bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive genomic landscape in Chinese patients with urothelial carcinoma.
Authors: Chen Haige , Zhang Ruiyun , Chen Shiqing , Bai Yuezong
Published: May 2020

e17009

Background: Recent therapeutic advances, such as immunotherapy and FGFR-targeted therapy, have greatly improved the prognosis of patients with urothelial carcinoma (UC). Revealing comprehensive genomic features could evolve our understanding of UC, however the genomic landscape in Chinese UC has not been fully elucidated. In the present study, we investigated the molecular features of Chinese UC patients. Methods: Genomic profiling was performed through next generation sequencing (NGS) from Chinese patients with UC between January, 2017 and November, 2019 in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab. DNA was extracted from formalin fixed paraffin-embedded (FFPE) tumor specimens or fresh tumor tissue. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay or Ventana PD-L1 SP263 assay. Data analyses were performed using SPSS and R 3.6.1. Results: A total of 298 Chinese UC patients who have undergone NGS were included in this study, including 210 (70.5%) male and 88 (29.5%) female patients. The median age was 66 (range, 19-91) years old. The most common somatic alterations were detected in TP53 (57.0%), KMT2D (42.6%), TERT (28.2%), KDM6A (26.5%) and PIK3CA (18.8%). Of the 243 patients who were evaluated for PD-L1 expression, 78 (32.1%) had a PD-L1 Tumor Proportion Score (TPS) of 1% or greater, and 18 (7.4%) had a PD-L1 TPS of 50% or greater. The median TMB value was 9.7 muts/Mb (range: 0-175.0). 138 (46.3%) patients harbored alterations in DNA damage repair (DDR) genes, including pathogenic or likely pathogenic mutations (MUT) and variants of unknown significance (VOUS). The most common somatic alterations in DDR genes were detected in ATM (9.4%), BRCA2 (9.4%), BRIP1 (5.0%), ATR (4.7%) and BRCA1 (4.7%). Significant differences of TMB were observed among DDR-MUT group, DDR-VOUS group and DDR-WT group (mTMB = 16.1, 14.0 and 7.3 muts/Mb, respectively, P < 0.001). Seven (2.4%) patients were identified as MSI-H, including five patients in DDR-MUT group (12.8%) and two patients in DDR-VOUS group (2.0%). Conclusions: This is the first large-scale comprehensive genomic analysis for Chinese patients with UC. These results provide a better understanding of molecular features in Chinese UC patients which may lead to an improvement in the personalized treatment for these patients.
Functional outcomes of older adults treated with radical cystectomy for muscle-invasive bladder cancer.
Authors: Osterman Chelsea K. , Deal Allison Mary , Nyrop Kirsten A. , Milowsky Matthew I. , Muss Hyman B. , Smith Angela
Published: May 2020

e17010

Background: Older patients with muscle-invasive bladder cancer (MIBC) may not be offered standard of care treatment with neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) based on their chronological age and concern for functional decline following therapy. Age-based differences in post-RC functional status or time to recovery are unknown. Methods: A total of 80 patients were included in this study. Patients ≥ 70 years were categorized as “older” and < 70 years as “younger.” To measure functional status, patients completed an initial geriatric assessment (GA) post-NAC and pre-RC, which was repeated at 1, 3, and 12 months post-RC. Results: Median age was 62 years for younger patients (41-69 years; n = 42) and 75 years for older patients (70-83 years; n = 38). Clinical stage at presentation was not different between groups, but older patients were significantly less likely to receive NAC (63% vs 83%, p = 0.047). There was no significant difference between groups in any physical function measure at baseline. At 1 month post-RC, older patients had significantly lower clinician (c) and patient (p) rated Karnofsky Performance Status (KPS) than younger patients (cKPS: 70 vs 80, p = 0.02; pKPS 60 vs 80, p = 0.03), with a significantly greater decrease from baseline (20 points vs 0 points) in both KPS scores compared to younger patients (cKPS p = 0.001; pKPS p = 0.005). Both groups had a significant decline in ability to complete instrumental activities of daily living (IADLs), but older patients also had significantly increased social activity limitations. At 3 months post-RC, older patients took significantly longer to complete the timed up and go test than younger patients (10.2 secs vs 9 secs, p = 0.02), but had no other differences in physical function measures. Older patients had no significant difference in any measure at 3 months post-RC compared to baseline, while younger patients had a significant improvement in social activity over this time frame. Conclusions: Older patients with MIBC experience a greater short-term decline in functional status post-RC compared to younger patients. However, they return to their baseline status within the same time frame as younger patients.
Systemic immune-inflammation index to predict survival in muscle-infiltrating urothelial carcinoma.
Authors: Obertova Jana , Palacka Patrik , Gallik Dalibor , Slopovsky Jan , Chovanec Michal , Kollárik Boris , Rejlekova Katarina , De Angelis Valentina , Sycova-Mila Zuzana , Hapakova Nikola , Mego Michal
Published: May 2020

