bluuebunny/crossref_metadata_2025 huggingface dataset:
Y-90 radioembolization comparative outcomes between solid tumor malignancies: A single institution experience.
Authors: Harris Joshua , Atluri Prashanti , Desouza Neha , Hoffman Jason , Eweka Abie
Published: September 2018

e15704

Background: Transcatheter arterial radioembolization with Y90 is a locoregional therapy for unresectable hepatic malignancy with a more favorable side effect profile compared to trans-arterial chemoembolization. Increasingly, TARE is being utilized in multiple tumor types, for patients with primary hepatic malignancy or metastatic disease that is either liver-dominant or liver-only in distribution. Methods: This single-institution, retrospective study included all patients with hepatic malignancy treated with TARE from May 2012 to June 2016. Primary diagnoses included colon, breast, HCC, carcinoid, pancreatic or gastric cancer. Response was determined according to RECIST 1.1 criteria, based on each patient's followup cross-sectional imaging. 67 doses were administered to 44 patients. The mean dose administered was 25.27 mCi. The primary endpoint was response to therapy. The secondary endpoint was time to progression, in the liver. Results: Initial post-treatment cross-sectional imaging was obtained at an average of 13.9 (± 3.55 weeks, 95% CI) weeks on all patients, with 68% of patients demonstrating partial response, 29% stable disease and 3% of patients with progression. Median imaging follow-up was 6.86 months (± 1.5 months, 95% CI). Over that time period, 16% of patients developed recurrent or disease progression in previously treated lesions. In these patients, the median time to liver progression was 66 weeks. Conclusions: TARE is an effective and durable means of attaining control of disease in the liver. Patients with HCC demonstrated the highest response rate overall. This data adds to the building body of evidence supporting the use of TARE, and is unique as it comparatively assesses TARE response rates in various hepatic malignancies. [Table: see text]
Germline BRCA1 mutations and pancreatic adenocarcinoma: A literature review.
Authors: Al-Taee Ahmad , Gill Ammara , Mahon Suzanne M. , Jallad Bassel
Published: September 2018

e15716

Abstract Background: Pancreatic adenocarcinoma (PAC) is the fourth leading cause of cancer-related deaths in the United States. Although the vast majority of cases are sporadic, up to 10% of cases are related to a hereditary cancer predisposition syndrome, the most common of which is germline BRCA mutation. Although BRCA2 mutation has been well described in the literature, data on BRCA1 mutation-associated PAC is limited. This work aims at reviewing the literature on BRCA1 mutation-associated PAC and discussing the relevant findings. Methods: We have searched the Pubmed database for articles using the search terms “pancreatic”, “BRCA”, BRCA1”, “adenocarcinoma” or any combination of these keywords. Data about epidemiology, staging, prior history of other tumors, and management were collected. Systematic data extraction and assessments of quality were carried out by two reviewers, and good agreement was found. Results: A total of 13 studies were selected for review and included a total of 149 patients. The prevalence rate of PAC among patients with germline BRCA1 mutations ranged between 0.002% and 0.03%. Moreover, the prevalence of BRCA1 mutations in patients with BRCA-related PAC was found to be between 27% and 30%. Of note, PAC was diagnosed as the first tumor in 74% of patients with BRCA1-related PAC. The most common stage at diagnosis was stage 4 (56%) followed by stage 2 (22%). Conclusions: Germline BRCA1 mutation-associated PAC is an under-recognized entity when compared to BRCA2 mutations. Given the incredibly poor prognosis and the growing interest in targeted therapies, physicians need to be familiar with BRCA1 mutations as a possible etiology of PAC. A significant number of patients with BRCA1 mutation-associated PAC were diagnosed with PAC as the first tumor. Therefore, upper gastrointestinal screening should be considered in patients with germline BRCA1 mutations.
Second-line (SL) chemotherapy containing oxaliplatin (OXA) in metastatic pancreatic cancer (PC): Whom should we trust?
Authors: Caparello Chiara , Vivaldi Caterina , Montagnani Francesco , Musettini Gianna , Pasquini Giulia , Pecora Irene , Catanese Silvia , Lencioni Monica , Falcone Alfredo , Fornaro Lorenzo , Vasile Enrico
Published: September 2018

e15719

Background: After the intensification of first-line treatment in metastatic PC the number of patients fit and able to receive a SL treatment is increasing; despite these results, the choice of SL chemotherapy remains a challenging issue. The role of OXA in SL setting has given conflicting results in CONKO-003 and PANCREOX trials; the reasons of this inconsistency are difficult to understand. Methods: In order to detect a possible advantage from the use of oxaliplatin in SL, we pooled together the results of randomized phase II/III studies adding OXA to fluoropyrimidines after a gemcitabine-based first-line. Hazard ratios (HRs) for progression-free (PFS) and overall survival (OS) with 95% confidence intervals (CIs) were extracted, while the number of events was used for RR to determine odds ratio (OR) with corresponding 95%CIs. Fixed-effect and random-effect models were used as appropriate, on the basis of the evidence of a non-significant or significant heterogeneity among trials, respectively. The Review Manager software was used (version 5.3). Results: Three studies were identified; main characteristics and results are summarized in the table. No benefit in overall survival derived from the use of OXA (HR 1.03, 95% CI, 0.64-1.67; p=0.90) but significant heterogeneity was reported (p=0.003); the addition of OXA produced a significant benefit in terms of PFS (HR 0.81, 95% CI 0.68-0.97; p=0.02) with a higher chance of response (OR 1.81, 95% CI 1.01-3.24; P=0.05). Interestingly heterogeneity between trials was less evident in PFS and RR than in OS suggesting that this could be a confounding element in the interpretation of data. Conclusions: The reasons of conflicting results concerning the use of oxaliplatin doublets in SL setting are not clear. Given the recent advances in first-line setting, it would be interesting to identify an optimal sequential strategy, hopefully in a personalized approach. [Table: see text]
The neutrophil to lymphocyte ratio as a prognostic factor among a diverse population with advanced pancreatic cancer.
Authors: Shusterman Michael , Jou Erin , Kaubisch Andreas , Chuy Jennifer W. , Rajdev Lakshmi , Tang Justin , Ohri Nitin , Aparo Santiago , Goel Sanjay
Published: September 2018

