bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular and immune landscape of FH-mutated kidney cancer.
Authors: Al-Share Bayan A , Wu Sharon , Alloghbi Abdurahman , Alkassis Samer , Guastella Anthony , Helmstetter Anthony , Nabhan Chadi , Korn W. Michael , Nazha Bassel , Barata Pedro C. , Ryan Charles J. , McKay Rana R. , Heath Elisabeth I.
Published: February 2022

382

Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by inactivating germline mutations in fumarate hydratase ( FH), predisposing individuals to development of certain cancers. Sporadic FH mutations have been described in different types of cancers, including kidney cancers, but the implications of somatic mutations are not well described. Here, we characterize the molecular landscape of kidney tumors with FH mutations. Methods: Tumors were analyzed using next generation sequencing of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq). Immune cell fraction was estimated by immune deconvolution (Quantiseq). Significance was determined by chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value <0.05). Results: Of 1956 kidney tumors, 31 had somatic pathogenic or likely pathogenic (P+LP; 1.58%) and 21 had variant of unknown significance (VUS; 1.07%) mutations in FH. Among the most commonly co-mutated genes, VHL (29.03% vs 38.1% vs 55.2%) and PBRM1 (9.68% vs 20% vs 29.8%) were less frequently mutated in P+LP compared to VUS and WT tumors; while NF2 (22.6% vs 5% vs 5.65%) was more frequently mutated in P+LP tumors compared to the others. In P+LP tumors, the HIPPO pathway (22.6% vs 4.76% vs 5.62%) was more frequently altered while the chromatin remodeling pathway (25.8% vs 28.6% vs 51.1%) was less frequently altered compared to VUS or WT tumors. P+LP tumors showed decreased NK cell infiltration (q=0.01) compared to VUS and WT tumors. Additionally, there was a trend towards increased CD8+ T cells and CTLA4 and PDCD1 expression in P+LP tumors compared to VUS but not WT tumors. Of the 1,956 kidney tumors, 315 were of clear cell renal cell carcinoma (ccRCC) histology. P+LP (n=4) ccRCC tumors showed a trend towards higher expression of immune checkpoint genes CTLA4 and IDO1 compared to VUS tumors (n=5). VHL expression was higher in P+LP ccRCC compared to VUS ccRCC tumors. P+LP ccRCC tumors showed a trend toward increased CD4+ (2.59% vs 0%) and CD8+ (2.14% vs 0%) T cells as well as T cell inflammation (25% vs 0%) and median Interferon score compared to VUS ccRCC tumors. Conclusions: P+LP FH mutated kidney tumors may have a different mutational and immune landscape than VUS FH mutated and WT tumors. Despite the small sample size, our study highlights potential therapeutic implications that will require further study.[Table: see text]
Molecular characterization of renal cell carcinoma with venous tumor thrombus: Genomic aberrations with renal vein wall invasion.
Authors: Dong Xiaoxi , Liu Cheng , Jia Shidong , Yu Jianjun , Ma Lulin
Published: February 2022

385

Background: Renal cell carcinoma (RCC) patients with tumor thrombus (TT) have been observed distinct phenotypes of TT: deeply invading into the wall of renal vein/inferior vena cava (IVC) (DITT) or minimal/non-invasion (NITT), with different surgical strategy and post-thrombectomy outcome. However, the molecular characters of DITT/NITT have not been investigated, due to operational challenges and limited patient access. Methods: In this study, primary tumor and TT samples from 68 patients having IVC thrombectomy were prospectively collected for DNA mutation profiling and RNA expression profiling, using Predicine panel-based next generation sequencing and transcriptome RNA-SEQ, respectively. Next-generation sequencing and bioinformatics data analysis was conducted in Colleges of American Pathologist (CAP)-accredited laboratory in Shanghai, China (Huidu Shanghai Medical Sciences Ltd.). Kaplan–Meier survival analysis was performed to analyze the correlation between DITT/NITT and clinical outcome, and p-values were calculated using log-rank test. Results: When metastasis was detected, patients with DITT showed significantly shorter overall survival comparing to patients with NITT (P < 0.05, log-rank test). However, this difference was not observed in non-metastatic group. Successful sequencing has been achieved in 100% (68/68) patients. NITT tumor bulks more frequently carried mutations in PTEN, TP53 and epigenetic regulators such as SETD2, PBRM1 and KDM5C and had higher expression of cell cycle related pathway genes. In contrast, DITT had lower expression of genes encoding cell adhesion and extracellular matrix molecules such as ADAM33, NCAM1 and FLRT2, which could contribute to higher invasiveness. Conclusions: To our knowledge, this is the first large study to systematically interrogate genomic landscape and molecular features of different TT phenotypes in RCC patients. The differential genomic mutation and gene expression landscapes across the two groups may reflect biologic differences and clinical implications such as tumor invasiveness and aggressiveness.
The prognostic role of sarcopenia and albumin in locally advanced renal cell carcinoma with IVC tumor thrombus.
Authors: Midenberg Eric , Patil Dattatraya H , Medline Alexandra , Higgins Michelle , Williams Milton , Nazha Bassel , Brown Jacqueline T , Ogan Kenneth , Psutka Sarah P. , Bilen Mehmet Asim , Master Viraj A.
Published: February 2022