e17022

Background: Systemic immune-inflammation index (SII) is a prognostic factor in patients with metastatic urothelial cancer (MUC). The objective of this prospective study was to evaluate the prognostic value of the SII at baseline before neoadjuvant cisplatin-based chemotherapy start in patients with muscle-infiltrating urothelial cancer (MIUC). Methods: Seventy-two patients (49 men) with MIUC (71 bladder, 1 upper tract) were treated with cisplatin-based neoadjuvant chemotherapy (NACT). Thitrty-nine patients (pts.) underwent radical cystectomy (RC), 18 pts. external radiotherapy (EXRT) with concomitant cisplatin chemotherapy, and 15 pts. had no local treatment (NLT) afterwards. SII was defined as PxN/L, based on platelets (P), neutrophils (N) and lymphocytes (L) counts. This study population was dichotomized by median SII into low and high groups. Disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared with logrank test. Results: At median follow-up of 13 months (range 2-40), 26 pts. relapsed and 24 of them died. Pts. with low SII at baseline had better DFS and OS compared to those with high SII (NR vs. 19 months, HR = 0.37, 95% CI 0.17-0.88, P = 0.0185 for DFS, 31 months vs. 20 months, HR = 0.43, 95% CI 0.19-0.98, P = 0.052 for OS, respectively). Subgroup analysis showed significant benefit for EXRT regarding of SII, however no differences were observed in both, RC and NL. Conclusions: The level of SII at baseline before neoadjuvant cisplatin-based chemotherapy initiation predicted survival in MIUC pts. Based on the level of SII, stratification of pts. into clinical trials could be possible. Pts. with high level of SII might be the candidates for the different therapeutic approaches. Key Words: Muscle-Infiltrating Urothelial Carcinoma. Systemic Immune-Inflammation Index. Neoadjuvant Chemotherapy. Disease-Free Survival. Overall Survival.
Comprehensive profiling of genomic in 80 Chinese patients with bladder cancer.
Authors: Yuan Zengjin , Yang Chunhe , Chen Jie , Zhu Yanhua , Xu Xiaohong , Wang Lingyu , Lin Rongbo , Yang Yining
Published: May 2020

e17024

Background: Bladder cancer (BLCA) is the ninth most common malignant disease and the thirteenth most common cause of cancer death worldwide, To understand the genomic landscape of Chinese BLCA patients, 80 cases were analyzed by comprehensive genomic profiling (CGP) for genomic alterations and genome wide signatures. Methods: Formalin Fixed Paraffin Embedded (FFPE) tumor and matched blood samples of 80 Chinese BLCA patients were obtained for next-generation sequencing (NGS)-based 642 cancer genes panel assay and bladder cancer genomic profiling was evaluated. Results: Collectively, in our Chinese BLCA cohort, multiple histological subtypes, including Non-muscle invasive bladder cancer (NMIBC) (20/80, 25%), muscle invasive bladder cancer (MIBC) (49/80, 61.25%), and other subtypes (11/80, 13.75%). The top ranked somatic gene alterations in Chinese BLCA patients were TP53 (49%), TERT (34%), KMT2D (33%), KMD6A (25%), CDKN2A (23%), FGFR3 (23%), FLG (19%), PIK3CA (19%), CCDN1 (18%), RB1 (18%). Some FGFR2/3 gene fusions were detected such as FGFR2-WDR11 and FGFR3-TACC3. Interestingly, some co-mutations were identified in our cohort, such as ERBB3 was co-mutated with MUC17, FAT1 was co-mutated with RB1 etc. (p < 0.01). Out of 15 most common canonical pathways, potentially targetable genomic alterations were mainly identified in RTK-RAS (74.68%), DNA damage response (53.16%), TP53 (53.16%),chromatin remodeling (51.90%), PI3K (44.30%), NOTCH (41.77%), Cell Cycle(32.91%), Hippo (29.11%) and WNT (29.1%) pathway. Additionally, chromatin remodeling and NOTCH pathways were commonly co-altered with MYC pathway, TP53、Hippo and NOTCH pathways were significantly co-altered with DNA damage response pathway. Across samples, 33 Chinese BLCA patients had high tumor mutational burden (TMB-H) ( > 10 mutations/Mb). Only 2 Chinese patients had high microsatellite instability (MSI-H). Conclusions: Our results displayed the landscape of genomic alterations in 80 Chinese BLCA patients. The genomic alterations identified in our study may provide an opportunity to discover potential strategies for targeted and immunotherapy in BLCA. Future studies should account for these genomic alterations.
Racial and gender disparities in stage at diagnosis for bladder cancer: Results from the surveillance, epidemiology, and end results (SEER) program, 2007 to 2016.
Authors: Gupta Sachin , Joshi Monika , Weng Xingran , Wang Li
Published: May 2020

e17032

Background: Little is known about the patterns of racial and gender disparities in bladder cancer (BC). This study will use national large database to explore those disparities. Methods: Data from the National Cancer Institute’sSurveillance, Epidemiology, and End Results (SEER) Program for cancer registries was used. Patients > = 18 years diagnosed with BC in the years 2007-2016 were identified from SEER 18 database. We used the data year 2007 because that was the year when insurance status was first collected in SEER. Chi-square tests and multinomial logistic regression were used. Results: A total of 78,151 (females: 25.58%) patients were included, with 82.74% being non-Hispanic whites, 5.83% non-Hispanic blacks, 6.69 % Hispanics and 4.74% others. Distribution of stage 0 through stage IV at diagnosis was 51.97%, 23.21%, 12.11%, 4.10% and 8.61% respectively. Blacks (P < 0.0001) and females (P < 0.0001) were diagnosed at later stages as in Table. e.g., 14.54% of blacks were diagnosed at stage IV, compared to 7.97% of whites; and 11.03% of females at stage IV vs. 7.77% of males. Racial disparity exists for any given insurance status. Within every age group, gender disparity exists. For example, for those under 50 years of age, 12.81% of women vs. 8.16% of men were diagnosed at stage IV. After controlling for age, marital status and insurance type, both gender (P < 0.0001) and race (P < 0.0001) were statistically significant in predicting stage at diagnosis. Conclusions: Racial disparity in stage at BC diagnosis was strong, with blacks suffering most from the disparity. Females were more likely to be diagnosed at later stages, and this gender disparity exists in all age groups and was not due to women living longer. The existence of both racial and gender disparities in BC makes black women most vulnerable to late diagnosis than any other racial/gender group. Oncologists treating BC patients should be aware of the racial and gender disparity. More research needs to be done to help improve early access to health care amongst female and minority BC patients. [Table: see text]
Neoadjuvant chemotherapy in muscle invasive bladder cancer: Real world data on safety and outcome.
Authors: Panthula Sree Vamsee Chetana , Philip Arun , Keechilat Pavithran , Jose Wesley Mannirathil
Published: May 2020

