bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of lymphocyte to monocyte ratio in resected small bowel adenocarcinoma as a predictor of survival.
Authors: Huffman Brandon M. , Jin Zhaohui , Yadav Siddhartha , Patel Shruti , Mahipal Amit , Halfdanarson Thorvardur Ragnar
Published: May 2019

e15799

Background: Lymphocyte to monocyte ratio (LMR) has been described as a prognostic factor in many solid tumors including colorectal adenocarcinoma. LMR has not been investigated as a prognostic factor in small bowel cancers. In this study, we aimed to evaluate prognostic factors in resected small bowel adenocarcinoma including LMR. Methods: Two hundred forty-one patients who underwent resection for stage I-III small bowel adenocarcinoma were retrospectively identified utilizing the pathology database at a single tertiary referral institution from 1994 to 2015. All patients had complete follow up data and were included in the survival analysis. One hundred sixty-nine patients had preoperative peripheral blood counts available for analysis. Plot of martingale residuals against LMR were used to establish best cutoff points for LMR. A training set for LMR included consecutively identified patients from 2006 to 2015, and a validation cohort including patients identified from 1994 to 2005 was used. Overall survival was performed utilizing Kaplan-Meier method, and Wilcoxon tests were used for statistical comparisons. Cox proportional hazards were performed and all tests were two sided. P value of < 0.05 was considered significant. Results: Median overall survival for the entire group was 54.5 months (95% CI: 37.2-81.2 months) with 5- and 10-year overall survival of 48% and 35%. The training set for LMR included 81 patients, and the validation set included 88 patients. The cutoff of 1.56 was chosen based on most significant p value (p = 0.002). When combined, the overall area under the curve (AUC) for LMR was 0.63, p < 0.01, (specificity 37.3%, sensitivity 90.1%, positive predictive value 33.1%, and negative predictive value 92.2%). There were 126 patients with LMR > 1.56 and 43 patients with LMR < 1.56 in the entire cohort. In multivariate analysis, LMR under 1.56 was a negative prognostic factor, HR = 2.20 (95% CI: 1.27-3.84, p < 0.01). In addition to LMR, age > 60 years and advanced T stage were independently negative predictors of overall survival in all patients. Conclusions: Lymphocyte-to-monocyte ratio < 1.56 is a validated negative prognostic factor in resected small bowel adenocarcinoma.
Validation of an artificial intelligence algorithm applied to a metabolic substrate analysis of urine for detection of urothelial cancer.
Authors: Kaludov Nikola , Siddiqui Mohummad Minhaj , Kates Max , Tripathi Hemantkumar , Salma Amatul Nasir , Lotan Yair , Steinberg Gary D.
Published: May 2019

e16008

Background: Urine tests such as urine cytology are commonly used for the diagnosis and monitoring of urothelial cancer. These tests are often limited by issues related to sensitivity or specificity. It is well known that derangement of cellular metabolism is one of the hallmarks of carcinogenesis. As urothelial cancer is in constant contact with urine, we hypothesize that metabolite composition in the urine may provide insight into possible urothelial cancer presence in the urinary tract. In this study, we evaluated a metabolomics based urine test for the detection of urothelial cancer. Methods: In this prospective, multi-institutional IRB approved study, urine samples were collected from a total of 57 urothelial cancer patients and non-urothelial cancer controls. Gas chromatography profiles of urine small molecule metabolites were generated to yield over 2400 data points of metabolite peaks and troughs for every urine sample. A machine-learning based algorithm (Abilis Life Sciences) was constructed to predict urothelial cancer versus non-cancer controls through analysis of peaks and trough patterns of urine metabolomics profiles. Predictions were made in a blinded fashion and descriptive statistics of test sensitivity and specificity were generated. Results: The urine metabolite composition of 57 patients were analyzed and urothelial cancer predictions were generated. The test demonstrated an overall accuracy of 89.5% (51 out of 57 cases correctly predicted). The sensitivity of the test was 97.1% (34 out of 35) and specificity was 77.3% (17 out of 22). The Positive Predictive Value is 87.2%, while the Negative Predictive Value is 94.4%. The area under the curve for the receiver operating characteristic curve was 0.87. Conclusions: Urine based metabolic profile analysis using artificial intelligence algorithms is a promising potential diagnostic test for detection of urothelial cancer. Further testing is ongoing to increase robustness of the validation.
Assessment of treatment patterns of nonmuscle invasive bladder cancer patients in privately insured patients.
Authors: Tyson Mark , Guo Amy , Rotter David , Papademetriou Eros , Spigelman Samuel , Potluri Ravi C.
Published: May 2019

