bluuebunny/crossref_metadata_2025 huggingface dataset:
Is it necessary to obtain a second review on outside pathology for patients referred with non-muscle invasive (NMI) bladder cancer?
Authors: Brown Jared , Hensel Caitlin , He Jiaxian , McDonald Megan , Newhall Philip , Riggs Stephen Boyd
Published: May 2020

e17049

Background: Correct pathological staging is paramount in treatment recommendations for patients with non-muscle invasive disease. As a referral center, we sought to evaluate the quality of outside pathology determined by College of American Pathology (CAP) recommendation as well as discordance in AUA risk group stratification. Methods: We retrospectively reviewed our database of patients who originally underwent resection of bladder tumors at external facilities that were subsequently referred to our cancer institute between 2015 and 2018. 75 initial pathologies were overread by one of our GU pathologists all with non-muscle invasive bladder cancer. We evaluated the discordance rate between outside pathology reports and our overread using the CAP criteria for reporting. Additionally, we included the association in risk stratification category as well as the change in risk stratification group following overread. Cohen’s kappa (κ) statistics were used to evaluate concordance in pathology report between LCI and external facilities. Comparisons of risk stratification between LCI and external facilities were analyzed using Fisher’s exact test. Results: 5 criteria for quality were evaluated to assess reporting. A relatively high agreement in reporting tumor grade between LCI and external facilities (κ = 0.65, p < 0.001) and moderate agreement in microscopic extent (κ = 0.41, p < 0.001). LVI was not commented on in 58.7% of outside reports. 6/12 (50%) of patients were upstaged from Low Risk (LR) to Intermediate Risk (IR), 2/11 (18%) from IR to High Risk (HR), and 6/46 (13%) from HR to MIBC (Table). Conclusions: Initial pathology reports from outside facilities were often lacking minimum criteria as recommended by the CAP. Furthermore, a significant number of patients were upstaged after review, including 13% of HR patients being overread as muscle invasive disease. Second review of outside pathology should strongly be considered as re-review may have implications on treatment recommendations. [Table: see text]
Clinical outcome of patients diagnosed with testicular sex cord stromal tumors.
Authors: Bukhari Syed Abdullah Javaid , Malik Maira Iqbal , Hutton Paul , Porfiri Emilio , Jafri Mariam
Published: May 2020

e17055

Background: Testicular Sex Cord Stromal Tumors (TSCST) are rare representing approximately 5% of testicular cancers. Leydig Cell Tumours (LCT) constitute 1-3% of testicular tumours, occur commonly in third to sixth decade and are up to 50mm in diameter. Sertoli Cell Tumours(SCT) constitute less than 1%, occur commonly in the fourth decade and have an average diameter of 35mm. High-risk histological features include; tumour size, increased mitotic activity, pleomorphic nuclei, necrosis, vascular invasion and rete testis invasion. Management is surgical with no standard chemotherapy or radiotherapy in adjuvant or metastatic setting. Methods: A retrospective review of epidemiology, radiological staging, histopathological features, relapse rate and treatment in 82 patients diagnosed with TSCST between 4/12/2001 -27/12/2018 at a tertiary referral centre. Results: 2,170 testicular cancer patients were diagnosed in this period of whom 82 patients (3.8%) had TSCST. 65 patients (2.9% ) had LCT,13 patients (0.59%) had SCT, 3 patients had Unclassified SCST and 1 patient had Mixed SCST. Median patient age for LCT was 43 years, SCT was 29 years, unclassified SCST was 46 years and for mixed SCST was 49 years (age range of TSCST was 18 - 82 years). Median size of LCT was 11mm (range 4 – 28 mm) in 43 patients and of SCT was 16mm (range 7 – 60mm) in 10 patients. 79 patients (3.6% ) presented with stage 1 disease. One patient with LCT and 4 high risk histological features on initial diagnosis had local retroperitoneal recurrence 4 years later and underwent surgical resection with 1year distant disease-free survival. On distant relapse, he was treated with mitotane. One patient presented with metastatic SCT with 4 histological high risk features. He was treated with carboplatin and etoposide. Median survival in the metastatic disease was 10.5 months. Conclusions: TSCST have an excellent prognosis with over 98% of patients are free of disease post-surgery. Our relapse rate is 1.2% which is lower than previously reported and is confined to patients with high risk features. Metastatic LCT and SCT are resistant to chemotherapy with poor survival.
The effect of primary granulocyte-colony stimulating factor prophylaxis on incidence of febrile neutropenia in patients with testicular germ cell tumors.
Authors: Hapakova Nikola , Chovanec Michal , Rejlekova Katarina , Kalavska Katarina , Obertova Jana , Palacka Patrik , De Angelis Valentina , Sycova Zuzana , Mardiak Jozef , Mego Michal
Published: May 2020

