bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of venous resections in cancer of the pancreatic head.
Authors: Kit Oleg I. , Katelnitskaya Oksana V. , Maslov Andrey A. , Maksimov Aleksey Yu. , Kolesnikov Evgeniy N. , Gevorkyan Yuriy A. , Trifanov Vladimir S. , Kozhushko Mikhail A , Snezhko Aleksandr V. , Petrov Dmitry S. , Fomenko Yuriy A.
Published: May 2020

e16785

Background: Studies have shown that pancreaticoduodenal resection (PDR) with resection and reconstruction of the venous segment does not interfere with surgical treatment for ductal pancreatic adenocarcinoma with suspected venous invasion. Venous resection improves survival compared to palliative interventions. However, the advantages and disadvantages of marginal resection, segmental resection with direct anastomosis, and venous segment prosthetics are not reflected. Methods: The study included 52 patients (23 women, 29 men) undergoing PDR with venous resection and reconstruction for cancer of the pancreatic head in 2015-2019. The average tumor size was 3.8 cm. Results: Superior mesenteric vein reconstruction (PTFE grafts) was performed in 17 patients (32.7%), sleeve resection with direct anastomosis - 24 (46.2%), marginal resection - 11 (21.1%). Venous reconstruction was planned in 78.8% of patients before the surgery. In the early postoperative period, thrombosis of the reconstructed zone was developed in two patients (3.8%), bleeding from the pancreatic bed - in one case (1.9%). Postoperative mortality was 5.8% (3 patients). After the final pathological examination, macroscopically incomplete resection was diagnosed only in the group with marginal resection and amounted to 3.8%. Microscopically incomplete resection was diagnosed in 9.6% of the studied preparations (in marginal resection of the vein wall - 3.8%, with direct anastomosis - 1.9%, SMV prosthetics - 3.8%). Most often, R1 resection was detected in the retroperitoneal resection margin (80%). The lowest 1-year survival was observed in the group with marginal resection (36.4%). No significant differences in survival rates were found in patients with direct venous anastomosis (62.5%) and venous prosthetics (64.7%) (RR 1.69; 95% CI 0.69-4.12, p > 0.05). Microscopically complete resection R0 improved the survival (RR 2.7; 95% CI 1.45-5.04, p < 0.05). Planning the venous resection was an additional risk factor affecting the completeness of resection (RR 4.6; CI 95% 1.5-14.5, p > 0.05). Conclusions: Expanding the surgery volume in PDR due to venous resection and reconstruction shows acceptable rates of postoperative morbidity and mortality. Planning the venous resection enhances the results of radical surgery.
Implementing a novel method to estimate the "Burden of Therapy" (BOTh) for patients with metastatic pancreatic cancer treated with gemcitabine plus afatinib vs. gemcitabine in the AIO ACCEPT trial.
Authors: Haas Michael , Abdul-Ahad Ayad , Snijder Robert , Waldschmidt Dirk Thomas , Stahl Michael , Reinacher-Schick Anke C. , Freiberg-Richter Jens , Kaiser Florian , Kanzler Stephan , Frickhofen Norbert , Seufferlein Thomas , Dechow Tobias Nicolaas , Mahlberg Rolf , Malfertheiner Peter , Illerhaus Gerald , Kubicka Stefan , Held Swantje , Boeck Stefan Hubert , von Bergwelt-Baildon Michael , Heinemann Volker
Published: May 2020

e16786

Background: The phase II ACCEPT trial included 119 patients (pts) with histologically proven pancreatic cancer without any previous systemic treatment for metastatic disease. Pts were randomized in a 2:1 ratio to receive either afatinib 40mg orally once daily + gemcitabine (1000mg/m2 iv weekly for three weeks followed by one week of rest, repeated every four weeks) or gemcitabine alone. The addition of afatinib did not lead to improved efficacy (7.3 vs. 7.4 months, HR 1.06, p = 0.80; data previously shown). The traditional analysis of adverse events was not able to reveal the actual patient´s burden in each of the treatment arms. Methods: BOTh is a highly sensitive, novel methodology utilizing patient-level data to derive a quantitative estimate for the “Burden of Therapy/Toxicity” (BOTh) that all or individual pts experience on each day of a clinical study*. The daily burden estimate is based on number and severity of adverse events (AEs) that occur contemporaneously and consecutively, in a combination of incidence and severity resulting in a major advantage over current methods. A chart displays the total burden experienced by pts on each day throughout the study and statistical analyses are performed with the area under curve. Results: The BOTh analysis revealed that the daily burden of toxicity for pts in the gemcitabine-alone arm was 6.8 compared to 11.5 in the combination treatment arm (p = 0.0005). However, the day to day variation in burden was higher in the gemcitabine-alone arm. The higher burden in the combination arm was already visible at a very early stage of the trial when most pts were still on treatment. Conclusions: Whereas the traditional analysis of AEs only gave a static interpretation, BOTh revealed a more dynamic view on burden of toxicity on pts taking single vs combination medication in a 200 day time frame. BOTh can facilitate better informed treatment selection. *Abdulahad A. et.al, Contemporary Clinical Trials Communications 4 (2016) 186-191. Funding: The ACCEPT trial was funded by an unrestricted financial grant by Boehringer Ingelheim. Clinical trial information: NCT01728818 .
Genomic-directed personalized matched targeted therapy approach may improve clinical outcomes among patients with advanced pancreatic cancer.
Authors: Shaya Justin , Kato Shumei , Patel Hitendra , Fanta Paul T. , Kurzrock Razelle
Published: May 2020

