bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world outcomes of genetic testing in a GU genetics clinic and evaluation of current guidelines.
Authors: Pace Annelise , Woodson Ashley Henriksen , Slack-Tidwell Rebecca , Daniels Molly S. , Pilie Patrick Glen , Litton Jennifer Keating , Hoskovec Jennifer M. , Jonasch Eric 
Published: March 2019

668 Background: Several known hereditary cancer syndromes confer an increased risk for genitourinary (GU)-related malignancies. Various guidelines indicate when to refer patients to genetic counseling for GU cancers, but there are limited data on the performance of these guidelines in clinical practice, and the association between testing outcome and clinical and familial features that may delineate a heritable syndrome. The purpose of this study is to determine the most common indications for ordering genetic testing in a GU Genetics Clinic and evaluate the relationship between the indication for germline testing and outcome. Methods: An IRB-approved retrospective chart review was performed for 350 patients seen in a GU Genetics Clinic at a single comprehensive cancer center from 2014-2018. Subgroups of patients were formed based on their indication for genetic testing. Exact binomial tests were used to compare the proportion of patients with a positive (pathogenic or likely pathogenic) germline variant for those with vs. without each indication. Results: All patients had a genetic evaluation due to a personal or family history of GU cancer. The majority (324 of 350, 92.5%) were evaluated for either renal cell carcinoma (RCC) or prostate cancer (PrCa). Among patients seen for RCC-related evaluation (n = 159), 23 patients (14.5%) tested positive. Meeting published clinical criteria for a hereditary RCC syndrome significantly predicted positive testing ( P< 0.001). No other indication for testing, including RCC diagnosis ≤ 46 years, predicted for positive germline genetic test results. No positive patients were identified by age of RCC onset alone. Among patients seen for PrCa-related evaluation (n = 173), 13 (7.5%) individuals tested positive; all positive variants were in ATM or BRCA2. A single patient (1/13) was identified by metastatic PrCa status alone. Conclusions: Our data suggest current algorithms lack specificity for selecting individuals with RCC or PrCa at risk for germline mutations, and need to be revised. Evaluation of pedigrees and identifying presence of syndromic features are essential and increase the probability of identifying individuals at risk for harboring a germline mutation.
Ipilimumab plus nivolumab (Ipi/Nivo) as salvage therapy in patients with immunotherapy (IO)-refractory metastatic renal cell carcinoma (mRCC).
Authors: Gul Anita , Shah Neil J. , Mantia Charlene , Hammers Hans J. , Ornstein Moshe Chaim , McDermott David F. , Atkins Michael B. , Rini Brian I. 
Published: March 2019

669 Background: Ipi/Nivo is now FDA approved for the first line treatment of patients (pts) with intermediate and poor risk mRCC but activity in IO refractory mRCC patients is still not well reported. Here we seek to report activity of Ipi/Nivo in IO refractory mRCC pts. Methods: In this retrospective review, we identified a total of 30 pts with mRCC from 4 academic medical centers across the USA who received salvage Ipi/Nivo after disease progression on IO therapy. Pts with only predominant clear cell histology were captured. Ipi/Nivo was administered as per CHECKMATE 214. Investigator-assessed response rate were noted. Immune related adverse events (irAE) were captured in accordance with CTCAE v5.0. Results: The baseline demographics included median age of 60 years (21-82), ECOG PS 0-2, and 73% (22) male and 27% (8) female. IMDC risk categories at the time of salvage Ipi/Nivo initiation were 23% (7), 60% (18) and 3% (1) with favorable, intermediate and poor risk, respectively. The median number of prior systemic therapies was 3 (1-6). Prior IO therapies included nivolumab monotherapy (14), avelumab plus axitinib (3), high dose interleukin-2 (3), pembrolizumab monotherapy (2) and Ipi/Nivo, nivolumab plus hypoxia inducible factor (HIF) inhibitor, atezolizumab plus interferon, atezolizumab monotherapy, pembrolizumab plus bevacizumab, pembrolizumab plus axitinib, varlilumab plus atezolizumab and an oral adenosine inhibitor (1 each). The median time on prior IO therapy was 7 months (1-50), best response was 3% (1) CR, 40% (12) PR, 23% (7) SD and 33% (10) PD. 73% (22) had restaging scans to assess response to ipi/nivo of which 17% (5), 3% (3) and 47% (14) showed PR, SD and, PD respectively. 37% (11) developed any grade irAEs and 6% (2) had grade ≥3 irAE including one patient with splenic rupture and one with rash and pneumonitis. Conclusions: Ipi/Nivo is feasible and safe in IO-refractory mRCC population with preliminary evidence of anti-tumor activity. Updated response data will be presented.
