bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of immune-related adverse events (irAEs) with clinical benefit in patients with metastatic urothelial carcinoma (mUC) treated with immune-checkpoint inhibitors (ICIs).
Authors: Pier Vitale Nuzzo , Pond Gregory Russell , Abou Alaiwi Sarah , Nassar Amin , Flippot Ronan , Choueiri Toni K. , Harshman Lauren Christine , Sonpavde Guru 
Published: May 2019

e16038 Background: In other cancers such as metastatic lung and melanoma, pts who experience irAEs may have a greater degree of clinical benefit. We sought to evaluate whether the development of irAEs correlates with clinical benefits in mUC pts. Methods: We identified mUC pts who received PD-1/L1 inhibitors at the Dana-Farber Cancer Institute (DFCI). The severity of irAEs was graded using CTCAE v.5.0. Clinical benefit was defined as any objective reduction (complete- or partial- response) in tumor burden. Fisher’s exact test was used to evaluate for differences in the proportion of pts experiencing clinical benefit between pts experiencing an irAEs within 90 days after starting therapy and those who did not experience an irAEs. The log-rank test assessed differences in progression-free survival (PFS) and overall survival (OS) between cohorts. Results: A total of 199 mUC pts were enrolled between July 2013 and October 2018 [median (range) age, 69.6 (26.6-89.0) years; 141 men (70.9%), 58 women (29.1%)]. 114 (57.3%) pts were treated with anti-PD-1 and 85 (42.7%) with anti-PD-L1. irAEs were observed in 67 pts (33.7%), of which 34 (17.1%) < 90 days from start of therapy. Common irAEs included 20 (29.9%) hypothyroidism, 17 (25.4%) colitis, 12 (17.9%) rash/pruritus, and 10 (14.9%) transaminitis. Grade ≥3 irAEs were observed in 14 pts (20.9%).13 (40.6%) pts with irAE < 90 days experienced clinical benefit compared with 21 (17.8%) of pts with no irAE (p-value = 0.008). No difference (p = 0.26 and 0.18) was observed for either PFS (6-month PFS = 19.2% vs 35.3% for no irAE and irAE < 90 days) or OS (1-year OS = 41.8% vs 57.7% for no irAE vs irAE < 90 days). Conclusions: The development of irAEs within 90 days from starting therapy in mUC pts may herald clinical benefit in pts with mUC. Further evaluation of this potential relationship in a large prospective study is warranted.
Analysis of three models to predict pathohistology in patients undergoing postchemotherapy RPLND for (pcRPLND) advanced nonseminomatous germ cell tumors (NSGCT).
Authors: Heidenreich Axel , Paffenholz Pia , Pfister David , Hellmich Martin , Albers Peter , Hiester Andreas , Nini Alessandro , Nestler Tim 
Published: May 2019

e16053 Background: We aim to validate the two best performing prediction models (Vergouwe and Leao) for final pathohistology in NSGCT patients undergoing pcRPLND and we introduce a new radiomics approach. Methods: A cohort of 496 patients treated between 2008 and 2018 was used to validate the 2 prediction modelsusing published formulas and thresholds.For group comparisons, we used t-test or chi-square test. ROC were plotted (sensitivity against 1-specificity) and AUC was calculated. We determined the optimal cut point and used bootstrapping (1,000 replications) to estimate its variability. A p-value of < 0.05 was considered statistically significant. For radiomics, lymph nodes identified on CT images, were semiautomatically segmented with 93 radiographic features (pyRadiomics package). A linear support vector machine algorithm was applied to analyze reproducible radiomics features. A continuous reduction of features analyzed was performed using Random Forest algorithms and ROC analysis. Results: The Vergouwe model had a significantly better AUC compared to Leao model (0.749 [CI 0.706-0.792] vs. 0.689 [0.642-0.736], p = 0.004) to predict benign histology. At a threshold of > 70% for the probability of benign disease, the Leao model would have avoided RLND in 8.6% with benign disease with an error rate of 5.6% for viable tumor. The Vergouwe model would avoid pcRPLND in 23.4% with benign disease with an error rate of 12.7% for viable tumor/teratoma. Of the 93 radiomic features analyzed, 51 features were reproducible. Applying the trained algorithm resulted in a AUC of 82% with a diagnostic sensitivity of 81% and a specificity of 83%. Conclusions: The discriminatory accuracy of both models is not sufficient to safely select patients for surveillance strategy instead of pcRPLND. The radiomics model is promising but needs prospective validation. Further studies including new biomarkers are needed to optimize the accuracy of potential prediction models.
Long-term sexual impairment in relationship with metabolic health in testicular germ-cell tumor survivors.
Authors: Chovanec Michal , Vasilkova Lucia , Petrikova Lucia , Obertova Jana , Palacka Patrik , Rejlekova Katarina , Sycova-Mila Zuzana , Hapakova Nikola , De Angelis Valentina , Kalavska Katarina , Svetlovska Daniela , Mladosievicova Beata , Mardiak Jozef , Mego Michal 
Published: May 2019