e17056

Background: Testicular germ cell tumors (GCTs) represent only one percent of all solid tumors; however, they are the most common solid malignancy in men 15-35 years old. Febrile neutropenia (FN) is a grievous complication of chemotherapy, frequently occurring in GCT patients. The aim of this retrospective study was to assess the effect of primary granulocyte-colony stimulating factor (G-CSF) prophylaxis on the incidence of FN in GCT patients. Methods: This study was conducted using the National Cancer Institute medical records database. Patients diagnosed with germ cell tumors treated with first line/adjuvant chemotherapy at the National Cancer Institute, Bratislava, Slovakia from January 2000 to December 2017 were eligible. Starting in January 2006, patients received G-CSF prophylaxis after every cycle of chemotherapy. Results: Out of 393 patients, 265 patients received primary G-CSF prophylaxis and 128 patients did not receive prophylaxis. The majority of patients (69.97%) were treated with bleomycin, etoposide and cisplatin chemotherapy. There were 61 deaths (15.5%) in our study population. 2- and 5-year OS of the study group was 86.8% and 83.1%, respectively. During the study period, 71 patients (18.1%) suffered FN events. Out of 128 patients who did not receive primary prophylaxis, 42 (32.8%) patients suffered FN, while only 29 (10.9%) patients with primary prophylaxis suffered FN ( P = 0.0000001). On subgroup analysis, FN incidence decreased in all groups with primary prophylaxis, except for patients with stage I GCT receiving adjuvant chemotherapy. Patients receiving G-CSF prophylaxis had significantly longer overall survival when compared to patients without prophylaxis. (HR = 0.44, 95% CI 0.26-0.75; P = 0.0009). Conclusions: Primary G-CSF prophylaxis was associated with significantly decreased FN incidence and longer overall survival in patients treated with first line chemotherapy and should be consider in all patients except stage I disease.
Testicular cancer in Hispanics: Are we approaching ethnic parity?
Authors: Janania Martinez Michelle , Garza Juan , Snedden Tyler William , Surapaneni Prathibha , Fernandes Flavia , Williams Madison H , Williams Ryan , Cox Travis , Blaize Jean-Pierre , Warnecke Brian , Djoufack Djoumessi Lakene Raissa , Yoo James , Kakarla Sushanth , Pippin Kelly , Moore Christine Ann , Lathrop Kate Ida
Published: May 2020

e17059

Background: Hispanics (HI) are the fastest growing ethnic group in the US, representing 52% of US population growth from 2010-2018. In the past decade, they have also experienced a rise in incidence of testicular cancer. Studies have shown that HI have a higher incidence of Non-Seminomatous Germ Cell Tumors (NSGCT), present at an earlier age, have advanced stage at diagnosis, and worse outcomes (including increased mortality) when compared to Non-Hispanics (NH). However, there is a paucity of data and a growing need to better characterize this patient population. To our knowledge, this is the largest cohort of testicular cancer patients from a single academic institution that serves primarily HI. Methods: We retrospectively reviewed 243 patients with Testicular Cancer, both Seminoma and NSGCT; all diagnosed between 2010-2018. Key variables included age, race/ethnicity, comorbidities, insurance status, diagnosis, stage, treatment received/response and vitality status in 2018. Continuously distributed outcomes were summarized with mean/standard deviation; categorical outcomes with frequencies/percentages. Significance of associations between categorical outcomes was assessed with Chi Square test of association. Results: We identified 243 patients with testicular cancer, 168 (69%) HI and 75 (31%) NH. See Table. Median duration of follow up was 18.7 months (SD 27.3). When comparing HI vs NH: 65% vs 64% achieved complete response after primary treatment (p value 0.982); 16% vs 23% had a disease relapse (p value 0.184); and 82 vs 90% were alive at end of 2018 (p value 0.257). Conclusions: Our study supports available data that HI present at an earlier age. However, we found no significant difference in insurance status, histology, stage at diagnosis and outcomes in HI compared to NH. HI predominance in our population could explain the lack of difference observed but further studies are needed. Research Sponsor: None.[Table: see text]
Clinical outcomes of checkpoint inhibitors in metastatic non-clear cell renal cell carcinoma and clear cell renal cell carcinoma with variant features.
Authors: Chang Guy vin , Ellithi Moataz , Elnair Radowan , Bleeker Jonathan
Published: May 2020

e17065

Background: Checkpoint inhibitors (CPI) are a well-established treatment option for advanced clear cell renal cell carcinoma (ccRCC); however, there is a paucity of data on efficacy of CPI on advanced non-clear cell renal cell carcinoma (nccRCC) and ccRCC with variant (sarcomatoid or rhabdoid) features. Recently, small series have demonstrated benefit for CPI in these entities. Methods: We performed a retrospective review of patients with metastatic nccRCC or ccRCC with variant features, who received a single agent CPI (nivolumab or pembrolizumab) or combination therapy (nivolumab and ipilimumab) between Feb 2016 – Oct 2019 at our integrated community-based health system. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). We used Kaplan-Meier survival analysis for PFS and OS. Results: A total of 26 patients met eligibility criteria; 11 patients with nccRCC (papillary n = 6, chromophobe n = 1, unclassified n = 4), 12 patients with sarcomatoid ccRCC, 2 patients with rhabdoid ccRCC, and 1 patient with both sarcomatoid and rhabdoid features. Sixteen patients received nivolumab, 3 received pembrolizumab, and 7 received a combination of nivolumab and ipilimumab. CPI was halted in 4 patients due to adverse effects including arthralgia, hyperthyroidism, hepatitis, and colitis. Among these 26 patients, 5 patients (19.2%) achieved complete response (CR), 3 patients (11.5%) achieved partial response (PR), and 10 patients (38.5%) had stable disease (SD). All patients who achieved CR or PR had a durable response throughout the follow-up period. At the median follow-up of 16.4 months, median PFS was 14.3 months, and median OS was not reached. Conclusions: In this retrospective series, the ORR of CPI in metastatic nccRCC and ccRCC with variant features was 30.7%, and disease control rate was 69.2%. These findings suggest that CPI may provide significant clinical benefit in patients with nccRCC and ccRCC with sarcomatoid and/or rhabdoid features. Sample size may limit inference and additional studies are needed.
Minimally invasive partial nephrectomy versus percutaneous cryoablation for stage Ia renal cell carcinoma: A cost-effectiveness analysis.
Authors: Wu Xiao , Uhlig Johannes , Shuch Brian M. , Kim Kevin
Published: May 2020