387

Background: Indicators of body composition and nutritional status, such as lumbar skeletal muscle index (SMI, cm2/m2) and hypoalbuminemia, are associated with adverse outcomes following surgery for localized renal cell carcinoma (RCC) but have yet to be described in patients with RCC and venous tumor thrombus. We hypothesize that preoperative sarcopenia, a severe deficit in lean muscle mass, and hypoalbuminemia will be associated with decreased overall survival (OS) and cancer specific survival (CSS) in nonmetastatic RCC patients undergoing radical nephrectomy and tumor thrombectomy. Methods: We retrospectively analyzed 103 nonmetastatic RCC patients who underwent radical nephrectomy and tumor thrombectomy from 2005 to 2020. Optimally fit BMI (kg/m2) and sex-stratified sarcopenia thresholds were calculated (BMI<30: SMI<47 for males, SMI<38 for females; BMI≥30: SMI<54 for males, SMI<47 for females). Sarcopenia and albumin risk groups were created based on their individual hazard ratios on univariable analysis and defined as low-risk (non-sarcopenic, normal albumin), medium-risk (non-sarcopenic, hypoalbuminemia), high-risk (sarcopenic, normal albumin), and very high-risk (sarcopenic, hypoalbuminemia). Associations between independent and combined sarcopenia and hypoalbuminemia (albumin<3.5 g/dL) with OS and CSS were evaluated using multivariable and Kaplan-Meier analyses. Results: Prevalence of sarcopenia and hypoalbuminemia were 51.2% and 44.7%, respectively. Median follow up time was 24.8 months and median time from preoperative imaging to surgery was 21 days. Sarcopenia was an independent predictor of OS (p=0.003) and CSS (p=0.006) whereas hypoalbuminemia was not (OS: p=0.096; CSS: p=0.718). When analyzing sarcopenia and albumin in combination, the high and very high-risk groups were significantly associated with decreased OS (high-risk: p=0.011; very high-risk: p<0.001) and CSS (high-risk: p=0.011; very high-risk: p=0.017). Kaplan-Meier curves showed a stepwise decline in median OS (p=0.0071) and CSS (p=0.0068) times with increasing risk. Conclusions: Simultaneous sarcopenia and hypoalbuminemia were associated with nearly a seven-fold decrease in OS and CSS in patients undergoing surgery for nonmetastatic RCC with IVC tumor thrombus.[Table: see text]
Sarcopenia as a predictor of perioperative morbidity in metastatic renal cell carcinoma patients undergoing radical nephrectomy and IVC tumor thrombectomy.
Authors: Midenberg Eric , Medline Alexandra , Patil Dattatraya H , Nazha Bassel , Brown Jacqueline T , Ogan Kenneth , Psutka Sarah P. , Bilen Mehmet Asim , Master Viraj A.
Published: February 2022

388

Background: Preoperative sarcopenia, as determined by the lumbar skeletal muscle index (SMI), has shown potential value for predicting adverse survival outcomes in metastatic renal cell carcinoma (mRCC) patients undergoing cytoreductive surgery. However, its utility for predicting perioperative morbidity in mRCC patients with IVC involvement is poorly elucidated. We hypothesize that preoperative sarcopenia, a severe deficiency in lean muscle mass, will be associated with major surgical complications and longer lengths of hospital stay in mRCC patients managed with radical nephrectomy and tumor thrombectomy. Methods: We retrospectively analyzed 99 mRCC patients who underwent radical nephrectomy and tumor thrombectomy from 2005 to 2020. Sarcopenia was diagnosed using optimally fit body mass index (BMI) and sex-stratified thresholds. For patients with a BMI < 30 kg/m², sarcopenia was defined as a SMI < 47 cm2/m2 for males and SMI < 38 cm2/m2 for females and for those with a BMI≥30 kg/m², as a SMI < 54 cm2/m2 for males and SMI < 47 cm2/m2 for females. Outcome measures were the presence of any major complications within 90 days after surgery, major complications within 1 year after surgery, and length of hospital stay post-nephrectomy ≥7 days. Major complications were defined as grade ≥3a on the Clavien-Dindo classification system. Associations between sarcopenia and major surgical complications and length of hospital stay were evaluated using multivariable analysis. Multivariable models were adjusted for age, race, gender, BMI, Charlson comorbidity index, T and N staging, Fuhrman grade, ECOG Score, and extent of IVC tumor thrombus. Results: Median time from preoperative imaging to surgery was 22 days (IQR 15-29). Of the 57 (58%) patients with preoperative sarcopenia in our cohort, 19 (33%) and 20 (35%) patients experienced a major surgical complication within 3 and 12 months after surgery, respectively, and 34 (60%) patients had a length of stay ≥7 days. Preoperative sarcopenia was significantly associated with the occurrence of a major complication within 90 days (OR = 4.84, 95%CI: 1.30-18.06, p = 0.019) and 1 year (OR = 6.43, 95%CI: 1.66-24.89, p = 0.007) after surgery. The presence of sarcopenia did not significantly change the odds of staying in the hospital for more than 7 days post-nephrectomy (OR = 1.41, 95%CI: 0.45-4.41, p = 0.551). Conclusions: Preoperative sarcopenia was associated with major surgical complications occurring within 3 and 12 months among mRCC patients after radical nephrectomy and tumor thrombectomy. Screening for sarcopenia preoperatively may assist in identifying patients at high-risk for increased perioperative morbidity, which ultimately may permit the implementation of preventive therapeutic strategies. Future validation is needed.
Active surveillance in metastatic renal cell carcinoma: A single-center cohort.
Authors: Schwartzman William , Elias Roy , Govil Malvika , Nosair Waseem , Christie Alana , Courtney Kevin Dale , Bowman Isaac Alex , Cole Suzanne , Arafat Waddah , Hammers Hans J. , Brugarolas James
Published: February 2022