Dichotomous sized-based clinical staging of localized renal masses affects management but not clinical outcomes.
Authors: Reinstatler Lael Suzanne , Stensland Kristian D. 
Published: March 2019

670 Background: Clinical staging of localized renal masses is assigned according to radiographic tumor diameter cut-offs, with T1 masses defined as 7 cm or less and T2 greater than 7cm. However, it is unknown if tumors with infinitesimal size differences exhibit oncologic behavior to warrant different surgical management. Arbitrarily dichotomizing otherwise similar tumors to different stage groups may inappropriately influence the management of renal tumors and affect patient outcomes. We evaluated differences in management and outcomes in otherwise similarly sized tumors among patients that differ only in clinical T stage. Methods: Data from the National Cancer Center Database was extracted on all patients with a diagnosis of stage T1 or T2 clear cell renal cell carcinoma (RCC). Analyses were limited to tumors on the cusp of T1/T2 staging to include: 69 mm, 70 mm, and 71 mm. Clinical data were compared and Kaplan-Meier and Cox proportional hazards survival modeling were performed. Results: A total of 2815 patients were included. There were 1882 stage T1 and 933 stage T2 tumors; there were no differences in demographics or comorbidity scores. Of 171 tumors reported to be 69 mm, 132 (77.2%) were staged as T1. Of 2339 70 mm tumors, 1686 (72%) were staged as T1. Of 305 71 mm tumors, 64 (21%) were staged as T1. For management, 11.7% of T1 masses were treated with partial nephrectomy vs 7.3% of T2 masses and 75.8% of T1 masses were treated with radical nephrectomy vs 80.7% of T2 masses (p<0.001). T2 masses were more likely to have lymph node dissection than T1 masses (15.1% vs 9.9%, p<0.001), but pathologic N and M staging was similar. On survival analyses, there was no difference in survival between T1 and T2 masses. Conclusions: In this analysis, tumors of similar size but different clinical stage exhibited similar survival, yet were managed differently according to assigned clinical T stage. Patients with large T1 or small T2 masses may be managed inappropriately if the treatment is based on dichotomized clinical staging alone. When possible, risk calculation using precise parameters such as tumor size as part of a prediction model is preferable to dichotomized rules of thumb when determining optimal treatment courses.
Analysis of toxicity and clinical outcomes (CO) in full versus reduced dose cabozantinib (cabo) in metastatic renal cell carcinoma (mRCC) patients (pts).