e17036

Background: The standard treatment for Muscle Invasive bladder cancer (MIBC),Radical Cystectomy and Neoadjuvant chemotherapy (NACT) has shown to improve survival. Data from Indian population is scarce, and we sought to explore the efficacy, tolerability and factors affecting the outcome of Neoadjuvant chemotherapy in our population. Methods: This was a Retrospective Observational study conducted at a tertiary care centre. Patients of MIBC treated between 2008 and 2019 were included in the analysis. The NACT consisted of Gemcitabine + Cisplatin (GC) or Gemcitabine + Carboplatin (GCa). The prognostic significance of the various clinico-laboratory parameters was assessed by the log rank test. The survival analysis was done by the Kaplan Meier method. Results: Total of 40 patients received NACT from 2008-2019. The median age of study group was 62 years. Male to Female ratio was 5:1. Out of 40 patients, 26 were treated with GC and the remaining 14 received GCa. Majority (80%) patients were administered either 3 or 4 cycles of NACT. Among 18 patients who demonstrated good radiological response after NACT completion, 13 had received Cisplatin. After NACT, 32 (80%) underwent Radical Cystectomy and 3 were treated with CTRT. The remaining 5 did not receive definitive treatment. Pathological complete response (PCR) was achieved in 10 out of 32 patients (31%). Out of 10 patients with PCR, 9 belonged to Cisplatin group and only 1 in Carboplatin group. In patients with PCR, 80% remained progression free at last follow up. Grade 3/4 toxicities were minimal. However, achieving a pathological CR did not translate into significant survival benefit in our study (p value 0.10). Median follow up time and overall survival for the cohort was 29.5 and 54 months respectively. Conclusions: Gemcitabine/Cisplatin as NACT resulted in superior radiological response, PCR, PFS and OS when compared to Gemcitabine/Carboplatin in MIBC. This regimen is well tolerated and we advocate for further prospective studies with GC in this setting. [Table: see text]
Retrospective analysis of an alternative immuno-score in clinical management of patients with pT2 urothelial carcinoma.
Authors: Colombo Piergiuseppe , Zucali Paolo Andrea , De Carlo Camilla , Giordano Laura , Hurle Rodolfo , Lazzeri Massimo , Elefante Grazia Maria , D'Antonio Federica , Regis Federica , Guazzoni Giorgio Ferruccio , Santoro Armando , Roncalli Massimo
Published: May 2020

e17038

Background: Within the mapping of the genome through the TCGA collaborative project, the urothelial carcinoma (UC) has recently revealed major intrinsic molecular subtypes, Basal, Luminal and Neural muscle-invasive UC. Here we propose a fast and standardized immuno-phenotypical score classification (Piescore), as a surrogate, which may discriminate Luminal, Basal or Neural UC and may correlate with histological and clinical variables in a mono-institutional cohort of patients treated with trans-urethral resection (TURB) and radical cystectomy (RC). Methods: This is a retrospective study of TURB specimens that harbored foci of HG pT2 (MIBC) UC from 116 pts who underwent RC. All the samples were assessed for immunohistochemical pattern, using relevant gene-expression-based markers for Basal type (CD44, CK5/6) and Luminal type (CK20 and pPARg). Piescore, investigated in both superficial and muscle-invasive component of the tumors, divided Basal and Luminal UC-types when at least 3 of the 4 markers were consistent with a specific phenotype, Mixed if two luminal and two basal markers were present simultaneously, and Neural when all four markers were negative. Results: Overall in muscle-invasive component, Piescore identified Basal phenotypes in 49 pts (42,2%), Luminal in 38 pts (32,7%), and Mixed in 9 pts (7,8%). No expression was identified in 20 pts (17,2%): 7 cases with morphological neuroendocrine differentiation and 13 cases with classical urothelial histology, all consistent with Neural phenotype. In 26,7% of cases (31/116 pts) we observed an immuno-phenotypical switch from superficial to deep component: 16 of 31 (51,6%) switched to Basal, 10 (32,2%) switched to Neural, and 5 cases (16,2%) to Mixed phenotype. No cases switched to Luminal. No cases have lost Basal phenotype from superficial to deep component, with the exception of one (switched to Neural). No statistically significant differences in terms of staging, DFS, and OS were observed in the different phenotypes. The presence of phenotypical switch did not affect angioinvasion, staging, DFS, and OS compared to non-switched cases. Conclusions: Piescore immunophenotyping (CD44, CK5/6, CK20 and pPARg) could be a simple surrogate able to stratify UC-TURB patients between Luminal vs Basal type. To our knowledge, preliminary results using the Piescore identify for the first time a phenotypical switch (to basal, Mixed or Neural) between superficial and deeper side of the same tumor, although this phenomenon did not show any prognostic implication.
Comprehensive genomic profiling (CGP) in patients with relapsed/refractory germ cell tumors (GCT).
Authors: Akel Reem , Anouti Bilal , Kern Sean , Cary Clint , Masterson Timothy A. , Jacob Joseph M , Bratslavsky Gennady , Danziger Natalie , Pavlick Dean , Hanna Nasser H. , Einhorn Lawrence H. , Ross Jeffrey S. , Adra Nabil
Published: May 2020