389

Background: Emerging data suggest that active surveillance (AS) may be safely implemented in a subset of patients (pts) with metastatic renal cell carcinoma (RCC) and indolent disease to delay the initiation of systemic therapy without undermining long-term survival. However, widespread adoption of AS has been limited by a lack of data on factors portending favorable outcomes. In this study we sought to characterize pts undergoing AS at a large academic medical center to identify factors associated with time on AS. Methods: We identified pts on AS using Kidney Cancer Explorer (KCE), the data management platform of the Kidney Cancer Program at UT Southwestern Medical Center (2005-2020), as well as input from medical oncologists. The AS cohort was defined by (1) having metastatic RCC (determined by either a suspicious lesion > 1cm or a positive biopsy), and (2) the absence of prior systemic therapy. Baseline characteristics and IMDC criteria were evaluated at the outset. Outcomes of interest included progression free survival (PFS), time to systemic therapy (TST), and overall survival (OS). Survival estimates were generated using Kaplan Meier methods. Cox proportional hazard models were used in univariate and multivariate analyses to identify baseline characteristics associated with TST. Results: We identified 37 pts with metastatic RCC undergoing AS; 31 pts (83.8%) had ccRCC, 28 pts (75.7%) had a favorable IMDC prognostic group, 18 pts (48.6%) had one metastatic lesion at baseline, and the cohort had an average tumor burden of 21mm. The majority of pts had clinical or radiologic progression with a median PFS of 10.8 months (95% CI: 8.13-23.31). The median TST was 37 months (95% CI: 24.3-94.9). In total, there were 11 deaths (none of which occurred prior to the initiation of systemic therapy) and median OS after the initiation of AS was 132.5 months (95% CI: 87.3-NR). Multivariate analyses showed that higher numbers of metastatic lesions at baseline were associated with a shorter TST (HR:1.45; 95% CI: 1.03-2.03, p = 0.03). At a median follow-up of 62.5 months, 11/37 (29%) of pts had not yet started systemic therapy. Conclusions: These results expand upon previous studies and support a role for AS to delay systemic therapy in selected pts with metastatic RCC.
Impact of neoadjuvant immune checkpoint inhibitor therapy on primary tumor size and complexity: Correlation with surgical quality and short term oncological outcomes.
Authors: Saidian Ava , Hakimi Kevin , Panian Justine , Ajmera Archana , Barata Pedro C. , Berg Stephanie A. , Chang Steven Lee , Choueiri Toni K. , Dzimitrowicz Hannah Elizabeth , Emamekhoo Hamid , Gross Evan , Kilari Deepak , Lam Elaine Tat , Nonato Taylor , Psutka Sarah P. , Thapa Bicky , Weise Nicole , Zhang Tian , McKay Rana R. , Derweesh Ithaar
Published: February 2022

390

Background:The concept of primary systemic therapy has gained increasing traction in the management of metastatic and locally advanced Renal Cell Carcinoma (RCC). Most series have evaluated the use of tyrosine-kinase inhibitors, however, with the emergence of immune checkpoint inhibitor therapy as first line agents in advanced RCC, further assessment of efficacy is warranted. We examined the effects of immunotherapy (IO) combinations on the primary tumor and consequent surgical quality and short-term oncological outcomes. Methods: We conducted a multi-center, retrospective analysis of patients with advanced/metastatic RCC having received IO followed by Radical (RN) or partial nephrectomy (PN). Primary outcome was achievement of Bifecta (composite outcome of complete resection and no 30-day post-operative complications). Predictors for achievement of Bifecta were assessed with logistic regression multivariable analysis. Secondary outcomes were change in maximal tumor dimension, RENAL nephrometry score and disease progression. Kaplan-Meier analysis was used to assess progression-free survival (PFS) for Bifecta and non-Bifecta patients. Results: We identified 52 patients with advanced RCC across 9 institutions who were eligible. The median age was 63 years and 60.4% were males. Median tumor size at diagnosis was 9.3 cm. 19.6% had T4 disease and 75% had AJCC Stage IV disease. IO treatment resulted in significant reductions in median tumor size (-25.4%; 9.7 cm vs. 7.3cm p = 0.0129) and RENAL nephrometry score (9 to 8, p = 0.032). 43 (83%) of patients underwent RN and (9) 17% had PN. Median tumor size was smaller for PN (8 vs. 4.1 cm, p < 0.001), and 30 day complication rates were higher (p = 0.024). Bifecta was achieved in 39 patients [33/42 (78.6%) RN and 6/9 (67%) PN, p = 0.264). Predictors for achievement of Bifecta were younger age (OR 1.06, p = 0.01), increasing reduction in tumor size (OR 1.187, p < 0.001), and shorter time between therapy and surgery (OR 1.07, p < 0.001). Kaplan-Meier analysis demonstrated longer median time to progression in the Bifecta-positive group compared to patients who failed to achieve Bifecta (75 vs. 30 months, p = 0.04). Conclusions: Pre-surgical therapy resulted in tumor size and complexity reduction. Tumor size reduction was predictive for achievement of Bifecta, which was associated with improved short term oncological outcomes. To our knowledge, this is the first series evaluating the effect of neoadjuvant systemic therapy on the primary tumor prior to surgical intervention.
Trends of kidney cancer burden from 1990 to 2019 in European Union 15+ countries.
Authors: Abdallah Nour , Jani Chinmay , Mouchati Christian , Jani Ruchi Tusharkumar , Bhatt Padmanabh , Salciccioli Justin , Khanna Prateek , Singh Harpreet , Shalhoub Joseph , McKay Rana R. , Marshall Dominic C
Published: February 2022