e15729

Background: The neutrophil to lymphocyte ratio (NLR), a marker of systemic inflammatory response, has been suggested as a prognostic marker in patients with pancreatic adenocarcinoma (PAC). Black and Hispanic patients have been underrepresented in studies evaluating the significance of NLR in PAC. We investigated the prognostic significance of NLR in patients with advanced PAC treated at the Montefiore-Einstein Center for Cancer Care (MECCC) in the Bronx, NY. Methods: We included patients who were chemotherapy naive and treated for unresectable or metastatic PAC at MECCC between 2006 and 2015. Demographics, clinical characteristics and treatment data were collected. Overall survival was determined by the Kaplan-Meier method and Cox proportional-hazards models were built to assess survival differences adjusting for clinically relevant and statistically significant variables. Results: 201 patients were included in the study. Median age was 65 (range 32, 90). 52% were male. 41 were White (19%), 71 Black (33%), 71 Hispanic (33%), and 33 Other (15.3%). 66 (30.6%) had unresectable disease and 135 (62.5%) metastatic disease. An NLR ≥ 4 was associated with a worse OS compared to an NLR ≤ 4 (median 10 vs. 16.4 months; HR 1.895; 95% CI 1.390, 2.585; P < 0.0001). Predictors of worse OS on univariate analysis were ever smoker status (HR 1.365; P = 0.05), metastatic disease (HR 1.736; P = 0.001), and albumin ≤ 3.5 g/dL (HR 2.558; P< 0.0001). An NLR ≥ 4 on multivariate analysis remained significantly associated with worse OS (HR 1.665; 95% CI 1.188, 2.334; P = 0.003) after adjusting for age, gender, ever smoker status, metastatic disease, and albumin. Conclusions: In a cohort with significant minority patient representation, an NLR ≥ 4 was associated with significantly worse overall survival in patients with advanced pancreatic cancer. An elevated NLR in advanced PAC may be an important independent predictor to risk stratify patients and predict poor OS in future analyses.
Calcium channel blockers use and overall survival in pancreatic cancer patients receiving gemcitabine.
Authors: Kraj Leszek , Śliwczyński Andrzej , Krawczyk-Lipiec Joanna , Woźniak Krzysztof , Waszczuk-Gajda Anna , Rybski Sebastian , Wyrwicz Lucjan
Published: September 2018

e15756

Background: Preclinical studies have shown that calcium channel blockers (CCB) may potentiate anticancer effect of chemotherapy via intra-cellular drug accumulation. Gemcitabine-based chemotherapy is commonly used in pancreatic cancer (PC) patients. The aim of this study was to determine whether CCB may affect overall survival (OS) in PC patients receiving gemcitabine-based chemotherapy. Methods: The retrospective cohort of PC patients treated with gemcitabine between 2007 and 2016 was identified in the Polish National Health Fund databases. Electronic records of prescriptions were searched to identify in this cohort patients receiving CCB (amlodipine, nitrendipine, felodipine, lacidipine). The primary endpoint was OS and it was determined by Kaplan-Meier methods and compared by the log-rank test. Results: In total 4628 PC patients treated with gemcitabine (median OS 7.7 months; 95% CI: 7.4-7.9) were identified. Among these 380 patients were prescribed any CCB. There was a significant difference (p < 0.001) in median OS between patients prescribed CCB (n = 380; OS 9.3 months; 95% CI: 7.8-11.0) and those who did not (n = 4214; OS 7.6 months; 95% CI: 7.3-7.8) with hazard ratio for death 0.70 (95% CI: 0.62-0.79). Notably, the survival curves tended to flatten in CCB group, with 24% of patients alive at 2 years (95% CI: 20-29%) and 15% alive at 5 years (95% CI: 11-19%), compared with 11% (95% CI: 10-12%) and 4% (95% CI: 4-5%) in controls respectively. Conclusions: The use of CCB in PC patients receiving gemcitabine-based chemotherapy was associated with improved OS. Further validation is needed to evaluate effectiveness of CCB-gemcitabine combinations in the management of PC.
Clinical and pathological features of solid pseudopapillary neoplasm (SPN) of the pancreas: A retrospective review of cases at Mayo Clinic.
Authors: Sanhueza Cristobal T. , Jin Zhaohui , Smyrk Thomas C. , Hartgers Mindy L. , Alberts Steven R. , Mahipal Amit
Published: September 2018

e15757

Background: SPN is a rare neoplasia of the pancreas, defined by the World Health Organization (WHO) as an epithelial low-grade malignant neoplasm, with a high-grade malignant transformation potential. Literature in this subject is scarce and limited only to small retrospective series. Methods: This is a retrospective study aiming to characterize patients with the diagnosis of SPN at Mayo Clinic between 1992 and 2016. Demographics, clinical and pathological features, recurrence rate and overall survival were recorded. Malignant SPN was defined as per the WHO 2010 classification (Perineural invasion, angioinvasion or deep tissue invasion) and compared to Benign SPN. Results: 44 patients with SPN were identified. 39 patients (88.6%) were female. Median age at diagnosis was 27.5 (Range: 13-64). The most frequent presentation was abdominal pain (52.6%), whereas 36.8% were diagnosed based on incidental imaging findings. Majority (60.4%) of the tumors were located at the pancreatic tail, and 48.5% were solid-cystic lesions. Vascular and lymph node involvement were infrequent. 15 cases (30.23%) were classified as malignant. Tumor size was associated with malignant behavior (Table). Three patients had a metastatic presentation. All but 1 patient were treated with surgery. R1 resection was more frequent in malignant SPN, and 2 patients experienced disease recurrence. Two Stage IV patients were treated with surgery and experienced long term survival, one of them without evidence of disease. There was only 1 death recorded. Conclusions: SNP presents predominantly on young women. The prognosis is excellent even in presence of malignant features, and a complete surgery remains as the main treatment. [Table: see text]
Correlation of early tumor shrinkage (ETS) and depth of response (DoR) with resectability in patients (pts) with unresectable locally advanced pancreatic cancer (LAPC) undergoing primary treatment with FOLFOXIRI.
Authors: Vivaldi Caterina , Catanese Silvia , Fornaro Lorenzo , Cappelli Carla , Caparello Chiara , Musettini Gianna , Pasquini Giulia , Pecora Irene , Lencioni Monica , Vasile Enrico , Falcone Alfredo
Published: September 2018