e16794

Background: Despite advances in pancreatic cancer management, 2-year overall survival (OS) remains to be less than 10% in patients with metastatic disease. Given this, novel therapeutic approaches are urgently needed. We hypothesize that a matched combination targeted therapy approach, which is customized based on patient’s cancer genomics, may have clinical efficacy among advanced pancreatic cancer patients. Methods: This is a single center retrospective analysis of advanced pancreatic adenocarcinoma patients treated at UC San Diego. All patients (N = 26) received matched targeted therapy based on genomic alterations detected by tissue NGS and/or blood cell-free DNA assays. This study followed the guidelines of the IRB-approved UCSD PREDICT study (NCT02478931). Results: In the cohort, median age was 67 and 62% (N = 16) were female. 27% (N = 7) received matched therapy front line and 73.1% (N = 19) received matched therapy in the second line or later. The median number of targeted agents administered was 3 (range 1-4). There was a significant improvement in progression-free survival (PFS) when matched therapy was administered in the first line when compared to second line or greater (7.0 vs 2.8 months, hazard ratio [HR]: 0.34, 95% confidence interval [CI]: 0.19-0.90, P = 0.031) and there was a difference in OS (1st line vs 2nd line or greater: 9.2 vs 4.4 months, HR: 0.58, 95% CI: 0.24-1.42, P =0.23). When stratified by Matching Score of ≥50% (high) and < 50% (low) (Matching Score is roughly equivalent to the number of alterations targeted by therapy divided by the total number of characterized alterations), patients who were treated with a high Matching Score demonstrated significantly prolonged PFS and OS when compared to those with a low Matching Score (PFS: 3.8 vs 2.0 months, HR: 0.34, 95% CI: 0.13-0.91, P =0.031, OS: 5.6 vs 3.3 months, HR: 0.33, 95% CI: 0.13-0.85, P =0.022). In patients with a Matching Score of ≥50%, the disease control rate (DCR) (defined as complete response, partial response, and stable disease ≥ 6 months) was 36.8% and among patients who received matched therapy first line, DCR was 71.3%. Representative cases who were successfully treated with matched targeted therapy will be presented. Conclusions: Combination matched targeted therapy, particularly in patients with a high degree of matching, showed improved clinical outcomes. While the sample size here is small and these data warrant further prospective investigation, matched combinatorial targeted therapy may offer patients a novel option for therapy.
POLO: Radiologic assessment of the impact of maintenance olaparib in patients (pts) with metastatic pancreatic cancer (mPaC).
Authors: Schwartz Lawrence Howard , Kindler Hedy L. , Hammel Pascal , Reni Michele , Van Cutsem Eric , Macarulla Teresa , Hall Michael J. , Park Joon Oh , Hochhauser Daniel , Arnold Dirk , Oh Do-Youn , Reinacher-Schick Anke , Tortora Giampaolo , Alguel Hana , O'Reilly Eileen Mary , Fromageau Jeremie , Ghiorghiu Dana C. , McGuinness David , Locker Gershon Y. , Golan Talia
Published: May 2020

e16800

Background: The Phase III POLO study (NCT02184195) demonstrated a benefit of maintenance olaparib over placebo in the radiologically assessed primary endpoint of progression-free survival (PFS) in pts with mPaC (median 7.4 vs 3.8 months [mo]; 12-mo rate 34% vs 15%). The impact of radiologic assessment of pancreatic lesions, which is considered challenging, was explored. Methods: Tumors were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review (BICR) in pts with mPaC treated with maintenance olaparib or placebo. PFS was analyzed in subsets of pts based on various event criteria. Results: All 154 randomized pts had mPaC prior to chemotherapy, of whom 122 had disease in the pancreas at POLO baseline (BL); 34% (53/154) had pancreas-only target lesions (TL), 26% (40/154) also had ≥1 TL outside of the pancreas, and in 19% (29/154) pancreatic disease was recorded as non-TL. Sensitivity analyses were consistent with the primary PFS analysis (Table), including when all pancreas lesion assessments were discounted (median PFS 7.4 vs 4.7 mo; 12-mo rate 38% vs 22%). Of 53 pts with pancreas-only TLs at BL, 34 had disease progression (PD); in 20 pts this was not solely based on TL measurements (16 had new lesions; 4 had multiple-cause PD). Confirmed objective responses occurred during study maintenance treatment in 20% of olaparib pts (18/92) and 10% of placebo pts (6/62). In pts with pancreas-only TLs at BL there were 7 responses in the olaparib arm (1 complete response [CR], 6 partial responses [PR]) and 2 (2 PR) in the placebo arm. In pts who had ≥1 TL outside of the pancreas at BL there were 11 (1 CR, 10 PR) and 4 (4 PR) responses, respectively. Responses were generally durable irrespective of TL location. Conclusions: The significant PFS benefit with maintenance olaparib over placebo shown in the primary analysis was consistent across all sensitivity analyses and was not impacted by radiologic assessment of pancreatic TLs. Taken together, these findings suggest that contrary to historically held belief, primary pancreas TLs may be appropriate for inclusion as sites of RECIST-evaluable disease and for assessment of treatment outcome. Clinical trial information: NCT02184195 . [Table: see text]
Prognostic biomarker potential of quantifying endotrophin in serum from pancreas cancer patients.
Authors: Willumsen Nicholas , Chen Inna , Nissen Neel Ingemann , Johansen Astrid Zedlitz , Johansen Julia S. , Karsdal Morten A.
Published: May 2020

