016–June 30, 2019). Patient deaths during the initial episode of care were also examined. Patients from a geographically concentrated metropolitan hub were divided into cohorts based on clinic access to an RD. Each patient’s initial six-month OCM episode of care was used for analysis. Results: Of the 389 OCM patients identified with pancreatic cancer from PP1-6, 203 were treated at 10 clinics with an RD and 186 in 17 clinics without an RD. In the RD cohort, 43.3% of patients were admitted to the hospital with an average LOS of 8.9 days. By contrast, 52.2% of patients in the non-RD cohort were admitted to the hospital with an average LOS of 10.0 days. TCOC for the 6-month episode was lower in the RD cohort at $37,185 versus the non-RD cohort at $40,907. During the initial 6-month episode of care, 37% of patients in the non-RD cohort died during the initial 6-month episode vs only 28% in the RD cohort. A higher percentage of patients in the RD cohort (35%) had ED or Observation visits, compared with the non- RD cohort (32%). Conclusions: Amongst OCM patients with pancreatic cancers, treatment at a clinic with an RD was associated with lower TCOC, reduced LOS for patients that were admitted to the hospital, and lower percentage of deaths in the first 6-month episode of care. The percentage of patients with ED and Observational visits was slightly higher in the cohort that had access to an RD. This analysis shows the potential benefit of RD services in an outpatient setting and justifies further study. Future multilevel modeling will evaluate the statistical significance of these results.[Table: see text]
TP53 gain-of-function mutations and impact on CDKN2A mutation on prognosis of pancreatic ductal adenocarcinoma.
Authors: Pan Minggui , Jiang Chen , Zhang Zheyang , Achacoso Ninah , Tse Pamela , Solorzano Aleyda , Chung Elaine , Sundaresan Tilak Kumar , Suga Jennifer Marie , Huang Jianliang , Thomas Sachdev P. , Habel Laurel A.
Published: June 2022

e16294

Background: Developmentally pancreas head derives from ventral bud while pancreas neck, body and tail derive from dorsal bud. Pancreatic ductal adenocarcinoma (PDAC) frequently harbors multiple mutations including KRAS, TP53, CDKN2A, and others. It is unknown how TP53 gain-of-function (GOF) and non-gain-of-function (non-GOF) mutations affect the prognosis. Methods: We retrospectively examined a cohort of 741 Kaiser Permanente (KP) patients with locally advanced/metastatic PDAC who had NGS performed to determine the association of KRAS (mutKRAS), TP53 (mutp53) and CDKN2A (mutCDKN2A) mutations (individually and in combination) with overall survival (OS). We used Cox modeling to estimate hazard ratios (HR) adjusted for age, sex, ethnicity, performance status, Charlston Comorbidity Index, chemotherapy received, anatomic location and co-mutations. We also analyzed the TCGA PDAC dataset to examine the association of OS with these same mutations. Results: In the KP cohort, patient ages ranged from 36 to 94 years and approximately 50% were female. In 384 patients PDAC was on the head, and 357 patients had PDAC on a non-head location (neck, body, and tail). Those with head PDAC had modestly better OS compared to non-head PDAC (HR = 0.87), and this appeared to be driven by the subsets of patients with wtp53 (HR = 0.68), with wtKRAS (HR = .74) and with wtCDKN2A (HR = .78). Approximately 67.5% of patients had mutp53, 89.2% had mutKRAS and 44.8% had mutCDKN2A. Among all KP patients, OS was similar for patients with mutp53 vs. wtp53 (HR = 1.05); worse for patients with mutKRAS vs. wtKRAS (HR = 1.26), and worse for patients with mutCDKN2 vs. wtCDKN2A (HR = 1.51). Interestingly, among patients with a GOF mutp53, those with mutCDKN2A had substantially worse OS vs patients with wtCDKN2A (HR = 2.56, 95% CI 1.46-4.50). In contrast, among patients with a non-GOF mutp53, patients with mutCDKN2A had only moderately worse OS compared to patients with wtCDKN2A (HR = 1.37, 95% CI 1.06-1.79). Analysis of the TCGA PDAC dataset showed that the number of mutations (0, 1, 2, or 3, of p53, KRAS and CDKN2A) was associated with incrementally worse OS ( p < .001). Conclusions: Better OS of head vs. non-head PDAC was primarily driven by patients with wtp53, wtKRAS, and wtCDKN2A. The adverse effect of mutCDKN2A on OS appears to be most pronounced in patients with GOF mutp53. Our TCGA analysis suggests interactions among TP53, KRAS and CDKN2A mutations in affecting PDAC survival.
HALP score as a biomarker for nutritional status to predict overall survival in patients post radical cystectomy.
Authors: Farag Christian Mark , Haji-Momenian Shawn , Whalen Michael Joseph
Published: June 2022