e17053

Background: Understanding the genetic alterations in patients with relapsed/refractory GCT (rrGCT) could delineate the pathogenesis of cisplatin resistance. Our study uses CGP to characterize genomic alterations (GA) in refractory GCT and correlate with clinical outcomes. Methods: 432 patients with rrGCT were seen at Indiana University between Jan 2016 to Sep 2019 of whom 52 patients underwent CGP using a hybrid-capture based commercial assay to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. PDL1 expression was determined by IHC (DAKO 22C3 antibody). Results: All patients relapsed after first-line cisplatin-based combination chemotherapy. Median age at diagnosis was 33 (range 15-68). Primary site of GCT was testicular in 85% and mediastinum in 8%. 6 patients had pure seminoma and 46 had non-seminoma. Platinum refractory disease, defined as serologic or radiographic progression within 4 weeks of first-line chemotherapy comprised 23% of patients. The primary tumor was used for sequencing in 6 cases (12%) and non-primary tumor metastatic site (lymph node, lung, liver, brain, omentum) in 46 cases (88%). The most common GA in the entire cohort were FGF6 (27%), FGF23 (27%), KDM5A (27%), CCND2 (27%), KRAS (18%), TP53 (14%), KIT (8%), APC (8%), ZNF217 (6%), MUTYH (6%), AURKA (6%), NRAS (6%), EGFR (6%), CTNNB1 (6%), GNAS (6%). Most common alterations for testicular primary tumors were FGF6, FGF23, KDM5A, CCND2, KRAS, TP53, KIT. For non-testicular primary GCT, most common GA were APC, TP53, EGFR. Most common GA for non-seminoma were FGF6, FGF23, KDM5A, CCND2, KRAS, TP53, APC. Most common GA for pure seminoma was KIT. Potentially targetable genomic alterations were found in 17 patients (33%). 10 of 17 patients (59%) tested had PDL1 score ≥1% and 3 patients had PDL1 ≥50%. Median TMB was 3.5 mutations/MB. There were 4 patients (8%) with TMB ≥ 10 mutations/Mb and 2 patients (4%) with TMB ≥ 20 mutations/Mb. 1 of 48 patients (2%) evaluated for MSI had MSI-High status. Isochromosome 12p was detected in the majority of samples where it was tested. Outcomes with GA-directed therapy will be presented at the conference. Conclusions: CGP can reveal potential therapeutic targets in patients with rrGCT including EGFR, ERBB3, KIT, and MET. Consistent with reported clinical trials in rrGCT, biomarkers predicting response to immune checkpoint blockade are uncommon with most patients having low TMB, absence of MSI-H status, and low expression of PDL1.
High-dose chemotherapy (HDCT) and peripheral-blood stem cell transplant (PBSCT) in patients age 40 or older with relapsed metastatic germ-cell tumors (mGCT).
Authors: Agrawal Vaibhav , Althouse Sandra K. , Abonour Rafat , Abu Zaid Mohammad Issam , Sullivan Cheryl K , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: May 2020

e17054

Background: HDCT plus PBSCT is effective salvage therapy for relapsed mGCT but has potential toxicity. Historically, age ≥ 40 years has been associated with greater toxicity and worse outcomes. Methods: 445 consecutive pts with relapsed mGCT were treated with HDCT and PBSCT with tandem cycles at Indiana University from between 2004-2017 per our institutional regimen ( N Engl J Med 2007; 357:340-8). Kaplan-Meier methods and log-rank tests were used for progression free survival (PFS) analysis. Results: 329 pts were age < 40 while 116 pts were age≥40 and HDCT was being used as 2nd line in 85% and 79%, respectively. Median follow-up time was 42.5 months (range 0.3-173.4). Pulmonary metastasis was more frequent in the age < 40 group (66% vs. 41%, P < 0.001). Patients age≥40 were more likely to have seminoma (45% vs. 14%, P < 0.001), were more likely not platinum refractory (80% vs. 63%, P = 0.0010), and were less likely to complete 2 planned tandem cycles of HDCT (86% vs. 93%, P = 0.03). Grade 3 or higher toxicities were similar between either cohort, except for greater pulmonary toxicity in age≥40 group (8% vs. 2%, P = 0.02). Treatment-related mortality was similar between both age groups: 10 patients (3%) in age < 40 and 4 patients (3.5%) in age≥40 group died from complications of HDCT. 2-year PFS for age < 40 vs. age ≥ 40 was 58.7% vs. 59.6% (P = 0.76) and 2-year OS was 63.9% vs. 61.5% (P = 0.93). When evaluating patients with pure seminoma: 2- year OS for age < 40 vs. 40-50 vs. ≥ 50 was 100% vs 90.3%, vs 81.4%, respectively (P = 0.09). For patients with non-seminoma: 2-year OS was 58.1% vs. 37.1% vs. 54.2%, respectively (P = 0.01). In multivariable analysis for PFS: significant factors predicting worse outcomes included platinum refractory disease (HR = 1.55, P = 0.03), primary mediastinal non-seminoma (HR = 2.41, P = 0.03), not completing 2 cycles of HDCT (HR = 2.47, P = 0.01), and hCG > 1000 at initiation of HDCT (HR = 1.92, P < 0.001). Age was not a significant factor predicting worse outcomes. Conclusions: HDCT plus PBSCT is effective salvage therapy in pts age≥40 with relapsed mGCT. Patients age > 40 experience similar rates of toxicity and treatment-related mortality as those < 40 years of age.
Localized testicular germ cell tumor surveillance: A Delphi consensus study.
Authors: DA Silva Angélique , Flechon Aude , Culine Stephane , Planchamp François , Murez Thibaut , Mejean Arnaud , Pasquier David , Fizazi Karim , Joly Florence
Published: May 2020