e16804

Background: Pancreas cancer (PC) is the most stroma rich tumor type defined by increased collagen deposition and remodeling (desmoplasia/tumor fibrosis), which result in poor prognosis and lack of treatment response. The cleavage product of the type VI collagen alpha 3 (COL6a3) chain, also knowns as endothrophin, has been shown to signaling properties and affect several pro-tumorigenic events by augmenting desmoplasia, angiogenesis, inflammation and tumor growth. Here we evaluate the clinical utility of a biomarker (PRO-C6) quantifying endothrophin in serum from patients with PC. Methods: Serum PRO-C6 was measured by ELISA (Nordic Bioscience) in 814 PC patients (n = 15, 201, 164 and 434 for stage 1-4, respectively) and 87 patients with benign conditions from the clinical study BIOPAC (NCT03311776, Denmark). PC was histologically confirmed, and patients received standard of treatment (surgical resection or palliative chemotherapy). PRO-C6 was compared between PC and benign conditions and correlated to stage. Association between OS and PRO-C6 in PC patients was analyzed by Kaplan-Meyer curves and Cox regression analysis alone, and after adjusting for age, gender, BMI, diabetes, smoking, performance status, cachexia, CA19-9, stage and metastatic sites. Results: PRO-C6 was elevated in PC compared to benign disease (p = 0.009) and increased with tumor stage (p = 0.0006). When dividing PRO-C6 into quartiles (Q1-Q4) a stepwise decrease was detected in median OS time (Q1:380 days, Q2:264 days, Q3:236 days, Q4:176 days, p < 0.0001). Patients in Q4 had 85% increased risk of dying compared to Q1 (HR:1.85, p < 0.0001). High PRO-C6 (Q4) remained associated with poor OS after adjusting for co-variates (HR: 1.66, p = 0.0018). Conclusions: Pretreatment serum PRO-C6 (a measure of the COL6a3 chain/endothrophin) is associated with PC and has independent prognostic value. This suggests that endothrophin, and the desmoplastic reaction, plays a key role in PC and indicate that PRO-C6 may provide means for a theragnostic approach for stratifying and treating PC patients in the future. Clinical trial information: NCT03311776 .
Adjuvant chemotherapy impact on the overall survival of completely resected small bowel adenocarcinoma: An updated meta-analysis.
Authors: Haddad Philip A. , Hammoud Dalia A. , Gallagher Kevin M.
Published: May 2020

e16806

Background: While the small intestine represents around 75% of the length and more than 90% of the gastrointestinal tract mucosal surface, it contributes around 2% of gastrointestinal tumors. Adenocarcinoma which constitutes 40% of all small bowel tumors is the most common histology. Complete surgical resection of early-stage small bowel adenocarcinoma (SBAC) is the only proven potentially curative therapy. Due to the rarity of this disease and the absence of randomized trials, the benefit of postoperative adjuvant chemotherapy (ACT) in patients with completely resected localized SBAC has been controversial. A meta-analysis conducted in 2018 found no survival benefit for adjuvant therapies in SBAC. However, this meta-analysis combined studies that used adjuvant chemotherapy and chemoradiotherapy and included studies contaminated by other less chemosensitive histologies and more advanced and sometimes metastatic disease. The purpose of this meta-analysis is to evaluate the impact of ACT on the overall survival (OS) of patients with completely resected SBAC incorporating more recent studies. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of resected small bowel adenocarcinoma, English language, publications from 2000 to the present, and comparative studies reporting OS with hazard ratios (HR) or Kaplan-Meier curves of patients that underwent ACT versus those that did not. Adjuvant chemoradiotherapy studies and those that reported aggregate OS for a cohort with mixed histologies were excluded. A meta-analysis was conducted using an inverse variance method with a random-effects model. Results: Nine retrospective series which included 2082 patients were selected and analyzed. The majority of SBAC patients that received ACT belonged to stages II & III. ACT was found to be significantly associated with better OS in patients with completely resected SBAC (HR 0.66, 95%CI: 0.56-0.78, p < 0.001). Conclusions: This is the first meta-analysis to show that adjuvant chemotherapy is associated with a survival benefit in patients with completely resected small bowel adenocarcinoma. In the absence of randomized clinical trials, this meta-analysis represents the most compelling data supporting the use of ACT in this patient population.
Comparison of oncologic outcomes for robotic-assisted radical cystectomy (RARC) versus open radical cystectomy (ORC) among locally advanced and node-positive patients: An analysis of the National Cancer Database (NCDB).
Authors: Reddy Akshay G , Sparks Andrew D , Darwish Christina , Whalen Michael Joseph
Published: May 2020

e17002

Background: Despite recent concerns of atypical recurrence following RARC, utilization of the modality is increasing. The presumed mechanisms are especially relevant in more aggressive disease, where the metastatic potential of tumor cells may be greater. This study aims to compare the oncologic efficacy of RARC to ORC among patients with stage pT3-4 or node-positive bladder cancer. Methods: A retrospective cohort analysis of pT3-4N0-3 and pT(any)-4N1-3 patients who underwent RARC or ORC from 2010-2016 was performed using the NCDB. Appropriate univariate and multivariable analysis were performed between treatment cohorts. Results: RARC was significantly associated with superior unadjusted survival compared to ORC (median survival relative to ORC; 23.6 mo. vs. 21.6 mo.; P= 0.001). Additionally, RARC was associated with lower proportions of unadjusted 30- and 90-day mortality, positive margin status, and shorter surgical inpatient stay (all respective P< 0.05). However, after adjusting for confounding covariates, multivariable analysis revealed no difference in mortality hazard or odds of secondary outcomes with the exception of inpatient stay (Table). RARC was also significantly associated with higher lymph node yield (increased incidence of > 14 lymph nodes examined relative to ORC; 55% vs. 40%; P< 0.01). Conclusions: RARC is no less safe than ORC for patients with locally advanced or node-positive bladder cancer on the basis of overall, 30- and 90-day survival outcomes. Unadjusted mortality and surgical outcomes in this population demonstrate advantages to the robotic modality. Perioperative benefits may favor RARC, but further randomized control studies are necessary to better elucidate differences between surgical approaches. [Table: see text]
Emerging clinical phenotype of bone metastatic urothelial cancer (mUC): Association of early osseous metastases (EOM) and outcomes.
Authors: Nelson Ariel Ann , Cronk Robert , Szabo Aniko , Lemke Emily , Giever Thomas A. , Burfeind John D. , Kilari Deepak , Riese Matthew John , Bylow Kathryn A. , Diamantopoulos Leonidas Nikolaos , Khaki Ali Raza , Nezami Behtash , MacLennan Gregory , Draves Mary Ann , Goolamier Gordon , Rosey Samantha , Calaway Adam , Grivas Petros , Ponsky Lee Evan , Hoimes Christopher J.
Published: May 2020