393

Background: Kidney cancer is among the most common cancers worldwide and is increasing in incidence. During 2020, around 400,000 new cases of kidney cancer were reported, with 180,000 estimated deaths. In recent decades, significant variability in the incidence and mortality of kidney cancer has been universally reported. This study aimed to compare geographical trends in incidence, mortality, and disability-adjusted life years from kidney cancer between European Union (EU) 15+ countries from 1990 to 2019. Methods: The mortality data of kidney cancer were extracted from the Global Burden of Disease Study database. Versions 10 and 9 of the International Classification of Diseases were adopted. Age-standardized incidence rates (ASIR), age-standardized death rates (ASDR), and disability-adjusted life years (DALYs) were collected, per year and per country of the EU15+ group. Mortality-to-incidence ratios (MIR) were calculated. Data was then dichotomized into males and females. Joinpoint regression was done for analysis of trends. Results: From 1990 to 2019, ASIRs increased in most of the countries except for Luxembourg for males, the United States of America (USA) for females, and Austria and Sweden for both sexes. The largest rises of ASIRs were in Denmark for males and females (+89.3% and +82.8%, respectively). ASDRs increased in 10/19 countries for males and 9/19 in females, with the highest rise in Denmark for males and females (+41.7% and +37.7% respectively), and the largest drop in Austria for males and females (-33.8% and -35.8% respectively). MIRs decreased in all countries, for both sexes, with the widest declines in Portugal for males (-29.0%) and in Ireland for females (-26.6%). Trends in DALYs were variable, with the highest rise in Denmark for males and females (+38.6% and +30.2% respectively) and the largest drop in Austria for males and females (-39.5% and -41.2%, respectively). In 2019, the highest ASIR was observed in the USA for males (16.7/100,000) and in Finland for females (8.3/100,000), the highest ASDR in the Netherlands for males (6.1/100,000) and Finland for females (3.0/100,000), highest MIR in Sweden for both genders (0.6/100,000 each), and highest DALYs in the Netherlands for males (132.3/100,000) and in Finland for females (62.6/100,000). Conclusions: The incidence and mortality from kidney cancer rose in most EU15+ countries from 1990 to 2019. Interestingly, an improvement in the outcomes is predicted by the drop in MIR in all countries.[Table: see text]
Accuracy of germ cell tumor histological subtype and stage within the Canadian cancer registry.
Authors: Holland Patrick , Karmas Tim , Merrimen Jennifer , Wood Lori
Published: February 2022

411

Background: Cancer registries are the mainstay for Canadian population-based cancer statistics and research. Data is collected in provincial and territorial registries including the Nova Scotia Cancer Registry (NSCR). The goal of this study was to determine the accuracy of the NSCR data regarding the diagnosis, primary site, histological subtype, and stage of germ cell tumors (GCT) when compared to the individual pathology reports and staging investigations from the chart. Methods: This analysis included all NSCR patients diagnosed with GCT from 2006-2015. From the NSCR, the date and method of diagnosis, primary site, histology, and stage were recorded. This data was also extracted from each patient’s chart record. Any discrepancies between the two sources were reviewed and reasons behind the discrepancies were recorded. Results: 239 unique patients were identified in the NSCR during the specified time period. Ten were excluded as no chart records were available to confirm accuracy. 229 patients make up the study cohort. Using NSCR data 57.6% had seminoma, 34.5% nonseminoma (NSGCT), and 7.9% other. Discrepancies in pathology were noted in 29 patients (12.7%) for a number of reasons including no appropriate coding option in the NSCR, multiple tumors, biopsy only specimens with misinterpretation of tumor marker elevation, and true coding error. Using NSCR staging data (available in 185 cases) 71.9% had stage I, 12.4% stage II, 11.9% stage III, and 3.8% other. Discrepancies in stage were noted in 33 patients (17.9%) with NSCR data downstaging 10 patients (5.4%) and upstaging 19 patients (10.3%) predominantly due to miscoding patients as stage IS. The site of the primary GCT was discrepant in 12 patients (5.2%) due primarily to difficulty coding post chemotherapy orchiectomy specimens and burnt out primary testicular lesions. The date of diagnosis was accurate within 1 week for all patients except one which differed by several months. Conclusions: Canadian cancer registry data is population based and used for many purposes including policy decisions and research. The NSCR higher level data such as date of diagnosis and overall pathological diagnosis appears relatively accurate. However, there are inaccuracies in more detailed information like histological subtype and stage. This study raises awareness of these gaps. It also highlights key areas for improvement in educating registry personnel who interpret and enter data about the uniqueness of GCT pathology, staging and interpretation of tumor markers.
Utilization of radiation therapy and impact on outcomes in spermatic cord sarcomas in the United States.
Authors: Matani Hirsch , Schuyler Kyle , Wegner Rodney E. , Beriwal Sushil , Horne Zachary D
Published: February 2022