e17066

Background: Minimally invasive partial nephrectomy (PN) and percutaneous cryoablation (Cryo) are treatment strategies for renal cell carcinoma (RCC). The purpose of this study is to assess the cost-effectiveness of PN and Cryo for stage Ia RCC. Methods: A decision-analysis model was constructed over 5 years from a health care sector’s perspective using TreeAge Pro Suite 2019 (TreeAge Software LLC, Cambridge, MA). The two evaluated strategies were PN and Cryo. The model incorporated the clinical course of stage Ia RCC after either treatment, including costs and quality of life associated with major complications, imaging surveillance (based on 2014 National Comprehensive Cancer Network guidelines), local and metastatic recurrences, and cancer-specific mortality. All clinical parameters were derived from the literature. A willingness-to-pay threshold of $100,000/quality adjusted life year (QALY) was used. 1 QALY is equivalent to 1 year of life in perfect health. Outcomes were measured by incremental effectiveness ratio. Base case calculations, Monte Carlo Simulations with 10,000 iterations using bootstrapping for parameters from their distributions, and multiple sensitivity analyses were performed. Results: Five-year local recurrence-free, metastasis-free, and cancer-specific survival from recent literature were 97.7% versus 95.9% ( p = 0.18), 98.0% versus 100% ( p = 0.14), 99.3% versus 100% % ( p = 0.7) for PN and Cryo. PN and Cryo yielded similar health benefits of 3.63 QALY and 3.64 QALY. Overall costs were $26,343 and $19,346 for PN and Cryo. A total of 89.28% of the 10,000 simulations showed higher cost-effectiveness of Cryo than PN. One-way sensitivity analyses varying long-term outcomes after Cryo while keeping outcomes after PN constant, revealed that Cryo is more cost-effective than PN when its local recurrence risk is < 3.94% per year (18.2% over 5 years), metastasis risk is < 1.51% per year (7.33% over 5 years), or cancer-specific mortality risk is < 0.96% per year (4.7% over 5 years). PN is more cost-effective if Cryo local recurrence risk is 3.5% higher than PN per year, when the metastasis risk is 1.1% higher than PN per year, or when its cancer-specific mortality is more than 0.9% higher than PN per year. Cryo is more cost-effective than PN if its cost is not more than $1,000 higher than PN. Conclusions: Our study showed that Cryo is more cost-effective than PN for stage Ia RCC patients with comparable effectiveness at a lower cost, based on multiple probabilistic and deterministic sensitivity analyses.
Clinical impact of early progression among patients (Pts) with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs) in first-line (1L) setting: IMPACT RCC real-world study.
Authors: Hutson Thomas E. , Liu Frank Xiaoqing , Pandya Shivani , Dieyi Christopher , Kim Ruth , Krulewicz Stan , Kasturi Vijay , Bhanegaonkar Abhijeet
Published: May 2020

e17079

Background: Previous research has indicated a high burden of illness among mRCC pts who progressed to second line (2L) systemic therapy, suggesting benefits to delaying 1L progression. This study examined the clinical impact of early vs delayed disease progression among mRCC pts treated with 1L TKI monotherapies followed by 2L therapy in the US Veterans Health Administration (VHA) database. Methods: Newly diagnosed mRCC pts treated with 1L TKIs followed by 2L therapy were identified between OCT2013-MAR2018 within the VHA database (1L start date = index date). Eligible pts were required to have continuous enrollment for ≥6 months post-2L therapy initiation unless the pt died. A Kaplan-Meier (KM)-derived median time to 2L therapy initiation was used as the cut-off to categorize pts into early (≤median) and delayed ( > median) progression cohorts. KM analysis and Cox proportional hazards models were used to compare and assess the impact of predictive factors on clinical outcomes including overall survival (OS), time to 2L discontinuation (index date to 2L discontinuation or death), and time to 3L treatment initiation (index date to 3L start or death) among pts in the early vs delayed progression cohorts. Results: Among 289 mRCC pts, the mean age was 67.4 years and the median time to 2L initiation was 6.1 months. Pt characteristics were similar between the early (n = 145) and delayed (n = 144) progression cohorts. During follow-up, the delayed progression cohort had better clinical outcomes than the early progression cohort did (Table below). Conclusions: Early progression is associated with worse clinical outcomes, confirming the need to delay disease progression among mRCC pts with effective 1L treatment strategies. Results indicate the need for use of more efficacious therapies, e.g. immuno-oncology-based combinations, in 1L that can delay disease progression and have potential to reduce disease burden. [Table: see text]
Decision tree model with tumor immune function genes for predicting response to anti-PD1 therapy in renal cell carcinoma.
Authors: Bi Xingang , Luo Zhiwen , Bi Xinyu
Published: May 2020