e17007

Background: Outcomes of patients (pts) with mUC with EOM have not thoroughly been described in the age of immuno-oncology. We hypothesized that EOM is associated with worse outcomes when compared to pts with non-osseous metastases (NOM). Methods: We used a multi-institutional database of pts with mUC who received systemic treatment (trt) between March 2005 and August 2019, to assess survival and palliative outcomes of pts with EOM vs NOM at the time of metastatic diagnosis (met dx). Wilcoxon rank-sum and chi-square tests were performed. Survival was estimated by Kaplan-Meier method, Cox regression analysis was performed. Results: We identified 270 pts, 72% men, mean age 67 ± 11 years, 28% never smokers. At met dx, 27% (n = 72) had ≥ 1 EOM; these pts were more likely to have de novo metastases vs. those with recurrent metastases (42% vs 19%, p < 0.001). Pts with EOM were more likely to have a change or stop in 1st line trt due to clinical progression (30.6% vs 15.7%, p = 0.006), and received fewer total lines of systemic trt, median of 1.0 (1.0-5.0) vs. 2.0 (1.0-8.0), p = 0.05. Pts with EOM had shorter median overall survival (OS) vs. those with NOM, (6.1 vs 13.7 months, p < .0001), HR = 2.79 (95% CI:1.95-3.97, p < .0001). Median OS was shorter for pts with EOM who received 1st line immune checkpoint inhibitor (n = 14) vs platinum-based chemotherapy (n = 43), (1.6 vs 9.1 months, p = 0.003). Pts with EOM received higher opioid analgesic doses at the first and last oncology outpatient visits compared to pts with NOM with mean morphine milligram equivalent (MME) dose of 60 ± 91 vs 28 ± 65 at first visit, p = 0.004, and 171 ± 214 vs. 94 ± 229 at last visit, p < 0.001. Conclusions: The presence of EOM in mUC is associated with worse outcomes vs. pts with NOM. Pts with EOM may benefit from 1st line platinum-based chemotherapy vs. checkpoint immunotherapy. Furthermore, pts with EOM experience more pain than pts with NOM and may benefit from early engagement with palliative care. Pts with EOM represent a population with a highly unmet need for systemic, targeted and/or radiation interventions. Molecular subtypes may further define these pts and analysis is planned. We encourage ongoing clinical trials to report outcomes in pts with EOM. A consensus on reporting of non-measurable disease is also needed. [Table: see text]
Systemic immune-inflammation index to predict survival in patients with metastatic urothelial carcinoma treated with second-line vinflunine.
Authors: Palacka Patrik , Katolicka Jana , Albertova Tana , Rejlekova Katarina , Obertova Jana , Hrncar Matej , Chovanec Michal , Slopovsky Jan , Mego Michal
Published: May 2020

e17019

Background: Based on our previous study, the systemic immune-inflammation index (SII) is a prognostic factor in patients with metastatic urothelial cancer (MUC) treated with platinum-based first-line chemotherapy. The objective of this retrospective analysis was to explore prognostic value of the SII at baseline of second-line chemotherapy with vinflunine in MUC population. Methods: We evaluated 70 consecutive MUC (53 bladder, 21 upper tract) patients (54 men) treated with second-line chemotherapy with vinflunine at four oncological departments since 2010. ECOG performance status (PS) ≤ 1 had 44 patients (pts.), haemoglobin < 10 g/dL was present in 25 pts. and liver involvement in 18 pts. SII was based on platelets (P), neutrophils (N) and lymphocytes (L) counts defined as PxN/L. This study population was dichotomized by median into low SII and high SII groups. Progression-free survival (PFS), overall survival (OS) and their 95% CI were estimated by Kaplan-Meier method and compared with logrank test. Results: At median follow-up of 9.0 months (1-29 months), 68 pts. experienced disease progression and 62 died. Pts. with low SII at baseline had significantly better PFS and OS opposite to those with high SII (HR = 0.61, 95% CI 0.37-1.00, p = 0.0318 for PFS, HR = 0.60, 95% CI 0.36-1.00, p = 0.0312 for OS, respectively). In addition to the prognostic factors by Bellmunt (ECOG PS ≥ 1, liver involvement, haemoglobin < 10 g/dL), we identified peritoneal metastases as a factor associated with significantly worse survival (HR = 0.28, 95% CI 0.11-0.72, p < 0.00001 for PFS, HR = 0.30, 95% CI 0.12-0.75, p < 0.00001 for OS, respectively). Conclusions: The SII at baseline of treatment with second-line vinflunine represents a prognostic factor for pts. with MUC. Based on SII, pts. could be stratified into clinical trials in future. MUC pts. with high SII might be candidates for a different treatment approach. Key Words: Metastatic Urothelial Carcinoma. Systemic Immune-Inflammation Index. Vinflunine. Progression-Free Survival. Overall Survival.
Single-institution experience of small cell bladder cancer at a community center.
Authors: Makary Mina , Garg Tullika , Bakht Delnaz , Solangi Zeeshan , Hassanzadeh Karen , Liu Haiyan , Panikkar Rajiv Prasanna , Vadakara Joseph , Zhang Li
Published: May 2020