Authors: Martini Dylan J , Shabto Julie M. , Liu Yuan , Carthon Bradley Curtis , Speak Alexandra , Hitron Elise , Russler Greta , Caulfield Sarah , Ogan Kenneth , Harris Wayne , Master Viraj A. , Kucuk Omer , Bilen Mehmet Asim 
Published: March 2019

671 Background: The full dose of cabo is 60 mg, but some pts are treated with a reduced dose with the clinical anticipation of adverse events (AEs). We compared AEs and CO in mRCC pts treated with full versus reduced dose cabo. Methods: We performed a retrospective analysis of 65 mRCC pts treated with cabo at Winship Cancer Institute from 2016-2018. CO were measured by overall survival (OS), progression-free survival (PFS), and objective response (OR). OS and PFS were measured from first dose of cabo to date of death and clinical or radiographic progression, respectively. OR was defined as partial response (PR) or complete response (CR) per RECISTv1.1. AEs were collected from clinic notes. Univariate analysis (UVA) of association between AEs and CO was performed using logistic regression model. Results: Most pts were males (68%) and the median age was 63 years. Most (79%) had clear cell RCC (ccRCC) and the majority were IMDC intermediate (59%) or poor (39%) risk. Most pts (68%) received 60 mg and 48% of these pts underwent a dose reduction for AEs. Nearly all pts (95%) who started on a reduced dose experienced AEs, compared to 66% for pts treated with 60 mg. OR rate was similar for pts on 60 mg (18%) and pts on a reduced dose (19%). The median survival was comparable in pts treated with 60 mg and pts treated with a reduced dose (10.9 vs. 8.8 months, p=0.92 for OS and 5.6 vs. 5.1 months, p=0.23 for PFS) per Kaplan Meier estimation. AEs, particularly gastrointestinal (GI) AEs, were associated with significantly lower chance of OR (Table). Conclusions: CO may be comparable in mRCC pts treated with full versus reduced dose of cabo, but a reduced dose of cabo may not be associated with decreased AEs. GI side effects may be a poor prognostic factor in mRCC pts treated with cabo. Larger studies are warranted to validate these findings. [Table: see text]
Rates of occult brain metastases in patients (pts) with advanced renal cell carcinoma (RCC): A cohort study from patients treated across 22 clinical trials.
Authors: Kotecha Ritesh , Redzematovic Almedina , Motzer Robert J. , Voss Martin Henner 
Published: March 2019

673 Background: National guidelines for RCC management only recommend brain imaging ‘if clinically indicated’; the rate of occult brain metastases is not defined. Early detection of CNS disease has major implications as it typically triggers early intervention with the aim to limit morbidity, including major complications of local progression. In an effort to define the utility of brain screening, we investigated the rate of occult brain metastasis in a large cohort of metastatic RCC pts. Methods: We performed a retrospective review of completed and actively accruing metastatic RCC clinical trials conducted at Memorial Sloan Kettering Cancer Center. Individual charts of pts screening for those studies with mandatory brain imaging at baseline were reviewed to identify subjects harboring occult brain metastases. We collected patient demographics, International Metastatic Database Consortium (IMDC) risk status, sites of metastatic disease, and tumor histology. Patients with neurologic symptoms were excluded. Descriptive statistics were applied to analyze findings across the cohort. Results: A total of 22 clinical trials for metastatic RCC conducted from 2004-2017 required brain imaging at baseline, and a total of 535 pts were screened in this context. A total of 25/535 pts were found to have occult brain metastasis (4.67%), which was multi-focal in 10/25 (40%) and sub-cm in 15/25 (60%). For these 25 pts, the mean age at diagnosis was 56 years (38-77), and IMDC risk score at enrollment was: 1/24 favorable (4%), 21/24 intermediate (88%), and 2/24 poor-risk (8%) patients. 18/25 patients presented with de novo metastatic disease; 13/25 had received prior therapies; and 24/25 patients (96%) had > 2 additional non-CNS sites of metastatic disease at time of screening. 21/23 pts and 2/23 pts were then treated with radiation and surgical resection, respectively. Conclusions: This retrospective cohort study shows a 5% rate of occult CNS disease in asymptomatic patients with advanced RCC. These findings can inform current screening guidelines for full disease assessment in metastatic RCC patients.
Positive surgical margins after radical nephrectomy for localized kidney cancer: Impact on survival.
