bluuebunny/crossref_metadata_2025 huggingface dataset:
The pattern of mucin 5AC (MUC5AC) expression using immunohistochemistry and its prognostic significance in patients with pancreatic ductal adenocarcinoma.
Authors: Manne Ashish , Mneimneh Wadad , Elkadi Osama , Escobar Daisy E , Coley James , Guzman Gabriel Bolanos , Fnu Sameeta Moh'd , Alkharabsheh Omar , Khushman Moh'd M.
Published: May 2020

e16756

Background: Mucin-5AC (MUC5AC) is a secreted form of mucin. Its expression correlates with poor outcome in uterine, ampullary adenocarcinoma and cholangiocarcinoma. Its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) is not well established. Here, we explored the pattern of MUC5AC expression using immunohistochemistry (IHC) and its prognostic significance in patients with PDAC. Methods: This is a retrospective study conducted at the University of South Alabama/Mitchell Cancer Institute. Between 2015-2019, 218 patients with PDAC were identified. Among this cohort, only 45 patients had tissue available for MUC5AC IHC staining. Two pathologists in- dependently scored the expression of MUC5AC. Staining percentage was estimated in 10% increments. Unpaired t test and log-rank Wilcoxon tests were used for statistical analysis. Results: In our cohort, the median age was 65 years (42-85). Males represented 55%. Caucasians, African Americans and other ethnicities (e.g. Asians) represented 71%, 25% and 4% respectively. Twenty patients (44%) had metastatic stage IV disease and 25 patients (56%) had non-metastatic disease. Positive cytoplasmic and apical MUC5AC expression by IHC was seen in 82% and 80% of patients respectively. The median apical MUC5AC expression was higher in metastatic patients compared to non-metastatic patients (67.5 % vs 30%, p = 0.0187 ) while there was no difference in the median cytoplasmic MUC5AC expression between metastatic and non-metastatic patients (13.7 % vs 12.5%, p = 0.3328). In non-metastatic patients, compared to patients with positive apical MUC5AC expression, no expression (0%) was associated with worse overall survival (OS) (43 vs 13 m, p = 0.0322). In metastatic PDAC, there was no difference in OS between patients with positive or no apical MUC5AC expression (18 vs 21 m, p = 0.781). Compared to patients with positive cytoplasmic MUC5AC expression, patients with no cytoplasmic MUC5AC expression (0%) had no difference in OS in both non-metastatic (40 vs 32 m, p = 0.986) and metastatic (36 vs 12.5 m, p = 0.487) patients. Conclusions: MUC5AC expression assessment using IHC is feasible in patients with PDAC. In our cohort, apical, but not cytoplasmic, MUC5AC expression was different between metastatic and non-metatstaic patients and showed prognostic significance in non-metastatic patients. To our knowledge, this is the first study to show prognostic significance of MUC5AC expression in patients with PDAC using IHC.
Evolution of clinical outcomes of metastatic pancreatic adenocarcinoma: A 10-year single-institution retrospective study.
Authors: Ellithi Moataz , Abdallah Mohamed A. , Shahid Mahum , Ailts Isaak , Waligoske Kate , Fanta John , Bell Matthew , Fischer McKenna , Nelson Morgan , Bleeker Jonathan
Published: May 2020

e16760

Background: Pancreatic adenocarcinoma represents the fourth leading cause of cancer-related death in the United States. A majority of patients have locally advanced or metastatic disease at the time of diagnosis. For many years, gemcitabine monotherapy was the standard of care for advanced disease, until recent studies demonstrated survival benefits for FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) and Gem/nab-P (gemcitabine/nab-paclitaxel). In this study, we evaluated the clinical outcomes in patients with metastatic pancreatic adenocarcinoma in a single health system before and after the incorporation of these newer treatments into practice. Methods: A retrospective study of metastatic pancreatic adenocarcinoma patients diagnosed between January 2009 to December 2018 with follow up until December 2019. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier survival analysis. Univariate and multivariable Cox regression analyses were used to explore predictors of survival. Results: 394 patients were diagnosed with metastatic pancreatic adenocarcinoma at Sanford Health hospitals during the study period. There was no statistically significant difference in OS between the cohort diagnosed between 2009-2013 compared to 2014-2018, with median OS of 4.7 and 3.6 months respectively; in those receiving at least one line of chemotherapy, the median OS was 6.7 and 7.3 months. While subgroup analysis of all study population based on the type of first-line chemotherapy showed improved survival with FOLFIRINOX and Gem/nabP as compared to gemcitabine monotherapy [10.7, 6.9, 4 months respectively] (Wilcoxon Test of Homogeneity of Survival Curves p = 0.0002). Univariate and multivariate Cox regression analysis of all study data revealed that at the time of the diagnosis, age (HR: 1.021, p = 0.0013), ECOG performance status > 1 (HR: 3.47, p = 0.0001), serum albumin (HR: 0.708, p = 0.0002), Neutrophil-to-Lymphocytes ratio (HR: 1.076, p≤0.0001) and platelets-to-lymphocyte ratio (HR: 0.998, p = 0.0031) were predictors of survival. Conclusions: Although newer treatments appear to offer improved survival for eligible patients, overall outcomes for metastatic pancreatic adenocarcinoma in this cohort were similar before and after the incorporation of newer treatment regimens. Further advances in the treatment and early detection of pancreatic cancer are needed to improve clinical outcomes.
Molecular validation of the 8th edition AJCC cancer staging system in patients with resected pancreatic cancer: Proposal of integrative translational staging system.
Authors: Lee Sung Hwan , Lee Sunyoung S. , Lee Ju-Seog
Published: May 2020