e17084

Background: No current models can predict prognosis as well as immunotherapy benefits in renal cell carcinoma (RCC). The current study was undertaken to develop and validate a simple decision tree model to predict survival and immunotherapy benefits in patients with RCC. Methods: Analysis on RNA expression in a reported clinical trial dataset identified tumor immune function genes differentially expressed between anti-PD-1 response and non-response RCC. The analysis on these genes in different populations and platforms to develop a Bi-Luo (BL) DTM. The predictive performance of the BL DTM on the prognosis and the immunotherapy outcome in RCC was comprehensively analyzed and validated. Then, the mechanism of BL classification on the immune microenvironment in RCC was extensively analyzed. Results: Immunologic genes expression alteration resulted in the sensitivity for anti-PD-1 therapy in RCC. Twelve tumor immune function genes were enriched based on anti-PD-1 response. Survival analysis and machine learning algorithms on 12 genes established a BL classification based on 545 RCC samples to differentiate patients into low risk (BL1) and high risk of poor survival (BL2) groups ( P < 0.0001). The BL classification was a better independent prognosis indicator ( P = 0.004). TIDE algorithm predicted the response of two subgroups to immune checkpoint blockade, and BL1 was more promising to respond to anti-PD-1 therapy ( P = 0.00003268). Our BL classification was visualized in a 3 genes-DTM (F2RL1, TNFRSF and WHSC1) with a high prediction accuracy (AUC = 0.84) in an external validation cohort. Furthermore, in a small-scale immunotherapy clinical trial dataset, our BL DTM had a high specificity (0.86) to identify the non-response RCC in anti-PD-1 therapy. Gene expression of immune inhibiting factors in BL2 subtype was higher than BL1 subtype (all P < 0.01), but less in tumor mutation burden ( P = 0.009). Moreover, we found that BL2 subtype had higher fractions of Tregs ( P < 0.001), CD8+ T cells ( P = 0.037) and lower fractions of resisting memory CD4+ T cells ( P < 0.001) than BL1 subtype. And most HLA subtype genes, namely HLA-G, HLA-E, HLA-DR, HLA-DQ and HLA-DP, were significantly down-regulated in BL2 subtype (all P < 0.05). Conclusions: Our BL based DTM could predict survival and has potential for identifying RCC patients who could not benefit from anti-PD-1 immunotherapy. Non-response of RCC to anti-PD-1 immunotherapy is strongly related to the down-regulation of the immune response.
Combination therapy with nivolumab and tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma.
Authors: Garmezy Benjamin , Zhang Tian , Laccetti Andrew Leonard , Economides Minas P. , Shah Amishi Yogesh , Tannir Nizar M. , Jonasch Eric , Msaouel Pavlos , Zurita Amado J. , Corn Paul Gettys , Venkatesan Aradhana M. , Brown Landon Carter , Kao Chester , Kinsey Emily Noelle , Harrison Michael Roger , Armstrong Andrew J. , George Daniel J. , Campbell Matthew T
Published: May 2020

e17090

Background: Two immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations are FDA-approved for patients (pts) with metastatic renal cell carcinoma (mRCC). Here we present a multicenter off-protocol experience with IO/TKI combinations after progression on monotherapy. Methods: We performed a retrospective analysis of pts with mRCC who received combination non-FDA approved off-protocol IO/TKI combination therapy from 11/2015 – 1/2019 at MD Anderson Cancer Center and Duke Cancer Institute. Results: 48 pts met criteria for study inclusion. At therapy start: median (med) age 65 years; 75% clear cell histology; 68.8% IMDC intermediate risk (20.8% favorable, 10.4% poor); 81.3% prior nephrectomy; med metastatic sites: 2; med prior systemic treatments: 2; most common metastatic sites: lung (58.3%), lymph node (52.1%), and bone (43.8%). Pts received nivolumab (nivo) in combination with the following: cabozantinib (n = 24, 50%), pazopanib (13, 27.1%), axitinib (6, 12.5%), lenvatinib (2, 4.2%), ipilimumab/cabozantinib (3, 6.3%). Med PFS was 13.7 months and med OS was not reached. The two largest cohorts received nivo + cabozantinib (N+C; med dose 40 mg daily) or nivo + pazopanib (N+P; med dose 400 mg daily). The N+C cohort had higher med metastatic sites (3 vs 2) and was more pretreated with agents unique to their IO/TKI combination (med 2 vs 0). In the N+P group, more pts had started on TKI prior to addition of nivo at progression (69.2% vs 45.8%), and fewer had IO monotherapy with TKI addition (30.8% vs 50%). With a med follow up of 14.0 months after combination start, the N+C cohort had a med PFS of 7.3 months (initiated TKI first: 4.8, IO first: 8.2) and med OS of 18.2 months (TKI first: 11.8, IO first: 24.3). The N+P cohort had med follow up of 20.5 months after combination, med PFS of 21.3 months (TKI first: 16.5, IO first: 21.8), and med OS was not reached. In the N+C group, 87.5% experienced any grade adverse event (AE), most common included fatigue (79.2%), diarrhea (42.7%), nausea (29.2%), hypertension (29.2%), and weight loss (25.0%). In the N+P group, 92.3% experienced any grade AE, including fatigue (76.9%), hypertension (38.5%), diarrhea (30.8%), nausea (30.8%), and weight loss (30.8%). There were no grade ≥3 AEs. Conclusions: Slow disease progression on nivo or TKI may be safely controlled with addition of IO/TKI therapy. Med PFS after addition of nivo to TKI appears similar (N+C) and improved (N+P) compared to nivo monotherapy (Checkmate-025). Med PFS after addition of TKI to IO was also similar (N+C) and improved (N+P) compared to historical controls.
The impact of the metastasis region on patients with metastatic renal cell cancer in the intermediate-risk group.
Authors: Karacin Cengiz , Basal Fatma Bugdaycı , Bilgetekin Irem , Oksuzoglu Omur Berna
Published: May 2020