e15777

Background: FOLFIRINOX is a reasonable option in LAPC. GONO FOLFOXIRI has been shown to provide similar efficacy in advanced disease. ETS and DoR, emerging as relevant endpoints in colorectal cancer, have been rarely investigated in LAPC. Methods: Unresectable LAPC pts treated with FOLFOXIRI were identified. Computed tomography (CT) scan was performed every 8 weeks; after that, multidisciplinary team assessed resectability. ETS was defined as the reduction of ≥20% of target lesions’ diameters at first evaluation. DoR was the % of maximal tumor shrinkage at the nadir compared to baseline. Primary endpoint was the correlation of ETS and DoR with radical (R0) resection. Secondary endpoints were correlation of ETS and DoR with overall survival (OS) and progression-free survival (PFS). Radiologist was blinded to survival data. Survival curves were estimated using the Kaplan-Meier method. Log-rank and chi-square tests were applied. Results: Sixty pts were included. Median age was 62 years (range: 34-74), tumor location was head in 68% and body-tail in 32%. At a median follow-up of 26.9 months, response rate was 37%, median OS and PFS were 15.7 and 10.3 months, respectively. Thirty patients (50%) underwent R0 surgery after chemotherapy. Two pts died due to early surgical complication and were censored at the date of surgery for survival analyses. Among 55 evaluable pts, ETS was reached in 19 pts and median DoR was -17% (range: -65 to +100). A strong association between ETS (p = 0.0002) and DoR (p < 0.0001) with R0 resection was observed. In the overall population, ETS was significantly associated with better PFS (14.5 vs 9.4 months, p = 0.037), while no difference in OS was shown (p = 0.63). DoR was significantly associated both with PFS (13.6 vs 7.8 months, p = 0.014) and OS (19.8 vs 14.5 months, p = 0.047). Conclusions: FOLFOXIRI may allow achieving resectability in selected pts. ETS and DoR are significantly associated with R0 resection. Maximizing response with active regimens could be an effective strategy in LAPC. Further validation of ETS and DoR as surrogate endpoints in larger prospective series is required.
Second-line treatment in patients with pancreatic ductal adenocarcinoma: A meta-analysis.
Authors: Sonbol Mohamad Bassam , Firwana Belal , Wang Zhen , Ahn Daniel H. , Borad Mitesh J. , Makhoul Issam , Ramanathan Ramesh K. , Bekaii-Saab Tanios S.
Published: September 2018

e15779

Background: There is paucity of data regarding the best available second-line treatment following progression on gemcitabine-based regimens in metastatic pancreatic ductal adenocarcinoma (PDAC). While a Nanoliposomal formulation of irinotecan (MM398) is considered a standard of care, there is conflicting data relating to the use of oxaliplatin in this setting. We performed a meta-analysis to determine the effectiveness of adding oxaliplatin (OX) or various irinotecan (IRI) formulations to a fluoropyrimidine (FP) as a second-line in PDAC patients. Methods: We searched different databases, including PubMed, Embase and Cochrane, to identify randomized controlled trials comparing FP monotherapy to FP combination therapy that includes either oxaliplatin (FPOX) or various irinotecan formulations (FPIRI) in PDAC patients who progressed after first-line treatment. Secondary analyses were planned to assess the effectiveness of FPOX and FPIRI compared to FP. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian and Laird random effects models. Results: Five studies (2 with FPIRI and 3 with FPOX) with 895 patients were identified. Patients randomized to FPIRI/FPOX had a significantly improved PFS (HR = 0.74, CI 0.62 to 0.89) and a trend towards an improved OS compared to FP monotherapy (HR = 0.88, CI 0.65 to 1.19). When comparing FPIRI to FP, there was an improvement in both PFS (HR = 0.64, CI 0.47 to 0.87) and OS (HR = 0.70, CI 0.55 to 0.89) in patients treated with the combination. Conversely, FPOX showed only a modest improvement in PFS (HR = 0.81, CI 0.67, 0.97) with no improvement in OS (HR = 1.03, CI 0.64 to 1.67). Conclusions: Combination chemotherapy with oxaliplatin or various irinotecan formulations seem to improve PFS vs. single agent FP. FPIRI, but not FPOX seem to confer an OS advantage. Oxaliplatin with FP following gemcitabine failure may need further confirmatory studies to establish its role in refractory pancreas cancer.
Modified IPCW model: A method for adjusting for bias in the estimation of overall survival due to the use of second and third line therapies in locally advanced or metastatic pancreatic cancer patients.
Authors: Iznaga Escobar N. E. , Luaces Patricia Lorenzo , Sanchez Valdes Lizet , Valenzuela Silva Carmen , Crombet Ramos Tania , Strumberg Dirk , Schultheis Beate , Ebert Matthias Philip , Kerkhoff Andrea , Hofheinz Ralf , Behringer Dirk M. , Schmidt Wolfgang E , Goker Erdem , De Dosso Sara , Kneba Michael , Yalcin Suayib , Overkamp Friedrich , Schlegel Frank , Dommach Markus , Rohrberg Robert ,   Tilman Steinmetz, Dirk Reuter, Ferdinand Bach, Rikrik A. Ilyas, Budhi H. Simon, Group Practice Hematology/Oncology Cologne, Cologne, Germany; Oncoscience AG, Wedel, Germany, InnoCIMAb Pte Ltd, Singapore
Published: September 2018