e17060

Background: Stage I testicular germ cell tumor (TGCT) has excellent cure rates and surveillance is fully included in patient’s management, particularly during the first years of follow-up. Surveillance guidelines differ between the scientific societies, with different recommendations concerning clinical and imaging frequency de-escalation and long term follow-up. We evaluated surveillance practice and schedules followed by French specialists and set up a DELPHI method to obtain a consensual surveillance program with an optimal schedule for patients with localized TGCT. Methods: An online survey on surveillance practice of stage I TGCT based on clinical-cases was conducted among urologists, radiotherapists and oncologists. Results were compared to AFU, ESMO and EAU guidelines. Then a panel of experts assessed surveillance proposals following a formal consensus method (DELPHI method). Statements were drafted after analysis of the previous survey and systematic literature review, with 2 successive rounds to reach a consensus. Results: Survey and DELPHI method were conducted between July 2018 and May 2019. 61 participated to the survey (69% oncologists, 15% urologists, 16% radiotherapists). About 65% of practitioners followed clinico-biological guidelines concerning 1 to 5 years of follow-up, only 25% discontinued surveillance after the 5th year, as recommended. No physician followed the ESMO guidelines of de-escalation chest imaging. A panel of 32 experts (78% oncologists, 16% urologists, 6% radiotherapists) was asked about 38 statements. Consensus was reached for 26 statements concerning clinico-biological surveillance modalities and end of surveillance after the 5th year of follow-up. For seminoma, abdominal ultrasound was proposed as an option to the abdominopelvic (AP) scan for the 4th year of follow-up. No consensus was reached regarding de-escalation of chest imaging. Conclusions: The survey proved that French TGCT specialists do not follow current guidelines. With DELPHI method, a consensus was obtained for frequency of clinico-biological surveillance, discontinuation of surveillance after the 5th year and discontinuation of AP scan on the 4th year of follow-up for seminoma. Questions remains concerning type and frequency of chest imaging.
CT abdomen only for active surveillance in patient with stage I germ cell tumor.
Authors: Ahmadi Hamed , Schuckman Anne K. , Bhanvadia Sumeet , Djaladat Hooman , Daneshmand Siamak
Published: May 2020

e17064

Background: Surveillance of stage I GCTs includes periodic imaging of chest, abdomen and pelvis. Currently the AUA guidelines recommends CT scan of the abdomen with or without the pelvis as well as chest x ray during active surveillance for these patients. Efforts to modify the surveillance protocols aim to minimize radiation exposure in this young patient population. Per our institutional protocol, we limit cross sectional imaging to CT of the abdomen only during surveillance of stage I disease. Here we report our outcomes to determine whether any recurrence was missed or delayed based on this protocol. Methods: All patient with clinical stage I GCT who have been under active surveillance and completed at least 2 year follow up at our institution were selected using our institutional testis cancer database. Clinical and demographic information were reviewed including recurrence pattern and tumor marker status at time of recurrence. Results: A total of 89 patients who had complete follow up information in the database were included in the study. 49/89 (55%) patients had non-seminoma or mixed GCT histology. 5/89 (5%) patients had history of cryptorchidism and 16/89 (18%) patients had history of inguinal surgery. 14/89 (15%) had relapse at a median of 6.8 months. Recurrence was first detected on surveillance imaging (Imaging recurrence) in 11/14 (78%), by rising tumor markers (marker recurrence) in 2/14 (14%), and on physical exam (clinical recurrence) in 1/14 (7%) patients. Of patients with marker or clinical recurrence, only one had evidence of retroperitoneal recurrence which was detectable by CT abdomen and the other two had lung metastasis detected by chest X ray. Only one patient with imaging recurrence had pelvic lymphadenopathy which was large enough to be seen on CT abdomen. Conclusions: CT scan of the abdomen only in combination with chest imaging, tumor markers and physical exam detected 100% of recurrences in this series. CT pelvis can be safely omitted during active surveillance of stage I GCT. Future modification in guidelines for surveillance protocols of stage I GCT may be warranted with further mounting evidence.
Receptor tyrosine kinases and growth factors expression in tumor thrombus cells in patients with renal cell carcinoma (RCC).
Authors: Volkova Maria , Tsimafeyeu Ilya , Khochenkov Dmitry , Olshanskaia Anna , Vashakmadze Niko , Khochenkova Yulia , Solomko Elyso , Ashuba Saida , Matveev Vsevolod Borisovich
Published: May 2020