e17091

Background: The majority of patients with metastatic renal cell carcinoma (mRCC) are in the intermediate-risk group, according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Some patients in the intermediate-risk group have similar overall survival (OS) with those in the good-risk group, while others with those in the poor-risk group. In our study, we aimed to evaluate the prognostic significance of the region of the metastasis and to classify the intermediate-risk group into two as favorable or unfavorable according to the metastasis region. Methods: We retrospectively analyzed the clinical data of patients with mRCC those in the intermediate-risk group seen at our Oncology Training and Research Hospital from 2010 to 2018. Patients who received at least one line of tyrosine kinase inhibitor (TKI) were included in the study. Overall survival was calculated. The log-rank test was used to check the statistical significance for OS. Results: Of 113 patients, median age 58 (range 34-78) years, 99 (88%) had more than one site of metastasis: 61 (54%) lung, 41 (36%) bone, 21 (18%) lymph node, and 19 (17%) brain metastasis. Nine patients received one, 86 patients received two, and 18 patients received three lines of systemic therapy. Median follow up was 14 (range 4 – 54) months. Median OS for patients with bone and/or brain metastasis was 10 (95% CI = 6.1 – 13.9) months compared to 16 (95% CI = 10.1 – 22.2) months for patients with lung and/or lymph node metastasis (HR = 1.675, p-value = 0.012). Conclusions: Our data suggest that the bone and/or brain metastasis in the intermediate-risk group mRCC patients treated with TKI are unfavorable prognostic factors.
Prognostic role of T3/T4 ratio in metastatic renal cell carcinoma (mRCC): Preliminary results of the threeFOUR multicenter study (Meet-Uro 14).
Authors: Maruzzo Marco , Verzoni Elena , Pierantoni Francesco , Galli Luca , Vignani Francesca , Buti Sebastiano , Pignata Sandro , Zanardi Elisa , Sbrana Andrea , Procopio Giuseppe , Zivi Andrea , Zielli Teresa , Mini Enrico , Roviello Giandomenico , Basso Umberto , Zagonel Vittorina
Published: May 2020

e17093

Background: Thyroid hormones metabolism can be altered in patients (pts) with chronic diseases and/or undergoing cancer treatments. The prognostic role of T3/T4 ratio has been investigated in metastatic colorectal cancer pts in whom a high T3/T4 ratio predicted longer survival. No data are available in mRCC. Methods: We retrospectively reviewed the clinical charts of pts with mRCC treated in first line for metastatic disease at 8 Italian Oncology Units before March 2017, having at least one response assessment and baseline complete thyroid panel data available. T3/T4 was calculated as the ratio of the two value of hormones and categorized in tertiles. Results: We identified 96 pts, median age 62 years (range 27-82), 72% males. Sunitinib wad administered in 56% of pts, pazopanib in 38%, nivolumab and ipilimumab in 6%. According to Heng Score, 33% of the pts were at favorable risk, 58% at intermediate risk, 9% at poor risk. With a median follow-up time of 42.8 months, median PFS was 24.8 months, estimated median OS was 71.6 months. Tertile distribution of patients was 36.4% in the high, 29.1% in the medium and 34.5% in the low subgroup. A baseline high tertile value (≥ 0.35) predicted longer PFS (39.4 vs 21.8 1vs 4.5 months, p = 0.01), while median OS has not been reached in the three tertiles, with survival at 24 months being 69.7%, 82.1% and 91.4%, respectively in the low, medium, high group (p = ns). The high T3/T4 ratio is also strongly associated with the chance to achieve a partial or complete response (42.8% vs 39.9% vs 21%, X squared test, p < 0.001). Heng prognostic model retained its prognostic role in this cohort (median OS was 77.1 vs 48.4 vs 22.3 months, p < 0.001, respectively for favorable, intermediate or poor risk group) and also predicted PFS (median PFS 38.2 vs 17.2 vs 8.4 months, p = 0.004). Baseline NLR ≥ 3 predicted shorter OS (46.5 vs 77.1 months, p = 0.02) in the whole group. Conclusions: In our retrospective multicenter experience, a high T3/T4 ratio was associated with longer PFS and a higher probability to respond to the treatment. Median OS had not been reached for all the subgroups, probably due to a favorable patients selection. A longer follow-up is needed to validate the prognostic value of T3/T4 ratio in this cohort.
Retrospective analysis of immune-related adverse events (irAE) in metastatic renal cell carcinoma (mRCC) patients treated with first-line ipilimumab and nivolumab (I+N).
Authors: Desai Kunal , Rybicki Lisa A. , Nizam Amanda , Wood Laura S. , Allman Kimberly D. , Martin Allison , Calabrese Cassandra , Gilligan Timothy D. , Gupta Shilpa , Ornstein Moshe Chaim
Published: May 2020

e17094

Background: Incidence of irAEs has grown with increasing use of immunotherapies and can affect multiple organ systems: I+N followed by N maintenance is approved as front-line therapy for intermediate & poor-risk mRCC. Most common associated irAEs are gastrointestinal, dermatologic & hepatic. The purpose of this retrospective, single-institution analysis is to describe irAE incidence and identify risk factors in mRCC pts treated with I+N. Methods: Patients with mRCC started on first-line I+N at the Cleveland Clinic between March 2018 and April 2019 were retrospectively reviewed. Patient demographics, tumor characteristics, radiologic response and irAE history were collected. IRAE incidence was estimated with cumulative incidence. Risk factors for IRAE were assessed with Fine and Gray competing risk regression. Results: Of forty-six (N = 46) pts with mRCC treated with 1L I+N, median age 60 (range: 34-81): 95% clear cell histology; IMDC risk 20%/56%/24% favorable/intermediate/poor respectively. 67% (N = 31) experienced ≥ 1 irAE with total of N = 44 irAEs. Most common systems affected included Gastrointestinal (27%), Musculoskeletal (23%), Dermatologic (14%) & Renal (9%). Most common irAEs were colitis (23%), arthralgia (16%), transaminitis (9%). 82% of irAEs were treated with front-line glucocorticoids and 14% required additional immunosuppressants. 82% of irAEs were attributed to the I+N induction phase and 32% required discontinuation of I+N. 1 pt died as result of irAEs. Incidence of irAEs at 1, 3 and 6 months was 20%, 52%, 59% respectively. Among 31 pts who developed irAEs, median onset from start of I+N was 1.6 months (range 0-11.7). None of the variables examined (i.e. age at I+N initiation, gender, race, IMDC risk, ECOG status, stage at diagnosis, prior nephrectomy, prior radiation therapy) were identified as statistically-significant risk factors for irAEs. Development of irAEs was not associated with progression-free survival (PFS). Conclusions: IRAEs from I+N in mRCC tend to occur early in treatment course and are associated with high rates of treatment discontinuation and need for corticosteroids and other immunosuppressants. The lack of association between baseline factors and development of irAEs should increase physician alertness to potential irAEs with any change in clinical status.
Survival outcomes of sarcomatoid renal cell cancer (sRCC) compared to clear cell renal cell cancer (ccRCC): An analysis of SEER data.
Authors: Gupta Ruby , Ionescu Filip , Jindal Vishal , Khoury John , Anusim Nwabundo Ifeyinwa , Jaiyesimi Ishmael A.
Published: May 2020