e16765

Background: Even though the 8th edition AJCC cancer staging system for pancreatic cancer has validated with major clinicopathologic factors in multiple clinical cohorts, there is still an unmet need for integrative consideration using multi-omics data to stratify the patients with pancreatic cancer elaborately. Methods: We performed a comprehensive analysis and profiling using genomic, transcriptomic, and proteomic data from TCGA-PAAD and other translational cohorts (4 cohorts, n = 340). Molecular features and major subtypes were analyzed mutually with clinical and pathologic factors, especially the 8th AJCC staging system. Results: Aggressive molecular subtypes, basal-like and squamous subtype, were significantly associated with a higher nodal stage, but tumor size didn't show a clear association with molecular features. The activated stroma of pancreatic cancer microenvironment was significantly correlated with poor differentiation and large tumor size. The mutational pattern of KRAS and several transcriptomic pathways such as eptihelial-mesenchymal transition and DNA repair were differently presented in each clinical stage from the 8th AJCC TNM staging system. The optimal algorithm was identified to show significantly higher performance for the prediction for cancer relapse and cancer-specific survival in discovery and validation cohorts. The in silico prediction for molecular target agents and immunotherapy were performed for final clusters from optimal stratification system revealed from the integrative analysis. Conclusions: Our comprehensive multi-omics analysis reveals clear needs for the combination of clinical staging and molecular profiling and provides crucial evidence for precision strategy in patients with resectable pancreatic cancer.
Racial disparities in pancreatic resection and survival among elderly patients: A SEER database analysis.
Authors: Park Seojin , Waters Dexter , Walsh Karen , Handley Nathan , Lavu Harish
Published: May 2020

e16784

Background: For localized pancreatic cancer treatment, surgical resection is the only potentially curative option. Currently, little is known about whether racial disparities exist in elderly patients’ access to resection and outcomes after resection. This study aims to understand the relationship between race/ethnicity and both resection rate and survival after surgery in elderly patients. Methods: The analysis included patients aged ≥65 years diagnosed with locoregional resectable (stage I and II according to the 6th AJCC TNM staging system) pancreatic cancer between 2007 and 2016 in the Surveillance, Epidemiology, and End Results database. Patients without complete surgical or survival data were excluded from the analysis. Multiple logistic regression was used to assess the association between race/ethnicity and receipt of resection. The effect of resection on 6-month and 5-year overall survival (OS) was evaluated using multivariate Cox proportional hazards regression, controlling for other clinical and demographic factors, such as sex, age, martial status, residence region, tumor location, tumor size, and year of diagnosis. Results: Of 12,829 patients, 4,310 (46.0%) received resection and 5,062 (54.0%) did not. Median follow-up among resected patients was 16 months (1-60 months), and 6-month and 5-year OS was 62.83% and 4.54%, respectively. The majority of the patients were white (73.1%), followed by Hispanic (9.3%), black (9.1%), and other (American Indian, Asian/Pacific Islander) (8.6%). Black (OR 0.69; 95%CI 0.60-0.80) and Hispanic patients (OR 0.78; 95%CI 0.68-0.90) were less likely to receive resection compared to white patients. While Hispanic patients had worse 6-month OS compared to white patients (HR 1.43; 95%CI 1.19-1.72), 5-year OS was not significantly different across the racial/ethnic groups. Other factors significantly worsened 5-year OS were being age 75 years or older, living in South region, and having tumor size greater than 50mm. Conclusions: Our findings support that racial disparities exist in resection rate in elderly populations. However, no racial difference was seen in the long-term survival after pancreatic resection. This may suggest that improving the access to resection for minorities with pancreatic cancer may improve their health outcomes. [Table: see text]
Combined recombinant humanized anti-PD-1 monoclonal antibody (JS001) and nab-paclitaxel/gemcitabine (AG) as the first-line therapy for patients with advanced pancreatic adenocarcinoma: Preliminary results of an open-label, phase Ib/II clinical study.
Authors: Cheng Ke , Li Zhiping , Cao Dan
Published: May 2020

e16792

Background: To determine evaluate the safety and efficacy of nab-paclitaxe, gemcitabine (AG) and Recombinant Humanized Anti-PD-1 Monoclonal Antibody (JS001) for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Methods: This was a single-arm, open-label, phase 1b/2 clinical trial of nab-paclitaxel plus gemcitabine plus Anti-PD-1 Monoclonal Antibody in which 11 patients with previously untreated advanced PDAC were enrolled from December 2018. Patients were treated with nab-paclitaxel 125 mg/m2 on days 1 and 8 plus gemcitabine 1000 mg/m2 on days 1 and 8 plus fixed dose of JS001 240mg on day 1 of a 21-day cycle until progression or toxicity or receiving maintance therapy. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Results: 11 chemotherapy naïve PDAC patients with a median age of 52 years old were treated. 5 were men and all patients had an ECOG of 0 or 1. Grade 3/4 events were observed in 27.3% of patients (2 patients presented hematological toxicity ), and JS001 was discontinued because of asymptomatic elevated cardiac biomarkers and hypothyroidism as immunotherapy-related toxicities in a female patient, no patient was discontinued AG therapy because of chemotherapy-related adverse events. Of the 11 evaluable patients, the disease control rate (partial response [PR] + stable disease[SD]) was 81.8%. There were 2 patients with PR and 1 patient with complete response respectively, and overall response rate (ORR) was 27.3%. The median progression-free survival (PFS) was 7 months and all patients survive at the last following-up in Jan-2020. All patients were proficient mismatch repair (pMMR) status. Whole-exome sequencing was performed on 7 patients, no immunotherapy-associated gene was detected, and next comprehensive analysis of somatic alterations was ongoing. Conclusions: Combined JS001 and AG can be safely given to chemotherapy naïve PDAC patients. Efficacy appears to be promising over previously reported results for standard AG chemotherapy every 28 days gemcitabine and nab-paclitaxel dosing. Comprehensive data available was ongoing to analysis the potential effect to efficacy of the combination.
Impact of surveillance among patients with resected pancreatic cancer following adjuvant chemotherapy.
Authors: Wong Selina , Gondara Lovedeep , Renouf Daniel John , Lim Howard John , Gill Sharlene
Published: May 2020