e17021

Background: Small cell bladder cancer (SCBC) is a rare malignancy with poor prognosis. Previous retrospective studies mainly focused on answering whether radical cystectomy is superior to radiation. Little is known about the disease characteristics and clinical course. Methods: Patients were identified via Geisinger cancer registry from 1991 to 2019, and retrospective chart review was performed through the electronic health records, EPIC. We described patient characteristics and outcomes. OS was measured from time of initial diagnosis to death or last follow up. Kaplan-Meier analyses were done on OS. Results: 50 patients were identified; 7 patients were excluded due lack of information. M: F≈1, 60% patients had pure small cell carcinoma (SCC) histology (≥ 95%), 37% with SCC and urothelial carcinoma mixed histology, MIB-1 index was 80-100%. Median OS for localized disease (IQR) was 22 months (9,73), and 11 months (7,16) for metastatic disease. For localized disease, OS were similar between patients with or without pure small cell history (P = 0.47). 8 patients were alive at 5 years; 3 patients received neoadjuvant chemotherapy followed by radical cystectomy, 2 patients underwent radical cystectomy alone, 2 patients had concurrent chemotherapy with radiation; 1 patient had complete pathological response to Cisplatin and etoposide chemotherapy, did not receive additional therapy and recurred 6 years later. Recurrence ranged from 6 to 79 months. 10 patients had disease progression despite of palliative chemotherapy. Conclusions: Small cell bladder cancer is a heterogenous disease, early stage disease can be curable but late recurrence does occur, continued surveillance is warranted even after 5 years. New treatment modality is in need to improve outcome for patients with metastatic disease.
Correlation of tumor mutational burden (TMB) with molecular profiling and clinical characteristics in patients with bladder cancer.
Authors: Natesan Divya , Martell Henry , Devine Patrick , Stohr Bradley A. , Grenert James P. , Van Ziffle Jessica , Joseph Nancy M. , Bastian Boris C. , Umetsu Sarah E , Onodera Courtney , Chan Emily , Desai Arpita , Wong Anthony C. , Porten Sima P. , Chou Jonathan , Friedlander Terence W. , Small Eric Jay , Fong Lawrence , Sweet-Cordero Eric Alejandro , Koshkin Vadim S
Published: May 2020

e17025

Background: Bladder cancers (BC) are frequently highly mutated. Next generation sequencing (NGS) can both shed light on mutational burden and the specific alterations that provide insights into the underlying biology of individual tumors. Methods: We retrospectively reviewed BC cases assessed with UCSF500, an institutional NGS assay that uses hybrid capture enrichment of target DNA to interrogate approximately 500 frequently mutated cancer genes. Hypermutated tumors were defined as having TMB > 10 mutations/Mb. Fisher’s exact test was used to compare patients (pts) with hypermutated (HM) and non-hypermutated (NHM) tumors. Results: From 2015 to 2019, 74 pts with BC underwent UCSF500 testing; 48 pts were evaluable for TMB, of which 19 pts (40%) had HM tumors. 17/19 pts were evaluable for mutational signatures; all 17 had APOBEC signatures. Signatures were not assessed in NHM tumors due to low TMB. Clinicopathologic characteristics and most common alterations in the two groups are listed in the table. More HM pts had responses to immunotherapy (IO) treatment (86% vs 40%, p = 0.13). Conclusions: In this single-institution BC cohort, HM tumors were common and APOBEC mutational signature was the common underlying biology in HM tumors. There were relevant differences in common alterations between HM and NHM tumors, including more FGFR3 mutations in NHM tumors. HM status and APOBEC signature were suggested as relevant predictive biomarkers of response to IO, which should be investigated further in larger BC cohorts. [Table: see text]
Intravesical therapy and risk of cystectomy and bladder cancer death after BCG fails.
Authors: Wong Risa Liang , Holt Sarah K , Guo Amy , Gore John L.
Published: May 2020

e17026

Background: Management of non-muscle-invasive bladder cancer (NMIBC) when BCG fails engages complex decision-making that incorporates consideration of radical cystectomy (RC) and several intravesical options. We sought to characterize trends in practice variation and health outcomes for patients receiving intravesical therapy and radical cystectomy for presumption of recurrent or progressive high-risk NMIBC that has failed BCG. Methods: We identified patients with high-risk NMIBC from SEER-Medicare diagnosed from 2004-2015 who completed a full dose of BCG treatment. We evaluated receipt of intravesical therapy after BCG fails based on a code for a transurethral resection of bladder tumor (TURBT) within 6 months of BCG treatment followed by a switch to a different intravesical agent, systemic therapy, or radical cystectomy. We constructed risk estimates for disease-specific survival and subsequent need for radical cystectomy and using the Kaplan-Meier method and multivariate Cox proportional-hazards models adjusted for competing risks of death and patient clinical/demographic factors. Results: Among high-risk NMIBC patients who received BCG in their first year of diagnosis (n = 14,369), 9.7% (n = 1,273) went on to receive intravesical therapy, 4.2% (n = 607) proceeded directly to cystectomy, 15.8% (n = 2,272) underwent re-induction with BCG, 7.0% (n = 1,009) initiated systemic chemotherapy and 4.4% died without receiving treatment after BCG. Median follow-up after the post-BCG recurrence was 29 months (IQR 42, 14-56). Those receiving intravesical therapy after BCG fails were older, had more comorbidities, resided in rural areas, and had higher proportion of clinical Ta cancers (p < 0.05 for all) compared with immediate RC patients. Intravesical agents after BCG fails are listed in the Figure. Among those undergoing intravesical therapy, 12.9% (n = 478) eventually underwent RC a median 13 months (IQR 20, 7-27) after treatment post-BCG (2-year cystectomy free survival 89.4% [95% CI 88.3-90.5%]). Actuarial 2-year and 5-year bladder cancer-specific survival was 84.0% (95% CI 82.3-85.7%) and 71.0% (95% CI 68.3-73.7%), respectively, after intravesical treatment post-BCG. Conclusions: The heterogeneity in treatments used for NMIBC that fails BCG indicates potential provider uncertainty in the management of this challenging clinical situation. The paucity of effective bladder-sparing therapies, which is reflected in a high 2-year risk of RC and bladder cancer-specific death, highlights the urgent need for new therapies in this patient population.
The role of HIF-1α in regulating NLRP3 inflammasome activation in bladder cancer.
Authors: Chen Yuan-Ru , Yeh Hsin-Chih , Chiu Fang-Yen , Wu Hsin-En , Fang Huei-Chen , Li Chia-Yang
Published: May 2020

