bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of radical cystectomy and increased risk of skeletal-related events in bone-metastatic urothelial carcinoma.
Authors: Almassi Nima , Easthausen Imaani J. , Ghafoor Soleen , Christos Paul J. , Donahue Timothy F. , Rosenberg Jonathan E. , Farooki Azeez 
Published: February 2020

477 Background: Bone metastases are common in patients with advanced cancer of the bladder or upper urinary tract; however, few studies have assessed the morbidity of bone metastases in these patients. We sought to characterize bone-associated morbidity by measuring the frequency of skeletal-related events (SREs) and identify predictors of SREs in this population. Methods: We retrospectively identified 328 patients with bone-metastatic bladder or upper urinary tract cancer managed at Memorial Sloan Kettering between 2000 and 2018. SREs were defined as presence of spinal cord compression from bone metastasis, pathologic fracture, treatment of bone metastasis with radiotherapy or surgery, or hypercalcemia of malignancy. SRE-free survival was estimated using Kaplan-Meier analysis; competing-risks regression analysis was used to identify predictors of SREs. Results: In total, 198 patients (60%) developed ≥1 SRE, including 84 (26%) with multiple SREs. The most common SREs were bone radiotherapy (n=165 [83%]), pathologic fracture (n=73 [37%]), and orthopedic surgery (n=39 [20%]). Median SRE-free survival was 7.4 months. On competing-risks regression analysis, history of radical cystectomy (hazard ratio [HR], 1.40; 95% CI, 1.05-1.86; P=0.02) and hip involvement at the time of bone metastasis diagnosis (HR, 1.65; 95% CI, 1.12-2.42; P=0.01) were independently associated with risk of SRE. Conclusions: SREs are common among patients with bone-metastatic cancer of the bladder or upper urinary tract and typically occur soon after the development of bone metastasis. Patients with a history of radical cystectomy or with hip involvement at the time of bone metastasis diagnosis have a higher risk of SRE.
Predictive value of fibroblast growth factor receptor (FGFR) alterations on anti-PD-(L)1 treatment outcomes in patients (Pts) with advanced urothelial cancer (UC): Pooled analysis of real-world data.
Authors: Kim William Y. , Rose Tracy L. , Roghmann Florian , Eckstein Markus , Jarczyk Jonas , Zengerling Friedemann , Sikic Danijel , Breyer Johannes , Bolenz Christian , Hartmann Arndt , Mayhew Gregory , Shibata Yoichiro , Uronis Joshua M. , Galluzzi Aaron , Sundaram Ramesh , Xia Qi , Wu Kathy , Santiago-Walker Ademi E. , Erben Philipp , Wirtz Ralph 
Published: February 2020

493 Background: The tumor microenvironment in UC harboring FGFR gene alterations is characterized by decreased T-cell infiltration and low immune marker expression, potentially implicating suboptimal response to immune checkpoint inhibitors. The association between FGFR gene mutations/fusions and anti-PD-(L)1 treatment outcomes in advanced UC was assessed using real-world pt data. Methods: A pooled dataset of matched clinical and genomic data for advanced UC pts treated with anti-PD-(L)1 in any line from the Bladder Cancer Research Initiative for Drug Targets in Germany (BRIDGE) Consortium and UNC-CH was assessed. FGFR status was defined by a prespecified panel of FGFR2/3 mutations and fusions. Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox proportional hazards models. Multivariate analyses were performed using potential prognostic covariates (sex, age, baseline tumor stage, urothelial histology, smoking history, primary tumor location, and ECOG) in a Cox regression model for OS to assess their impact on the effect of FGFR alterations. Results: Median OS for FGFR+ pts (n=28) who received any line of anti-PD-(L)1 therapy was 9.5 mo vs 7.5 mo for FGFR− pts (n=139) (HR: 1.03, 95% CI: 0.60-1.76, p=0.93). Median OS for pts treated with first-line anti-PD-(L)1 was 5.42 mo in FGFR+ pts (n=10) and was not reached for FGFR− pts (n=31) (HR: 2.06, 95% CI: 0.68-6.24, p=0.19); median OS in second-line anti-PD-(L)1 was 6.5 mo (FGFR+; n=14) vs 5.7 mo (FGFR−; n=86) (HR: 0.89, 95% CI: 0.44-1.81, p=0.74). The multivariate analyses showed a significant trend of poorer OS in FGFR+ pts with first-line anti-PD-(L)1 (HR: 10.42, 95% CI: 1.45-74.97, p=0.02); wide CI may be attributed to small sample size for some categories in several covariates. Conclusions: Treatment with first-line anti-PD-(L)1 in FGFR+ pts may be associated with poorer OS outcomes in FGFR+ pts; however, this trend was not observed in FGFR+ pts treated with any line and second-line anti-PD-(L)1. Investigation of the predictive value of FGFR alterations to immunotherapy outcomes in larger real-world pt datasets is warranted.
Histologic subtype and response to immune checkpoint inhibitor (ICI) therapy in advanced urothelial cancer (aUC).
Authors: Miller Natalie J. , Khaki Ali Raza , Diamantopoulos Leonidas Nikolaos , Bilen Mehmet Asim , Sacristan Santos Victor , Morales-Barrera Rafael , Devitt Michael Edward , Nelson Ariel Ann , Shreck Evan , Assi Hussein , Rodriguez-Vida Alejo , Lythgoe Mark , Drakaki Alexandra , Joshi Monika , Isaacsson Velho Pedro , Moses Marcus W. , Galsky Matt D. , Sonpavde Guru , Yu Evan Y. , Grivas Petros 
Published: February 2020