e16060 Background: Treatment for germ-cell tumors (GCT) results in long-term sexual difficulties in GCT survivors, as we have shown previously. This study aimed to correlate the long-term sexual difficulties with serum parameters of metabolic functioning. Methods: GCT survivors (N = 155) from a national cancer center completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire at a median 10 years of follow up (range 5-32). Twenty-nine (18%), 30 (19%) and 20 (13%) survivors have suffered from severe difficulty to achieve erection, maintain erection and achieve orgasm, respectively. Severe difficulty was characterized as a score of 0-2 (scale 0-5) in respective questions from the questionnaire. Sexual impairment was then correlated with parameters of metabolic functioning assessed from peripheral blood of all survivors drawn at the day of the clinical visit. Results: Survivors with difficulty to achieve erection had significantly higher levels of alanine-aminotransferase (ALT), aspartate-aminotransferase (AST) and lactate-dehydrogenase (all P < 0.05). Impaired ability to achieve an orgasm also correlated with significantly higher levels of ALT, AST and LDH (all P < 0.05). Survivors with difficulty to maintain erection had higher levels of LDH (P = 0.02) and AST (trend for P = 0.06), but not ALT ( P = 0.5) and their cholesterol levels were significantly higher ( P = 0.04). Furthermore, survivors with higher levels of glucose ( P = 0.04), thyroid stimulating hormone ( P = 0.04), but not of free-thyroxin ( P = 0.3) suffered from difficulty to achieve orgasm. Conclusions: Our prospective study shows that an impairment in sexual function resulting from curative treatment of GCTs may be related to metabolic health. Higher liver enzymes may be indicative of endothelial dysfunction and cardiovascular disorder. Long-term sexual impairment in GCT survivors should be a subject of further translational research to uncover the underlying molecular mechanisms.
Circulating tumor (ct)-DNA alterations in patients with testicular germ tumors.
Authors: Nassar Amin , Agarwal Archana , Nagy Rebecca , Curran Catherine , Abou Alaiwi Sarah , Lanman Richard B. , Talasaz AmirAli , Sweeney Christopher , Sonpavde Guru 
Published: May 2019

e16063 Background: Testicular germ cell tumors (GCT) infrequently harbor somatic mutations. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. To our knowledge, ctDNA genomic alterations observed in in testicular GCTs have not been heretofore described. We report ctDNA profiling of patients (pts) with testicular GCTs. Methods: 31 Pts with testicular GCTs from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Two patients had one serial ctDNA sample. De-identified demographic data were collected in addition to data for ctDNA alterations. Guardant360 is a CLIA-certified ctDNA panel that assesses single nucleotide variant and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants reported at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or found in OncoKB were considered pathogenic. Results: Of 31 patients with testicular GCTs, 162 ctDNA alterations were detected in 26 patients (84%) across 41 genes (Table). A median number of 3 alterations (range 1-19) was detected per sample. Among the 162 alterations, 88 were believed to be pathogenic and detectable in 20 patients (65%). 12/31 pts (39%) were documented to be post systemic therapy. The median age was 38 years (range 20-61). The most common pathogenic somatic alterations were KRAS (n = 12/88, 14%), CCND2 (n = 8/88, 9%), MET (n = 8/88, 9%), CDK6 (n = 7/88, 8%), TP53 (n = 6/88, 7%), and RAF1 (n = 5/88, 6%). In 2 patients with serial samples, 5 novel pathogenic alterations were detected in the second sample including FGFR2, APC, CDK6, RAF1, and MAPK1. Conclusions: ctDNA alterations were frequently detected in resistant testicular GCTs and appear similar to alterations previously described in tumor tissue analyses of testicular GCTs. Given that ctDNA offers a non-invasive means of profiling tumor DNA, further development of this promising modality is warranted to determine it's relevance in clinical practice. [Table: see text]
Novel risk stratification criteria of metastatic renal cell carcinoma (mRCC) patients (pts) treated with immune checkpoint inhibitors (ICI).
Authors: Martini Dylan J , Liu Yuan , Shabto Julie M. , Carthon Bradley Curtis , Russler Greta , Hitron Elise , Caulfield Sarah , Kissick Haydn , Harris Wayne , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim 
Published: May 2019

