bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.