e16504

Background: Radical Cystectomy (RC) is the gold-standard treatment for recurrent high grade T1 or muscle-invasive bladder cancer. Nutritional status is a well-defined independent predictor of overall survival post-RC. Various prognostic biomarkers have been proposed as surrogates for nutritional status to help predict postoperative outcomes. These biomarkers include albumin, anemia, thrombocytopenia and sarcopenia. Recently, the Hemoglobin, Albumin, Lymphocyte, Platelet (HALP) score has been postulated as an all-encompassing biomarker and has been shown to predict overall survival (OS) post-RC in a single previous study. Due to the paucity of studies looking at HALP and RC outcomes, and optimal cutoffs for HALP have not been defined. Our study sought to analyze and optimize HALP thresholds for OS, as well as examine the Psoas Muscle Index (PMI) as a possible additional predictor that can be used with HALP. Methods: Seventy-three RC patients were evaluated from 2010 to 2021. Of 73 RC patients, 50 had sufficient pre-operative laboratory data to calculate HALP. Sixty-two patients had CT scans to analyze PMI, which was calculated using patient height and the psoas major muscle cross-sectional area measured at the L3 vertebral level. Patient date of surgery, tumor grade and stage, American Society of Anesthesiologists (ASA) Classification, survival status, and date of last contact were extracted from our institutional cancer registry. X-tile software was used to find optimal biomarker cutoffs for HALP. The Cox Proportional Hazards model was used to identify predictors of OS. Results: Median age was 67 (58-74) years, 58 (79.5%) were male, and 36 (49.3%) received neoadjuvant/adjuvant chemotherapy. Forty-seven (64.4%) had pathological stage ≥pT2, 25 (35.7%) had lymph-node involvement, and 4 (5.5%) had palliative surgery. Median HALP score was 28 (21 – 42). Median PMI was 569 (456 –700). Fifty-six (76.7%) had an ASA ≥ 3. Median follow up was 29.3 months (12.0– 51.9). Forty-eight (65.8%) were alive at last follow-up. HALP (continuous variable) was a significant predictor of OS on multivariable Cox regression analysis (HR 0.95, 95% CI 0.90 - 0.99) (P = 0.021), adjusting for age, sex, and node involvement; PMI and ASA were not significant. X-tile analysis showed an optimal HALP cutoff of 25.0. Patients with HALP < 25 had inferior OS (median, 32.5 months) compared with those with HALP ≥ 25 (median, not reached) (P = 0.025). Conclusions: We conclude that patients with low HALP Score were shown to have a significantly inferior OS, with an optimum HALP cutoff of 25.0. We further suggest that the HALP score can be a reliable prognostic biomarker to assist in nutritional management before surgery. PMI was not a significant predictor of OS and did not add value to HALP score. Future studies may investigate better measures of sarcopenia, which could potentially be combined with HALP score to better predict OS in RC patients.
Single cell transcriptomic characterization of natural killer (NK) cell populations in clear cell renal cell carcinoma and association with clinical outcomes.
Authors: Xu Wenxin , Bharadwaj Maheetha , Birch Grace , Schindler Nicholas , Labaki Chris , Saliby Renee Maria , Bakouny Ziad , Freeman Dory , O'Toole Jillian , Lee Gwo-Shu Mary , McGregor Bradley Alexander , Hirsch Michelle S. , Shukla Sachet A. , McDermott David F. , Signoretti Sabina , Romee Rizwan , Choueiri Toni K. , Braun David A.
Published: June 2022