e17073

Background: To our knowledge, this is a first study describing the expression of the receptor tyrosine kinases (RTKs) and growth factors (GFs) in venous tumor thrombus cells and comparing results with the expression in primary RCC. Methods: Formalin-fixed paraffin-embedded specimens of tumor thrombus and primary tumor removed from 25 untreated pT3a-T4N0-1M0-1 RCC patients were evaluated by immunohistochemistry with primary antibodies to VEGF-A, FGF2, VEGFR1, VEGFR2, FGFR1, FGFR2, PDGFRα, and PDGFRβ (Abcam/Santa Cruz Biotech) and REAL™ EnVision™ Detection System (Agilent). The extent of expression was compared with 25 specimens of primary tumor tissue (selected from the same patients). Significant differences in the expression among these groups were assessed by chi-squared and Fisher's exact tests using a semi-quantitative method (H-score). The analysis of the correlation between expression levels and RCC characteristics was also performed. Results: Mean age was 62.0 (35-74) years. pT3a, pT3b, pT3c and pT4 stages were detected in 4 (16.0%), 13 (52.0%), 7 (28.0%), and 1 (4.0%) patients. Lymph node metastases were found in 9 (36.0%) cases, 15 (60.0%) patients had 1 or more metastatic sites. All RTKs and GFs were heavily expressed in primary tumor cells. Tumor thrombus cells were characterized by significant lower expression levels of VEGFR1, VEGFR2, and PDGFRα (p < 0.05 for all). Tendency to lower expression of VEGF-A (p = 0.06), FGF-2 (p = 0.046), FGFR1 (p = 0.077), and FGFR2 (p = 0.09) was observed in tumor thrombus cells (Table). VEGFR2 expression levels were 2-times reduced in patients with supradiaphragmatic thrombus (H-score = 21.4±12.0) compared to infradiaphragmatic thrombus (H-score = 55.0±8.5, p = 0.042). Furman grade correlated with the expression levels of VEGFR1 (p = 0.035) and FGFR1 (p = 0.022) in primary tumor cells; tumor invasion into venous wall correlated with the expression levels of VEGFR1 (p = 0.023) and FGFR2 (p = 0.005) in thrombus cells. Conclusions: RCC invasion into veins is accompanied by a decrease in expression of RTKs and GFs. Further studies are needed to understand the biological significance. [Table: see text]
Single-institution analysis of ablations versus partial nephrectomies for small renal masses.
Authors: Sun Fionna , Dreyer Zachary , Moudgil Pranav , Studzinksi Diane , Vartanian Stephen
Published: May 2020

e17074

Background: Renal cell carcinoma (RCC) has the highest mortality rate of the genitourinary cancers with detection rising annually for small ( < 4cm) renal masses (SRM). Nephron-sparing partial nephrectomy (PN) is recommended over other approaches such as ablations (Abl). This study aims to evaluate the outcomes and costs associated with treating patients with SRM RCC that undergo PN, laparoscopic cryoablation (lcryo), or various percutaneous ablations-cryoablation (pcryo), microwave (pmv), and radiofrequency (prf). Methods: A retrospective chart review of 295 patients that had either a PN or Abl from 2010-2019 at Beaumont Hospital- Royal Oak was performed. 189 patients with SRM were analyzed. Data collected included demographics, comorbidities, pathology, 30-day ED readmission, recurrence rate, and hospital-billed costs and charges. Data was analyzed using Mann-Whitney, chi-square, unpaired t-tests, Kruskal Wallis post-test, and Dunn’s multiple comparison test. Results: 133 patients with an index Abl (6 lcryo, 73 pcryo, 44 pmv, and 10 prf) and 56 patients with an index PN were analyzed. Mean tumor size for Abl (2.34cm; 90% biopsy-confirmed RCC) and PN (2.48cm; 87% histology confirmed RCC) was comparable. The populations undergoing PN or Abl were similar for both demographics and comorbidities except for age at index procedure (PN 58, Abl 71, p < 0.01). Length of stay (LOS) following index procedure differed with an avg PN LOS = 2.74 days and Abl LOS 0.52 (p < 0.01). 55% of PN patients presented to the ED within 30 days (38% readmitted) whereas only 8% of Abl patients did (42% readmitted)(p < 0.01). The recurrence rate for PN compared to Abl was 23% to 14%, respectively (p = 0.14), with an average follow-up time of 4.95 years for PN and 2.78 years for Abl (p < 0.01). Total hospital charge analysis showed PN being 1.57 the charge of all Abl types (p < 0.01) while cost analysis demonstrated PN being more costly than Abl as a whole by 2.79x (p < 0.01). When evaluating ablation subtypes, trends were noted lcryo being comparable to PN in both charge and cost while percutaneous interventions pmv, pcryo, and prf displayed lower charge and cost when compared to both PN and lcryo. Conclusions: With treatment decisions for SRM RCC are multifactorial, this single-site study demonstrated similar populations with comparable pathologies undergo both PN and Abl procedures. Complication and readmission rates differ between PN and Abl and consideration should be made for these variables as well as the costs associated with each procedure type when managing SRM RCC.
Data to decisions: The impact of online education on immunotherapy in advanced renal cell carcinoma.
Authors: Parikh Kinjal , Lucero Katie , Warren Charlotte , Van Laar Emily Sherene , Carothers Ann , Kadkhoda Haleh , Rini Brian I.
Published: May 2020

e17076

Background: Cytokine therapy was initially the only immunotherapy for patients with advanced renal cell carcinoma (RCC). The advent of targeted therapies ushered in a new area of precision medicine in the treatment paradigm. Recently, immunotherapy in the form of immune checkpoint inhibitors has shown improved outcomes as compared to targeted therapies and has become a mainstay in treatment. As immunotherapy use moves into earlier stages of disease and combination therapies are explored, education remains essential to optimize patient outcomes. Through the partnership between Medscape Oncology and the Society for Immunotherapy of Cancer, educational activities were designed to increase the knowledge and competence among oncologists surrounding the role of immunotherapy in patients with advanced RCC and uncover remaining educational needs. Methods: The 2 educational activities included a 30-minute online, video discussion with 2 faculty presenters and synchronized slides and a text-based online activity with 2 patient cases and interactive questions. Educational effectiveness was assessed with repeated paired pre/post assessment where learners served as their own controls. The first activity launched September 19, 2018, the second activity launched December 19, 2018, and the data were collected and are reported through December 27, 2019. Results: A total of 9474 learners participated from September 2018-December 2019 including 1029 oncologists. Participation in education resulted in significant improvements for oncologist who answered all pre/post questions for an activity during the study period (n = 302). Improvements in knowledge and competency were observed in the following areas: Knowledge regarding the latest clinical trial data on the use of cancer immunotherapies for the treatment of RCC (49% vs. 74%, p < .001). Knowledge regarding the immune checkpoint inhibitor regimens on the care of patients with RCC (49% vs. 70%, p < .001). Competence related to choosing the most appropriate regimen for patients with mRCC across the continuum of care (54% vs. 76%, p < .001). Conclusions: Participation in online, video- and case-based CME-certified educational activities resulted in statistically significant gains in oncologist knowledge and competency surrounding the use of immunotherapy in advanced RCC. These results demonstrate the value and benefit of multi-modal and sequential activities on improving knowledge and competence outcomes for oncologists caring for patients with advanced renal cell carcinoma.
TCGA Kidney Cell Atlas: A differential gene expression database for the dissection of tumor-specific gene modules.
Authors: Alimohamed Saif , Geller James I. , Aronow Bruce
Published: May 2020

