bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.