e17101

Background: Renal cell carcinoma (RCC) with sarcomatoid differentiation is a highly aggressive form of RCC. The presence of even a small component of sRCC was shown to independently predict poor survival compared to RCC without sarcomatoid features. We studied the epidemiology and survival outcome of sRCC compared to ccRCC by reviewing the SEER data. Methods: Patients (pts) with histologically confirmed sRCC and ccRCC between 2012-2015 were reviewed in SEER database. Variables included age, gender, ethnicity, histologic grade, stage at diagnosis, and nephrectomy. Primary outcome was 5 year Disease Specific Survival (DSS). Data was analyzed using Kaplan Meier curves and Cox proportional hazards model. Results: A total of 31, 293 pts with RCC were identified in SEER database between 2012 to 2015. 611 pts had sRCC while 30, 682 had ccRCC. The two groups had almost similar demographic features, including mean age (63 ±12 for sRCC vs 61±12 years for ccRCC), male: female ratio (vs 2.3:1 vs 1.7:1) and Caucasian ethnicity (82% vs 85%). More than half of sRCC patients (62%) were metastatic at diagnosis compared to only 11% of ccRCC, which presented most commonly as stage I disease (63%). The histologic grade was higher in sRCC patients (43% grade 4 vs 45% grade 2 in ccRCC subjects). Nephrectomy rates were almost similar for stages I-III in the two groups (94% in sRCC vs 93% in ccRCC) while lower in stage IV sRCC (44% vs 54%). Across all stages and at every time point, sRCC was associated with increased mortality in the univariate analysis. In the multivariate regression analysis (table), advanced stage was the strongest independent predictor of mortality (HR 11.9), followed by high histologic grade (HR 3.6) and sarcomatoid histology (HR 2.9). Nephrectomy was protective (HR 0.3). Age was associated with worse outcomes (HR 1.016 per unit change). Conclusions: sRCC are more aggressive and tend to present as metastatic disease. sRCC has worse outcomes across all stages compared to ccRCC even after adjusting for potential confounders. Advanced stage and histologic grade remain the two strongest predictors of disease-specific mortality, sarcomatoid histology demonstrated a significant impact on outcome. [Table: see text]
Survival in metastatic renal cell carcinoma (mRCC) patients over two decades: Does age mater?
Authors: Eggers Hendik , Schuenemann Christoph , Grünwald Viktor , Rudolph Linda , Tiemann Maria-Luisa , Reuter Christoph W. , Ganser Arnold , Ivanyi Philipp
Published: May 2020

e17103

Background: Although the therapeutic landscape changed dramatically in the recent past, little is known about the outcome of elderly mRCC patients, a cohort underreported in clinical trials. Therefore, this analysis addresses changes in OS between treatment periods and age. Methods: mRCC patients treated at Hannover Medical School from 01/2003 - 12/2018 were retrospectively identified. Treatment periods were defined from 01.01.2003–31.12.2009 (P1) and 01.01.2010 –31.12.2018 (P2). Age groups were defined according to WHO (age≤60 years = not old, age 60-75 = older, age ≥76 = old). Descriptive statistics, Kaplan-Meier analysis and logistic regression were applied. Results: Overall, 314 patients showed a median OS of 39.7 (95%-CI: 33.1-46.3) months. Median OS is significantly longer for patients treated in period two (P1 vs. P2: 59.1 vs. 35.1(HR 0.64, 95%-CI 0.48-0.86) months. Median OS increase in median OS between treatment periods was shown within all age groups and was most apparent in the old patients (P1 vs. P2; not old, 35.1 vs. 68.9 months (HR 0.71, 95%-CI 0.45-1.13); older 40.1 vs. 59.1 months (HR 0.62 (95%-CI 0.40-0.97); old 18.8 vs. 45.7 months, (HR 0.43, 95%-CI 0.18-1.05). Conclusions: This observed increase in OS between treatment periods might reflect the advance of therapeutic options. Interestingly, the OS increase throughout treatment periods was independent of age subgroups. Although data need further analyzes, currently it can be hypothesized, that age should not council utilization of therapeutic armamentarium in mRCC.
Skeletal muscle density as a positive predictive factor for nivolumab therapy in patients with metastatic renal cell carcinoma.
Authors: Ekenel Meltem , Sari Murat , Aliyev Samil , Basaran Mert
Published: May 2020