e17078

Background: The Cancer Genome Atlas project has become a leading source for data that has allowed the identification of a broad range of human cancer tumor types and subtypes and has revealed deep complexity with respect to the differentiation, or lack thereof, among human cancers. In particular, differential gene expression analyses have revealed a wealth of active oncogenic pathways, underlying gene mutation drivers, discriminative markers, and candidate therapeutic targets. Despite its rich composition, several factors have led to it not attaining the utility it would seem to offer. Methods: To study this, we dissected molecular subtypes in the TCGA and used the Pan-Kidney (n = 1022 samples) Portion within it to determine where obstacles seem to limit its utility. We re-clustered the renal carcinomas to create more appropriate histology annotations for these samples. The molecular subtypes were then found through K-means using differentially expressed known developmental regulators per histological annotation. After deriving these new annotations, the histology and molecular subtypes were compared to one another via T-test to generate gene modules that characterize these classes/subclasses. Results: We identified a number of factors that include inconsistent metadata attributes, apparent misclassification of histological subtypes, and molecular subtypes that do not match with that obtained by focused approaches to rederive principle subclasses. Our gene modules showed a molecular subtype of clear cell renal carcinoma that was enriched for vascular development and nephron development. In general, the clear cell renal carcinoma and papillary renal cell carcinoma cohorts both showed significant co-expression with atlases that were enriched for genes involved in kidney development. Conclusions: Our atlas highlights the limitations of the current TCGA atlas and provides another tool to capture the rich insights from the TCGA repository through the efforts explained above, highlighted by its use in kidney carcinoma.
A non-interventional retrospective study to describe early clinical experience with cabozantinib in patients with advanced renal cell carcinoma (aRCC) in the United Kingdom.
Authors: Pillai Manon , Powles Thomas , Szabados Bernadett , Savage Philip , Fife Kate , Klair Bhupinder , Perrot Valérie , Michael Agnieszka , Venugopal Balaji
Published: May 2020

e17089

Background: Cabozantinib is approved in the UK in treatment-naïve adults with intermediate or poor risk aRCC or following prior VEGF-targeted therapy. Here we describe treatment pathways and clinical outcomes of patients with aRCC who received cabozantinib early and later in the UK managed access program (MAP) as disease severity may differ in these patient populations. Methods: A non-interventional retrospective chart review study was carried out in six specialist centres in the UK to describe early clinical experience with cabozantinib in patients with aRCC (CERES, NCT03696407). Progression-free survival (PFS) and overall survival (OS) were calculated from cabozantinib initiation using the Kaplan-Meier method. Patients were grouped into those who initiated cabozantinib early (Aug 2016-Feb 2017) or late (Mar-Aug 2017) in the MAP. Results: Overall 100 patients were eligible; median (95%CI) PFS was 6.01 (5.16; 7.85) months and median OS was 10.84 (7.92; 16.85) months. Patients in the early MAP group received a mean (SD) of 2.2 (1.4) lines of prior therapy, most commonly sunitinib (n = 32, 56.1%) and pazopanib (n = 30, 52.6%). Patients in the late MAP group received a mean of 1.9 (SD 1.2) lines of prior therapy, most commonly pazopanib (n = 23, 53.5%) and sunitinib (n = 19, 44.2%). At least one post-cabozantinib therapy was prescribed in 44.6% (25/57) and 27.9% (12/43) of patients in the early and late groups, respectively, most commonly nivolumab (both groups). See table for characteristics and outcomes by MAP group. Conclusions: Cabozantinib was effective in this small, real-world study of patients receiving treatment as part of a MAP. The results are supportive of the data seen in the registrational study, METEOR. Patients enrolled early in the MAP were possibly more heavily pre-treated but overall outcomes were similar to those who enrolled later. [Table: see text]
Response to checkpoint inhibitors (CPI) in sarcomatoid renal cell carcinoma (sRCC).
Authors: Sheng Iris Yeong- Fung , Wei Wei , Desai Kunal , Allman Kimberly D. , Martin Allison , Wood Laura S. , Nehez Sarah , Taylor Susan , Gupta Shilpa , Gilligan Timothy D. , Ornstein Moshe Chaim
Published: May 2020