e16795

Background: Pancreatic adenocarcinoma carries a poor prognosis and high risk of recurrence even after surgery and adjuvant chemotherapy (AC). Guidelines recommend against routine surveillance imaging due to lack of evidence supporting a survival benefit. With current first-line chemotherapy options, it is unclear whether surveillance scans allow for early detection of asymptomatic disease and therefore an opportunity to offer fit patients chemotherapy. We describe the patterns of surveillance in patients followed at a Canadian provincial cancer agency and determine whether routine imaging after AC is associated with receipt of palliative chemotherapy (PC). Methods: A retrospective review was completed to identify patients treated at British Columbia (BC) Cancer centres between January 1, 2010 and December 31, 2016 who had undergone curative intent resection and received at least one cycle of AC. Baseline characteristics, number of scans done after completing AC to recurrence, and PC were collected. Logistic regression analysis was performed. Results: A total of 151 patients followed at BC Cancer were identified. Patients who recurred within 28 days after AC were excluded, leaving 142 patients, of which 115 patients had recurrence (81%). We defined 2 cohorts based on number of scans done between completion of AC and recurrence: those with 0-1 scans were “symptomatic” recurrences (22 patients, median age 68y, 64% female, and 91% node-positive) and those with > 1 scan were “surveillance” recurrences (93 patients, median age 64y, 43% female, and 81% node-positive). Patients who underwent surveillance scans were more likely to receive PC at time of recurrence, though statistical significance was not reached (OR 2.11, 95% CI 0.75-6.58, p = 0.17). Conclusions: Despite guidelines, the majority of patients treated in BC underwent surveillance imaging. Within the limits of our sample size, we demonstrated a trend towards increased likelihood of receiving PC in patients who receive surveillance scans following AC. With efficacious PC options available, studies to determine whether receipt of PC in asymptomatic recurrences detected on imaging translates into improved survival and/or quality of life are warranted.
Skeletal muscle index and adverse events during a bladder cancer treatment episode.
Authors: Ngo Steven , Diamantopoulos Leonidas Nikolaos , Maldonado Reno , O'Malley Ryan Blair , Laidlaw Grace , Fintelmann Florian J. , Holt Sarah K , Gore John L. , Schade George R. , Lin Daniel W. , Grivas Petros , Montgomery Robert B. , Hsieh Andrew Caleb , Cheng Heather H. , Yezefski Todd , Schweizer Michael Thomas , Yu Evan Y. , Wright Jonathan L. , Psutka Sarah P.
Published: May 2020

e17016

Background: While sarcopenia is associated with increased mortality in bladder cancer, there is limited data in patients treated with neoadjuvant chemotherapy (NAC) that associates skeletal muscle index (SMI) and adverse treatment-associated outcomes. Herein, we evaluate associations between baseline SMI and severe adverse events (SAEs) during NAC and post-radical cystectomy (RC) 90-day Clavien ≥3 complications. Methods: SMI (cross sectional area of skeletal muscle, cm2 / height2, m2) was measured on an axial computed tomography (CT) image at the level of the third lumbar vertebral body, within 60 days prior to NAC and RC. Patients were classified as being sarcopenic, according to sex-specific consensus definitions: Male: SMI < 55, Female: SMI < 39. Associations with SAEs during NAC and 90-day Clavien grade 3-5 complications were assessed with multivariable logistic regression. Results: CT scans of sufficient quality (2005-18) were available for 143 patients. There were no significant differences in clinicopathologic characteristics between the study cohort and patients without available imaging (N = 261). Median SMI for men and women was 52.1 and 40.9 cm2/m2; 86 (60%) were sarcopenic. SAEs were observed in 92 patients (64%), resulting in hospitalization during NAC in 27 (19%), while 20 (14%) patients did not complete planned NAC due to SAEs. After adjusting for age, performance status, and clinical stage, SMI was not independently associated with NAC-associated SAEs. Postoperative complications occurred in 82 (57%) patients, including infectious complications (39; 27%), wound dehiscence (8; 6%), 90-day readmission (27; 19%). Wound healing complications including dehiscence, clinically significant hernia, urine leaks, or fistulae occurred in 33 (23%). While SMI was not independently associated with risk of complications overall (OR: 1.00, 95% CI: 0.96 - 1.03), it was associated with infectious complications (OR: 0.96, 95% CI: 0.92 - 0.99, p = 0.02), and wound dehiscence (OR: 0.93, 95% CI: 0.86 - 0.99, p = 0.02) with a trend towards significance for associations with any wound-healing complications (OR: 0.96, 95% CI: 0.91 - 1.00, p = 0.08). Conclusions: In the largest reported series of post-NAC patients with RC and detailed follow-up, pretreatment SMI was not associated with SAEs during NAC but was associated with serious infectious complications and wound dehiscence after RC. This data highlights the potential value in measuring SMI to identify patients at risk for select SAEs. Future studies should assess the benefit of prehabilitation before and during NAC.
Predicting residual tumor for T1 high-grade bladder urothelial carcinoma before second transurethral resection specimens.
Authors: Takeuchi Ario , Shiota Masaki , Inokuchi Junichi , Eto Masatoshi
Published: May 2020