e16012

Background: 75–85% of bladder cancer patients present with non-muscle invasive disease (NMIBC). While transurethral resection of bladder tumors (TURBT) is the initial standard treatment for visible lesions, there is variation in the utilization of adjuvant intravesical treatments in the real world. This study aims to assess current treatment patterns in privately insured NMIBC patients. Methods: Bladder cancer patients were identified from Truven MarketScan Commercial and Medicare Supplemental databases using ICD-9/ICD-10 codes. In the absence of tumor staging information, patients were considered to have NMIBC based on diagnosis of CIS or an algorithm centered on the use of TURBT, intravesical treatments and absence of immediate progression to muscle invasive disease. Patients were included in the final cohort if they had one year of continuous insurance coverage prior to index diagnosis, and were without any bladder cancer treatment during this period. Results: 18,683 patients met the eligibility criteria and had a median follow-up of 23 months; the mean age was 68.6 years and 75% were male. The median time from diagnosis to TURBT was 8 days. 54% of the cohort had an intravesical treatment (35% specifically with Bacillus Calmette–Guérin (BCG), with median time from TURBT of 69 days). 77% of BCG-treated patients received 5 or more administrations during induction. However, only 22% of patients received maintenance BCG after induction. 16% of the total cohort developed a recurrence or progression during the available follow-up; five percent underwent a cystectomy, while seven percent were diagnosed with metastatic disease. Only 4% of patients with 5 or more BCG administrations during induction met the definition for being BCG-unresponsive; this is influenced by the low adherence to BCG maintenance protocol. Conclusions: Only a third of NMIBC patients are given intravesical BCG treatment. Adherence to BCG maintenance protocols is suboptimal. Rates of cystectomy/ exenteration are low, suggesting patients’ preference of bladder preservation and the unmet need for new bladder-sparing alternatives.
Association of early bone metastases and outcomes of the bone predominant metastatic urothelial carcinoma (BP mUC) phenotype.
Authors: Nelson Ariel Ann , Wright Matthew David , Khaki Ali Raza , Diamantopoulos Leonidas Nikolaos , Kyasaram Ravi Kumar , Nezami Behtash , Dawsey Scott , Patel Krupen , Eitman Cheryl , MacLennan Gregory , Grivas Petros , Mendiratta Prateek , Ponsky Lee Evan , Hoimes Christopher J.
Published: May 2019

e16016

Background: Prior analyses demonstrated worse outcomes with the BP mUC clinical phenotype. UC molecular subtypes that may correlate with the BP phenotype have been defined, however molecular subtyping is not a readily available standard practice. We hypothesized that BP mUC has worse prognosis vs. non-BP (NBP) mUC and evaluated patient (pt) characteristics associated with the mUC subtype, responses and outcomes. Methods: We searched the electronic medical record (EMR) to identify pts with mUC who received systemic therapy in the metastatic setting. Demographic, clinicopathologic, treatment (trt), response, progression-free survival (PFS), overall survival (OS ) from start of first line trt. Imaging was reviewed to identify NBP or BP disease. Logistic regression, Cox proportional-hazards and Kaplan-Meier analyses were performed. Results: 149 mUC pts were identified (64% male, 68% smokers ), median age at 1st line trt was 68 years. 70% had de-novo mets, 46% to lung and 27% to liver. 22% of pts were BP, of these, 36% were de-novo metastatic. In non- de-novo metastatic pts (70% of pts), first progression of disease to bone was associated with development of the BP phenotype (OR = 30.46, 95% CI 6.37 to 145.61; p < 0.0001). BP pts had higher rate of death (HR = 2.28, 95% CI 1.45 to 3.58, p = 0.0004), shorter PFS from 1st line trt, (11.7 vs 14.9 weeks, p = 0.032) as well as shorter OS from 1st line trt (24.6 vs 56.6 weeks, p = 0.002) compared to NBP pts. There was no difference in PFS between BP and NBP groups for pts treated with 1st line platinum-based chemotherapy (11.8 vs 18.3 weeks, p = 0.091) or for BP pts treated with 1st line immunotherapy vs platinum-based chemotherapy (11.71 vs 11.86 weeks, p = 0.135). Conclusions: Early bone metastases are associated with the development of the BP metastatic phenotype. BP pts have worse PFS and OS from 1st line trt compared to NBP pts. PFS remains poor when BP pts are treated with either platinum-based chemotherapy or immunotherapy in the first line setting. Imaging to determine the presence of bone metastases may routinely be pursued and careful attention paid on follow up imaging. Clinical trials and prospective registries focusing on efficacy endpoints for BP mUC are needed.
Genomic landscape of circulating tumor (ct)-DNA alterations in patients with penile cancer.
Authors: Agarwal Archana , Nassar Amin , Nagy Rebecca , Curran Catherine , Abou Alaiwi Sarah , McGregor Bradley Alexander , Talasaz AmirAli , Lanman Richard B. , Sonpavde Guru
Published: May 2019