e15787

Background: Nimotuzumab, a unique and affinity differentiated anti-EGFR antibody had been used in combination with gemcitabine on the treatment of pancreatic cancer patients. The aim of the study was to evaluate overall survival. Methods: Patients with newly diagnosed, locally advanced or metastatic pancreatic cancer, KPS ≥ 70 %, 18-72 years old, with adequate renal and liver function were included. Pts received gemcitabine 1000 mg/m2and nimotuzumab or placebo fixed dose of 400 mg once a wk, for 3 wks, followed by a 1-wk rest (d1, 8, 15, q28) until disease progression or unacceptable toxicity. The primary endpoint was OS and secondary PFS, ORR, CBR, safety and QoL. For OS determination, a KM log-rank test was used and a modified IPCW with a cox regression as a secondary analysis. On this evaluation using a modified IPCW model, 41.7% of pts from treatment arm and 42.7% from control arm who received 2nd and 3rd line treatment were censored after progression, while pts that did not receive 2nd and 3rd line treatment were weighted to compensate for the bias created by censoring switchers to 2nd and 3rd line treatment. Results: 192 pancreatic cancer pts were recruited. Ninety-six pts (62 male and 34 female) with a median age of 67 years, range (31, 83) were randomized to treatment arm and 96 pts (57 male and 39 female) with a median age of 64 years, range (41, 82) were randomized to control arm. In the primary analysis, median OS [95% CI] in the treatment arm was 8.57 mo [5.93, 10.90] vs 6.03 mo [4.97, 7.60] in the control arm. The HR [95% CI], 0.83 [0.62, 1.12] and p = 0.23 and when a modified IPCW model as a secondary analysis was used to remove the effect of 2nd and 3rd line therapies, the median OS was statistically significant with a HR [95% CI], 0.81 [0.67, 0.98] and a p = 0.030. The median PFS [95% CI] was 4.43 mo [3.67, 6.00] in the treatment arm vs 3.47 mo [2.60, 4.03] in the control arm with a HR [95% CI] 0.68 [0.51, 0.92] and p = 0.012. Conclusions: A modified IPCW model had proven that addition of nimotuzumab to gemcitabine increases median overall survival of newly diagnosed chemotherapy-naïve locally advanced or metastatic pancreatic cancer patients. Clinical trial information: NCT00561990.
Clinical characterization of pancreatic ductal adenocarcinomas (PDAC) with mismatch repair (MMR) gene mutations.
Authors: Hu Zishuo Ian , Varghese Anna M. , Shia Jinru , Zervoudakis Alice , Lowery Maeve Aine , Yu Kenneth H. , Chalasani Sree Bhavani , Robson Mark E. , Stadler Zsofia Kinga , Caron Philip , Kelsen David Paul , Klimstra David , Kelly Daniel W. , O'Reilly Eileen Mary
Published: September 2018

e15791

Background: Tumors with mismatch repair-deficiency (MMRD) have a high mutational burden and have good responses to immunotherapy (Le, NEJM, 2015). We describe the natural course, clinicopathological, and genomic status of MMRD PDAC patients (pts) at Memorial Sloan Kettering Cancer Center (MSKCC). Methods: MSKCC institutional registry and ICD billing database queried from 2006-2016 for PDAC pts with genetically confirmed mutations in mismatch repair (MMR) genes. Mutation # determined via MSK-IMPACT, a targeted tumor next generation sequencing (NGS) test (Cheng, J Mol Diagn, 2015). Results: 5/607 (0.8%) PDAC pts had Lynch syndrome (LS) (confirmed germline mutations) (Table 1). Of the 5 LS pts, all had > 10 mutations in NGS, with 4 of 5 having > 50 mutations. 4 of 5 (80%) are alive at last follow-up (survival 30-314 months). N=4 had extensive personal/family history of cancer. Of N=3 who had resected disease, all 3 had recurrence at 11, 49 and 311 months, and all are alive (survival: 69-314 months). Of N= 2 pts that had unresectable tumors, one passed away at 30 months while the other is on checkpoint inhibitor trial and is alive at 30 months. In contrast, 7/607 (1.1%) PDAC pts had somatic mutations in MMR genes with an average of 5.7 mutations in NGS, with 4/7 having <5 mutations. 4/7 (57%) are deceased at last follow-up (survival: 10-42 months). Conclusions: All cases with germline mutations in the MMR genes, with one exception, had high mutation #. All cases with somatic mutations in the MMR genes had low mutation #. Germline mutations in MMR genes and high mutational burden may predict for a prognostically favorable subgroup of PDAC pts with high susceptibility to immune oncology agents. [Table: see text]
A propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic.
Authors: Kulkarni Girish S. , Hermanns Thomas , Wei Yanliang , Bhindi Bimal , Satkunasivam Raj , Bostrom Peter , Kuk Cynthia , Li Kathy , Erlich Annette , Templeton Arnoud J. , Sridhar Srikala S. , van der Kwast Theodorus , Chung Peter W. M. , Bristow Robert G. , Milosevic Michael F. , Warde Padraig Richard , Fleshner Neil Eric , Jewett Michael A.S. , Bashir Shaheena , Zlotta Alexandre
Published: September 2018