e17018

Background: Second transurethral resection (TUR), which is now recommended for all T1 high-grade bladder urothelial carcinoma, may not be necessary for patients with minimal tumor burden at the first TUR. T1 microstaging by the recognition of the muscularis mucosae or vascular plexus may be one promising method for evaluating tumor burden, but is sometimes technically difficult to assess. The number of TUR chips with tumor invading into lamina propria (T1chips) is easy to assess and can be available for all patients with T1 bladder urothelial carcinoma. Our aim was to determine clinicopathological factors which can predict the existence of residual tumor on the second TUR specimens for T1 high-grade bladder urothelial carcinoma. Methods: A total of 50 patients were diagnosed with T1 high-grade bladder urothelial carcinoma after the first TUR. We performed second TUR for the 50 patients. The median interval from the first and the second TUR was 6 week (range, 2-10). Voided urine cytology was taken in all patients between the first and the second TUR, at least 1 week after the first TUR. The existence of proper muscle tissue was confirmed in all specimens for the first and the second TUR. Tumor size, the number of tumor, the presence of carcinoma in situ (CIS), the number of TUR chips containing lamina propria invasion (T1chips) were recorded for the first TUR specimens. Results: A total of 20 (40%) patients had residual tumor on the second TUR. The second TUR stage was: T0 30 (60%); Ta/is 7 (14%); T1 9 (18%); and T2 4 (8%), respectively. In univariate analysis, positive urine cytology before the first TUR (48% vs 0% in negative), positive urine cytology between the first and second TUR (76% vs 21% in negative), and multiple T1 chips on the first TUR specimens (58% vs 6% in one T1 chip) were associated with residual tumor on the second TUR. In addition, in multivariate analysis, the number of T1 chips on the first TUR and urine cytology between the first and the second TUR were the significant predictors for residual tumor on the second TUR. Of 15 patients with multiple T1 chips and positive urine cytology between the first and the second TUR, 13 (87%) had residual tumor on the second TUR, compared to 0% (0/15) in those with one T1 chip and negative urine cytology between the first and the second TUR. Conclusions: Second TUR may not be necessary for all patients with T1 high-grade bladder urothelial carcinoma. The number of T1 chips on the first TUR and urine cytology between the first and the second TUR are useful factors for predicting second TUR stage.
MSK-ACCESS for the detection of fibroblast growth factor receptor-3 (FGFR3) mutations in plasma cell-free (cf)DNA of metastatic urothelial carcinoma (mUC) patients (pts) pre- and on erdafitinib (erda) therapy.
Authors: Sarfaty Michal , Teo Min Yuen , Funt Samuel Aaron , Lee Chung-Han , Aggen David Henry , Ratna Neha , Regazzi Ashley Marie , Al-Ahmadie Hikmat , Brannon Angela Rose , Berger Michael F. , Solit David B. , Rosenberg Jonathan E. , Bajorin Dean F. , Iyer Gopa
Published: May 2020

e17034

Background: The pan-FGFR inhibitor erda was recently FDA-approved for pretreated mUC pts harboring FGFR2/3 alterations. We explored concordance of FGFR3 mutation profiles between the primary tumor and cfDNA using the MSK-ACCESS platform. We also correlated changes in FGFR3 cfDNA mutant allele fraction (MAF) with response to drug. Methods: Plasma samples were collected from mUC pts started on erda at baseline, on treatment (tx), and at progression. Demographic and clinical characteristics were obtained. Baseline tumors were sequenced with MSK-IMPACT (ref) and plasma samples were sequenced using MSK-ACCESS, a cfDNA platform that sequences 129 genes using unique molecular indexes to generate > 15,000x coverage and detection of somatic mutations down to 0.1% MAF. Results: Between 08/2019-1/2020, 11 pts received erda 8mg daily. Of these, 3 pts increased dose to 9mg daily based on phosphorus level, 4 required dose reductions and 6 dose interruptions. In 5 pts, erda was discontinued for disease progression. FGFR3 S249C was the most frequent alteration detected (64%) followed by Y373C (18%), R248C and S371C (both 9%). Pre-treatment plasma FGFR3 profiles were concordant with tissue in 91% (10/11) of pts and additional FGFR3 mutations were detected in 3 cases (27%, Table), including 1 pt with an FGFR3-TACC3 fusion and hotspot mutations only in cfDNA. In 2 responding pts, the mutant allele was undetectable on erda. Conclusions: A high degree of concordance between primary tumor and cfDNA FGFR3 mutation detection was observed. FGFR3 mutations exclusive to cfDNA were found in a subset of pts. Further pt accrual and follow-up are ongoing to assess for correlations between erda response and tx-related changes in cfDNA MAF, and to assess whether cfDNA can identify resistance mechanisms. [Table: see text]
Phase Ib study: APL-1202 (APL) in combination with Bacillus Calmette-Guerin (BCG) in recurrent non-muscle invasive bladder cancer (NMIBC).
Authors: Sfakianos John , Shore Neal D. , Zhuang John
Published: May 2020

e17039

Background: APL is a selective human methionine aminopeptidases II (MetAP2) inhibitor. In preclinical studies, APL has demonstrated both anti-angiogenic and anti-tumor activities as well as a potential synergistic effect with BCG or PD-1. A. This phase 1b study assesses the tolerability and pharmacokinetics (PK) characteristics of oral APL and intravesical BCG combination in HR NMIBC pts. Methods: Pts who had received a prior induction course of BCG within 12 weeks (wks) of enrollment and were scheduled to receive either maintenance or another induction course of BCG were given 750 mg/day APL (2x125 mg tablet, TID) for 12 wks. The tolerability and PK of APL was evaluated one wk prior to first BCG instillation and during combination use with BCG. AEs were evaluated to assess safety and tolerability. Wilcoxon matched-pair signed-rank test was used for PK analysis. Results: Six pts (4M, 2F) with a median age of 72.5 yrs (range 58-81 yrs) were enrolled; 4 pts had grade 3 Ta and 2 pts had Tis. Four and 2 pts received induction and maintenance course of BCG, respectively. Six AEs of grade 1 or 2 were reported by 3 pts, and they were respiratory and head congestion, acid reflux, rash, bronchitis, nausea, and cystitis. None of these AEs were judged to be related to APL. Five pts completed the study and 1 pt dropped out due to a grade 1 cystitis after receiving 4 wks of APL and 2 doses of BCG. The PK results suggested similar PK characteristics (plasma AUCtau, Cmax and t1/2, and urinary excreted faction Ae%). Conclusions: APL was well tolerated when given for 12 wks to NMIBC pts who also received induction or maintenance BCG. Further study of APL in combination with BCG is warranted. Clinical trial information: NCT03672240.
PD-L1 and neutrophil to lymphocyte ratio (NLR) as predictive panel of prognosis in bladder cancer.
Authors: Qin Tao , Yu Hao , Wang Bo , Tan Cui , Hong Huangming , Hu Hai , Yao Herui
Published: May 2020