419

Background: Spermatic cord sarcomas are a rare entity with management consisting of radical orchiectomy and the value of adjuvant radiation being unclear, as the literature consists of heterogeneous case series spanning multiple decades with limited numbers of patients. Methods: The National Cancer Data Base was queried for men who underwent orchiectomy for spermatic cord sarcomas between 2004 and 2018 with known surgical margin status. Kaplan-Meier with log-rank test and Cox proportional hazards tests were utilized for overall survival (OS) calculations. Associations were determined with bivariate regression analysis. Results: A total of 912 men were identified who met inclusion criteria. Six hundred seventeen (67.7%) had liposarcomas (LS) while 32.3% had non-lipsarcomatous (NLS) histologies. 5/10-year OS for men with LS was 85.1%/67.4% and 74.1%/58.4% for NLS, respectively (p < 0.001). 238 (26.1%) men were treated with adjuvant radiation therapy with similar distributions between LS and NLS. Utilization of radiation was significantly associated with moderate-poorly differentiated histology (HR 3.228 [95%CI 2.241-4.649] p < 0.001), radical orchiectomy (HR 1.477 [1.062-2.054] p = 0.020), positive surgical margins (HR 1.826 [95%CI 1.257-2.652] p = 0.002), but not histologic subtype or tumor size. There was no difference in OS for LS nor NLS with respect to the application of adjuvant radiation, but in men with moderately-poorly differentiated LS treated with adjuvant radiation, 5-year OS was 86.8% vs. 68.6% (p = 0.148). In men with well-differentiated LS, 5-year OS was 93.6% with XRT vs 89.5% (p = 0.623). Adjuvant XRT did not impact OS in men with positive surgical margins, nor did it have an impact on OS for NLS regardless of disease grade or margins. Conclusions: Adjuvant radiation therapy is utilized for approximately one quarter of men diagnosed with spermatic cord sarcomas. XRT may impact OS for men with moderately-poorly differentiated liposarcomas; further research with patient-level data is required.
Viable germ cell tumor and teratoma can be distinguished from necrosis in postchemotherapy retroperitoneal lymph node dissection specimens by a combination of microRNA-371a-3p and 375-5p.
Authors: Nestler Tim , Kremer Lara , von Brandenstein Melanie , Koeditz Barbara , Paffenholz Pia , Hellmich Martin , Pfister David , Heidenreich Axel
Published: February 2022

421

Background: Our objective was to identify a combination of microRNAs (miRNA) to differentiate between viable tumor (V) or teratoma (T) and necrosis/fibrosis (N) in pcRPLND specimens of metastatic nonseminomatous germ cell tumor (NSGCT) patients with residual masses ≥1cm after chemotherapy. Our hypothesis is that a biomarker guided therapy could reduce overtreatment with pcRPLND in patients with only N. Methods: Forty-eight patients were identified, n = 16 each with T/V/N. Representative regions of T/V/N were microdissected, subsequently total RNA was isolated and miRNA expression was analyzed for miR-371a-3p, 375-3p, and 375-5p using qPCR. ROC analysis was performed for each miRNA and for all combinations in order to determine the discriminatory capacity of V and T vs. N. Results: For the group comparisons of V vs. N miR-371a-3p achieved the highest fold change (FC) of 31.1 (p = 0.023) while for T vs. N miR-375-5p performed best (FC 64,2; p < 0.001). Likewise, the most accurate AUC for V was 0.75 using miR-371a-3p, for T 0.80 using miR-375-5p. Combining the best performing miRNAs for V and T resulted in an AUC of 0.94 with a sensitivity of 93.75, specificity of 93.75, PPV of 96.8 and NPV of 83.3. Conclusions: In pcRPLND tissue samples V and T could be distinguished from necrosis/fibrosis by combining miR-371a-3p and miR-375-5p with great accuracy. This combination of miRNAs might serve as new biomarker in the future, in order to spare miRNA-negative patients from pcRPLND. However, further studies analyzing patient’s serum are needed to confirm the clinical impact of these biomarkers.
Biomarkers of gut microbial transfer and their association with cognitive impairment in long-term survivors of testicular germ cell tumors.
Authors: Chovanec Michal , Kalavska Katarina , Obertova Jana , Palacka Patrik , Rejlekova Katarina , Sycova-Mila Zuzana , De Angelis Valentina , Orszaghova Zuzana , Lesko Peter , Svetlovska Daniela , Mladosievicova Beata , Mardiak Jozef , Pastorek Michal , Vlkova Barbora , Celec Peter , Mego Michal
Published: February 2022

426

Background: Survivors of testicular germ cell tumors (GCT) may suffer from long-term cognitive impairment. We hypothesized that disruption of intestinal barrier during chemotherapy and/or radiotherapy may be a contributing factor of cognitive dysfunction within the gut-blood-brain axis. Methods: GCT survivors (N = 142) from National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function questionnaires during their annual follow-up visit at 9-year median (range 4-32). Biomarkers of gut microbial transfer and dysbiosis (GMT) high mobility group box-1 (HMGB-1), lipopolysaccharide (LPS), d-lactate and sCD14 were measured from peripheral blood obtained during the same visit. Each questionnaire score was correlated with biomarkers of GMT. Survivors were treated with orchiectomy only (N = 17), cisplatin-based chemotherapy (N = 108), radiotherapy to the retroperitoneum (N = 11) or both (N = 6). Results: GCT survivors with higher sCD14 had worse cognitive function perceived by others (CogOth domain) (mean ± SEM; 14.6 ± 0.25 vs 15.4 ± 0.25, p = 0.019), lower perceived cognitive abilities (CogPCA domain) (20.0 ± 0.74 vs 23.4 ± 0.73, p = 0.025) and lower overal cognitive function score (109.2 ± 0.74 vs 116.7 ± 1.90, p = 0.021). There were no significant cognitive declines associated with HMGB-1, d-lactate and LPS. Survivors treated with ≥ 400mg/m2 of cisplatin based chemotherapy had higher LPS (567.8 ± 42.7 vs 462.9 ± 51.9, P = 0.03). Survivors treated with chemotherapy + radiotherapy vs orchiectomy only had non-significantly higher sCD14 (7279.9 ± 810.1 vs 5851.0 ± 481.7, P = 0.09). Conclusions: sCD14 may serve as a promising biomarker of cognitive impairment in long-term cancer survivors. While chemotherapy and radiotherapy-induced intestinal injury may be the underlying mechanism, further research using animal models and larger patient cohorts are needed to explore the pathogenesis of cognitive impairment in GCT survivors.
Prognostic factors associated with malignant somatic transformation (MST) of germ cell tumors (GCT) in a Mexican cohort: The experience of the Instituto Nacional de Cancerología, Mexico (NCIM).
Authors: Sobrevilla-Moreno Nora , Pérez-Montiel Delia , López-Macias Diego , Gonzalez-Rodriguez Diana , Sobrevilla-Calvo Pedro , Avitia Miguel Angel Alvarez
Published: February 2022