495 Background: Urinary tract cancer can be pure urothelial carcinoma (PUC) or variant UC (VUC, defined here as pure non-UC or mixed UC + non-UC); VUC often has a worse prognosis. Little is known about outcomes for patients (pts) with VUC receiving ICI. We hypothesized that VUC does not compromise ICI efficacy in pts with aUC. Methods: We performed a retrospective cohort study across 18 institutions. Demographic, clinicopathologic, treatment and outcomes data was collected for pts with aUC who received ICI. Pts were stratified to PUC vs VUC; VUC was further divided by histologic subtype, i.e. squamous, neuroendocrine (NE), etc. We compared overall response rate (ORR) using logistic regression, progression free survival (PFS) and overall survival (OS) using Kaplan-Meier and Cox proportional hazards; p<0.05 was significant. Results: 519 consecutive pts were identified; 405, 414 and 411 included in ORR, OS and PFS analyses, respectively. Demographics included mean age 69, 27% female, 66% ever smokers, 15% upper tract disease, 54% with extirpative surgery. ORR to ICI between pts with PUC and VUC was comparable (both 28%, p=0.86) without significant differences for individual subtypes vs PUC. Median OS for pts with PUC was 11.0 vs 9.9 mo for VUC (p=0.45), but only 3.7 mo for those with NE features (HR=3.01 [95% CI 1.63-5.57] vs PUC, p<0.001). Median PFS was 4.1 vs 5.2 mo for PUC vs VUC (p=0.46) and 2.8 mo for NE (HR=1.85 [95% CI 0.94-3.61] vs PUC, p=0.07). Conclusions: ORR to ICI and OS were comparable across histologic types; however, OS was shorter for tumors with NE features. VUC should not exclude pts from receiving ICI in routine practice and clinical trials.[Table: see text]
p16INK4a expression and survival outcomes in patients with penile squamous cell carcinoma: The M.D. Anderson Cancer Center Experience.
Authors: Chahoud Jad , Pham Rachel , Guo Ming , Pickering Curtis R. , Qiao Wei , Khanna Abha , Netto Frederico , Pettaway Curtis Alvin , Rao Priya 
Published: February 2020