e16027

Background: Penile cancer is a rare disease associated with HPV infection and is known to harbor recurrent somatic genomic alterations in the ERBB (HER)-family, CDKN2A, TP53, NOTCH1 and PIK3CA. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. To our knowledge, the genomic alterations observed in ctDNA for penile cancer have not been described before. We report ctDNA profiling of patients with advanced penile cancer. Methods: Sixteen pts with metastatic penile cancer from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Three patients had at least one serial ctDNA sample. De-identified demographic data were collected. Guardant 360 is CLIA-certified ctDNA panel that assesses single nucleotide variants and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants seen at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or reported in OncoKB were considered pathogenic. Results: The median age was 64 years (range 40-77). 4 pts (25%) were documented to be post platinum-based chemotherapy. The median number of ctDNA alterations detected per sample was 2 (range 0-6). Overall, genomic alterations were detected in 15/16 patients (94%) across 21 genes (table 1). Alterations were most frequently detected in TP53 (9/16, 56%), CDKN2A (5/16, 31%), TERT promoter (5/16, 31%), PIK3CA (3/16, 19%) and ERBB2 (3/16, 19%). In 3 patients with serial samples, 9 novel pathogenic alterations were detected in the second sample including ATM, CDKN2A, ARID1A, CCND1, CDK6, EGFR, PDGFRA, PIK3CA, and SMAD4. Conclusions: ctDNA alterations in patients with advanced penile cancer were frequently detected with similar prevalences to previously described tumor tissue analyses. New alterations observed on serial ctDNA assays may provide insights regarding tumor biology and inform drug development. [Table: see text]
Association of immune gene expression profiling with vinflunine clinical benefit in metastatic urothelial cancer (mUC).
Authors: de Velasco Guillermo , Dueñas Marta , Bernardini Alejandra , Pinto Alvaro , Alonso-Gordoa Teresa , Puente Javier , González-Peramato María Pilar , Paramio Jesus , Castellano Daniel E.
Published: May 2019

e16034

Background: There are limited treatment options for mUC after platinum-based chemotherapy failure. Immune checkpoint inhibitors (ICI) have shown a durable benefit but only in a minority of patients (20-25%). Vinflunine remains as a therapeutic option without validated biomarkers. In this study, we sought to analyze the molecular determinants of vinflunine response in mUC. Methods: mUC patients from 4 University Hospitals in Spain who received second-line vinflunine after platinum-based chemotherapy were classified in non-responders (NR: progressive disease ≤3 months; N = 10) or responders (R: response ≥ 6 months, N = 14). Targeted- sequencing of 275 cancer-related genes and a PanCancer Immune Profiling Panel were performed on pre-treatment tumors. Selected genes were evaluated by RT-qPCR and protein expression was detected by immunohistochemistry. Results: The most common alteration, TP53 mutations, had a similar frequency in R (7/14, 50%) and NR (4/10, 40%). Mutations in 5 genes: ERBB3 (4/14; 28,6%), KTM2C (4/14; 28,6%), PI3KCA (4/14; 28,6%), ARID2 (3/14; 21,4%) and FGFR3 (3/14; 21,4%) were identified only in R. Mutations in ERBB4 (3/10, 33,3%) and BCOR (2/10, 20%) were identified only in NR. Estimated TMBs were not significantly different among the R (13 per Mb) and NR (9 per Mb) samples. According to gene expression profiling, NR had high cytotoxic cells infiltrate and T cells as well as high counts of TILs compared to R. In addition, expression of IDO, MAGE A4, and SOCS1, that has been associated with response to ICIs, were down-regulated in R compared with NR. Conclusions: Gene profiling showed that low-expression levels of immune-related genes are significantly associated with clinical benefit from vinflunine. Validation and complementary studies are ongoing in patients treated with ICIs.
Neoadjuvant chemotherapy for muscle-invasive bladder cancer: Dana-Farber Cancer Institute (DFCI) experience.
Authors: Curran Catherine , Agarwal Archana , Nassar Amin , Abou Alaiwi Sarah , Kumar Vivek , Mossanen Matthew , Preston Mark A. , Steele Graeme , McGregor Bradley Alexander , Kilbridge Kerry L. , Sonpavde Guru
Published: May 2019