427

Background: MST is a rare entity defined as the development of somatic non-germ cell malignancies within GCT, its incidence varies between 2.7% and 8.6% of GCT’s. Previously reported favorable prognostic factors include synchronous diagnosis of MST and GCT, absence of non-pulmonary visceral metastases (NPVM) and presence of rhabdomyosarcoma. Methods: Retrospective study to describe prognostic factors of MST in GCT in a Hispanic population. Patients (pts) with diagnosis of MST from 2006 to 2019 were identified from the GCT database of the NCIM. Pts’ characteristics and outcomes were collected from clinical charts and recorded. Overall survival (OS) was performed with the Kaplan Meier (KM) method in the whole cohort and in patients with advanced disease (AD) (stage II and III). Comparisons were calculated with the log-rank test for KM and Chi squared test for categorical factors. Results: Seventy-one pts with MST were included in the overall population (OP). Non-seminoma 95.8%; testicular primary 97.2%; clinical stage (CS) I 32.4%, II 16.3%, III 49.3%; S2-S3 42.3%, 39.6% poor IGCCCG prognosis, 11.3% NPVM. Type of MST: 56.3% rhabdomyosarcoma (RMS), 21.1% spindle cell sarcoma, 12.7% PNET, 9.9% adenocarcinoma. 18.3% more than 1 MST histology. Median follow-up: 43.8 months (m). For the OP, mOS 71.1m (95% CI 80.0 – 119.2). OS for CS I have not been reached (NR). Forty-seven pts with AD were included, mOS 37m (95% CI 9.69 – 64.36). Characteristics associated with prognosis for OS for the OP and the AD cohorts are summarized in table. Pts with AD and RMS had more frequently a synchronous tumor (87.5% vs 58.3%, p=0.02) and absence of surgery for MST (70.8% vs 37.5%, p=.02). Conclusions: As far as we know, this is the largest cohort of hispanic pts with MST. Prognostic factors differed between OP and AD cohorts. Pts with MST and AD have a poor prognosis. Synchronous diagnosis of MST and presence of rhabdomyosarcoma are adverse prognostic factors for AD pts. Further study with a larger population is needed to verify these findings. Univariate analysis for OS.[Table: see text]
First line avelumab in PD-L1+ve metastatic or locally advanced urothelial cancer (aUC) patients unfit for cisplatin (cis): The ARIES trial.
Authors: Iacovelli Roberto , Ciccarese Chiara , Brunelli Matteo , Battelli Nicola , Buttigliero Consuelo , Caserta Claudia , Buti Sebastiano , Santini Daniele , Naglieri Emanuele , Galli Luca , Verri Elena , Ermacora Paola , Milella Michele , Masini Cristina , Aprile Giuseppe , Milesi Laura , Spina Francesco , Rizzo Mimma , Sperduti Isabella , Fornarini Giuseppe
Published: February 2022

439

Background: Avelumab (ave) was approved as maintenance therapy after platinum-based first line (1L) therapy for patients (pts) with aUC based on ph. 3 Javelin Bladder 100 study (NCT02603432), showing significant overall survival (OS) improvement. Here we tested the activity of ave as 1L of therapy in cis-unfit pts with aUC and PD-L1+ve expression. Methods: ARIES is a single-arm, multi-site, open-label phase II trial. Enrolled pts had aUC, were cis-unfit (at least one of: ECOG-PS = 2, CrCl < 60 mL/min, grade ≥2 peripheral neuropathy/hearing loss, progression within 6-mos before the end of neo/adj chemo), had not previously received chemo for aUC and PD-L1≥5% (SP263) centrally assessed. Pts received ave 10 mg/Kg IV Q2W until progression, unacceptable toxicity and withdrawal, whichever occurred first. The primary endpoint was the 1-year OS. Key secondary endpoints were median-OS, -PFS, ORR and safety. Results: A total of 198 eligible cis-unfit pts have been tested for PD-L1 and 71 (35.6%) have been found positive. Among enrolled patients (N = 71), median age was 75 y, 35 (49.3%) had visceral disease, and 22 (31.0%) had ECOG-PS = 2; 50 (70.4%) had CrCl < 60 mL/min and 9 (12.7%) progressed within 6-mos from the end of neo/adj chemo. At the cut-off data (Oct 7, 2021), median follow up was 9.0 mo and 13 patients are still on treatment. The median OS was 10.0 mos (95% CI, 5.7-14.3), and 40.8% of patients were alive at 1-year. The ORR for all patients was 22.5%; complete response, 1.4% (n = 1); partial response, 21.1% (n = 15). Clinical benefit was 43.6% (n = 31). Median PFS was 2.0 mos (95% CI, 1.4-2.6). Among the 56 pts who received at least 3 cycles (29 days) of therapy the median OS was 16.0 vs 1.0 mos. Five (7.0%) grade 3 ave-related adverse events, and no treatment-related death were reported. Conclusions: Ave is active and safe in pts with cis-unfit, PD-L1+ve aUC and poor baseline characteristics. Clinical trial information: NCT03891238.
Evaluating therapeutic bladder cancer trial disparities in race/ethnicity.
Authors: Iyer Ishaan , Zhang Sylvia , Borno Hala
Published: February 2022