5 Background: Penile Squamous Cell Carcinoma (PSCC) is associated with high risk human papillomavirus (HR-HPV) in about 50% of cases. The immunohistochemical test for p16INK4a (p16) is highly correlated with HR-HPV expression and used as prognostic marker for squamous cell carcinomas in various sites. The prognostic role of this marker in PSCC remains unclear. We studied whether the expression of HPV or p16INK4a is associated with survival in a large PSCC cohort. Methods: We conducted a single institution analysis of PSCC patients who received treatment between 1991-2017.Patients with a confirmed diagnosis of PSCC and available tissue were tested for HR-HPV status using the Cobas PCR assay. Histological subtype, tumor grade, LVI and p16 staining patterns were confirmed by an experienced pathologist. Patient characteristics were summarized using descriptive statistics of clinico-pathologic variables. Kaplan-Meier was used to estimate median overall survival (OS) and cancer specific survival (CSS). Log rank test, univariate and multivariate Cox models were applied to identify the prognostic factors for survival. Results: We identified 147 patients with PSCC, with available tissue for testing. The median follow-up was 5.2 years (95% CI; 4.48, 6.68y). Patients with p16(+) tumors showed a significantly longer median OS and CSS in comparison to the p16(–) group (p=0.038 and p=0.012), with respective 5 year OS probability of 73% (95% CI; 0.74, 0.98) in comparison to 56% (95% CI; 0.46, 0.67) and 5 year CSS probability of 89% (95% CI; 0.7, 1) in comparison to 64% (95% CI; 0.54, 0.75). In contrast, HPV status by PCR did not predict survival outcomes, with 5 year CSS probability for HPV(+) of 75% (95% CI; 0.61, 0.91) compared to 65% (95% CI; 0.55, 0.78) for HPV(–) patients. Multivariable analysis to evaluate the association with CSS, showed that p16(+) along with lymph node status was associated with lower risk of death (HR=0.28, 95%CI; 0.09-0.8, p=0.002), and OS (HR=0.49, 95%CI; 0.19-1.24, p=0.13) after adjusting for the covariates. Conclusions: Tumor p16 status was an independent prognostic factor for CSS in our PSCC cohort providing unique information above that of lymph node status alone.
Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB Trial.
Authors: Rodriguez-Moreno Juan Francisco , de Velasco Guillermo , Bravo Fernandez Inmaculada , Alvarez-Fernandez Carlos , Fernandez Ricardo , Vazquez-Estevez Sergio , Virizuela Juan Antonio , Gajate Pablo , Font Albert , Lainez Nuria , Barquín García Arantzazu Martínez , Ruiz-Llorente Sergio , Beltran Luis , Rodríguez-Antona Cristina , Berraondo Pedro , García-Donas Jesús 
Published: February 2020

542 Background: Cisplatin-based chemotherapy remains the perioperative treatment in muscle-invasive bladder carcinoma (MIBC). Recent evidence suggests that immune checkpoint inhibitors could be incorporated in this setting. Olaparib is a PARP inhibitor with well-established activity in HRD tumor. Results from trials assessing the combination of durvalumab and olaparib suggest a synergistic effect. However, a molecular characterization is crucial to warrant a rational development. Methods: A phase II clinical trial was designed to assess the impact of neoadjuvant treatment with the combination of durvalumab plus olaparib in the molecular profile of MIBC (NCT03534492; SOGUG-2017-A-IEC(VEJ)-2). Efficacy and safety were secondary objectives. Subjects with cT2-T4a MIBC aimed for cystectomy were treated during 6 to 8 weeks pre-cystectomy. Diagnostic and surgical samples, pre and postreatment blood samples have been collected for the molecular analysis. We present results regarding efficacy and safety. Results: From November 2018 to October 2019 28 patients have been enrolled. 52%/48% of patients had PS 0/1. Median age was 70. TNM stage was: pT2 in 73,6% patients, pT3 in 10.6%, pT4 in 15.8% and 10.6% presented nodal spread. 13 patients have completed neoadjuvant treatment so far and 12 have undergone cystectomy. A wound dehiscence and one death related to surgical procedures were postoperative complications. Pathological complete response rate is 44,5%. Radiological evaluation is ongoing. 10 serious adverse events non-treatment related have been communicated. Any grade of toxicity has been reported in 91% of patients but adverse events grade 3-4 was detected in only 8.3% of cases. Grade 1 pruritus was the unique IR adverse event described in one patient. PARP inhibitors-related adverse events were grade 1 nausea and vomiting (25%), and grade 1 anemia (25%). Conclusions: Preliminary clinical data suggest that Durvalumab in combination with Olaparib could be active and well-tolerated neoadjuvant treatment of MIBC. Molecular characterization and biomarker discovery will be presented separately. Clinical trial information: NCT03534492.
Association of KRT20 and KRT5 with response to neoadjuvant chemotherapy in patients diagnosed with muscle invasive bladder cancer.
Authors: Roghmann Florian , Reike Moritz , Wirtz Ralph , Kriegmair Maximilian , Erben Philipp , Tully Karl , Weyerer Veronika , Eckstein Markus , Hartmann Arndt , Wezel Felix , Bolenz Christian , Tannapfel Andrea , Noldus Joachim , Juette Hendrik 
Published: February 2020