e16037

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) extends overall survival in muscle invasive bladder cancer (MIBC) patients (pts) and pathologic complete response (pCR) is associated with improved survival. We conducted a retrospective study at DFCI to examine the impact of different chemotherapy regimens and renal function on pCR and tolerability. Methods: Pts who underwent RC for MIBC were retrospectively studied. Descriptive statistics were calculated, and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic effect of candidate factors (age, gender, chemotherapy regimen, creatinine clearance [Cr Cl] by Cockroft Gault formula) on pCR (ypT0), < ypT2N0 rate and early discontinuation for toxicities. Results: 196 patients treated with NAC were identified from 2002 -2018 (Table). Unconventional regimens (split dose cisplatin or carboplatin combined with gemcitabine) exhibited lower pCR rate (14%), but a moderate < ypT2N0 rate (36%). Among those receiving conventional cisplatin-based regimens, we did not identify an association between renal function (Cr Cl < 60 vs. ≥60 ml/min), age, gender and specific regimen (Cisplatin/Gemcitabine, MVAC, ddMVAC) with pCR or early discontinuation ( < 4 cycles) for toxicities, although the < ypT2N0 rate was numerically higher for MVAC/ddMVAC. The modest size of this cohort limited the analysis. Conclusions: pCR rates were similar with ddMVAC/MVAC and GC for MIBC, with potential superiority of MVAC/ddMVAC to GC for a subset of pts. If Cr Cl ≥50 ml/min, it may be reasonable to consider conventional cisplatin therapies as non-conventional NAC appeared to yield lower depth of benefit emphasizing need for evaluation of new tolerable regimens. [Table: see text]
Impact of facility patient volume on overall survival in patients with muscle invasive bladder cancer undergoing trimodality bladder preservation therapy.
Authors: Fischer-Valuck Benjamin Walker , Rudra Soumon , Gabani Prashant , Mueller Ryan , Gay Hiram Alberto , Michalski Jeff M. , Abraham Christopher , Baumann Brian Christopher
Published: May 2019

e16039

Background: There is an association between higher hospital and urologist case volume and improved survival outcomes for patients with bladder cancer. Limited data on facility volume and outcomes exists following trimodality bladder preservation with TURBT followed definitive chemoradiation (CRT). Methods: The National Cancer Database was queried for patients from 2004-2013 with urothelial bladder cancer (cT2-4aN0M0) receiving definitive CRT after TURBT. High-volume bladder preservation case volume (BPCV) was defined as facilities in the > 70th percentile of trimodality bladder preservation cases per ten years examined. We compared OS between high- and low-BPCV using Cox proportional hazard models. CRT was defined as > = 5040cGy pelvic RT with chemotherapy given within 21 days. Propensity matching was performed to match high- and low-volume centers. Results: A total of 666 treatment facilities treating 1,635 patients with bladder preservation were identified with a median follow-up of 26 months (range 2-136 months). A 70th percentile cutoff identified 497 patients that received treatment at 64 high-volume facilities. Median OS of patients treated at high BPCV centers was 37.0 months (95% CI, 27.9-33.6) versus 32.3 months (95% CI, 27.3-46.7) for patients treated at low BPCV centers (P = 0.004). High BPCV facilities were independently associated with a decreased hazard of death (HR, 0.86, 95% CI, 0.75-0.98; P = 0.031). When BPCV was analyzed as a continuous variable, an increasing number of bladder preservation cases per institute was also independently associated with improved OS (HR: 0.98, 95% CI, 0.97-0.99; P = 0.044). In the propensity score matched cohort, median OS of patients treated at high BPCV was 36.1 months (95% CI, 26.5-45.8) versus 28.1 months (95% CI, 23.9-32.3) for patients treated at a low BPCV facility (P = 0.016). Conclusions: In this observational cohort, treatment at a high BPCV facility was associated with improved OS. Causal factors for this finding may include greater institutional expertise in multidisciplinary bladder cancer care and potential advantages in treatment technology.
Phase II study of avelumab in multiple relapsed/refractory testicular germ cell cancer.
Authors: Mego Michal , Svetlovska Daniela , Chovanec Michal , Rejlekova Katarina , Obertova Jana , Palacka Patrik , Sycova-Mila Zuzana , De Giorgi Ugo , Mardiak Jozef
Published: May 2019