e17095

Background: sRCC have a generally poor prognosis though recent clinical trial data suggest improved outcomes with CPI. We present a real-world experience of metastatic sRCC patients (pts) treated with a variety of CPI. Methods: Pts with sRCC treated with CPI Cleveland Clinic from 1/1/2015 to 12/31/2019 were identified. Overall survival (OS) was estimated using Kaplan-Meier and compared by log rank test. Results: Of 28 eligible pts identified with sRCC, median age 58, 82% Caucasian, all KPS score > 80%, 86% had IMDC intermediate/poor risk disease, 75% were clear cell, and 71% had prior nephrectomy. 46.4% had prior non-CPI systemic therapy. CPI therapy in this cohort included: 46% nivolumab monotherapy, 18% axitinib/pembrolizumab, 21% ipilimumab/nivolumab, 4% atezolizumab/bevacizumab, 7% atezolizumab, 4% carboplatin/pemetrexed/pembrolizumab. At a median follow up of 13.6 months (range 6.5-31.4), ORR was 36% (4% CR, 32% PR) and median OS was 13.8 months (95% CI: 9.23-NA). Median time to response was 3.2 months (range 2.4-13.1) and median duration of response was 8.1 months (range 0-25.5). Ten of the 13 patients started subsequent therapy due to progression. At the time of analysis, 39% were still alive and 25% of patients were still on initial I/O therapy (7+ -30+ months). There were no clear correlations between specific disease-related factors (including IMDC risk, time-to treatment of > or < 1 year, or prior systemic therapy) and response (all were p > 0.05). Conclusions: ORR and CR rates were lower in this real-world population of metastatic sRCC pts compared to clinical trial data, which should be a result of various CPI treatments and lines of treatment. However, these data highlight the heterogeneity of sRCC in general and need for additional investigations into impact of percentage of sarcomatoid features, genomic analyses, line of therapy, and CPI choice to optimize outcomes in sRCC pts.
Understanding the treatment effect modification of mono- or combination PD-1/PD-L1 inhibitor therapies on survival outcomes in patients with metastatic renal cell carcinoma: What does the literature say?
Authors: Sati Neha , Boyne Devon J , Brenner Darren , Arora Paul
Published: May 2020

e17097

Background: PD-1/PD-L1 inhibitors are immune checkpoint inhibitors widely used in the treatment of metastatic renal cell carcinoma (mRCC) and other cancers. There is a lack of understanding regarding which factors predict response to these therapies. To address this gap, a systematic literature review and meta-analyses were conducted. The objectives of this study were to a) conduct a systematic literature review of studies examining factors that modify the clinical efficacy of PD-1 or PD-L1 inhibitors among patients diagnosed with mRCC and b) quantitatively synthesize the magnitude to which each predictive factor modifies the effect of PD-1/PD-L1 inhibitors. Methods: Electronic databases MEDLINE and COCHRANE were searched for studies published in English from 2006 onwards. We included all phase II/III randomized trials that provided subgroup analyses of any baseline characteristics regarding the effect of PD-1/PD-L1 inhibitors, alone or as part of a combination therapy, with respect to overall or progression-free survival among patients with mRCC. We developed a novel quantitative approach to synthesize subgroup findings across trials. The ratio of the subgroup-specific hazard ratios (HRs) from each study were pooled using a random effects meta-analysis whereby ratios of 1.00 would indicate that the subgroup-specific HRs were equal in magnitude. Results: From an initial 662 studies, five trials were judged to be eligible for inclusion. Meta-analyses suggested the treatment effect of PD-1/PD-L1 inhibitors in mRCC patients was modified by age (overall survival: ratio of HRage > 75 vs. HRage < 65= 1.51; 95% CI:1.01-2.26; I2= 0%, p= 0.04), PD-L1 expression (progression-free survival: ratio of HRPD-L1 > 10% vs. HRPD-L1 < 1%= 2.21; 95% CI:1.14-4.27; I2= 2.26%; p= 0.01), and sarcomatoid tumor presence (progression-free survival: HRno sarcomatoid differentiation vs. HRsarcomatoid differentiation= 1.54; 95% CI:1.07-2.21; I2= 0%; p= 0.02). Conclusions: Evidence suggests that older age, lower levels of PD-L1 expression, and absence of sarcomatoid tumour differentiation diminish the clinical efficacy of anti-PD-1/PD-L1 immunotherapies among mRCC patients.
Gender impact on renal cell carcinoma survival: A population-based analysis.
Authors: Baidoun Firas , Ruhban Inas A. , Saad Anas M , Gad Mohamed , Al-Husseini Muneer J. , Ornstein Moshe Chaim , Gupta Shilpa , Rini Brian I.
Published: May 2020

e17099

Background: Prior evidence has suggested that females diagnosed with renal cell carcinoma (RCC) present at an earlier stage compared to males, but a survival difference between males and females has been controversial. We aimed to evaluate the impact of gender on RCC survival in the US. Methods: Data of RCC patients diagnosed between 1973 and 2015 in the US was obtained using Surveillance Epidemiology and End Results (SEER) database. We studied the overall and cancer-specific survival of patients diagnosed with RCC in the US according to gender using multivariable covariate-adjusted Cox models and Kaplan-Meier test. Results: We reviewed 155,430 RCC patients, of which 96,656 were males, and 58,774 were females. The median overall survival of female patients was 122 months and was significantly higher than male patients (98 months). Cancer-specific survival showed similar trends with females having significantly higher survival (p-value < 0.001). Adjusted for age, race, stage and grade of cancer, undergoing cancer-targeted surgery, and marital status, female sex was associated with improved overall and cancer-specific survival outcomes; HR = 0.829 (p-value < 0.001), and HR = 0.923 (p-value < 0.001), respectively. Conclusions: Females have a significantly better overall and cancer specific survival compared to males diagnosed with renal cell carcinoma. In previous studies this disparity was attributed to the lower grade and earlier stage of RCC presentation in females, but gender-based disparity persisted in this analysis after adjusting for patient baseline and tumor characteristics. This raises the question of the hormonal effects on the progression of RCC.