e16521

Background: Natural killer (NK) cells are thought to play a key role in the immune response against cancer, including clear cell renal cell carcinoma (ccRCC). However, the transcriptomic landscape of NK cells in ccRCC and the mechanisms of NK cell evasion by ccRCC are poorly understood. Methods: We analyzed scRNA-sequencing (10x Genomics) data from tumor specimens and adjacent non-tumor tissue from ccRCC at various clinical stages. Clustering analysis and NK cell lineage markers were used to identify distinct NK cell populations. Differential gene expression analysis was used to characterize each cluster compared to the total population of NK cells. Results were correlated with clinical stage. Gene signatures, derived from NK cell subclusters of interest, were then used to interrogate bulk transcriptomic datasets and associate expression with clinical outcomes. Results: Single-cell RNA-sequencing data was analyzed from 13 patients, corresponding to > 23,000 individual NK cells. Clustering analysis revealed 11 distinct NK cell subsets, including two “resident” NK cell clusters that were enriched among patients with metastatic disease. These clusters expressed CD9, ITGA1/CD49a, and ITGAE/CD103. Further examination of these clusters showed a common panel of differentially expressed genes, including decreased expression of cytotoxicity markers and upregulation of inhibitor checkpoints such as KLRC1/NKG2a. A gene expression signature representing this resident NK cell phenotype was associated with worse overall survival in two large, independent patient cohorts (TCGA and CheckMate-025). Conclusions: Among patients with ccRCC, a retrospective single cell transcriptomic analysis revealed heterogeneous NK cell populations. A seemingly dysfunctional, “resident” NK cell phenotype is enriched among patients with metastatic disease and is associated with worse survival in patients with advanced ccRCC, including those treated with immune checkpoint inhibitors. Restoration of NK cell function could be a future therapeutic opportunity among patients with ccRCC.
TSC1-mutant bladder cancer expression signature in relation to nuclear localization of TFE3 and potential for targetable dependency.
Authors: Probst Clemens Kemena , Adib Elio , Losko Magdalena , Du Heng , Hirsch Michelle S. , Giannikou Krinio , Kwiatkowski David J.
Published: June 2022

e16532

Background: Mutation and inactivation of the tumor suppressor gene TSC1 is a recurrent (6-10%) event in bladder cancer, but whether it functions as a driver event for tumor development has been uncertain. Methods: We performed differential gene expression and pathway analyses using RNA-seq data from the curated TCGA TSC1 mutant BLCA (n = 26) and TSC1 wild-type BLCA (n = 382) cohort and compared to an internal cohort of putative TSC1/TSC2-driven tumors (n = 63). Mechanistic studies, as well as RNA-seq and H3K27ac ChIP-seq analyses, were conducted in 2 TSC1 mutant/WT BLCA cell lines. Results: Comparison of The Cancer Genome Atlas (TCGA) TSC1-mutant bladder cancers ( TSC1mBLCA) with TCGA TSC1 wildtype tumors ( TSC1WTBLCA) identified a conserved TSC-associated expression signature, similar to ones seen in syndromic TSC tumors. GSEA and DESeq2 analyses implicated both mTORC1 hyperactivation, as well as activation of lysosomal pathways in TSC1mBLCA. We validated our findings by IHC analysis of a separate cohort of TSC1mBLCA (n = 5), compared to TSC1WTBLCA (n = 5). In addition, we found that TFE3, a transcriptional regulator of lysosomal gene expression, was relatively highly expressed in BLCA (compared to other MiT-TFE genes) and was localized to the nucleus in TSC1mBLCA but not in TSC1WTBLCA. Mechanistic studies of two TSC1mBLCA cell lines and their respective TSC1 addback derivatives, recapitulated the phenotype found in human tumors and demonstrated that TFE3 was both post-translationally modified and predominantly nuclear in TSC1-null cell lines compared to TSC1 addbacks. RNA-seq and H3K27ac ChIP-Seq analyses showed that TSC1mBLCA cell lines retained elements of the TSC-associated expression signature that was seen in TSC1mBLCA tumors, confirming differential activation of TFE3 in response to TSC1 loss. Nuclear localization of TFE3 in TSC1mBLCA cell lines was only partially reversed by rapamycin treatment and was unaffected by treatment of Torin1. SiRNA mediated knockdown of TFE3 significantly decreased cell growth and viability in TSC1mBLCA cell lines and did not result in compensatory upregulation of TFEB and MITF. Conclusions: Our findings indicate that TSC1 mutant bladder tumors retain elements of a conserved transcriptional signature that is characterized by nuclear localization and activation of TFE3. Aberrant TFE3 activation likely contributes to TSC1mBLCA development and may therefore be amenable to targeted therapy.
Five-year survival stratification using “the Cancer Of the Bladder Risk Assessment” (COBRA) score for micropapillary and sarcomatoid urothelial carcinoma of the bladder variants.
Authors: Rivera Carlos , Jabbal Iktej Singh , Yaghi Marita , Saravia Diana , Muruve Nicolas , Ercole Barbara , George Tiffany L. , Nahleh Zeina A. , Arteta-Bulos Rafael Eduardo
Published: June 2022