e17028

Background: Bladder cancer is one of the most common malignancies of urinary system with the forth incidence rate and the eighth leading mortality rate in male genitourinary tumors. Hypoxia environment activates the hypoxia‐signalling pathway, principally via hypoxia‐inducible transcription factors (HIF) to activate numerous target genes which mediate embryonic vascularization, metabolism, tumor angiogenesis and the other processes to supply tissues with blood and oxygen. Inflammasomes are multiprotein signal responsible for the maturation of proinflammatory cytokines IL-1β and IL-18 as well as trigger the inflammatory cell pyroptosis. Recent study showed that HIF-1α promotes NLRP3 inflammasome activation in bleomycin-induced acute lung injury. However, the role of HIF1α in regulating the progression of bladder cancer has not been examined so far. The present study aimed to investigate the effect of HIF-1α on NLRP3 inflammasome activation in urothelial carcinoma. Methods: In this research, urothelial carcinoma cell lines were treated with NLRP3 inflammasome inducers, LPS/ATP, to induce NLRP3 inflammasome activation. Results: Our preliminary results showed that both T24 and 5637 bladder cancer cells can be induced NLRP3 inflammasome activation and IL-1β secretion. In addition, hypoxia also induces the secretion of IL-1β in T24 cells. We further investigated the effect of NLRP3 inflammasome activation in modulating EMT-related protein levels, migration and invasion in bladder cancer T24 cells. Our results demonstrated that NLRP3 inflammasome activation promotes tumor growth and metastasis in bladder cancer cells. Furthermore, knockdown of HIF1α reduces both inflammatory response and migratory activity in bladder cancer. Conclusions: Collectively, these results suggest that targeting NLRP3 inflammasome might offer potential to treat hypoxic malignant tumor in bladder carcinoma.
Oncologic outcomes of complete transurethral resection prior to neoadjuvant chemotherapy for muscle-invasive bladder cancer.
Authors: Pak Jamie Sungmin , Haas Christopher R , Vila Reyes Helena , Anderson Christopher B. , DeCastro Guarionex Joel , Benson Mitchell C. , McKiernan James M.
Published: May 2020

e17029

Background: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) is the standard of care for muscle-invasive bladder cancer (MIBC). Prior studies have shown that pT0 response at RC can be attributed to NAC and high-quality transurethral resections (TURBT) prior to NAC. Therefore, we sought to assess the association of completeness of pre-NAC TURBT with response and survival outcomes. Methods: This was a single-institution, retrospective review of patients who received NAC for clinically localized MIBC (≥cT2, N0) from 2000 to 2017. Exclusion criteria were receipt of non-cisplatin-based NAC or radiation (n = 15), and insufficient documentation of TURBT (n = 26). Complete TURBT (cTURBT) was defined as tumor resection in entirety and/or resection to normal appearing muscle in operative reports, or repeat pre-NAC TURBT revealing clinical T0 (cT0). After NAC, patients either underwent repeat TURBT or immediate RC, as per the treating physician. Patients refusing RC were placed on an active surveillance/delayed intervention (ASDI) protocol of cytology, cystoscopy, and imaging at 3-4 month intervals. Primary endpoint was durable complete response (dCR): pT0 at RC or remaining cT0 on ASDI for ≥1 year. Secondary endpoints included OS and durable down-staging (dDS): ≤pT1 at RC or remaining ≤cT1 on ASDI for ≥1 year. Results: Of a total 93 patients, 62 (67%) underwent pre-NAC cTURBT. Those with cTURBT had lower rates of variant histology (13% vs 32%, p = 0.03), hydronephrosis (15% vs 39%, p < 0.01), and more often pursued ASDI (60% vs 26%, p = 0.01). Patients with cTURBT were more likely to attain dCR (37% vs 13%, p = 0.01) and dDS (60% vs. 26%, p < 0.01). On multivariate (MV) analysis, cTURBT was a significant predictor of dCR and dDS; this remained true on subset analysis excluding 11 patients with ≥cT3 on restaging TURBT. On Kaplan-Meier analysis, patients with cTURBT had improved 5-year OS (78% vs. 46%, p < 0.01). On MV analysis controlling for variant histology, lymphovascular invasion, and hydronephrosis, cTURBT was the only significant predictor of OS, also on subset analysis excluding the 11 patients with ≥cT3 on restaging TURBT. Conclusions: A pre-NAC cTURBT is associated with improved oncologic outcomes and OS in this MIBC cohort. The extent to which cTURBT represents a selection criterion for having lower clinical stage or a therapeutic advantage in response to NAC is difficult to isolate from a retrospective study. However, this study suggests cTURBT should be pursued when feasible to potentially optimize outcomes after NAC.
Sarcomatoid urothelial carcinoma: Oncologic outcomes from a tertiary center and SEER-Medicare data.
Authors: Sekar Rishi Robert , Diamantopoulos Leonidas Nikolaos , Khaki Ali Raza , Vakar-Lopez Funda , Tretiakova Maria S. , Psutka Sarah P. , Holt Sarah K , Gore John L. , Schade George R. , Lin Daniel W. , Hsieh Andrew Caleb , Lee John Kyung , Yezefski Todd , Schweizer Michael Thomas , Cheng Heather H. , Yu Evan Y. , True Lawrence D. , Montgomery Robert B. , Grivas Petros , Wright Jonathan L.
Published: May 2020