e16003

Background: Multidisciplinary management improves complex treatment decision making in cancer care, but its impact for bladder cancer (BC) has not been documented. While radical cystectomy (RC) is currently viewed as the standard of care for muscle-invasive bladder cancer (MIBC), radiotherapy-based, bladder-sparing trimodal therapy (TMT) combining transurethral resection of bladder tumor, chemotherapy for radiation sensitization and external beam radiotherapy has emerged as a valid treatment option. In the absence of randomized studies, we compared the oncological outcomes between patients managed by RC or TMT using a propensity-score matched cohort analysis. Methods: Patients seen in our multidisciplinary bladder cancer clinic (MDBCC) from 2008 to 2013 were retrospectively reviewed. Those who received TMT for MIBC were identified and matched (for gender, cT and cN stage, ECOG status, Charlson comorbidity score, treatment date, age, CIS, hydronephrosis) using propensity scores, to patients who underwent RC. Overall survival and disease-specific survival (DSS) were assessed with Cox Proportional hazards modeling and competing risk analysis, respectively. Results: 112 patients with MIBC were included after matching, 56 treated with TMT and 56 by RC. Median age was 68.0 years and 29.5% were cT3/cT4. At a median follow up of 4.51 years, there were 20 (35.7%) deaths (13 from BC) in the RC group and 22 (39.3%) deaths (13 from BC) in the TMT group. 5 year DSS was 73.2% and 76.6%, in the RC and TMT groups, respectively (p = 0.49). Salvage cystectomy was performed in 6/56 TMT patients (10.7%). Conclusions: In the setting of a MDBCC, TMT yielded survival outcomes similar to matched RC patients. Appropriately selected MIBC patients should be offered the opportunity to discuss various treatment options including organ-sparing TMT.
Serial measurements of myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint inhibitors (CI).
Authors: Ornstein Moshe Chaim , Diaz-Montero C. Marcela , Rayman Patricia A. , Elson Paul , Haywood Samuel , Kim Jin Sub , Pavicic Paul G , Finke James , Rini Brian I. , Kaouk Jihad , Lamenza Marcelo , Dann Priscilla , Schach Kim , Devonshire Sarah , Ko Jennifer S , Haber Georges-Pascal , Ernstoff Marc S. , Hoimes Christopher J. , Garcia Jorge A. , Grivas Petros
Published: September 2018

e16005

Background: MDSC are a heterogeneous population of immunosuppressive cells with potentially predictive implications in UC pts receiving CI. We hypothesized that MDSC populations may change after CI exposure. Methods: Serial peripheral blood samples were collected from mUC pts treated with CI. MDSC were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSC were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. The Wilcoxon signed rank and rank sum tests were used to assess changes in MDSC populations while on CI. Results: 17 pts treated with CI (9 atezolizumab [A], 8 pembrolizumab [P]) had ≥ 2 MDSC samples for analysis. Median age at diagnosis was 71 (46-81), 12 men, 29% never smokers; 53% / 29% / 18% ECOG PS 0/1/2 and 59% visceral metastasis at the time of 1st sample collection. 10 pts received CI as 1st line therapy (Tx) in metastatic setting; 7 pts received chemotherapy as 1st-line Tx for mUC (6 platinum-based, 1 docetaxel) and CI as 2nd-line Tx. In 16 pts with samples before 1stdose, there was a relative decrease (median 36.3%, range -59.7 to +21.2) in PBMC % I-MDSCs between 1st and 2nd samples (p=0.06). Interestingly, PBMC %M-MDSC and %I-MDSC tended to increase compared to baseline in pts treated with P, while they tended to decrease in pts treated with A (Table). Conclusions: In this cohort of pts with mUC treated with CIs,MDSC changes differed based on CI (anti-PDL1 or anti-PD1). Further study in larger cohort with various prior Tx lines and longer follow up as well as correlations with Tx response, toxicity and outcomes are ongoing. [Table: see text]
Standard of care for MIBC is becoming more standard.
Authors: Miller Kelly LR , Albandar Heidar , Key David , Haluschak John J.
Published: September 2018

e16011

Background: Despite consensus guideline recommendations, the management of muscle invasive bladder cancer (MIBC) varies dependent on institution setting. The risk of recurrence of localized bladder cancer after cystectomy is substantial and associated with stage. The current standard of care for possibly T2 and certainly T3-T4 MIBC is neoadjuvant cisplatin (NAC) based chemotherapy followed by cystectomy. As recent as 2011, only 12% of patients in this category actually received NAC (Feifer et al. 2011). Similar statistics have been confirmed in the US and Canada. Given there is a 13% reduction in risk of death with use of NAC, the adherence to this recommendation needs to improve. We hypothesize that in a multispecialty community practice where barriers to care are reduced that the percentage of eligible patients receiving NAC is significantly higher than previously reported. Methods: After IRB exemption obtained, patients from 2012-2015 with MIBC who underwent cystectomy were examined. Data collection included age, sex, date of consultation, dates and type of chemotherapy received, eGFR, date of surgery and surgical pathology report staging. Data were analyzed using Kolmogorov-Smirnov, Shapiro-Wilk, Mann-Whittney and Kruskal-Wallis statistical tests. Results: The average patient age was 69 years old with a male predominance. Approximately 54% of patients received neoadjuvant chemotherapy; however, three of those patients did not receive the recommended cisplatin based regimen. Fifty percent of patients received NAC and 57% of cisplatin eligible (age < 80, eGFR > 30) patients received NAC. The average time to cystectomy was 171 days among those receiving NAC, with a decrease in time to cystectomy correlating with age. Conclusions: In a community group practice, adherence to standard of care recommendations for higher stage MIBC patients to receive NAC are significantly higher than recently reported values, 50% vs 12%, respectfully. This was achieved while maintaining acceptable time to cystectomy. This supports our hypothesis that when barriers to care are decreased in a community group practice, high quality standards of care can be effectively delivered. In the future, 5 year overall survival will also be important to evaluate in this population.
Nomogram to assess survival benefit of new over historical agents as salvage therapy for metastatic urothelial carcinoma (mUC) in non-randomized trials.
Authors: Sonpavde Guru , Pond Gregory Russell , Rosenberg Jonathan E. , Choueiri Toni K. , Bellmunt Joaquim , Regazzi Ashley Marie , Mullane Stephanie Anne , Necchi Andrea , Raggi Daniele , Lee Jae-Lyun , Lee Soon Il , Simpson Joseph , Derleth Christina Louise , Shih-Wen Lin , Bajorin Dean F.
Published: September 2018