e17107

Background: Immunotherapy has shown promising clinical responses in patients with metastatic Renal Cell Carcinoma (mRCC) at second-line therapy. Since objective response rates are highly variable, it is utmost important to identify patients who may benefit from immunotherapy to avoid unnecessary adverse effects and costs. Therefore, predictive as well as prognostic markers need to be studied extensively. To our knowledge, none of the body composition measurements such as fat content or skeletal muscle density have been assessed for this purpose. The objective of the current study is to analyze whether skeletal muscle (either muscle mass or muscle density) and adipose tissue play a prognostic role in patients with mRCC who were treated with immunotherapy at second line. Methods: We retrospectively analyzed 14 patients with mRCC who were progressed after tyrosine kinase inhibitor therapy and treated with Nivolumab between March 2016 and September 2019. Skeletal muscle density (SMD), skeletal muscle and adipose tissue were assessed with computed tomography imaging. Overall Survival (OS) and Progression Free Survival (PFS) were estimated by using the Kaplan-Meier method. Results: The median OS was 13,1 months and it was strongly associated with SMD; the median OS was significantly longer in patients with high SMD compared to patients with low SMD (6,9 months vs 18,5 months; P < 0,05). Also in our analysis, SMD separated the intermediate-risk group into 2 groups with different median OS periods, ranging from 8,1 months (95% confidence interval [95% CI], 5,1 months-11,1 months) in patients with intermediate-risk Heng score and low SMD to 21,5 months (95% CI, 14 months-27 months) in patients with an intermediate-risk Heng score and high SMD. Other parameters calculated for adipose tissue or skeletal muscle did not cause any significant change in survival analysis. Conclusions: High SMD appears to be associated with improved outcome in our small patient population. It could be a predictive factor when immunotherapy, Nivolumab, is considered for therapy of mRCC patients at second line.
A novel artificial intelligence biomarker: Validation of the automated bone scan index (aBSI) in veterans with metastatic prostate cancer.
Authors: Durkal Vipal P. , Nickols Nicholas George , Rettig Matthew
Published: May 2020

e17507

Background: Prostate cancer commonly metastasizes to the bone and is associated with reduced survival, pathologic fractures and bone pain. The assessment of bone lesions is made with the technetium Tc99m(99mTc) bone scan, which relies on the subjective interpretation of radiologists and has a wide interobserver variability. There is an unmet need for a more objective and quantifiable measurement tool. Progenics Pharmaceuticals has introduced an automated bone scan index (aBSI), which employs artificial intelligence to quantify skeletal tumor burden. The automated bone scan index has been prospectively validated and is reproducible in large Phase III studies. The aBSI was validated by our study in the Veteran population at the West LA VA Medical Center. Methods: The first positive technetium 99 Tc99m bone scans of veterans diagnosed with metastatic, castration-sensitive prostate cancer were evaluated. Since 2011, a total of 107 evaluable patient bone scans were studied (n = 107). Patients with visceral metastases were excluded to evaluate only those with skeletal metastases. An automated bone scan index (aBSI) was generated for each scan using the Progenics Pharmaceuticals’ artificial intelligence platform. Multivariate analysis of aBSI with overall survival, prostate cancer specific survival, time from diagnosis to first positive bone scan, age at diagnosis, ethnicity, and Gleason score was assessed. Results: The study demonstrated a wide range of aBSI values (Range 0-16.84). Values calculated above the Median aBSI value (1.0) were prognostic for Overall Survival (p = 0.0009) and Prostate Cancer-Specific Survival (p = 0.0011). Patients in the highest quartile of aBSI values (range 5.2-16.84) showed a statistically significant Prostate Cancer-Specific Mortality (p = 0.0300) when compared to the lowest two quartiles (Range 0-1.07). The time from diagnosis to the first positive Tc99m bone scan statistically correlated with aBSI values (p = 0.0016). Multivariate analysis using Cox regression was utilized in the final statistical analysis of prostate cancer-specific mortality and overall survival. Conclusions: The automated Bone Scan Index provides a quantifiable and validated artificial intelligence biomarker to address an unmet need among metastatic prostate cancer patients. This tool was validated among Veterans, a pertinent population that is commonly affected by metastatic prostate cancer.
The impact of circulating free tumor DNA (cfDNA) in testicular germ cell tumors (TGCT) management.
Authors: Kubala Eugen , Bakardjieva-Mihaylova Violeta , Skvarova-Kramarzova Karolina , Slamova Martina , Triska Petr , Donatova Zuzana , Rozsypalova Aneta , Rosova Blanka , Trka Jan , Buchler Tomas , Boublikova Ludmila
Published: May 2020

e17519

Background: The clinical management of testicular germ cell tumors (TGCT) has not changed much for decades; most importantly, novel prognostic factors indicating the need of adjuvant chemotherapy and factors related to the development of cisplatin resistance would be needed. Circulating free tumor DNA (cfDNA) is an easily available and valuable source of genetic material, which may bring clinically relevant information. Methods: After ethical committee approval and patient informed consent, peripheral blood (PB) samples were taken from TGCT patients at the diagnosis (after orchidectomy), after 2 cycles of chemotherapy, at the end of treatment, and at relapse or disease progression, if applicable. Clinical data of all patients were recorded. The PB samples were processed immediately after collection, plasma was separated by centrifugation, cfDNA was extracted by QIAmp Circulating Nucleic Acid kits (Qiagen), its quality and quantity was assessed by capillary electrophoresis (Agilent) and qPCR for a house-keeping gene. Selected samples were subjected to whole exome sequencing using SureSelectXT HS + Human All Exon v6 kits (Agilent) on NextSeq (Illumina) platform, together with the corresponding primary testicular tumor and peripheral blood mononuclears as a germ-line control. Statistical analyses were performed using non-parametric tests. Results: Sixty-three samples of 41 patients have been analyzed. The median amount of detected cfDNA did not significantly differ from non-malignant controls, was similar in seminoma and non-seminoma pts, but was significantly higher (p = 0.01) in pts with disease progression. In pts with elevated cfDNA levels, these decreased after 2 and 4 cycles of chemotherapy. In 5 sequenced pts, molecular aberrations (somatic missense or frameshift mutations) were found in genes CDC27 (2 pts), RBMX (4 pts), TPTE2 (3 pts), and TSPAN16 (1 pt). These aberrations were also detected in primary tumors but with lower frequencies, and were not present in germ-line DNA. CDC27 mutations have been described in TGCT previously. The other genes have not yet been linked to TGCT, although their role in spermatogenesis and cell proliferation is well known. The presence of mitochondrial DNA was not detected in cfDNA. Conclusions: High levels of cfDNA are detectable in pts with disease progression where they reflect the total tumor load; the molecular analysis of cfDNA revealed novel aberrations that may play a role in TGCT development. Supported by grants MH CZ - DRO00064190TN, CDRO00064203FNM and MEYS NPU I LO1604
Genomic analysis of castration sensitive and resistant prostate cancer patients by multiple-gene targeted sequencing.
Authors: Fan Liancheng , Fei Xiaochen , Dong Baijun , Xue Wei , Zhao Tingting , Zou Xuan
Published: May 2020