Authors: Ryan Stephen , Sarkar Reith , Bindayi Ahmet , Eldefrawy Ahmed , Hamilton Zachary , Murphy James Don , Derweesh Ithaar 
Published: March 2019

676 Background: Impact of positive surgical margins (PSM) in patients undergoing radical nephrectomy (RN) in localized renal cell carcinoma (RCC) is poorly understood. We sought to understand the impact of PSM for on overall survival (OS) after RN in clinically localized RCC. Methods: Retrospective analysis of patients from the US National Cancer Database who RN for clinically localized (cT1a-cT2b cN0M0) RCC between 2003-13, were stratified into their pathological stage group [pT1a, pT1b, pT2a, pT2b, and pT3a ( = Upstaged)] and analyzed by final margin status. Cox Regression Multivariable analysis (MVA) was performed to investigate associations of PSM and covariates on OS. Kaplan-Meier analysis (KMA) of OS was performed for PSM verses NSM for the overall cohort and by stage. Results: 37,656 RN events [14312 (38%) pT1a, 13598 (36.1%) pT1b, 6551 (17.4%) pT2a, 2937 (7.8%) pT2b, and 4286 (11.3%) with pT3a upstaging]. PSM rate was 0.9% overall (0.4% pT1a, 0.4% pT1b, 0.4% pT2a, 0.4% pT2b, and 4.7% pT3a upstaged). On MVA for all-cause mortality, PSM was independently predictive for decreased OS (HR 1.51, p < 0.001), along with increasing age (HR 1.04, p < 0.001), non-Caucasian race (HR 1.199, p < 0.001), increasing charlson score (HR 2.23, p < 0.001), non-private insurance (HR 1.61, p = 0.001), high grade histology (HR 1.21, p = 0.001), and sarcomatoid histology (HR 3.61, p < 0.001). Pathologic T-stage was also predictive of decreased OS (Referent pT1a, HR 1.17, 1.47, 1.74, and 1.93, for pT1b, pT2a, pT2b, pT3a, respectively; all p < 0.001). KMA revealed worsened 5-year OS for PSM vs. NSM for the overall cohort (62.4% vs. 81%, p < 0.001), pT2a (61% vs. 79.4%, p = 0.013), and pT3a (50% vs. 68.3%, p < 0.001) groups. Conclusions: PSM is a rare event after RN, but is associated with worsened OS, particularly in pT2 and pT3a upstaged patients. Mechanism of decreased OS cannot be clarified given limitations of the NCDB, these suggest that PSM may pose increased oncologic risks in higher pathological stage. Consideration of further definitive strategies (ex: preemptive wide field resection) may be warranted in select circumstances. Furthermore, our findings call for re-consideration of exclusion of PSM patients from adjuvant therapy trials.
Is there a correlation between Gleason score and maximum standardized uptake value in locally advanced prostate cancer patients?
Authors: Cem Onal , Torun Nese , Guler Ozan Cem , Reyhan Mehmet , Akkus Yildrim Berna , Yapar Ali Fuat 
Published: March 2019

68 Background: The aim was to assess the intensity of 68Ga-PSMA uptake in the primary tumour in patients locally advanced prostate cancer treated with definitive radiotherapy. Also correlation between the maximum standardized uptake value (SUVmax) of primary tumour and the Gleason score (GS) or prostate-specific antigen (PSA) level was assessed. Methods: The data of 201 biopsy-proven prostated cancer patients were retrospectively analysed. Median age of entire cohort was 68 years (range; 45 – 85 years). PET/CT images were analysed visually and semiquantitatively by measuring the SUVmax. The SUVmax of the primary tumour was assessed in relation to both PSA level and GS. Results: Median age of entire cohort was 68 years (ranged 45 – 85 years). Median PSA value at diagnosis was 20.3 ng/mL (ranged 2.1 – 301.0 ng/mL). Forty-two patients (23.9%) was in intermediate risk group, and 159 patients (79.1%) had high risk disease. Seventy two patients (36.8%) had regional lymph node metastasis. Median SUVmax of primary tumor and metastatic lymph nodes were 13.0 (ranged 1.3 - 84.3) and 12.6 (ranged 3.6 – 64.5), respectively. Patients with GS 7 or lower had significantly lower SUVmax compared to patients with GS > 7 (12.1±8.4 vs. 20.9±16.4; p < 0.001). However, there was no significant difference in SUVmax of tumors with GS of 3+4 and 4+3 (14.8±8.6 vs. 16.3±12.7; p = 0.6). Patients with PSA ≥10.0 ng/mL exhibited significantly higher uptake than those with PSA levels < 10.0 ng/mL (12.1±8.4 vs. 20.9±16.4; p < 0.001). SUVmax of intermediate risk patients was significantly lower than that of high risk patients (12.7±11.1 vs. 19.8±16.8; p = 0.01). In 72 patients with lymph node metastasis SUVmax was significantly higher compared to 129 patients without lymph node metastasis (24.9±21.3 vs. 14.7±10.6; p < 0.001). Conclusions: Tumours with GS 7 or lower, patients with PSAvalues ≤10 ng/mL, intermediate risk patients and patients without regional lymph node metastasis showed significantly lower 68Ga-PSMA uptake. 68Ga-PSMA-PET/CT should be preferentially applied for primary staging of prostate cancer in patients with GS > 7, PSA levels ≥10 ng/ml, high risk patients and patients with regional lymph node metastasis.