e17040

Background: PD-1/PD-L1 blockade significantly improved survival for bladder cancer. PD-L1 expression might not be an ideal marker for patient selection in isolation. Several studies demonstrated that alternative markers such as NLR, a biomarker of systemic inflammation response to therapy, correlated with outcomes in a variety of cancers including bladder cancer, might be a predictor for patient selection and the response to immunotherapy. However, no reporters have been made combination of NLR and PD-L1 in predicting prognosis in bladder cancer. Methods: Suitable tissue of 100 FFPE blocks of bladder cancer patients treated in Sun Yat-Sen Memorial Hospital Sun Yat-sen University were stained with PD-L1 antibody. Clinicopathological data and pretreatment complete blood count were retrospectively collected. All patients were classified into high NLR group and low NLR group at cut-off 3.0. Kaplan-Meier and Cox proportional hazard models analyses were used to assessed the predictor of combined PD-L1/NLR for disease-free survival (DFS) and overall survival (OS). Results: Patients were mostly male (79%) with high grade () lymph node positive (21%), T3-4 (33%) . The positivity of PD-L1 expression was 22% (22/100) at cut-off 1%. Univariate analysis showed that PD-L1 expression was positively associated with larger tumor size, higher grade, positive lymph node metastases. Median DFS and OS were 35 months and 37 months, respectively. Both PD-L1 expression and NLR were associated with DFS and OS. COX analysis model showed that PD-L1 and NLR were independent prognostic factors for tumor prognosis. Of interest, when patients were divided in two groups based on PD-L1/NLR: patients with PD-L1+/high NLR as group 1 and other patients as group 2, group1 had significantly shorter DFS and OS (DFS, X2 = 4.146, P = 0.042; OS, X2 = 10.274, P = 0.001). COX proportional hazards regression models indicated that PD-L1+/high NLR was correlated with a significantly shorter DFS and OS (DFS, hazard ration [ HR] = 2.572, P = 0.05; OS, HR = 3.811, P = 0.003). Conclusions: The study indicated that combined use of PD-L-1/ NLR as predictive biomarker for survival. This feasible panel may be optional maker applied to select patients for immunotherapy.
Retrospective study to assess the efficacy and safety of checkpoint inhibitors in advanced urothelial carcinoma in real-world setting.
Authors: Sevillano Fernandez Elena , Puente Javier , Vidal Natalia , Pinto Alvaro , Garcia Sanchez Lourdes , Fiorini Aldo , Chara Velarde Luis Enrique , Ariza Irene Nalda , Cassinello Javier , Rodriguez Angel , Galvan Ruiz Saray , Rodriguez-Moreno Juan Francisco , Barquin Arantzazu , Ruiz Sergio , Navarro Paloma , Yagüe Monica , Grande Enrique , García-Donas Jesús
Published: May 2020

e17043

Background: Checkpoint Inhibitors (CPI) have become a new standard of treatment in advanced urothelial carcinoma. However, little is known regarding the outcome of patients in daily practice.We aimed to assess tumor response and toxicity of CPIs in a cohort of patients treated in “real world” conditions. In parallel, a comprehensive molecular study in tumor samples from these patients, is ongoing. Methods: We designed an observational retrospective study within the “Grupo Centro” collaborative group. Adult patients diagnosed of metastasic urothelial carcinoma (mUC) and treated with CPIs between 2011-2019 in any of the 20 centers of the group, were eligible. Results: Up to date 100 patients have been included (82% males) with a median age of 74 years (48 -96). In 82% patients primary was bladder cancer. Most common metastasic sites were bone (26%) and liver (16%).With a median follow up of 10,6 months(mo) median progression free survival (mPFS) was 6,6mo (1,4-95,4 range) and median Overall Survival (mOS) was 21.3mo (3,8-121,8). 38% of patients received CPIs in first line(L): atezolizumab:27, pembrolizumab: 10, nivolumab:1. The median number of cycles was 8,2. Up to 51% received platinum-based combinations in first line. 69% (69/100) pts received 2L treatment: 68% with CPIs, 27,5% with chemotherapy and 4% with FGFR inhibitors (as part of a clinical trial). 2L mPFS was 3,5 mo (1,9-25.9). 23% (23/100) patients received 3L, of them 26% (6/23) were treated with CPIs. 3L mPFS:8,3mo(0,4-43,8). As a whole, patients treated with CPI accross different lines, achieved complete response in 8% of the cases, partial response in 18% and stable disease in 15%. Up to 44% of cases presented progressive disease as best response and evaluation was not available in 15%. Most common G1-2 AEs related to immunotherapy were: asthenia:31%,pruritus:16% and anorexia: 9%.10% pts experienced G3-4 toxicity: asthenia G3: 4, diarrhea G3: 1, erythrodysesthesia G3:1, arthromyalgia G3: 1, cardiac arrest G4:1,pneumonitis G4:1,anemia G3:1. Conclusions: This study confirms the efficacy and security of CPIs in real world. Response rates and toxicity profile were comparable to those reported in clinical trials.
Impact of concurrent angiotensin inhibitors on outcomes with PD1/L1 inhibitors for patients (pts) with metastatic urothelial carcinoma (mUC).
Authors: Curran Catherine , Pond Gregory Russell , Nuzzo Pier Vitale , Abou Alaiwi Sarah , Nassar Amin , Wei Xiao X. , Kilbridge Kerry L. , McGregor Bradley Alexander , Ravi Praful , Ravi Arvind , Sonpavde Guru
Published: May 2020