e17033

Background: Sarcomatoid urothelial carcinoma (SUC) is a rare and aggressive bladder cancer variant with little evidence regarding prognostic characteristics and response to neoadjuvant chemotherapy (NAC). In this study, we delineate oncologic outcomes in patients with SUC after radical cystectomy (RC), presenting data from our institutional database and SEER-Medicare. Methods: We retrospectively queried our institutional database to identify consecutive patients with cT2-4 SUC and conventional (non-variant) UC (CUC) who underwent RC (2003-2018). SEER-Medicare database was also searched for patients with cT2-4 SUC (2004-2015). Clinicopathologic/treatment data were captured. Overall survival (OS – diagnosis to death) was estimated with the Kaplan-Meier method. T-test, χ2 test and log-rank test were used for group comparison analysis. Factors significant in univariate analysis for OS were included in the multivariate (MVA) Cox proportional hazards model. Results: Institutional RC database yielded 38 patients with SUC and 287 with CUC, while 190 patients with SUC were identified from SEER-Medicare [83 (44%) had RC]. Platinum-based NAC was given to 17/38 (45%), 162/287 (56%) and 26/83 (31%) patients, respectively. Institutional patients with SUC had significantly higher rates of pT3/4 disease at RC (66% vs. 35%, p < .001) and lower rates of complete pathologic response (ypT0N0) following NAC (6% vs 35%, p = .02). Median OS in patients who had RC was significantly inferior in our institutional SUC vs. CUC group (20 vs. 121 months, p < .001) and 21 months in the SEER-SUC cohort. No significant difference in OS was identified between NAC+RC vs. RC alone, both in the institutional (17 vs. 20 months, p = 0.66) and SEER-SUC cohort (24 vs. 20 months, p = 0.56). In MVA for the entire institutional cohort (SUC+CUC combined), SUC was independently associated with worse OS, when adjusted for advanced age, pT/N stage, performance status, NAC, lymphovascular invasion, surgical margins (HR, 95% CI: 2.3, 1.4 - 3.8, p = .001). Five patients had an abdomino-pelvic cystic recurrence, with median time to recurrence < 5 months. Conclusions: Patients with SUC treated with RC had high rates of extravesical extension, poor response to platinum-based NAC and worse OS compared to patients with CUC. Data from SEER showed a comparable OS to our SUC cohort. NAC was not associated with improved OS in any SUC cohort (institutional or SEER). A unique pattern of rapid abdomino-pelvic cystic recurrence, mimicking post-RC abdominal fluid collections, was also identified.
Magrolimab and gemcitabine-cisplatin combination enhance phagocytic elimination of bladder cancer.
Authors: Kiss Bernhard , Volkmer Anne Kathrin , Feng Dongdong , McKenna Kelly Marie , Mihardja Shirley , Chao Mark , Takimoto Chris H.M. , Liao Joseph C , Volkmer Jens-Peter , Weissman Irving L.
Published: May 2020

e17035

Background: CD47 is an antiphagocytic signal and macrophage checkpoint that bladder and other cancer cells over-express to evade innate immunity. Magrolimab (Hu5F9-G4) a CD47 blocking antibody, promotes phagocytosis of cancer cells by macrophages and is being tested in several clinical trials (NCT02953509, NCT03248479, NCT02953782, NCT03558139). Chemotherapies synergize with magrolimab by increasing “eat me” signals on cancer cells, and thus enhancing phagocytosis. This synergy has been shown in MDS and AML, whereby magrolimab+azacitidine has shown encouraging efficacy in pre-clinical and clinical studies. This study aimed to investigate the effect of magrolimab as monotherapy and in combination with gemcitabine-cisplatin chemotherapy in bladder cancer. Methods: Phagocytosis of urothelial bladder cancer cells (639V) was evaluated in vitro with magrolimab alone and in combination with chemotherapy (gemcitabine + cisplatin). Treatment in vivo was evaluated in a xenograft mouse model. 639V cells were transplanted into NSG mice and upon confirmation of engraftment mice were randomized into 4 treatment cohorts: control (PBS), magrolimab, chemotherapy (cisplatin + gemcitabine), and magrolimab in combination with chemotherapy. In the first experimental setup treatment was started early in small tumors and in the second experimental setup treatment was started late after tumors have grown to large size. Tumor growth was monitored by in vivo bioluminescent imaging. Metastases were evaluated postmortem. Results: Chemotherapy increased calreticulin on bladder cancer cells. Magrolimab enhanced phagocytosis of bladder cancer cells in vitro and combination of magrolimab with chemotherapy further increased phagocytosis compared to either therapy alone. Magrolimab and chemotherapy, each alone decreased tumor growth in vivo but only combination of magrolimab with chemotherapy showed a strong inhibition of tumor growth, resulting in a significantly prolonged survival compared to all other treatment cohorts. This was shown for both, small tumors and large tumors. Metastases formation in liver and lungs was completely inhibited by treatment with magrolimab, whereas mice treated with chemotherapy alone or PBS control showed metastases in these organs. Conclusions: Magrolimab treatment in combination with chemotherapy was efficacious in preclinical in vitro and in vivo studies in bladder cancer and provides a novel treatment opportunity for patients with bladder cancer and other solid tumors.
The neural phenotype in invasive urothelial carcinoma patients: Alternative score detection and prognostic implication.
Authors: Zucali Paolo Andrea , Colombo Piergiuseppe , De Carlo Camilla , Giordano Laura , Hurle Rodolfo , Lazzeri Massimo , Elefante Grazia Maria , D'Antonio Federica , Regis Federica , Perrino Matteo , De Vincenzo Fabio , Guazzoni Giorgio Ferruccio , Roncalli Massimo , Santoro Armando
Published: May 2020