446

Background: Racial clinical trial disparities in bladder cancer outcomes remains a critical problem in the United States. This study sought to examine representation by race and sex among therapeutic bladder cancer clinical trials that informs the standard of care in bladder cancer management. Methods: Published clinical trial data that inform clinical management were identified from the National Comprehensive Cancer Network guidelines and by clinician input from 2009 to 2021. The characteristics of participants, including sex and race, were collected. Clinical trials were categorized by clinical setting: metastatic bladder cancer (MBC), muscle invasive bladder cancer (MIBC), and non-muscle invasive (NMIBC). Bladder cancer incidence by race were collected from the Surveillance, Epidemiology, and End Results (SEER) Program. SEER incidence data by race was compared to the racial/ethnic breakdown of bladder cancer clinical trial participants and evaluated using hypothesis testing (chi-square). Results: A total of 28 clinical trials were assessed, with a pooled sample of 8003 participants. race was reported for 1786 participants. A total of 17 clinical trials did not report race. The population data from SEER details bladder cancer distributions as 89.52% White, 5.80% Black, 0.33% American Indian/Alaska Native, and 4.36% Asian or Pacific Islander. Chi-square analysis demonstrated significant differences in racial representation for MBC (p< 0.0001) and NMIBC (p=0.0423) settings. No significant differences were observed in the MIBC (p= 0.1954) setting. Conclusions: This study observed that the distributions of race in MBC and NMIBC clinical trials are different from that of the population affected by bladder cancer. It is imperative for therapeutic cancer clinical trials to achieve adequate representation to ensure standard of care therapies in bladder cancer management benefits all.[Table: see text]
Identification of muscle-invasion status in bladder cancer patients using natural language processing and machine learning.
Authors: Yang Ruixin , Zhu Di , Howard Lauren , De Hoedt Amanda M. , Klaassen Zachary William Abraham , Freedland Stephen J. , Williams Stephen B.
Published: February 2022

447

Background: Mortality from bladder cancer (BC) increases exponentially once it invades the muscle. At the population level, accurate delineation of these patients is challenging. Methods: To develop and validate a natural language processing (NLP) model for automatically identifying muscle-invasive BC (MIBC) patients, aiding in population-based BC research. All patients with a CPT code for transurethral resection of bladder tumor (TURBT) (N = 76,060) were selected from the Department of Veterans Affairs (VA) Corporate Data Warehouse database. A sample of 600 patients (with 2,337 full-text notes) who had TURBT and confirmed pathology results were selected for NLP model development (500 patients) and validation (100 patients). Muscle-invasion (yes/no), unknown, or no cancer, were confirmed by detailed chart review of pathology notes. The NLP performance was assessed by calculating the sensitivity, positive predictive value (PPV), and overall accuracy at the individual note and patient levels. Results: In the validation cohort, the NLP model had overall accuracy of 88% and 92% at the note and patient levels. Specifically, PPV and specificity for predicting muscle-invasion on note level were 83% and 70%, respectively. The model classified non-muscle invasive BC (NMIBC) with 98% sensitivity at both the note and patient levels. Although the sensitivity for MIBC was 70% for note-level determination, the sensitivity was 86% when evaluated at the patient level. When applying the model to 71,200 patients VA-wide, the model classified 13,642 (19%) as having MIBC and 47,595 (66%) as NMIBC. The NLP model was able to identify invasion status for 96% TURBT patients at the population level. Inherent limitations include relatively small training set given the size of the VA population. Conclusions: This NLP model for identifying muscle-invasion at the population level had high accuracy. The NLP model may be a practical and accurate tool for efficiently identifying BC invasion status and may potentially aid in population-based BC research in the VA.
Effect of neoadjuvant chemotherapy (NAC) on patient preferences for adjuvant treatment in muscle-invasive urothelial carcinoma (MIUC): A multi-country discrete choice experiment (DCE).
Authors: Broughton Edward I , Steinberg Gary D. , Harrison Michael Roger , Braverman Julia , Jaffe Dena H. , Will Oliver , Senglaub Steven S. , King-Concialdi Kristen , Beusterien Kathleen
Published: February 2022

454

Background: Patient preference is an important factor in selecting appropriate treatment choices. Although underutilized, the standard of care for MIUC is with NAC, whereas evidence for adjuvant therapy is less clear. With the introduction of novel adjuvant treatments such as immune checkpoint inhibitors, treatment options are expected to expand. This study examines whether preferences for adjuvant therapy is impacted in MIUC patients receiving NAC. Methods: A cross-sectional, web-based survey included patients ≥ 18 years old who self-reported being diagnosed with MIUC and underwent radical cystectomy or nephroureterectomy without recurrence. Patients were recruited from the US, UK, Canada, France, and Germany (May–Sep 2021). A DCE using 2 adjuvant treatment profiles included 8 attributes: cancer-free survival, overall survival (OS), hypothyroidism requiring life-long hormone therapy, risk of a serious adverse event (requiring medical intervention/possible hospitalization), nausea, fatigue, diarrhea, and a dosing regimen (frequency of treatment and monitoring); an opt-out option of no treatment was also shown. Patients were grouped according to self-reported receipt of NAC. Descriptive statistics and hierarchical Bayesian logistic model with estimated preference weights were used. Relative importance estimates (mean ± standard error), or how much the attribute ranges accounted for the variation in preferences, were computed for each attribute. Bivariate comparisons used t-tests. Results: This interim analysis identified 205 patients (70.7% of target sample; US, n = 99; Germany, n = 60; UK, n = 31; Canada, n = 14; France, n = 1). Of 82 patients (40.0%) receiving NAC, 32.7% were patients > 65 years and 55.1% were male; receipt of NAC did not differ by age ( P = 0.248) or sex ( P = 0.731). Patients were willing to accept increased risk in toxicities for increased treatment efficacy. Specifically, mean relative importance of treatment attributes showed that difference in median OS (25 months compared to 78 months) was most important (34.6% ± 1.6), although less so for those who did not receive NAC (30.2% ± 2.4 vs 37.5% ± 2.0; P = 0.022). Patients chose an adjuvant treatment option over ‘no treatment’ 91% of the time, with similar findings by NAC status. Conclusions: Preliminary data indicates that receipt of NAC impacts preferences for adjuvant treatment attributes. However, regardless of these attributes, patients still preferred adjuvant treatment over none. These results suggest that providing standard of care NAC does not reduce patient preference for adjuvant therapy; rather, patient preferences for adjuvant treatment attributes vary by treatment history, with implications for improving quality of care and outcomes.
Long-term cost comparisons of radical cystectomy versus trimodal therapy for muscle-invasive bladder cancer.
Authors: Golla Vishnukamal , Shan Yong , Farran Elias Joseph , Vu Kevin , Stewart Courtney A. , Khaki Ali Raza , Keegan Kirk A. , Kamat Ashish M. , Tyler Douglas S. , Freedland Stephen J. , Williams Stephen B.
Published: February 2022