e16012

Background: Surrogate endpoints of benefit in mUC phase 2 salvage therapy trials are necessary to identify promising drugs, particularly for checkpoint inhibitors where response and progression-free survival are inadequate. We developed a nomogram using prognostic variables from phase 2 trials of historical agents to estimate 12 month survival to which observed survival in phase 2 trials could be compared. Methods: Data were obtained from phase 2 trials of salvage therapy for mUC for survival and 5 prognostic factors: hemoglobin, performance status, liver metastasis, treatment-free interval and albumin. Patients (pts) were randomly allotted to discovery:validation (DIS:VAL) datasets in a 2:1 ratio. A nomogram was developed for estimating 12-month survival. Calibration plots were constructed in the VAL dataset by plotting estimated vs. observed 12-mo survival and data bootstrapped to assess performance. The nomogram was applied to external nonrandomized salvage therapy data: 1) retrospective pemetrexed data or 2) trials of atezolizumab: PCD4989g and IMvigor210. Results: Data were available from 340 pts receiving sunitinib (n = 77), everolimus (n = 45), docetaxel + vandetanib or placebo (n = 109), pazopanib (n = 42), paclitaxel (n = 36) and docetaxel (n = 31). Calibration and prognostic ability of the model was acceptable (c-index = 0.634, 95% CI = 0.596-0.652). Observed 12-month survival for pts on pemetrexed (n = 127, 23.5% [95% CI: 16.2%-31.7%]) were similar to nomogram-predicted survival (19% [95% CI: 16.5-21.5], P> 0.05), while observed result with atezolizumab (n = 403, 39.0% [95% CI: 34.1-43.9]) exceeded predicted result (24.6% [95% CI: 23.4-25.8], P< 0.001). Conclusions: Atezolizumab was associated with a significantly longer 12-mo survival compared to nomogram-predicted survival while pemetrexed was not. This nomogram incorporates baseline prognostic factors to provide expected 12-mo survival of phase 2 patient cohorts with which to compare observed survival, providing a useful tool to quantify benefit in phase II studies while controlling the impact of clinical variables.
Systemic immune-inflammation index to predict survival in Caucasian patients with metastatic urothelial carcinoma.
Authors: Palacka Patrik , Mego Michal , Mikulova Terezia , Chovanec Michal , Kalavska Katarina , Svetlovska Daniela , Obertova Jana , Rejlekova Katarina , Sycova-Mila Zuzana , Kajo Karol , Mardiak Jozef
Published: September 2018

e16015

Background: The systemic immune-inflammation index (SII) is a prognostic factor in various malignancies that probably reflects a state of immunity. The objective of this retrospective analysis was to explore prognostic value of the SII at baseline and at week 6 during first-line platinum-based chemotherapy in Caucasian population with metastatic urothelial cancer (MUC). Methods: We evaluated 185 consecutive MUC (152 bladder, 72 upper tract) patients (139 men) treated with first-line platinum-based chemotherapy at National Cancer Institute between 2000-2015. Median Karnofsky index was 90% (30–100%), visceral metastases were present in 86 patients. SII was based on platelets (P), neutrophils (N) and lymphocytes (L) counts defined as PxN/L. Progression-free survival (PFS), overall survival (OS) and their 95% CI were estimated by Kaplan-Meier method and compared with logrank test. The study population was dichotomized by median into high SII and low SII groups. Multivariate Cox regression analysis included Karnofski index, status of visceral metastases together with baseline SII and SII at week 6, respectively. Results: At median follow-up 10 months (1-139 months), 170 patients experienced disease progression and 168 of them died.Patients with low SII at baseline had significantly better PFS and OS opposite to those with high SII (HR = 0.62, 95% CI 0.45-0.84 for PFS and HR = 0.52, 95% CI 0.38-0.71 for OS, respectively). Similarly, patients with low SII at 6 weeks had significantly better PFS and OS compared to those with high SII (HR = 0.61, 95% CI 0.45-0.83 for PFS and HR = 0.54, 95% CI 0.40–0.74 for OS, respectively). Multivariate analysis confirmed independent prognostic value of baseline SII and SII at week 6 for PFS and OS. Conclusions: Both, the SII at baseline and at week 6 during treatment with first-line chemotherapy represent independent prognostic factors for Caucasian population with MUC. Based on SII, patients could be stratified into future clinical trials. MUC patients with high SII might be candidates for an experimental first-line treatment.
Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics.
Authors: Li Qingdi Quentin , Sanford Thomas , Krane Spencer , Hammerich Kai Hans , Trepel Jane B , Neckers Len , Agarwal Piyush K.
Published: September 2018