Hypofractionated, accelerated radiotherapy to the prostate bed: Five-year outcomes of a prospective phase I/II study.
Authors: Martell Kevin , Cheung Patrick , Morton Gerard , Chung Hans T. , Deabreu Andrea , Zhang Liying , Pang Geordi , Alayed Yasir , Mamedov Alexandre , Gladwish Adam , Loblaw Andrew 
Published: March 2019

7 Background: There have been few studies to date that examine the role of hypofractionated radiotherapy for prostate cancer in the post-operative setting. This study reports on the 5-year outcomes from a single institution, prospective, phase I/II study on hypofractionated prostate bed radiotherapy. Methods: Patients enrolled in this study were all eligible for post-operative radiotherapy and received a prescribed dose of 51Gy in 17 fractions to the prostate bed. On subsequent follow-up, GI/GU toxicity was assessed using the NCI CTCAE v3.0, PSA was evaluated and quality-of-life was assessed using the EPIC questionnaire. Results: A total of 30 patients were enrolled between 2008 and 2011. Median age was 65 [52-75] years. Median pre-treatment PSA was 0.12 ng/ml [0.01-1.42]. Twenty-four (86%) patients had Gleason 7 disease, 13 (43%) had pT3 disease and 20 (67%) had positive margins. Twenty-six (87%) patients underwent radiotherapy as salvage treatment. No patient experienced CTCAE grade 3/4 toxicity. Two (7%) patients experienced at least one CTCAE grade 2 late GI toxicity and 11 (37%) had at least one late grade 2 GU toxicity. At baseline and 5 years post radiotherapy, mean EPIC urinary domain score were 80 (SD: 18) and 82 (17). Mean EPIC bowel domain score were 93 (13) and 93 (15). One (4%) patient had a minimally clinically important change (MCIC) in urinary domain score and 1 (4%) patient had a MCIC in bowel domain score. Nelson-Aalen estimated cumulative incidence of biochemical failure were 31% (nadir+0.2) and 18% (nadir+2.0) at 5 years. Four-year PSA ≥0.4 was highly predictive of subsequent rise to nadir+2.0 at 5 years (Nelson-Aalen cumulative hazard: 1.45; standard error: 0.701; p < 0.0001). Five (17%) patients received hormonal therapy for biochemical failure. Nelson-Aalen estimated cumulative incidence of hormone therapy use was 14% at 5 years. Conclusions: In this phase I/II study, hypofractionated post-operative radiotherapy appears to have good clinical efficacy without significant late toxicity. Phase III studies are warranted. Clinical trial information: 042-2009.
MiR-34a to enhance the radiosensitivity of 22RV1 and 22RV1-radiation resistance prostate cancer cell lines.