e16045

Background: Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. PD-L1 expression is significantly higher in germ cell tumors (GCTs) in comparison to normal testicular tissue and high PD-L1 expression is associated with inferior progression-free and overall survival compared to patients with low PD-L1 expression. This study aimed to determine the efficacy and toxicity of PD-L1 antagonist, Avelumab, in patients with refractory GCTs. Methods: From November 2017 to January 2018, 8 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies (median 5, range 2 – 6); 5 tumors (62.5%) were absolutely refractory to cisplatin and 5 patients (62.5%) had visceral non-pulmonary metastases. Avelumab was administered at a dose of 10mg/kg biweekly until progression or unacceptable toxicity. The primary end point was 12-weeks progression-free survival (PFS). If < 8 responses to study therapy will be observed among the first 15 patients, the study will be terminated. Results: Median age was 29 years (range: 22 – 52 years). During a median follow-up period of 2.6 months (range: 0.3 - 14.4), 7 (87.5%) patients experienced disease progression and 6 patients (80.0%) died. Twelve-week PFS was 0%, median PFS was 1.4 months, 95%CI (0.9 – 1.4) and median OS was 2.7 months, 95% CI (1.0 – 3.3). No objective response was observed. Avelumab was well tolerated, no severe adverse event was observed. Conclusions: This study failed to achieve its primary end point and our data suggest lack of Avelumab efficacy in unselected multiple relapsed/refractory TGCTs. Clinical trial information: NCT03403777.
Impact of rural/urban residence on relative survival (RS) in patients with kidney cancer: An analysis of 14576 patients from the Austrian National Cancer Registry (ANCR).
Authors: Marszalek Martin , Karim-Kos Henrike E , Madersbacher Stephan , Rauchenwald Michael , Hackl Monika
Published: May 2019

e16072

Background: Access to medical diagnostics and treatment might be limited for patients living in rural areas compared to urban residents. To evaluate the potential impact of urban/rural residence, we analyzed trends in RS for patients diagnosed with kidney cancer between 1998 and 2015 in Austria. Methods: All patients with kidney cancer aged ≥18 years, diagnosed between 1998 and 2015 were derived from the ANCR (N = 22,041). Patients were categorized into two groups: rural (N = 7,53) and urban (N = 10,552) based on a complex algorithm considering infrastructure, commuter interrelations, accessibility of centers and tourism at the time of diagnosis. Relative survival was calculated based on complete follow-up until December 31st, 2016. Poisson regression modeling was used to evaluate survival differences between the two groups and to calculate the relative excess risk of dying (RER). Analyses were performed for the total patient population and primary metastatic patients (M+, N = 2,490). Results: Distribution of age and surgical treatment did not differ between rural and urban patients. Five-year RS was 75% for rural patients compared to 73% for urban patients (RER for rural: 0.85, 95%CI 0.80-0.91). In M+ patients, 5-year RS was 14% for urban patients and 15% for rural patients (p = .02) Multivariate analysis showed that residence remained as an independent predictor for survival in the overall kidney cancer population (RER of rural patients 0.84, 95%CI 0.78-0.89). For M+ patients the RER of rural patients was 0.86 ( 95%CI 0.79-0.94) compared to urban M+ patients. For patients without surgery, rural patients were even stronger benefited in their survival than urban patients (overall population: RER 0.77, 95% CI 0.71-0.83; M+ patients: RER 0.81, 95%CI 0.72-0.91) wherereas in surgical patients RS did not differ between rural and urban patients. Conclusions: An advantage in RS was observed for kidney cancer patients living in rural areas. This advantage was evident in metastatic and non-metastatic patients, especially in patients who did not undergo surgery for (metastatic) kidney cancer. These results suggest that access to medical health care for kidney cancer patients in Austria is not limited by rural residence.
Real-world outcome study among patients with renal cell carcinoma (RCC) receiving checkpoint inhibitors (CPIs).
Authors: Phatak Hemant , Kim Ruth , Yu Ting , Dreyfus Jill , Gayle Julie A. , Wassel Christina L. , Krulewicz Stan , Zheng Ying
Published: May 2019