e17525

Background: Previous studies showed the significant diversity of the genomic landscapes between castration sensitive prostate cancer (CSPC) and castration resistant prostate cancer (CRPC). AR, TP53/RB1, and BRCA2/ATM have been reported to contribute to the development of CRPC. In addition, CDK12 has recently reported to lead to the worse response to AR-targeted therapies. We are aimed to clarify the landscape of somatic gene alterations in CSPC and CRPC by multiple-gene targeted sequencing and discover the differential genes between the two treatment stages in order to guide clinical treatment. Methods: We recruited 413 prostate cancer patients including 230 CSPC and 183 CRPC. Cell-free DNA was extracted from plasma samples. Targeted sequencing of 50 genes was performed, which involved in DNA damage repair (DDR) pathway, AR pathway, TP53/RB1, etc. Chi square test or Fisher test were used to analyze the differences between two cohorts. Results: A total of 33.04% (76/230) CSPC patients carried somatic gene alterations, including 16.96% (39/230) in DDR pathway, 19.57% (45/230) in AR pathway and 7.39% (17/230) in TP53/RB1. The most frequent altered gene in CSPC was FOXA1 (9.13%,21/230), followed by NCOR2 (6.52%,15/230) and TP53 (5.65%,13/230). For CRPC patients, 66.67% (122/183) carried somatic gene alterations, including 44.81% (82/230) in DDR pathway, 49.73% (91/230) in AR pathway and 25.68% (47/183) in TP53/RB1. The most frequent mutated gene in CRPC was AR (33.33%,61/183), followed by FOXA1 (23.50%,43/183) and CDK12 (17.49%,32/183). Mutation frequencies of certain genes in CRPC patients were significantly higher than CSPC patients, including CDK12 (p < 0.001), BRCA2 (p = 0.006), ATM (p = 0.003), ATR (p = 0.007), AR (p < 0.001), FOXA1 (p = 0.001), SPOP (p = 0.002), ZBTB16 (p = 0.02), TP53 (p = 0.001), RB1 (p = 0.04) and PTEN (p = 0.001). Conclusions: It was the first study which explored the genomic alterations in Chinese CSPC and CRPC patients by liquid biopsy. These findings confirmed the genomic diversity between CSPC patients and CRPC patients, which could guide the individualized and precise management of prostate cancer in general practice. Furthermore, our findings indicated that somatic alterations in AR, CDK12, BRCA2, ATM and TP53/RB1 might contribute to the development of CRPC.
Determination of biologic and prognostic feature scores from whole slide histology images using deep learning.
Authors: Eminaga Okyaz , Abbas Mahmoud , Semjonow Axel , Brooks James D , Rubin Daniel
Published: May 2020

e17527

Background: In cancer, histopathology is a reflection of the underlying molecular changes in the cancer cells and provides prognostic information on the risk of disease progression. Therefore, whole slide images may harbor histopathological features that have a biological association and are prognostic. Methods: This study has extracted histopathological feature scores generated from hematoxylin and eosin (HE) histology images based on deep learning models developed for the detection of pathological findings related to prostate cancer (PCa). Correlation analyses between the histopathological feature scores and the most relevant genomic alterations related to PCa were performed based on the original results and diagnostic histology images from TCGA PRAD study (n = 251). We extracted feature scores from tumor lesions after applying tumor segmentation and several data transformation using five models developed for detection of cribriform or ductal morphologies, Gleason patterns 3 and 4, and the presumed tumor precursor. For prognostic evaluation, we performed survival analyses of 371 patients from the TCGA PRAD dataset with biochemical recurrence (BCR) using a Cox regression model, Kaplan Meier (KM) curves. We applied the bootstrapping resampling for the uncertainty evaluation and C-statistics for the randomness measurement. Results: The feature scores were significantly correlated with the androgen receptor protein expression, an androgen-signaling score, mRNA expression, and androgen receptor splice variant 7. In addition, feature scores were associated with SPINK1 overexpression, the heterozygous loss of TP53, and SPOP mutations. Additionally, the mRNA and miRNA clusters identified by the TCGA research team for PCa. These features were independent of Gleason grade and were non-random. The survival analyses revealed that a model, including three of five feature scores, achieved a c-index of 0.706 (95% CI: 0.606-0.779). The KM curve showed that these risk groups based on the Cox regression model are significantly discriminative (Log-rank P-value < 0.0001). The low-risk group (n = 177) achieved a 2-year BCR-free survival rate (BFS) of 97.4% (95% CI: 94.9 - 100.0%) and a 5-year PFS of 88.3% (95% CI: 80.6 - 96.7%). In contrast, the high-risk group (n = 194) showed a 2-year PFS of 86.3% (95% CI: 81.1 - 91.8%) and a 5-year BFS of 66.9% (95% CI: 54.6 - 0.82.1%). Conclusions: Our findings uncover the potential of feature scores from histology images as digital biomarkers in precision medicine and as an expanding utility for digital pathology.