e16534

Background: The Cancer of the Bladder Risk Assessment (COBRA) score is a validated risk stratification tool for patients with urothelial carcinoma of the bladder (UCB) after cystectomy. Radical cystectomy with or without neoadjuvant chemotherapy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Lymph node density and the presence of positive lymph nodes have been demonstrated to be critical prognostic tools. Our goal was to evaluate 5-year overall survival (OS) on UCB variants: micropapillary and sarcomatoid, stratified by COBRA score and the presence of lymph nodes. Methods: We sampled the National Cancer Database (NCDB) for bladder cancer patients diagnosed with de novo micropapillary and sarcomatoid UCB between 2004 and 2018 and treated with radical cystectomy. 5-year Kaplan-Meier survival plots were utilized to assess OS differences amongst different COBRA score groups and stratified by the presence of lymph nodes (LNs). A multivariable Cox regression model was used to compare hazard ratios, adjusting for significantly unbalanced factors. A p-value < 0.05 was considered statistically significant. Results: A total of 1382 patients met the inclusion criteria. The average age was 68.10 + 10.31 years. 75% were male. Micropapillary represented 50.1% of selected histologies, followed by 49.5% sarcomatoid. For all combined histologies, 5-year OS percentage for patients with cystectomy and stratified by COBRA score (0-7) were 66% COBRA 0, 54% COBRA 1, 34% COBRA 2, 29% COBRA3, 15% COBRA > 4) (p < 0.001). 5-year OS for patients with cystectomy stratified by LN status was 54% for LN negative and 24% for LN positive (p < 0.001). Substratification of the cohort according to the presence of LNs and COBRA score have shown a numerical drop in 5-year survival and a notable decrease in median survival amongst compared groups. The risk of death was almost 5 times higher in patients with a high COBRA score (> 4) than in patients with a COBRA score of 0 (HR = 5.15, p < 0.001). Conclusions: COBRA score could contribute to clinical decision-making as a risk stratification tool for patients with UCB variants, micropapillary and sarcomatoid. 5-year OS decreases with higher COBRA scores, and LN status plays a major role in 5-year OS for these two UCB variants.[Table: see text]
Impact of PD-L1 expression on conventional urothelial bladder carcinoma (UCB) genomic alteration (GA) profile.
Authors: Necchi Andrea , Grivas Petros , Spiess Philippe E. , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Graf Ryon , Danziger Natalie , Ross Jeffrey S.
Published: June 2022

e16535

Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been used as a biomarker to predict immune checkpoint inhibitors response in UCB. We hypothesized that the GA profiles would differ between UCB featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UCB with known PD-L1 tumor cell expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alteration (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included in this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UCB featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amplification (P = .05). The gender, age and GA per tumor frequencies were similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p = .02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. The mean gLOH scores were similar in both groups. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UCB cases where a mutational signature could be determined, 15/33 (45%) of PD-L1H and 34/112 (30%, p = 0.14) of PD-L1N UCB featured an APOBEC gene signature; 79% of PD-L1H and 83% of PD-L1N featured European ancestry (p = 0.61). Conclusions: PD-L1H and PD-L1N subtypes of UCB differ in their genomic profiles. PD-L1N UCB features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UCB but also in designing trials that may combine ICPI with targeted therapies.[Table: see text]
Time-of-day infusion of immunotherapy in metastatic urothelial cancer (mUC): Should it be considered to improve survival outcomes?
Authors: Ortego Ignacio , Molina-Cerrillo Javier , Pinto Alvaro , Santoni Matteo , Alonso-Gordoa Teresa , Lopez Criado M. Pilar , Gonzalez-Morales Alejandro , Grande Enrique
Published: June 2022