562 Background: Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival. Those with a pathological complete response (pCR) usually have the best prognosis. In the literature, improved response to NAC has been associated with basal tumor characteristics in MIBC so far. The aim of the present study was to examine the association of luminal (KRT20) and basal (KRT5) mRNA expression patterns at transurethral resection (TUR) with pCR at RC after NAC in a contemporary cohort of consecutive MIBC patients. Methods: Clinical Data and formalin fixed paraffin embedded tumor tissue samples from TUR and RC of 49 patients with MIBC were retrospectively analyzed. Using RT-PCR KRT20 and KRT5 mRNA expression were measured in 40-∆Ct values and normalized against the control gene CALM2. Statistical analyses comprised nonparametric and chi2 testing, partition models and spearman correlation analyses. Results: The study cohort had a median age of 63 years and consisted of 38/49 (78%) males. After NAC, 17/49 (35%) patients had cPR. Using partition models, we found that patients with high-KRT20 (≥39.5 ∆Ct) had a higher chance of pCR (57% vs. 26%, p=0.04). Using a cutoff for KRT5 at <38.1 ∆Ct within the subgroup of patients with low-KRT20 (<39.5 ∆Ct, n=35), we found poorest response among low-KRT20/low-KRT5 compared to low-KRT20/high-KRT5 and high-KRT20 (13% vs. 37% vs. 57%, p=0.29), respectively. For low-KRT20/low-KRT5, low-KRT20/high-KRT5 and high-KRT20 median KRT5 was 34.8 vs. 39.5 vs. 34.1 ∆Ct ( p=0.001) and median KRT20 was 37.9 vs. 32.9 vs. 40.1 ∆Ct,( p=0.001), respectively. Conclusions: Patients with MIBC showing high expression of KRT20 were more likely to show pCR at RC after NAC. Moreover, we were able to identify a high risk group of patients with lowKRT20/lowKRT5 that was less likely to achieve pCR at RC after NAC. Our findings are contradicting previous studies and need further verification in larger cohorts. However, our results might be useful for treatment stratification in MIBC patients.
Cost-effectiveness of radical cystectomy versus trimodality therapy for muscle invasive bladder cancer.
Authors: Suskovic Nathan , Raldow Ann C. , Royce Trevor Joseph , Smith Angela 
Published: February 2020

575 Background: Muscle invasive bladder cancer (MIBC) comprises 25% of all bladder cancers at the time of diagnosis. Radical Cystectomy (RC) has traditionally been the gold standard curative treatment for MIBC. Trimodality therapy (TMT) with maximal transurethral resection of bladder tumor, chemotherapy, and radiation is a treatment alternative and Category 1 recommendation by the NCCN. TMT has shown equivalent survival for carefully selected patients. However, the comparative cost effectiveness between RC and TMT is unknown. Therefore, the purpose of this study was to compare the cost-effectiveness of RC versus TMT for MIBC. Methods: We developed a Markov model using TreeAge software to simulate a 5-year outcome for one million 65-year old hypothetical patients with MIBC undergoing either RC or TMT. Hypothetical patients in the RC treatment pathway would have an adverse event, no adverse event, or immediate death after surgery. After RC, patients either would have no evidence of disease or transition to locoregional recurrence, metastatic recurrence, or death. Hypothetical patients in the TMT treatment pathway would either have an adverse event or no adverse from treatment. After TMT, patients either would have disease-free bladder intact survival or transition to locoregional failure, metastatic recurrence, or death. Patients with locoregional failure from TMT transition into non-salvageable disease or salvageable disease. Patients with salvageable disease prompted a salvage cystectomy. Model probabilities and utilities were extracted from the literature. Costs were derived from 2019 National Medicare Fee Schedule. Results: RC and TMT were associated with quality adjusted life years (QALY) of 2.88 and 3.38 respectively (incremental QALYs of 0.5 favoring TMT). The mean costs of RC and TMT were $37,107 and $23,916 respectively. TMT was less expensive with an incremental cost of $13,191. Conclusions: In patients aged 65 and older with MIBC, TMT was the dominant strategy as compared to RC, as it was both cheaper and associated with increased QALYs based upon model assumptions. The results of this study are the first to evaluate the cost effectiveness of RC and TMT.
A phase I/II trial of sitravatinib (sitra) combined with nivolumab (nivo) in patients (pts) with advanced clear cell renal cell cancer (aCCRCC) that progressed on prior VEGF-targeted therapy.
Authors: Msaouel Pavlos , Thall Peter F. , Yuan Ying , Wang Xuemei , Jonasch Eric , Gao Jianjun , Campbell Matthew T. , Shah Amishi Yogesh , Corn Paul Gettys , Tam Alda , Ahrar Kamran , Rao Priya , Sircar Kanishka , Der-Torossian Hirak , Tannir Nizar M. 
Published: February 2020