e16068 Background: IMDC risk criteria is the gold standard for predicting outcomes for mRCC pts. We developed novel risk groups for mRCC pts treated with ICI. Methods: We performed a retrospective review of 100 ICI-treated mRCC pts at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression-free survival (PFS) were used to measure outcomes; OS was the primary outcome. We obtained baseline monocyte-to-lymphocyte ratio (MLR), body mass index (BMI), and metastatic (met) sites. We created a new variable (D_met) that combines number and sites of met: 0 = < 2 met sites; 1 = ≥ 2 met sites without liver metastases (mets); 2 = ≥ 2 met sites with liver mets. Cox proportional hazard model and Kaplan-Meier method were used for association with OS and PFS. Recursive partitioning and regression tree analyses were used for risk stratification. Discrimination of the risk score was measured by Uno C-statistics. Results: The pts were 66% males, 78% clear cell RCC (ccRCC), and 71% received anti-PD-1 monotherapy. Very poor risk pts (MLR ≥ 0.93 or MLR < 0.93, BMI < 24, and D_Met = 2) had significantly shorter OS and PFS than good risk pts (MLR < 0.93, BMI ≥ 24, and D_Met = 0) in univariable and multivariable analysis (UVA and MVA, Table). The Uno C-statistic for our risk grouping criteria compared to IMDC is 0.687 vs 0.566 (p = 0.061) for OS and 0.594 vs 0.541 (p = 0.78) for PFS. Conclusions: Risk grouping using MLR, BMI, and number and sites of mets may predict survival in mRCC pts treated with ICI. These results should be validated in a larger, prospective study. [Table: see text]
Long term relative survival (RS) in patients with primary metastatic kidney cancer: An analysis of 2,167 patients from the Austrian National Cancer Registry (ANCR).
Authors: Marszalek Martin , Karim-Kos Henrike E , Madersbacher Stephan , Hackl Monika , Rauchenwald Michael 
Published: May 2019

e16069 Background: The introduction of thyrosinkinase inhibitors (TKI) changed the treatment of metastatic kidney cancer fundamentally. In Austria, TKI was in troduced in 2006. To elaborate the potential impact of TKI therapies, we studied trends in OS for patients diagnosed with primary metastatic kidney cancer between1998 and 2015 in Austria. Methods: All patients with primary metastatic kidney cancer aged ≥18 years, diagnosed from 1998-2015 were derived from the ANCR (n = 2,490). Patients diagnosed from 2004-2005 (n = 323) were excluded (transition period of systemic therapies). To evaluate survival differences between patients treated before and after the introduction of Sunitinib (preTKI-era and TKI-era), three periods were defined: 1998-2003 (preTKI-era; N = 937), 2006-2010 (TKI-era P1; N = 687) and 2011-2015 (TKI-era P2; N = 543). Follow-up was complete until December 31st, 2016. RS rates were estimated by using method. The Cox proportional hazard model was used to calculate hazard ratios (HR). Results: A total of 2,167 patients was included in the analysis. The median age of the study population was 70 yrs and did not differ between the three eras. The incidence of T1 tumors increased from 6.9% in the preTKI-era to 10% in the TKI-era while T4 tumors decreased from 15% to 8% (p < .001). Surgery rate declined from 50% in the preTKI-era to 43% in 2011-2015 (p = .02). Five-year RS for patients undergoing surgery slightly increased from 18% in the preTKI-era to 23% in TKI-era P1 (p = .04). For patients without (p = .04). For patients without surgery 5-year OS improved from 5.2% in the preTKI-era to 9.1% in TKI-era P1 (p < .001). Apart from surgery, survival gain was observed for younger patients ( < 75 yrs) of +6% (p = .01), older patients ( > = 75 years) of +0.2% (p = .03) and for T3/T4 tumors of +6% (p = .002). The Relative Excess Risk of dying (RER) for patients treated in the TKI-eras was reduced compared to the preTKI-era (HR 0.78, 95% CI 0.76-0.95) adjusted for sex, age, T-stage and surgery. Survival advantage for patients undergoing surgery remained significant (HR: 0.46, 95% CI 0.41-0.52) after adjustment for TKI-era, sex, age, T-stage. Conclusions: Patients with primary metastatic kidney cancer treated in the TKI era show improved RS compared to the cytokine era. Most benefit was observed in non-surgical patients, younger patients and for T3/T4 disease. Surgery remains as an important therapy for additional survival benefit.
Prognostic and predictive biomarkers for clear cell renal cell carcinoma utilizing next generation sequencing.
Authors: Zekri Jamal , Meliti Abdelrazak , Baghdadi Mohammed Abhas , Sobahy Turki , Imtiaz Saba 
Published: May 2019