e16030

Background: Heat shock protein 90 (HSP90) is a chaperone for many proteins integral development of cancer, making inhibition of HSP90 an attractive strategy for cancer treatment. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we present a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder cancer in response to HSP90 inhibition. Methods: We assessed the antitumor activity of five HSP90 inhibitors in 5637 bladder cancer cell line using MTS, cell viability, and caspase 3/7 assays. We then performed a proteomic analysis of cells before and after treatment with the HSP90 inhibitors and assessed for changes. Results: We show that the five HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells. HSP90 inhibitors also had differential effects on cell survival between bladder cancer cells and uroepithelial cells. Our proteomic study quantified 518 twofold up-regulated and 811 twofold downregulated proteins common to both AUY922 and ganetespib treatment (P < 0.05). The subsequent bioinformatic analysis revealed that those differentially expressed proteins were involved in chromatin modifications and cell death-associated pathways. Further, quantitative proteome studies identified 14 different types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells, suggesting that HSP90 inhibitors may exert multiple cytotoxic actions in bladder cancer cells by inhibiting HSP90 activity or altering the structure of chromatin. Conclusions: This study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder cancer cells, and supports the notion that HSP90 inhibitors both as single agents and in combination might provide new therapeutic options for bladder cancer treatment and thus warrant further preclinical exploration.
Real-world experience with atezolizumab (atezo) in advanced urothelial cancer (UC).
Authors: Barata Pedro C. , Gopalakrishnan Dharmesh , Elson Paul , Koshkin Vadim S. , Ornstein Moshe Chaim , Diaz-Montero C. Marcela , Haywood Samuel , Rayman Patricia A. , Finke James , Lamenza Marcelo , Devonshire Sarah , Profusek Pam , Allman Kimberly D , Martin Allison , Beach Jennifer , Schach Kim , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A. , Grivas Petros
Published: September 2018

e16031

Background: Atezo was recently FDA-approved for patients (pts) with UC (IMvigor210 trial). We assessed the safety and efficacy of Atezo in the real world setting and explored the role of putative biomarkers. Methods: Data from 44 consecutive non-trial pts with UC treated with ≥1 dose of Atezo 1200mg IV q3w at Cleveland Clinic (May - Dec 2016) were available. Demographic, clinicopathologic, biomarker data, including blood neutrophil to lymphocyte ratio (NLR) and myeloid derived suppressor cell (MDSC) populations [LinloCD33+/HLADR-(Total), and Granulocytic(CD15+CD14-), Monocytic(CD15-CD14+), Immature(CD15-CD14-), CD11b+ subsets], were collected. Response, progression-free survival (PFS) and overall survival (OS) were measured (RECIST v1.1). Adverse events (AE) were reported (CTCAE v4.03). Outcome data were analyzed with Fisher’s exact test, chi-square tests, log rank test and proportional hazards models. Results: Median age was 68y (34-88), 68% men, 68% pure urothelial histology, 27% never smokers; 61% PS > 0, 61% visceral metastases, 57% CrCl < 60 mL/min, 84% bladder primary, 61% prior cystectomy. In metastatic setting, 25% had ≥2 prior systemic therapies, 84% prior platinum-based regimen, and 9% no prior therapy. With median follow-up of 3.3 months ( < 1 - 6.6) and median number of 3 doses, in 38 pts evaluable for response, 21% had PR; 24% SD; 61% progressed, 27% died; estimated median (m)PFS was 3 months (95%CI 2.2 - 4.3) and mOS was 5.2 months (95%CI 4.6 - NR). Only 3/27 eligible pts got subsequent treatment. Number of metastatic sites, 2 Bellmunt prognostic factors, and NLR ≥ 5.0 negatively impacted response, PFS and OS. MDSC populations (data available in 14 pts) demonstrated non-significant correlation with worse outcome and elevated NLR. Most frequent all-cause AE ( > 20%) were fatigue (60%, G3:9%), anorexia (33%, G3:7%), elevated creatinine (26%, G3:5%); 1 pt had G4 hyperbilirubinemia. There were no treatment-related deaths. Conclusions: To our knowledge, this is the largest real-world experience with Atezo in UC. Response and toxicity were comparable to IMvigor210 trial; estimated mOS was shorter but with limited follow up. Higher NLR had negative prognostic value, while the role of MDSCs merits further exploration.
Prognostic impact of primary tumor location in advanced urothelial carcinoma: The EORTC series.
Authors: Moschini Marco , Shariat Shahrokh F. , De Santis Maria , Bellmunt Joaquim , Sternberg Cora N. , Tombal Bertrand F. , Collette Laurence , Roupret Morgan
Published: September 2018

e16034

Background: The prognostic relevance of the primary location of urothelial cell carcinoma (UCC) on outcomes is poorly documented. This parameter has been studied in 3 EORTC trials in advanced UCC that included patients with different initial primary tumor locations. Methods: We used the data prospectively collected in three EORTC advanced UCC studies 30924 (M-VAC versus High dose M-VAC), 30986 (MCAVI versus GC, among patients unfit for CDDP), 30987 (GC-Paclitaxel versus GC, among patients fit for CDDP). Ineligible patients and other tumor locations were excluded. Patients all had measureable distant metastases or unresectable UCC and WHO performance status 0-2. Patients were grouped by primary tumor location as bladder (BCa) versus upper urinary tract (UTUC). PFS and OS by tumor location was tested in Cox proportional hazard regression stratified by study and treatment using at 2-sided α of 0.05. Results: Of the 1,039 patients, 85.3% and 14.7% patients had BCa and UTUC, respectively. Patient and disease characteristics (Table) suggested better performance status and slightly more males among patients with GCa. With a median follow up of 4.8 years (IQR:4.0-6.7), 733 deaths were recorded and 925 had progressed or died. OS and PFS did not differ significantly by tumor location overall (P=0.317 and P=0.685 respectively, Table 1), but there is significant heterogeneity across treatments (heterogeneity P=0.0450 for OS and P=0.0121 for PFS) with a suggestion of differential results in the M-CAVI arm for unfit patients. Conclusions: Primary UTUC location is uncommon in advanced UCC and did not seem to markedly impact PFS or OS. However, the findings may vary according to treatment. [Table: see text]
Endoglin (CD105) expression in non-seminomatous germ cell tumors.
Authors: Sikaria Swati , Chopra Shefali , Xiong Shigang , Yang Dongyun , Theuer Charles P. , Hu James
Published: September 2018