612 Background: Sitra is a receptor tyrosine kinase (RTK) inhibitor targeting TAM receptors (Tyro3, Axl, MerTK), split family receptors (VEGFR2 and c-Kit) and c-Met. Inhibition of these RTKs has direct biological activity against aCCRCC and can also enhance immunotherapy with nivo by reducing immunosuppressive regulatory T-cells, myeloid derived suppressor cells, and type 2 tumor-associated macrophages. We therefore hypothesized that the addition of sitra to nivo will produce higher clinical activity than nivo alone. Methods: The objective of this phase I/II trial is to evaluate the safety and efficacy of sitra + nivo in pts with aCCRCC that progressed on up to two prior VEGF-targeted therapies. Eligibility criteria were similar to those used for CheckMate 025. The late-onset Bayesian EffTox design is used to account for potential late-onset immune-related toxicities, and allow optimal dose-finding of sitra from four dose levels (60, 80, 120, 150 mg/day) continuously based on both efficacy and toxicity. Additional objectives include estimation of survival times and correlative biomarkers. Results: A total of 38 pts have enrolled as of 22 October 2019 with 34 pts evaluable for response at ≥12 weeks. Tumor reductions have been noted in 28/34 pts (82.3%) with objective responses demonstrated in 13/34 pts (ORR = 38.2%), median progression-free survival of 10.5 months (95% CI 7.6 – 13.5), and 23/34 pts (67.6%) achieving disease control ≥ 6 months. Toxicities requiring dose-reduction of sitra within 12 weeks from treatment initiation have been noted in 14/34 pts (41.2%). The most common treatment-related adverse events include fatigue, diarrhea, palmar-plantar erythrodysesthesia, hypertension, and elevated lipase. There was one nivo-related Grade 5 event (myasthenia gravis). Updated dose-finding, safety and efficacy data will be presented. Conclusions: The combination of sitra + nivo has not demonstrated unexpected safety signals and produces higher objective responses and longer disease control compared with what is historically expected with nivo alone in pts with aCCRCC that progressed on prior VEGF-targeted therapy. Clinical trial information: NCT03015740.
Provider referral patterns following nephrectomy in high-risk locoregional renal cell carcinoma.
Authors: Dzimitrowicz Hannah Elizabeth , Esterberg Elizabeth , Miles LaStella , Zanotti Giovanni , Borham Azah , Harrison Michael Roger 
Published: February 2020

636 Background: It is unclear whether post-nephrectomy patients with renal cell carcinoma (RCC) in real-world practice settings are typically assessed for recurrence risk post-operatively and whether patients at high risk of recurrence are seen by providers who can evaluate candidacy for adjuvant systemic therapy (AST), clinical trials, or alternative surveillance schedules. Methods: We identified all patients with locoregional RCC who underwent nephrectomy within Duke University Health System between April 1, 2015 and March 31, 2019 via an institutional database. Medical records were reviewed to identify patient characteristics, post-nephrectomy treatment and referrals, and follow up. Patients with tumor stage 3 or higher and tumor grade 2 or higher, regional lymph-node metastasis, or both, were classified as high risk of recurrence. Results: Of 500 patients with locoregional RCC who underwent nephrectomy, 111 (22.2%) had high risk of recurrence (Table). 15 patients with high risk disease (13.5%) were referred to a medical oncologist for discussion of AST. Fourteen of the 15 referrals took place in 2018 or later. 7 of 29 (24.1%) high risk patients were referred for discussion of AST in 2018 and 7 of 9 (77.8%) in 2019. All referrals were made by urologists to medical oncologists. Two patients received AST – one as part of a clinical trial and one node-positive patient received standard-of-care sunitinib. In the cohort of high-risk patients, follow up data was available for 83 patients with median follow up time of 1.16 years; 31 patients (37.4%) developed recurrent disease. Conclusions: Within a single large academic institution, despite increasing numbers of patients with locoregional RCC at high risk of recurrence being referred to medical oncologists after nephrectomy, few patients received AST. These findings highlight the need for continued efforts at identifying effective AST and referring patients most likely to benefit.[Table: see text]