e16070 Background: The management of the clear cell renal cell carcinoma (cc-RCC) has evolved over the past decade. Clinical patients’ and tumor characteristics have a limited role in predicting the outcome of these patients. The search for reliable prognostic and predictive biomarkers should be pursued in particular during the current era of next generation sequencing (NGS) technology. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimens of cc-RCC were sequenced using NGS and a customized gene panel testing for 72 tumor-related genes. High potential variants were defined by mutation effect (stop-loss, stop-gain, frame-shift substitutions or non-synonymous SNV) and class (pathogenic or likely pathogenic). Cases with identical variants were identified. Results: In total, all 47 cases had 69,052 variants, of which 20,453 were classified as high potential variants. Identical alterations in 15 genes were present in all samples. These genes are: MUC3A, MUC12, MUC7, SRRT, MUC2, MUC5AC, MUC5B, MUC22, MUC6, CR1, MUC4, MUC16, MUC19, MUC17 and MERTK. The numbers of identical and non-identical variants in these 15 genes were counted for each sample. Median number of variants was 377 and was selected as a cut off to define cases with high ( > 377) and low (≤377) variants number (HVN and LVN respectively). For the whole cohort, HVN was associated with shorter overall survival compared to LVN (Median 50 months vs. not reached; Log Rank P = 0.041). In the 11 patients who received anti-angiogenic tyrosine kinase inhibitors (TKIs), HVN was associated with a trend of shorter progression free survival (Median 5 vs. 10 months; Log Rank P = not significant). Conclusions: Alterations in SRRT, CR1, MERTK and MUCIN family genes are very common in RCC. HVN ( > 377) is associated with worse prognosis and may predict decreased benefit from anti-angiogenic TKIs.
The clinical outcome of renal cell carcinoma with rhabdoid and sarcomatoid differentiation.
Authors: Samiei Arash , Tayshetye Pritam , Sanguino Angela , Miller Ralph , Lyne John , Cohen Jeffrey , Mao Shifeng 
Published: May 2019

e16083 Background: Renal cell carcinoma (RCC) with rhabdoid (RD) or sarcomatoid differentiation (SD) represents high-grade RCC with an aggressive clinical behavior. Little success has been reported in treating these patients. No standard management has been established and there is a lack of insight in these entities because of their relatively low incidences. We reviewed a cohort of RCC patients with RD and SD and correlated the pathologic features with their clinical outcomes. Methods: A retrospective study of RCC patients with RD or SD feature at a single center from 2008 to 2016 was conducted. Patient characteristics, pathology findings, clinical management, and survival data were collected. Results: A total of 36 RCC patients, with median age of 65 [47-88] years old, were included. The male-to-female ratio was 2.6:1. Among them, 24 were with pure SD and 12 with RD (7 pure and 5 mixed features). At diagnosis, 14 patients (38.9%) presented with stage IV disease. The median follow-up was 21 [2-53] months. Of the 36 patients, 24 developed metastasis, including 16/24 (67%) with SD, 4/7 patients (57%) with pure RD, and 4/5(80%) with mixed features. Mortality rate was 79% for SD, 75% for RD and 100% for those with mixed features. The overall survival was 23, 22, and 13 months for SD, pure RD and those with mixed features, respectively. 12 patients were treated with tyrosine kinase inhibitors (TKI) in first-line and 7 with immune checkpoint inhibitors (ICI) in the second or third line setting. Longer duration of treatment was seen with ICI than TKI, 12.8 [5-25] vs 5.9 [1-18] months (p = 0.03). Partial response was seen in 6/7 (86%) and stable disease in 1/7 (14%) patients treated with ICI. No survival benefit was seen in patients treated with TKI alone (p = 0.60). Patients received ICI had significantly prolonged overall survival compared to those received TKI alone, 31.4 vs 17.8 months (p < 0.001). Conclusions: The presence of RD or SD portends poor outcome in RCC with conventional management, especially in those with mix of both features. However, these patients had exceptionally high response and improved survival if treated with ICI. A prospective study using ICI focusing on RCC patients with these pathologic features is warranted and could provide hope for such dismal entities.
Association of body mass index (BMI) with clinical outcomes in 203 metastatic clear cell renal cell carcinoma (ccRCC) patients (pts) treated with immuno-oncology (IO) agents.
Authors: Ged Yasser , Lee Chung-Han , Sanchez Alejandro , Duzgol Cihan , Chaim Joshua , Carlo Maria Isabel , Foster Ashley , Akin Oguz , Feldman Darren R. , Hakimi A. Ari , Patil Sujata , Motzer Robert J. , Furberg Helena , Voss Martin Henner 
Published: May 2019