e16541

Background: Immune-checkpoint inhibitors (ICIs) are key in the current management of mUC pts. Recent data in melanoma revealed a link in between the circadian rhythm of the immune-system and expected activity with ICIs (Quian et al, Lancet Oncol 2021). In preclinical models naïve CD4 and CD8 T cells in blood have shown to approach nadir levels around 4 P.M., and therefore, to lower adaptative immune responses after that time. We aimed to correlate the activity of single agent ICIs for the systemic treatment of mUC pts depending on the time of administration. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 1 in Italy of patients with mUC who initiated treatment with anti-PD1 or anti-PDL1 as 1st or subsequent line. ICIs were administered and managed according to product labelling. Time cut-off as adaptive immune-modulation for ICIs administration was considered after 4:30 PM. We divided pts into those who received at least 20% of their infusions after 4:30 PM and those who received fewer than 20% after that time. Other data such as patient characteristics and adverse-events related to the treatment were also collected. We carried out a survival analysis by a Cox regression model. Results: From 2016, 92 pts were treated with single agent ICIs for mUC. Most of the pts (n = 62; 67.4%) received less than 20% of the doses after 4:30 PM, while a lower proportion (n = 26; 28.3%) received at least 20% of the doses after that time. Median follow-up time of immunotherapy was 8.6 months. 35 (38.0%) and 57 (62.0%) pts received ICIs as 1st and subsequent lines of treatment respectively. There were no differences in the proportion of pts in 1st vs subsequent lines and time of administration, nor other well prognostic baseline factors like PD-L1 expression, or Bajorin or Bellmunt’s scoring. A significant benefit in both PFS (11.38 vs 3.58 months; HR 2.66: 95%CI 1.53-4.63; p = 0.001) and in OS (14.04 vs 6.80 months; HR 2.62: 95%CI 1.48-4.63: p = 0.001) benefited to pts who received less than 20% of the doses after 4:30 PM. Response rate also favored (59.3% vs 16.0%) the earlier administration of the treatments. Neither corticosteroids concomitant use nor immune-related toxicity appeared to impact on these outcomes. Conclusions: Time of the day administration of ICIs may influence the efficacy of ICIs in mUC pts. Although the small size of the sample and the short median follow-up is something to be considered, this data are promising and consistent with the previous studies. Prospective confirmation is needed.
Competing endogenous RNA network features and prostate tumor cell sensitivity to radiotherapy.
Authors: Kutilin Denis S. , Zinkovich Mikhail S. , Gusareva Marina A. , Shevchenko Aleksey N. , Faenson Aleksandr V. , Solntseva Anna A. , Fatkina Natalya B. , Vasilieva Ekaterina O. , Filatova Elena V. , Kosheleva Natalia G , Tolmacheva Ekaterina A. , Martynova Ksenia V. , Gappoeva Madina A. , Udalenkova Irina A. , Khomutenko Irina A. , Rozenko Lyudmila Ya , Pavlyatenko Inna V. , Gvaramiya Astanda K. , Kit Oleg I.
Published: June 2022

e17008

Background: Radiotherapy (RT) is one of the main treatments for prostate cancer (PC). The effectiveness of RT depends on the initial radioresistance of tumor cells provided by their certain molecular features - the transcriptional activity of genes, miRNAs and long non-coding RNAs (lncRNAs). Together, these indicators form a competing endogenous RNAs network (ceRNAs). The aim of this work was to study the ceRNA features in PC patients with different responses to RT. Methods: The study included 400 patients with PC, 90 of them developed biochemical recurrence after RT (Novalis TX, TFD = 75 Gy). Tumor tissue samples were obtained by biopsy. The RNA fraction was isolated and purified using the RNeasy Plus Universal Kits. Bioinformatic search for miRNAs was performed using a modified TarPmiR algorithm. The miRNA-lncRNA interactions were assessed by bioinformatics. Expression of AKT, ATM, BRIP, BRCA1/2, CDK1, CDKN1B, CCND1/3, EXO1, H2AX, KU70, PTEN, RAD50, RAP80, RIF1, RNF168, TOPB1, TP53, XRCC4, BAX, CASP-8, -3, -9, MDM2, BCL2, RBBP8, EP300 genes, miRNA and lncRNA were determined by RT-qPCR. Differences were assessed using the Mann-Whitney test (Bonferroni correction was used). Results: The expression of CDK1, CDKN1B, RBBP8, XRCC4, BRCA2, RAD50 genes in tumor tissues of patients with biochemical recurrence (group 1) was higher (p < 0.005) and the expression of TP53 and BCL2 was lower than the values in tumor tissues in patients without recurrence (group 2). Bioinformatic search for miRNAs targeting the CDK1, CDKN1B, RBBP8, XRCC4, BRCA2, RAD50, TP53 and BCL2 revealed 1725 miRNAs, 78 of which were validated (miRDB) and had a minimum free energy of miRNA-mRNA interaction. Patients in group 1 showed differential expression of miRNAs targeting genes BCL2 (increased miR-139-5p, miR-4446-5p, miR-211-5p); CDK1 (decreased miR-330-3p, miR-5580-3p, miR-429), CDKN1B (decreased miR-6841-3p); RAD50 (decreased miR-433-3p, miR-3691-5p); RBBP8 (decreased miR-130b-3p); TP53 (increased miR-6884-5p, miR-149-3p, miR-6860, miR-4728-5p, let-7b-5p); XRCC4 (decreased miR-4489) and BRCA2 (decreased miR-7151-3p). The interaction of these miRNAs with 160 lncRNAs was mathematically predicted. Patients in group 1 demonstrated increased expression of lncRNAs LINC00641, SCAMP1, MALAT1, MATN1-AS1 (miR-429) , LINC00657 and GAS5 (miR-433-3p), CCAT1 (miR-130b-3p) and reduced expression of S NHG3, DHRS4-AS1 (miR-139-5p) and MAL2 (let-7b-5p). Conclusions: Our study of the ceRNA network features and RT effectiveness for PC established the mechanisms of radioresistance development and its predictors.
Early metabolic syndrome in testicular germ cell tumors : A prospective study from India.
Authors: Pandey Prashant , Dabkara Deepak , Ganguly Sandip , Ghosh Joydeep , Roy Somnath , Mondal Debapriya , Gupta Sujoy , Nair Reena , Biswas Bivas
Published: June 2022