e17044

Background: Preclinical data indicate that angiotensin inhibition may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Since (TGF)-β appears to be associated with resistance in patients with mUC receiving PD1/L1 inhibitors, we investigated whether angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may enhance the outcomes of mUC pts receiving PD1/L1 inhibitors. Methods: Data from mUC pts who received PD1/L1 inhibitors at the Dana-Farber Cancer Institute (DFCI) was obtained. Data for ACEI and ARB administration was collected with concurrent administration defined as ongoing therapy from the time of starting PD1/L1 inhibitor treatment. A Cox logistic regression was used to investigate the impact of concurrent ACEI/ARB on any regression of tumor (ART, any decrease in size of tumor on scan) defined as any tumor regression after controlling for known prognostic factors (performance status, sites of metastasis, neutrophil/lymphocyte ratio, platelet count, hemoglobin). Results: Data was available for 178 pts with mUC who received pembrolizumab (79), atezolizumab (83), nivolumab (15), and durvalumab (1). Prior platinum chemotherapy was administered in 153 pts (86%). 33 pts (18.5%) received AECI/ARBs: 24 pts (13.5%) received ACEI and 9 pts (5.1%) received ARBs. Of 145 patients who did not receive an ACE-inhibitor nor an ARB, 49 (33.8%) patients experienced ART and their median overall survival (OS) was 9.1 months. Among/33 patients who did receive an ACEI or an ARB, 17 (51.5%) exhibited ARTand their median OS was 17.0 months. Multivariable analysis controlling for known prognostic factors revealed that patients who received ACE inhibitors or ARBs had greater ART (HR 3.0 [95% CI 1.25-7.17], p = 0.014) and improved OS, (HR 0.49 [95% CI 0.28-0.88] p = 0.016). Conclusions: In this hypothesis-generating study, concurrent angiotensin inhibitors including ACEI or ARBs were associated with significantly better outcomes in mUC pts receiving PD-1/L1 inhibitors. These results require validation in a larger mUC dataset in conjunction with probing the effect in other malignancies.
Lack of assocation of robotic radical cystectomy with increased incidence of local pelvic recurrence.
Authors: Madi Rabii
Published: May 2020

e17045

Background: Robotic radical cystectomy (RRC) might be associated with an increased incidence of local pelvic recurrence and peritoneal seeding. We performed an institutional study evaluating the incidence and type of cancer recurrence following RRC. Methods: Between January 2012 and July 2019, 100 consecutive robotic radical cystectomies (RRC) were performed by a single surgeon RM. Pre-and Peri-operative characteristics were analyzed. Early and late, local and distant recurrences were studied, with the assumption that early local recurrences might suggest technical causative factors. Results: Median age was 63 ( IQR: 57-75). Male to female ratio is 2 to 1. Median BMI was 27.7 ( IQR: 24-32). 70% of patients were white, 27% were black, 2% were Hispanic, and 2% were Asians. Indications for cystectomy were refractory CIS in 6%, T disease in 26%, T2 disease in 52%, T3 disease in 5%, and T4 disease in 11%. Console time was 249 minutes ( IQR: 205-318). 70% of patients underwent ileal conduit, 30% underwent neobladder. 85% of patients underwent extended PLND and median blood loss was 150 ml, no patient required transfusion. Final pathology showed T0, Ta, CIS, T1, T2, T3, and T4 diseases in 2%, 5%, 10%, 10%, 21%, 36%, and 16% respectively. Median hospital stay was 6 days and 34% of patients had 30 days complications. 50% of patients had more than 36 months follow-up and overall, 24% of patients had cancer recurrences. Only 3 patients had recurrence within 3 months. Patient 1 had PT1, N1 disease with recurrences in common iliac lymph nodes and was treated by chemotherapy and is in complete remission. Patient 2 had pT3b N1 SCC with 3 months CT scans showing extensive pelvic and systemic recurrences and expired 6 months after surgery. Patient 3 had pT3a, N1 disease and had recurrence in the aorto-caval LN, received chemo-and immune therapy and has no evidence of disease. Conclusions: Our experience with robotic radical cystectomy did not show an increased incidence of early or local recurrence that could be attributed to the surgical approach. We believe that adherence to oncological principles is achievable with robotic approach.
Impact of preoperative neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) on overall survival or recurrence free survival in muscle-invasive bladder cancer at cystectomy.
Authors: Dawsey Scott , Sheng Iris Yeong- Fung , Ornstein Moshe Chaim , Wei Wei , Lee Byron H , Mian Omar Y. , Rini Brian I. , Garcia Jorge A. , Gilligan Timothy D. , Gupta Shilpa
Published: May 2020