e16103 Background: Obesity is a known risk factor for the development of ccRCC. For malignant melanoma, higher BMI was recently associated with improved outcomes to IO therapy (McQuade, Lancet Onc, 2018), a potential explanation being an obesity-associated inflammation effect. The association of BMI and clinical outcomes in mccRCC pts treated with IO therapy is unknown. Methods: Baseline characteristics and outcomes on therapy were retrospectively collected for pts with mccRCC who received IO-only regimens for at least 4 weeks at our institution. BMI and IMDC risk categories were determined for all pts at IO initiation. The log-rank statistic was used to test the associations between BMI with overall survival (OS) and progression free survival (PFS) and the chi-square test for the association with objective response rates (ORR). Results: Of the 203 eligible pts, 31% were normal weight, 36.5% were overweight, and 32.5% were obese. 24% of pts received IO as first line treatment. IMDC favorable vs intermediate/poor risk was 11 vs 89% in normal weight pts, 20 vs 80% in overweight pts and 20 vs 80% in obese pts. Median follow up time for survivors was 28.6 months (3.4-88). Obese and overweight pts experienced longer OS than those who were normal weight (P=0.01) (normal weight vs. obese, HR 2.0, 95% CI 1.20-3.37). However, this association became non-significant after adjusting for IMDC risk. RECIST evaluations were available for 107 pts. A higher ORR was seen in obese (41%) compared to overweight (15%) or normal weight (28%) pts (P=0.03). We found no association between BMI and PFS. Findings are summarized in the table below. Conclusions: In mccRCC pts treated with IO, obesity associates with superior outcomes, but does not appear to be independent of IMDC risk score. Research into the underlying mechanisms of obesity as a possible biomarker of IO clinical benefit is warranted. [Table: see text]
A systematic review of the characteristics of thyroid metastases from clear cell renal cell carcinoma.
Authors: Khaddour Karam , Marenych Nadiia , Liu Jerry X. , Ward Wendy , Pappa Theodora 
Published: May 2019

e16113 Background: Thyroid gland is an uncommon site for metastases from clear cell renal cell carcinoma (CCRCC) and literature is scarce. Due to the variable and often long lag time before development of metastases in patients with CCRCC, thyroid nodules may be misdiagnosed initially as benign. This systematic review aims at a better understanding of the nature of these metastases. Methods: A bibliographic search was performed using PubMed (1990-2019), key words being “renal cell carcinoma, thyroid, kidney cancer, clear cell.” 147 cases were analyzed. The patient’s characteristics assessed were: age, sex, stage, size of metastases, lag time, diagnostic modality, initial symptoms, treatment and outcome in last documented follow up. Binary logistic regression, spearman and ANOVA were performed to identify differences between the existing variables. Results: The mean age (±SE) was 64± (10) years in males and 64 (±11) in females. The mean lag time to diagnosis of thyroid metastasis was 8.7 (±6.3) years. Gender distribution of the patients was 46.3% male, 52.4% female. There was a weak correlation between lag time and size of metastases, not statistically significant. Size of metastases was significantly higher in symptomatic patients (6.06±3.51cm) compared to those with painless mass (4.6±0.29cm) and asymptomatic ones (3.93±1.99cm) (p = 0.03). Fine Needle Aspiration (FNA) was diagnostic in 29.4% of cases, 47.1% were non diagnostic. Most patients (80.3%) underwent thyroid surgery. At 1 year follow up, 55.6% of patients operated were alive versus 35.3% who did not have surgery, though this was not statistically significant (p = 0.1). Conclusions: A larger size of thyroid metastasis was more likely to present with symptomatology. A high index of suspicion is warranted when evaluating thyroid nodules in CCRCC patients. There was no significant difference in outcome between patients who underwent surgery and those who did not. With the wider use of immune check-point and tyrosine kinase inhibitors in metastatic CCRCC, surgery may eventually be reserved only for palliative purposes.