e17010

Background: Metabolic syndrome (MS) is a known complication in patients of testicular germ cell tumors . Early metabolic syndrome is not well-defined and literature on the same is scarce. Methods: This is a single institutional prospective cohort study of patients with testicular germ cell tumors from Jan’2020 to June 2021 with a minimum follow-up of 6 months after treatment completion. Patients were evaluated for MS as per NCEP ATP (National Cholesterol Education Program Adult Treatment Plan) III criteria and partial MS was defined if any one abnormal criteria was present. Clinicopathologic and treatment characteristics were correlated with development of MS. Results: Thirty-six (25 nonseminomatous tumor and 11 seminoma) were included with median age of 29 yrs (range: 18-44). Treatment protocol was - platinum based chemotherapy [BEP (n = 7), EP(n = 18),VIP(n = 4) ]in 81% (n = 29/36), single agent carboplatin in 8% (n = 3/36), and surveillance only in 11% (n = 4/36) patients. Incidence of complete metabolic syndrome noted in 42% (n = 15) and partial metabolic syndrome in 36% (n = 13) of patients after median follow-up of 13.2 months (range-6-22). Deranged parameters detected were - high serum triglyceride (≥150 mg/dl) in 64% (n = 23/36), low serum HDL cholesterol (< 40 mg/dl) in 53% (n = 19/36), high blood pressure (≥130/85 mm of Hg) in 47% (n = 17/36), high waist circumference (> 110 cm) in 6% (n = 2/36) and high fasting plasma glucose (≥5.6 mmol/L) in 22% (n = 8/36) of patients. Median weight gain was 5 Kg (range: 2-14). The median time to development of metabolic syndrome was 143 days (range: 90-461). Hypogonadism (testosterone < 433ng/dl.) showed positive correlation (degree of freedom = 0.3143) and C-reactive protein showed negative correlation (degree of freedom -0.3090) with MS, respectively. Conclusions: Majority of Testicular germ cell tumor patients (n = 28, 78%) had features of early MS, irrespective of treatment modalities. Patients with hypogonadism are more likely to develop early MS. Larger prospective studies are warranted to assess the incidence of early MS in patients with testicular germ cell tumors and to formulate appropriate health intervention to mitigate its significant long-term effects on mortality and morbidity.
What is the impact of ischemic heart disease on PSA testing?
Authors: Panzone John , Welch Christopher , Wu Maximillian S , Jacob Joseph M , Shapiro Oleg , Basnet Alina , Bratslavsky Gennady , Goldberg Hanan
Published: June 2022

e17014

Background: Prostate Specific Antigen (PSA) testing can improve early prostate cancer detection. However, numerous factors can influence patients’ willingness and ability to undergo PSA testing. Methods: We performed a cross-sectional study investigating the impact of various degrees of ischemic heart disease (IHD) on PSA testing. We assessed 3,822 male respondents aged 55-75 from the 2018 year of the National Health Interview Survey (NHIS). Men were stratified according to the degree of IHD (none, history of angina pectoris (AP), history of myocardial infarction (MI), or history of neither, but with a diagnosis of IHD). Multivariable logistic regression analysis was used to assess the relationship between IHD and being tested for PSA, adjusting for known cofounders. Results: Multivariable logistic regression demonstrated that males with a history of IHD (no MI or AP) were more likely to have ever been PSA tested than males without IHD (p = 0.012, OR = 1.630, 95% CI 1.115-2.383), as seen in Table. Additionally, older age (p < 0.001), having a partner (vs. no partner p < 0.001), homosexual sexual orientation (vs. heterosexual orientation p = 0.007), and a history of cancer (vs. no history p < 0.001) all increased likelihood of being PSA tested. In contrast, Asian race (vs. White, p = 0.001), and being a current smoker (vs. no smoking history, p < 0.001) decreased the likelihood. Interestingly, males with a history of a symptomatic IHD (MI or AP) were not shown to be more likely to undergo PSA testing. Conclusions: Our results suggest that males with non-symptomatic IHD are more likely to be PSA tested. Males with symptomatic IHD do not seem to undergo more PSA screening, perhaps due to lower suggested life expectancy. Awareness of discrepancies in PSA testing in men with IHD should be raised. Table - Multivariable logistic regression analyses demonstrating relationships with likelihood of being PSA tested.[Table: see text]
Predictive significance of tumor-associated miRNA-21 and -221 expression in patients with prostate cancer.
Authors: Tryfonyuk Liliya , Borikun Tetiana , Zadvornyi Taras , Rossylna Olha , Pavlukovich Natalia
Published: June 2022