e17050

Background: The role of Neutrophil to Lymphocyte Ratio (NLR) and Platelet to Lymphocyte Ratio (PLR) in prognostication of MIBC is not clearly understood. There is growing evidence that, as markers of inflammation, they may have prognostic utility in MIBC at radical cystectomy (RC). Methods: We performed a retrospective analysis of MIBC patients who underwent RC at the Cleveland Clinic from 2/2015 to 1/2018. 84 patients were identified who were either diagnosed with TaN0M0 treated with Neoadjuvant Chemotherapy (NAC) or T1-T4N0M0 disease treated with or without NAC. For NAC, 27 patients received gemcitabine and cisplatin, 2 patients received gemcitabine and carboplatin, 4 patients received unknown regimen, and 3 patients received MVAC. Of the patients, there were 1 with Ta, 34 with T1, 44 with T2, 1 with T3 and 4 with T4 disease. Complete Blood Count with Differential closest to or on the day of resection was used. NLR and PLR were calculated by dividing Absolute Neutrophil Count and Platelet Count by the Absolute Lymphocyte Count, respectively. PLR and NLR were dichotomized at the median. Outcomes were analyzed via Kruskal-Wallis test. Results: Median follow up of patients was 28.8 months. Median NLR and PLR were 15.7 and 263, respectively. Mean NLR and PLR were 18.9 and 310, respectively. NLR and PLR did not correlate with overall survival, recurrence free survival, T or N stage post resection, or pathological response. Females were found to have a higher NLR than males. Conclusions: Contrary to previous reports, our study did not find any prognostic value of NLR and PLR in MIBC patients at RC. Further evaluation of PLR and NLR in MIBC and correlation with molecular features may help understand its potential prognostic role in patients undergoing surgical resection.
Response to guadecitabine (SGI-110) combined with cisplatin and gemcitabine (GCG) in platinum refractory germ cell tumors (GCTs).
Authors: Crabb Simon J. , Huddart Robert A , Brown Emma , Dunkley Denise , Downs Nichola , McDowell Cathy , Catto James WF , Griffiths Gareth Owen , Danson Sarah , Reid Alison Helen
Published: May 2020

e17057

Background: Treatment options for platinum refractory GCTs are limited. Platinum resistance derives, in part, from tumour suppressor gene promotor methylation. In vitro, this reverses on co-administration of a DNA hypomethylating agent. Guadecitabine is a next generation hypomethylating agent. SPIRE is a phase Ib/IIa clinical trial to establish a GCG dose/schedule. Methods: We report 2 platinum refractory GCT patients (pts) treated (txd) in SPIRE with GCG (guadecitabine 20 mg/m2, SC, day (D) 1-5; cisplatin 70 mg/m2, IV, D8; gemcitabine 1000 mg/m2, IV, D8 + 15; filgrastim 300 μg, SC, D15-21; q21). Results: Pt 1: 21 yo man, testicular mixed GCT (seminoma/malignant teratoma intermediate). Prior tx: 2001, orchidectomy; 2005, 3 x BEP (bleomycin, etoposide, cisplatin) + retroperitoneal lymph node dissection. 2015, 2 x TI (paclitaxel, ifosfamide), 3 x TIP (cisplatin, ifosfamide, paclitaxel); 2016, 3 x HDCE (high dose carboplatin/ etoposide + autologous stem cell transplantation); 2017, 6 x GOP (gemcitabine, oxaliplatin, paclitaxel). In 2017, received 6 x GCG in SPIRE for CT confirmed lung metastases (mets) and rising β-hCG (human chorionic gonadotropin). Response: RECIST stable disease with metabolic CR on PET in lungs and > 90% β-hCG reduction. In Cycle 6, pt developed symptomatic brain mets, treated with WBRT (40Gy, 20#) + cyberknife to the six mets completed 2018. Since 2018, ongoing complete marker and radiologic (brain and systemic) remission (20 months). Pt 2: 44 yo man, primary mediastinal non-seminomatous GCT. Prior tx: 2008, 4 x BEP + mediastinal mass resection; 2015, 4 x TIP; 2016, 1 x HDCE. In 2017, received 5 x GCG in SPIRE for a PET avid mediastinal/pulmonary relapse and AFP (alpha-fetoprotein) rise. Response: RECIST stable and > 50% AFP reduction for 6 months (subsequent progression with intracerebral metastasis). Treatment was well tolerated. Grade 4 neutropenia/ thrombocytopenia occurred in both and febrile neutropenia in pt 1. Both required a 25% dose reduction in Cis/Gem. Conclusions: GCG produced exceptional clinical responses in both platinum refractory GCT pts. Prospective evaluation is warranted. Clinical trial information: 16332228.
Accuracy of clinical staging in stage I and IIa/b testicular nonseminomatous germ cell tumors (NSGCT) and implications on survival.
Authors: Srivastava Arnav , Patel Hiren V. , Kim Sinae , Kim Isaac , Singer Eric A. , Jang Thomas L
Published: May 2020

e17058

Background: Clinical stage (CS) dictates treatment in men with testicular cancer and its inaccuracy may affect clinical outcome. We evaluate the accuracy of clinical staging in men with CS I and CS IIA/B NSGCT and explore the implications of inaccurate staging on overall survival. Methods: Using the National Cancer Database (NCDB), we abstracted all patients with clinical Stage I-IIB NSGCT who received a primary retroperitoneal lymph node dissection (RPLND) from 2004 to 2014. Primary RPLND was defined as RPLND performed for CS I-IIB patients without prior chemotherapy. CS was cross-tabulated with pathologic nodal staging data. Survival for patients who were accurately staged (CS I patients with pN0 disease, CS IIA patients with pN1 disease) and for CS I patients found to have pN+ disease was determined using the Kaplan Meier method. Results: 1,639 CS I-IIB patients underwent primary RPLND. Among CS I patients, 23% had upstaging of disease (pN1-3), of which 13.9%, 8%, and 1.1% were pN1, pN2, and pN3, respectively (Table). Pathologic N1-3 disease was higher in CS IB vs. CS IA patients (35.1% vs 14.2%, respectively). Of CS IIA patients, 23.1% had pN0 disease, while 44.8%, 13.4%, and 1.3% had pN1, pN2, and pN3 disease, respectively. At a median follow-up of 56.3 months, mortality rates for CS I patients who had pN1, pN2, and pN3 disease were 2.8%, 4%, and 9.1%, respectively, and < 1% for men with pN0 disease. 10-year overall survival for CS1 patients was significantly less favorable if upstaged to pN2 or pN3 disease after RPLND vs. pN0 or pN1. Conclusions: Nearly a quarter of patients with CS I NSGCT are under-staged and are found to have pN1-3 after RPLND. Nodal disease burden is associated with survival. Novel imaging techniques and biomarkers are needed to improve the sensitivity of detecting NSGCT. [Table: see text]
Effect of long-term peripheral neuropathy induced on cisplatin-based chemotherapy or radiation to the retroperitoneum in testicular germ cell tumor survivors.
Authors: Chovanec Michal , Galikova Dominika , Vasilkova Lucia , De Angelis Valentina , Rejlekova Katarina , Obertova Jana , Sycova-Mila Zuzana , Palacka Patrik , Kalavska Katarina , Svetlovska Daniela , Mladosievicova Beata , Mardiak Jozef , Mego Michal
Published: May 2020