e16073

Background: North America has one of the highest rates of RCC, and in 2018, 65,340 new cases were diagnosed in the US alone. Tyrosine kinase inhibitors have been a mainstay treatment for RCC. However, the first CPI, nivolumab, was approved by the FDA as a second-line treatment for RCC in late 2015 and as a first-line therapy in combination with ipilimumab in 2018. In this study, real-world outcomes in patients with RCC receiving CPIs were examined. Methods: An observational study was conducted from March 1, 2015, to December 31, 2017, using the Premier Healthcare Database, a hospital discharge database. Patients with RCC aged ≥18 years were identified by ICD-9/10 codes and were included if they received a CPI during the study period, irrespective of treatment line. Comorbidities were assessed in a 6-month look-back period commencing at the time of first CPI treatment and RCC diagnosis. 34 distinct immune-related adverse events (irAEs) were identified in a 90-day look-back period from time of the irAE to determine if patients had received a CPI during that time. Patients were followed for 90 days after the irAE to determine if CPI treatment was reinitiated. Results: During the study period, 1228 patients with RCC received a CPI, of whom 719 (59%) had ≥1 irAE. Approximately 95% of patients received nivolumab and the remaining 5% received an off-label CPI. At the time of initial CPI treatment, patients who experienced any irAE during the study period had a higher Charlson Comorbidity Index (5.1±3.2 vs 4.2±3.0; p < 0.001) and were more likely to be hospitalized on an emergent basis than those without an irAE (9.0% vs 5.1%; p = 0.005). Patients with an irAE also had a higher average number of previous immune-related or immunocompromised comorbid conditions (0.33±0.57 vs 0.12±0.36; p < 0.001). After experiencing an irAE, 65% of patients reinitiated a CPI within 90 days. Conclusions: The majority of RCC patients receiving a CPI, mostly anti-PD-1 agents, experienced an irAE, and patients with irAEs had a higher comorbidity burden than those without irAEs. Most patients with irAEs reinitiated CPI treatment within 90 days.
Efficacy and safety of approved first-line tyrosine kinase inhibitor (TKI) treatment in patients with metastatic renal cell carcinoma (mRCC): A network meta-analysis based on phase II/III randomised clinical trials (RCTs).
Authors: Manz Kirsi , Fenchel Klaus , Eilers Andreas , Morgan Jon , Wittling Kirsten , Dempke Wolfram CM
Published: May 2019

e16074

Background: During the last decade several novel treatment options including TKIs and immune checkpoint inhibitors have been developed for the treatment of mRCC patients. However, results from direct comparisons (head-to-head RCTs) to determine the optimal treatment are lacking for most of these agents. In this network meta-analysis we attempted to indirectly compare efficacy and safety of first-line TKIs in patients with mRCC. Methods: PubMed, Embase, Medline, the Cochrane Central Register of Controlled Trials were searched (English language only). Abstracts of conferences of relevant medical societies were also included from database inception (January 1, 2007) to January 15, 2019. A systematic manual search (including data requests from the publication authors) was also performed. For the purpose of this network meta-analysis only phase II/III RCTs assessing approved first-line TKI therapy for mRCC were analysed. The analysis was done using the software R with the netmeta package. Progression-free survival (PFS) was the primary endpoint; grade 3 and 4 adverse events (AEs) were secondary endpoints. Results: A database search identified 12 studies meeting the eligibility criteria reporting on 4,460 patients. For PFS cabozantinib and sunitinib were found to be superior to sorafenib, however, when compared to tivozanib, PFS did not significantly differ between the TKIs. Furthermore, tivozanib was found to have the highest probability of being the safest drug as first-line treatment in terms of grade 3 and 4 AEs (ranking safety, p score 0.9344). Conclusions: No significant PFS differences for all TKIs currently used for first-line treatment of mRCC have been found when compared with tivozanib. Compared with all approved TKIs tivozanib appears to be the best choice for first-line treatment of these patients because it has demonstrated the most favourable safety profile. These results may provide guidance to oncologists when making treatment decisions for mRCC patients.
The impact of gastric acid suppressive agents on pazopanib exposure.
Authors: Lubberman Floor , Gelderblom Hans , Hamberg Paul , Vervenne Walter , Van Herpen Carla M.L.- , Van Erp Nielka P.
Published: May 2019