e17015

Background: It is thought that the occurrence and progression of tumors, such as prostate cancer (PCа), may be due to decreased levels of tumor-inhibiting microRNAs and/or overexpression of oncogenic microRNAs, but their specificity and role in tumor progression are contradictory. That is why the study of the possibility of using miRNAs as prognostic markers is especially relevant. Objective: to investigate the features of tumor -associated microRNAs-21 and -221 expression in PCa tissue with different risk of progression and to determine the relationship of their indicators with the molecular profile of tumors. Methods: The study was conducted on the clinical material of 60 patients with PCa stage II-III, who were treated in Rivne Regional Hospital and Rivne oncological center during 2018-2021 years. Determination of the risk of PCa progression was performed by D'Amico et al. (1998). Immunohistochemical study of Ki-67 expression (clone MIB -1) and androgen receptors (AR) (clone 441) were performed on paraffin sections of tumor tissue using the Ultra Vision LP Detection System (Thermo Scientific, USA). Determination of microRNA-21 and -221 levels were determined using real-time quantitative PCR. Statistical processing of the results was performed using GraphPad Prism 8. Results: It is determined that a characteristic feature of PCa with a low risk of progression by D'Amico et al . are low expression of oncogenic miRNA-21 and -221 in tumor tissue. In particular, in the PCa samples of high risk of progression (n = 30) the level of miRNA-21 was 3.2 times (p < 0.05), and miRNA-221 was 1.35 times (p < 0.05) higher compared to tumor tissue of patients with low progression (n = 30). The existence of a direct correlation between the expression of miRNA-21 and the proliferative activity of PCa (ρ = 0.63; p < 0.05) is shown. We found that the expression of miRNA-221 is associated with a high level of AR expression (ρ = 0.43; p < 0.05) . Conclusions: The obtained data indicate the relationship of tumor -associated microRNA-21 and -221 with the risk of tumor progression and such molecular biological characteristics of tumors as proliferative activity and receptor status, which indicates the prospects for their further study as additional markers for predicting of PCa course.
Real-world treatment patterns in the U.S. and trends pre-post CARD trial among patients with metastatic castration-resistant prostate cancer.
Authors: Ghantoji Shashank , Yu Channing , Sawhney Amrita , Byrne Clare , Tang Jackson , Runeckles Kyle , Patel Jeetvan
Published: June 2022

e17024

Background: Numerous treatments with different mechanisms of action are approved for metastatic castration-resistant prostate cancer (mCRPC). The sequencing for management of these patients has been evolving post availability of trials such as the CARD trial, looking at clinical outcomes post androgen receptor pathway inhibitor (ARPI) and docetaxel. This study examined real-world treatment patterns and sequencing among United States patients with mCRPC. Methods: This retrospective cohort study used Flatiron Health electronic health record data from Jan 1, 2013 to June 30, 2020 (study period). Included patients were male aged ≥18 years, had a confirmed diagnosis of mCRPC within the study period, and received ≥1 systemic therapy post-mCRPC diagnosis. Index date was the date of first-line (1L) therapy initiation post-mCRPC diagnosis. Patient characteristics and treatment patterns were evaluated descriptively. Across analyses, treatments were grouped as follows: ARPI (abiraterone, enzalutamide), taxane (docetaxel, cabazitaxel), sipuleucel-T, radium-223, targeted therapy (TT; olaparib, rucaparib), mitoxantrone, combo therapy (any combination regimen containing ≥1 of the preceding therapies), and other (any other therapy or combination of therapies). Results: 2,588 patients were included in the study; mean±SD age was 72±8 years and 66% were White. The most common 1L therapy was ARPI (63%), followed by taxane (11%), combo therapy (11%), radium-223 (6%), sipuleucel-T (6%), and other therapy (2%). No patient received TT or mitoxantrone alone in 1L. Median time to next treatment post-1L was longest for combo therapy (8.1 months) and ARPI (7.6 months) and shortest for sipuleucel-T (3.4 months). The most common sequence of treatment for mCRPC patients was 1L ARPI to another ARPI at second-line (2L) (29%); taxane and combo therapy (both 14%) were the next most common (Table). Treatment patterns were similar pre- and post- read-out of the CARD trial. Conclusions: The majority of mCRPC patients who receive 1L ARPI will receive another at 2L rather than switching to an alternative type of treatment.[Table: see text]
Assessment of serial serum chromogranin A (CGA) and CGA/PSA ratio and treatment response with abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Lewis Akeem Ronell , Costello Brian Addis , Quevedo Fernando , Pagliaro Lance C. , Weinshilboum Richard M. , Wang Leiwei , Kalari Krishna Rani , Kohli Manish , Tan Winston , Giridhar Karthik
Published: June 2022