e17062

Background: Treatment for testicular germ cell tumors (GCTs) results in late chemotherapy-induced peripheral neuropathy (CIPN). This study aimed to evaluate impact of curative treatments on different subtypes of self-reported peripheral nerve damage. Methods: GCT survivors (N = 186) followed-up annually at National Cancer Institute in Slovakia have prospectively completed European Organisation for Research and Treatment of Cancer (EORTC) CIPN20 questionnaire at 10 years of median follow-up (range 4-25). EORTC CIPN20 scoring allowed to obtain subscales on sensory function, motor function and autonomy function as well as an overall score. Study groups consisted of survivors treated with chemotherapy (N = 141) and radiotherapy to the retroperitoneum (N = 15). The control group consisted of survivors cured with orchiectomy alone (N = 30) Results: GCT survivors cured with chemotherapy reported higher impairment in overall peripheral neurological function compared to controls (mean score ± SEM: 24.2 ± 0.5 vs. 22.3 ± 1.1, P = 0.03). CIPN20 subscales have shown greater impairment in motor function (P = 0.04), but not in sensory/autonomy functions (both P > 0.05) in chemotherapy group versus controls. Survivors treated with BEPx3 or EPx4 reported similar CIPN in all subscales (all P > 0.05). Motor function was worse in survivors who received ³400mg/m2 of cisplatin compared to ones who received < 400mg/m2 (mean score ± SEM: 9.5 ± 0.2 vs. 8.9 ± 0.3, P = 0.04). Interestingly, patients treated with radiotherapy to the retroperitoneum (but not with chemotherapy) suffered from significantly more peripheral neuropathy in all measured domains compared to the controls (all P < 0.02) Conclusions: Evaluation of long-term perceived peripheral neuropathy after treatment for GCT has shown primarily motor function impairment after chemotherapy. Moreover, significant peripheral neuropathy in all observed CIPN20 subscales after radiotherapy to the retroperitoneum suggests this symptom is not exclusive to cisplatin-based chemotherapy.
Intrarenal renin-angiotensin system in hypertensive patients with localized kidney cancer.
Authors: Osokin Roman , Komarova Ekaterina , Aboyan Igor , Maksimov Aleksey Yu. , Ischenko Roman , Shatova Olga , Komarova Elizaveta
Published: May 2020

e17069

Background: In the last decade, the relationship between arterial hypertension and the risk of developing kidney cancer has been pointed out. Some studies have shown that the metabolic imbalance of the components of the renal renin-angiotensin system (RAS) is associated with the development and progression of kidney cancer. Aim: To study the state of RAS in tumor and peritumoral tissues in hypertensive patients with kidney cancer. Methods: In patients with localized kidney cancer T1N0M0 and grade I-II arterial hypertension without special treatment (n = 40; KC + AH) in the samples of tumor (TT), peritumoral (PTT) and histologically unchanged tissue (HUT), the levels of angiotensin 1 and 2, 1-7 (AT1 and AT2, AT (1-7)) of angiotensin-converting enzymes (ACE and ACE2) were determined by ELISA. The comparison group consisted of patients with RC without impaired blood pressure (n = 55, KC). Results: In patients with KC, the level of AT1 is 1.5 times higher (p < 0.05), and AT2 is 1.6 times higher (p < 0.05) in TT against the background of unchanged content in PTT compared with HUT. The level of ACE is higher than HUT by 2.7 times, ACE2 - by 1.6 times (in all cases p < 0.05), and in PTT it is identical in HUT. In patients with KC + AH, the level of AT1 and AT2 in the TT is 1.8 times higher (p < 0.05) and 2.1 times (p < 0.01), respectively, the content of AT(1-7) is 1.6 times (p < 0.01). In PTT, AT1 is 1.6 times higher (p < 0.01) and AT2 is 1.9 times higher (p < 0.05), significantly lower than only AT2 in the TT (1.2 times at p < 0, 05). The level of AT(1-7) in the PTT is identical to the values in the GNT. The content of ACE and ACE2 in TT is 3.6 and 2.9 times higher, respectively, and in PTT is identical to that in TT. Correlation analysis revealed a reliable direct relationship in the studied groups for all parameters, while in the PTT of hypertensive patients, the relationship between the average blood pressure and the RAS peptide content had a higher tightness. Conclusions: An increase in the levels of angiotensin 1 and 2, angiotensin-converting enzymes ACE and ACE2 in the tumor tissues and peritumoral tissue in patients with localized kidney cancer, regardless of the presence of arterial hypertension at initially higher values in hypertensive patients, was shown. The presence of arterial hypertension in patients with KC changes the metabolism of local RAS in peritumoral tissue and is associated with an increase in the correlation between changes in the components of RAS and arterial hypertension.