455

Background: Earlier studies on the cost of muscle-invasive bladder cancer treatments are limited to short-term periods of cost. Our study objective is to compare the 2- and 5-year costs associated with trimodal therapy (TMT) versus radical cystectomy (RC) benchmarked against costs for patients who received no curative treatment. Methods: This cohort study used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Medicare expenditures were summed from inpatient, outpatient, and physician services within 2 and 5 years of diagnosis to determine total costs Total Medicare costs at 2-and 5-years following TMT versus RC were compared using inverse probability of treatment-weighted (IPTW) propensity score models. Results: A total of 2,537 patients aged 66-85 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer from January 1, 2002 through December 31, 2009. Total median costs for patients that received no definitive/systemic treatments (RC, TMT, radiotherapy alone, or chemotherapy alone) were $73,780 vs. $88,275 at 2-and 5-years respectively. Total median costs were significantly higher for TMT than RC at 2-years ($372,839 vs. $191,363, p<0.001) and 5-years ($424,570 vs. $253,651, p<0.001), respectively. TMT had higher outpatient median costs than RC (2-yr: $318,221 vs. $100,900; 5-yr: $367,092 vs. $146,561) with significantly higher costs largely associated with radiology, medications, pathology/laboratory, and other professional services. Conclusions: TMT vs. RC was associated with higher long-term costs among patients with muscle-invasive bladder cancer largely driven by outpatient expenditures. Reduction in costs associated with radiology, medications, pathology/laboratory, and other professional services may improve the value of TMT.[Table: see text]
Contemporary treatment and survival differences in patients with urothelial versus nonurothelial bladder and upper tract carcinomas: Analyses from the National Cancer Database (NCDB).
Authors: Aragon-Ching Jeanny B. , Wang Hongkun
Published: February 2022

463

Background: Non-urothelial bladder and upper tract cancers are known to have worse prognosis than urothelial cancers. Further descriptive analyses of patterns of demographic presentation, stage, metastases and response to chemotherapy and immunotherapy are explored through the NCDB database. Methods: The primary objective of this retrospective review is to evaluate trends and differences between upper tract urothelial cancers (UTUC) versus non-urothelial (nUTUC) histologies (squamous, sarcomatoid, small cell or neuroendocrine, adenocarcinoma) and bladder urothelial cancer (UC) and bladder non-urothelial cancer (nUC) and compare the demographics, disease characteristics, treatment, incidence of stage and survival according to NCDB. Results: Data from diagnosis in year 2004 – 2017 were extracted from the NCDB. A total of 649939 cases of whom 630423 were urothelial and 19516 were non-urothelial for both bladder and upper tract cancers were identified. More men were diagnosed with urothelial carcinoma, UTUC (62%) and bladder UC (75%). The median age was similar for both groups, 71.4 years (UC) and 70.1 years (nUC). Majority were Caucasian at 91.6% (UC) and 85.7% (nUC) while African-American patients consisted of 5.26% in the UC and 10.8% in the nUC cohorts. Primary surgery occurred more frequently in the UC cohort (94.7%) compared to the nUC (87%). More patients were diagnosed with stage IV cancer in the nUC group (21.9%) compared to UC at 4.6%, and overall survival was slightly worse with nUC for stage IV cancers with median OS of 7.92 mos (CI, (7.75, 8.08) for UC vs 6.14 mos (CI, (5.78, 6.47) nUC; logrank p = < 0.001, although the biggest numeric difference was in the stage 0 and stage I patients with mOS of 110.13 mos (CI, 109.44, 110.82) versus 46.09 mos (CI, 42.09, 50.66), p < 0.001. Use of chemotherapy resulted in improved overall survival in the UC group with mOS of 73.53 mos (CI, 72.61, 74.41) compared to nUC at 17.28 mos (CI, (16.59, 17.87), p < 0.0001 and use of immunotherapy similarly yielded improvement in the UC group with mOS of 115.98 mos (CI, 114.33- 117.65) compared to nUC at 64.49 mos (CI, 45.67, 88.51); p < 0.0001. Conclusions: Urothelial cancer of both bladder and upper tract origin compared to non-urothelial cancers tend to have better prognosis in both presentation at diagnosis and with early stage cancers as well as treatment in advanced stages with chemotherapy or immunotherapy, highlighting the need for better therapeutic strategies for non-urothelial cancers.