e17036

Background: Elevated serum CGA is associated with an intrinsic or treatment-related neuroendocrine differentiation in men with mCRPC. We previously demonstrated that elevated serum CGA was negatively associated with OS in men with mCRPC. Fluctuations in serum CGA during mCRPC therapy is not well known. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with AA therapy. Methods: Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial (“PROMOTE”; NCT#01953640) with uniform serum processing performed prior to initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients (pts) receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded). All patients underwent a composite response assessment at 12-weeks with imaging/PSA/QOL questionnaires. Kaplan Meier estimates, and Cox Regression models were used to calculate association with time-to-treatment failure (TTF) analyses, defined as time from treatment initiation to AA/P discontinuation based on disease progression (BlueSky Statistics, Chicago, IL, USA). Results: Of the 71 eligible pts, 67/71 had paired baseline and 12-week CGA and 70/71 pts had a baseline and a 12-week PSA available. The median baseline CGA was 83.0ng/ml (range: 53.0 - 127.0 ng/ml), median baseline PSA was 14.4 ng/ml (range: 6.4-40.2 ng/ml), and the median TTF was 10 months (range: 6-25 months). The median CGA after 12 weeks of AA/P was 98.0 ng/ml (58.0 -148.0 ng/ml) and we observed a CGA rise in 41/67 (61.2%) pts. An increase in chromogranin was associated with a lower risk of treatment failure (HR: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6 -16.0). An elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). Conclusions: We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in pts with mCRPC were associated with a favorable response to AA/P. Further studies are needed to assess if rising CGA during therapy reflects neuroendocrine differentiation and may indicate a sign of treatment effect targeting the androgen susceptible cells. Clinical trial information: NCT#01953640.
Survival benefit of postoperative adjuvant chemotherapy for patients in poor-differentiated early-stage cervical cancer: A multicenter, cohort study.
Authors: Lu Huaiwu , Xu Miaochun , Zhou Ying , Zhao Bingbing , Ren Fang , Wei Luwei , Chen Qing , Zhang Bingzhong , Lin Zhongqiu
Published: June 2022

e17509

Background: Postoperative adjuvant therapy decisions for early-stage cervical cancer (ESCC) without high risk factor, including parametrial extension, positive nodes and positive margins, now depend on Sedlis criteria, which do not mention the degree of differentiation. In this study, we aimed to explore the benefit of adjuvant chemotherapy for patients of ESCC with poor differentiation but without positive Sedlis criteria after radical hysterectomy, and develop a score to predict the recurrence risk in these patients, so as to further improve the indications of postoperative adjuvant therapy for patients of ESCC. Methods: Patients of ESCC with pathologically proven poor differentiation after radical hysterectomy were prospectively included in a multicenter study. Univariate Cox proportional hazards regression were developed to evaluate the independent risk factors for recurrence. The log-rank test was performed to compare the progression-free survival (PFS) and overall survival (OS) of adjuvant chemotherapy (ACT) and no further treatment (NFT) groups. Selected variables were analyzed in a Multivariate Cox Regression Model and used to build a nomogram for ESCC to predict the survival probabilities. Results: In total, 352 patients were randomly assigned to two groups, a training group and a validation group, at a ratio of 1:1 (176 patients: 176 patients). In both of training and validation cohort, the ACT groups had longer PFS than the NFT groups ( P= 0.007 and 0.016, respectively), while the differences of OS were not statistically significant ( P= 0.922 and 0.107, respectively). In the multivariate analysis, ACT was proved an independent prognostic factor for the PFS (P = 0.048), and the strongest predictor of PFS even analyzing with other potential independent prognostic factors (HR 0.116, 95%CI 0.014-0.981). Five factors, including postoperative treatment, histologic type, isthmus uteri involvement, FIGO stage, SCCA level, were included in the nomogram to predict survival probabilities in the training cohort and performed well in the validation cohorts. Conclusions: For the patients of ESCC who don't meet to Sedlis criteria but with poor differentiation, ACT after radical hysterectomy can reduce the recurrence rate.