Authors: Thoms John , Aoki Satoko , Belbin Thomas 
Published: March 2019

74 Background: Radiation therapy (RT) is a standard treatment option for men with prostate cancer (PCa), yet men still fail RT at a rate of up to 50%. MicroRNAs (miRNAs) can influence the tumor RT response, and the abundance or lack of specific miRNAs can alter radiosensitivity through alteration of survival pathway signals. We show that altered expression of miR-34a plays an important role in radiosensitivity. Methods: Both clinical and molecular data from TCGA-PRAD cohort were analyzed. MiR-34a expression was also determined in an independent cohort of 30 patients with PCa treated with RT. An RT resistant subline (22RV1-IRR) from the parental 22RV1 line was generated. MiR-34a expression level was determined in 22RV1, 22RV1-IRR and PrEC cells. 22RV1 and 22RV1-IRR cells were transfected with miR-34a mimics. Stable clones overexpressing miR-34a were generated. The influence of miR-34a on cellular proliferation, migration, clonogenic survival and response to RT was measured using standard assays. Results: Analysis of TCGA-PRAD data showed that low levels of miR-34a was associated with biochemical recurrence (BCR). In our cohort of 30 PCa patients treated with RT, miR-34a was consistently under expressed and associated with BCR. MiR-34a was down regulated in 22RV1 cells compared to PrEC cells and further down regulated in 22RV1-IRR cells. 22RV1 - IRR cells expressed lower levels of TP53, but overexpressed cMYC, BIRC5 (survivin) and E2F3. MiR-34a mimics resulted in a decreased expression of survivin at the mRNA and protein level in 22RV1 and 22RV1-IRR cells. MiR-34a expression was unregulated in response to RT in both cell lines. Survivin and E2F3 expression were down regulated in response to RT in both cell lines. MiR-34a mimics suppressed cell proliferation in 22RV1 and 22RV1-IRR cells. MiR-34a mimics also suppressed cellular migration, by the wound healing assay, in both 22RV1 and 22RV1-IRR cells. Stable clones overexpressing miR-34a were associated with increased radiosensitivity via clonogenic survival assay. Conclusions: Together, these data suggest that low expression of miR-34a is associated with BCR and overexpression of miR-34a enhances radiosensitivity by the downregulation of survivin and E2F3.
Bowel and bladder reproducibility in image-guided SBRT prostate: Results of a patterns of practice survey.
Authors: Mandia Jeremy , Escorcia Freddy , Ning Holly , Salerno Kilian Elizabeth , Citrin Deborah E. , Rowe Lindsay S. 
Published: March 2019

76 Background: Use of prostate stereotactic body radiotherapy (SBRT) as treatment for localized prostate cancer (PCa) is increasing. Given the high dose (>5Gy) per fraction (Fx) being delivered, SBRT requires careful preparation and delivery to ensure accuracy and precision. Guidelines and data on best practice for bowel and bladder preparation are lacking. Therefore, we surveyed practicing radiation oncologists (RO) to document practice patterns for prostate SBRT. Methods: From June to October 2018 we completed a nationwide survey of 1395 American Society for Therapeutic Radiology and Oncology (ASTRO) members who self-identified as managing PCa. A SurveyMonkey link was sent via email, and analysis included practicing RO who treat PCa with SBRT. Results: 204 responses were received with 32% (64/204) using SBRT. 80% (51/64) provided the fractionation used: 33% (17/51) use 35Gy to 36.25Gy, and 17.6% (9/51) use >40Gy in 5 Fx, and 1 used >9Gy Fx. 94% use implantable devices for localization (83% fiducial markers, 17% radiofrequency transponders). 65% (42/64) use a hydrogel spacer. 75% (48/64) use daily cone beam CT (CBCT) for image guidance. The majority use a 5 mm PTV, with 3 mm posteriorly. For bladder and bowel preparation 97% (62/64) provided preferences. For bladder, 90.3% (56/62) required a comfortably full bladder for both simulation and treatment. For simulation, 92% (57/62) have a bowel protocol (BP) to optimize rectal reproducibility. 51.6% (31/62) have patients empty their bowels prior, and 51.6% (31/62) prescribe a BP. Diet alteration was recommended by 77% (48/62). 86% (53/62) used a BP during SBRT treatment. Of those using a BP, 67% (43/64) continued it throughout SBRT with 30% (19/64) continuing BP unless symptoms change management. Only 3% (2/64) stop BP after simulation. Conclusions: The variability of data in the literature on effective BP for treatment reproducibility for PCa is reflected in the varied patterns of practice seen in our survey. Consensus on bladder preparation is seen for a majority of practitioners. A variety of BP regimens are employed.