e17037

Background: Recent molecular subtyping studies (NGS) identified a subset (5-15%) of muscle invasive urothelial carcinoma (MIBC) with transcriptomic patterns consistent with neuroendocrine (NE) differentiation in the absence of NE histology (NE-like), representing a potentially high risk subgroup of carcinoma which may require a different treatment strategy. We recently set an alternative immuno-phenotypical score (Piescore), to discriminate Luminal from Basal from Neural carcinoma. Aim of this study was to test the ability of Piescore in identifying NE-like cases in a mono-institutional cohort of patients treated with trans-urethral resection and radical cystectomy (RC) and to correlate them with clinical outcomes. Methods: Transurethral resection specimens harbored foci of HG pT2 (MIBC) UC from 116 pts who subsequently underwent RC have been submitted for immunohistochemical analysis, using relevant gene-expression-based markers for Basal type (CD44, CK5/6) and Luminal type (CK20 and pPARg). Piescore divided Basal and Luminal types when at least 3 of the 4 markers were consistent with a specific phenotype; Mixed if two luminal and two basal markers were present simultaneously; NE-like when all four markers were negative. Results: Overall, the Piescore identified Basal phenotypes in 49 patients (42,2%), Luminal in 38 (32,7%), and Mixed in 9 (7,8%). No expression was identified in 20 patients (17,2%): 7 cases with morphological NE differentiation and 13 cases with classical urothelial histology, all consistent with NE-like phenotype. Interestingly, in 10/13 patients the NE-like phenotype was only documented in the muscle invasive component of the tumor whereas in the non-invasive component they retained Luminal phenotype in 9 cases and Basal in one. With a median follow up of 188 months, the pathological stage of disease (pT2 versus ≥pT3 and/or N+) and the tumor vascular invasion (absent versus present) resulted prognostic (Stage: 5-years DFS rate 65% versus 30%, p = 0.038; 5-years OS rate 69% versus 32%, p = 0.017) (vascular invasion: 5-years DFS rate 47% versus 24%, p = 0.020; 5-years OS rate 54% versus 21%, p < 0.001) in all population. No statistically significant differences in terms of pathological stage of disease, vascular invasion, DFS, and OS were observed in NE-like cases compared with non-NE-like cases. Conclusions: The NE-like urothelial carcinoma identified by Piescore immunophenotyping (CD44, CK5/6, CK20 and pPARg) did not show any statistically significant association with worse prognosis.
Neoadjuvant cisplatin based therapy in bladder cancer: Is less enough?
Authors: Abbasi Saqib , Al-Jumayli Mohammed , Hildebrand Hannah , Wulff-Burchfield Elizabeth Marie , Lee Eugene K. , Taylor John A , Holzbeierlein Jeffrey , Martin Grace , Parikh Rahul Atul
Published: May 2020

e17046

Background: Patients receiving neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC) often are not able to complete three or four cycles of therapy which is standard of care. Pathological completed response (pCR) is a surrogate marker for long term survival. We set out to determine if pCR differed based on total tolerated cycles prior to surgery in those receiving cisplatin based NAC. Methods: Data was gathered at our institution on patients receiving neoadjuvant gemcitabine with cisplatin (GC), or dose dense methotrexate, vinblastin, adriamycin, cisplatin (ddMVAC)). The primary outcome was pCR, and secondary outcome was downstaging. pCR was compared between those who received 1-2, 3, and 4 cycles. Results: A total of 92 patients receiving NAC during the years of 2014 to 2019. 12 received 2 or less cycles, 22 received 3, and 57 completed 4. Age was not significantly different between groups (69.7, ≤ 2), (69.0, 3), (67.4, 4). Gender differences were noted: (41.7% female, ≤ 2), (22.7% female, 3), (12.3% female, 4), p = 0.05. The rates of pCr among the three groups were: (16.7%, ≤ 2), (22.7%, 3), (40.4%, 4), p = 0.14. Downstaging was seen in: (33.3%, ≤ 2), (59.1%, 3), (52.6%, 4), p = 0.35. Conclusions: While not statistically significant our study suggests a trend on pCR rates related to the total of cycles of neoadjuvant chemotherapy prior to surgery. Limitations include retrospective design and small sample size.
Panel-derived TMB and immune-related GEP are associated with the response to immune checkpoint inhibitors (ICIs) in urothelial cancers.
Authors: Tan Kien Thiam , Chen Shu-Jen , Hsieh Yi-Lin , Su Yu-Li , Jan Yi-hua , Cheng Jen Hao , Hsu An , Huang Wan-Ting , Zhuo De-Wei , Wang Woei-Fuh , Wei Datsen George
Published: May 2020

e17047

Background: Tumor mutational burden (TMB) and gene expression profile (GEP) have emerged as potential biomarkers for the prediction of response to the immune checkpoint inhibitor (ICI) treatment. An interferon-g gene signature was shown recently to predict ICI response in a pan-cancer setting. For TMB, not only did TMB-high patients experience better clinical outcome with ICI, but panel-derived TMB was also shown to be comparable to the gold standard, TMB derived from whole exome sequencing. Here, we evaluate possible correlations between panel-derived TMB, as well as immune-related GEP, with ICI response in urothelial cancers. Methods: FFPE tumor tissues from 30 patients with urothelial cancers who had previously received ICI as monotherapies or combination with chemotherapies at Kaohsiung Chang Gung Memorial Hospital were retrospectively tested for targeted next-generation sequencing (ACTOnco) and quantitative PCR-based GEP (ACTTME), for the identification of nonsynonymous variants across 440 cancer-associated genes and expression levels of > 90 immune-related genes, respectively. TMB was calculated by using the sequenced regions of ACTOnco to estimate the number of somatic nonsynonymous mutations per megabase of all protein-coding genes. For ACTTME, Cq values were normalized to internal control before group analysis. RECIST criteria were used to categorize tumor response to the treatment. Results: Patients were defined as responders (CR/PR) and non-responders (SD/PD) according to the RECIST criteria. In the ICI monotherapy cohort, the responders (n = 8) had significantly higher TMB than non-responders (n = 15) (Median 16.2 muts/Mb vs. 6.5 muts/Mb, p= 0.0035). In contrast, for the cohort receiving ICI combination therapy, several genes implicated in hypoxia (HIF1A), suppressive cell types (Treg & MDSC) and immune checkpoint (PD-L2) were significantly elevated ( p< 0.05) in the non-responder group by 2 to 8 folds. Conclusions: Despite the fact that the cohort size is small, this study showed panel-derived TMB, as well as immune-related GEP, can potentially serve as predictive biomarkers to identify urothelial cancer patients for immune checkpoint inhibitor therapy.