e16036

Background: Nonseminomatous germ cell tumors are known for hematogenous spread and new therapeutics are needed. Endoglin (CD105) is a cell-surface protein that is overexpressed on endothelial cells and a potential target for anti-angiogenic therapy. Preclinical studies demonstrate overexpression of CD105 in tumor vasculature and targeting CD105 in murine models have resulted in tumor regression. We examine CD105 expression in tumor cells and tumor vasculature of patients with non-seminomatous germ cell tumor. Methods: Slides of NSGCT were incubated with rabbit anti-human CD105 followed by horseradish peroxidase-labeled anti-rabbit IgG and then with substrate chromogen followed by hematoxylin counterstaining. Human kidney served as positive internal control. Endoglin positivity was assessed in tumor cells and vasculature and graded (0-3+). Results: 37 total samples were obtained, 4 were excluded (3 seminoma, 1 pure teratoma) All 37 specimens had positive endoglin staining in tumor vasculature. Of 33 specimens, 79% (26/33) had positive staining for endgolin, whereas 21% did not (7/33). (Table 1)Of patients with relapsed or refractory disease, 83% (5/6) stained positively for CD105. While this is a small sample size, 3+ staining was seen in 50% of patients (n=6) with relapsed or refractory disease, but vs 18.5% of patients (n=27) in 1stremission (Fisher’s exact test p =0.14). Conclusions: Endoglin was highly expressed in tumor and tumor vasculature of NSGCT. This small pilot study suggests high (>50%) expression correlating with relapsed or refractory disease. Further samples from patients with relapsed or refractory disease are being collected and analyzed. Endoglin is a potential target for study in non-seminomatous germ cell tumors. [Table: see text]
Germ cell tumors: Survival analysis and experience from a low- to middle-income country.
Authors: Yasmeen Samia , Hannan Abdul
Published: September 2018

e16044

Background: We performed a retrospective analysis of Germ-Cell Tumor patients presenting to Shaukat Khanum Cancer Hospital, Pakistan to have a greater understanding of the presentation & outcomes in South-east Asia. Methods: A search of hospital registry identified 105 patients between Jan-Dec 2013, out of which survival data was available for 99. Final cut off for data collection: Sept 2016. Electronic records were reviewed & analyzed for outcomes, survival & relapse. Results: Median age: 29(18-66) years. Median Follow-up: 33(6-46) months. Testicular primary 96(91.4%). Retroperitoneal 5(4.76%). Mediastinal GCT 4(3.8%). 87(82.85%) underwent orchiectomy while upfront chemotherapy was started in 9(9.45%). Pure Seminoma 46(43.8%). Non-Seminoma 59(56%). Highest level of B-hCG for seminoma: 3607IU/L (Minimum 2.9). Highest level of AFP for Non-Seminoma: 30000IU/L (Range 0.35-30000). Median LDH: 533IU/L (Range 253-23760). Most common Non-Seminoma components: embryonal and yolk-sac tumors. Chemotherapy regimen: Etoposide/Carboplatin 39(37.1%), Bleomycin/Etoposide/Cisplatin 29(27.6%). Carboplatin for Stage-I Seminoma: 17(16.1%). 11(11.5%) patients expired due to advanced disease. Lost to follow up 14(14.7%). 76(79.8%) were alive without any disease while 4(4.02%) were alive with PD. One stage-I seminoma relapse was successfully cured with EP, while 14 Non-seminoma relapses were retreated with VeIP. Eight relapses achieved cure, while 6 had refractory disease. Off total 11 deaths, five had PD, Cisplatin induced stroke: 1, Bleomycin toxicity: 3, Neutropenic sepsis: 1. One relapse as melanoma. Median survival: yet not reached. Conclusions: Our data suggest almost same results corresponding to international literature. Most of our patients present with huge disease burden, which may not change the risk stratification, but alters prognosis. [Table: see text]
Pre-treatment neutrophil to lymphocyte ratio (NLR) association with curative intent metastasectomy (MSX) in metastatic renal cell carcinoma (RCC).
Authors: Fares Aline Fusco , Araujo Daniel Vilarim , Ricardo Eliza Dalsasso , Corassa Marcelo , Formiga Maria Nirvana Cruz , Costa Walter Henriques , Guimaraes Gustavo Cardoso , Zequi Stenio C. , Cunha Isabela
Published: September 2018

e16051

Background: NLR is a marker of inflammation and when elevated is associated with poor outcome in many tumors, including RCC. Hereby we evaluate the association of NLR with the likelihood of curative intent MSX. Methods: We retrospectively studied 846 patients diagnosed with metastatic RCC between 2007 and 2016. 116 patients fulfilled inclusion criteria: previous nephrectomy, no sarcomatoid features and available tumor specimens from metastatic site. Regression tree for censored data method was used to find the best NLR cut-off value. NLR was examined baseline – prior to MSX or targeted therapy. Chi-square test was used to evaluate associations between variables. We estimated overall survival (OS) using Kaplan-Meier curves. Cox proportional hazards regression models were fitted to evaluate the prognostic significance of NLR in univariable and multivariable analysis. Results: The median OS for the whole cohort was 45 months (95% CI, 27.6 to 62.4 months), and the median follow-up was 78.2 months. The best cut-off NLR value was 4.07. Higher NLR was associated with shorter OS when compared to the lower NLR cohort (11.5 months vs 68.3 months HR = 0.26, 95% CI: 0.15 – 0.97, p ≤ 0.0001, respectively). Univariate analysis revealed that bone metastasis and poor IMDC criteria were associated with worse OS and that MSX and lower NLR were associated with better OS. On multivariate analysis MSX, lower NLR and favourable/intermediate group on IMDC criteria were associated with a decreased risk of death (HR = 0.41, 95% CI 0.19-0.85, p = 0.018 and HR = 0.45, 95% CI 0.22-0.90, p = 0.025, HR = 0.35, 95% CI 0.16-0.79, p = 0.012, respectively). We found a positive association of lower NLR and curative intent MSX (p = 0.002). Conclusions: NLR is a prognostic marker in metastatic RCC and a ratio ≤ 4,07 is associated with a higher likelihood of curative intent MSX.