e16076

Background: Pazopanib has been registered for advanced soft tissue sarcoma (STS) and metastatic renal cell carcinoma (mRCC). The uptake of pazopanib is 40% reduced when a proton pump inhibitor is concomitantly used. Nevertheless, still a large group of cancer patients need a form of gastric acid suppressive agents (GAS, e.g. proton pump inhibitors or H2-anagonists) due to gastrointestinal adverse events. Recently, it was demonstrated that the use of pazopanib with GAS resulted in shorter overall survival and progression free survival in patients with STS. In order to limit the effect of GAS on pazopanib absorption, the advice is to take the GAS 1 hour after pazopanib. In that way the pazopanib is dosed at the lowest gastric pH value. However, the effect of this most optimal controlled intake on pazopanib absorption is unknown. Therefore, we investigated whether this controlled intake algorithm affects pazopanib exposure. Methods: In the DIET study, pazopanib trough concentrations (Ctrough) were measured at predefined moments. In this study a total of 80 patients with mRCC and STS were included. The concomitant use of GAS was recorded and taken according the intake algorithm. Patients were subdivided into two groups (with GAS or without GAS). Results: Of the 80 patients, 22 patients were treated with pazopanib in combination with GAS. In patients treated with pazopanib without GAS the geometric mean(GM) pazopanib Ctrough level was 29.1 mg/L (95% CI 26.4 -31.8) compared to 22.4 mg/L (95% CI 18.0-27.8) (p = 0.01) in those treated with GAS. Conclusions: Patient who use pazopanib with controlled intake of GAS had a 23% lower pazopanib exposure. Therefore, we advice that in patients, who are unable to quit their GAS agent, pazopanib trough concentrations should be monitored in order to prevent shorter treatment benefit. Clinical trial information: NCT02138526.
Characterization of tumor mutational burden (TMB), PD-L1, and DNA repair genes to assess correlation with immune checkpoint inhibitors (ICIs) response in metastatic renal cell carcinoma (mRCC).
Authors: Labriola Matthew , Zhu Jason , Gupta Rajan , McCall Shannon , Jackson Jennifer , White James R , Weingartner Elizabeth , Kong Eric , Simone Peter , Papp Eniko , Gerding Kelly , Simmons John , George Daniel J. , Zhang Tian
Published: May 2019

e16079

Background: ICIs have revolutionized treatment for mRCC; however there are limited predictive biomarkers for response to ICIs. PD-L1 status is still controversial, demonstrating little predictive utility in mRCC. TMB is predictive for response to ICIs in melanoma and non-small cell lung cancer (NSCLC), but has not been validated in mRCC. Here, we assess the correlations between TMB and PD-L1 status with outcomes to ICI treatment in mRCC. Methods: 34 patients (pts) with mRCC who had previously received ICIs at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated using a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. PD-L1 status was tested via the Dako 28-8 PD-L1 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated based on RECIST criteria. Results: Pts were grouped by overall response following ICI therapy into either progressive disease (“PD”, n = 18) or disease control group (“DC”, n = 16), defined as either stable disease, partial response, or complete response. Pts displayed a TMB range from 0.36 to 12.24 mutations/Mb with a mean score of 2.83 muts/Mb, with no significant difference between the PD and DC groups (mean 3.01 muts/Mb vs. 2.63 muts/Mb, p > 0.05). 9 of 32 evaluable samples were PD-L1 positive, with 4 in the PD group and 5 in the DC group. Notably, the DC group displayed a significant enrichment of mutations in genes affiliated with DNA repair (including BRCA1, BRCA2, FANCA, FANCB, FANCG, FANCM, MSH3, MSH6, RAD50, RAD51C, RAD51D, RAD54B, RECQL4, and SLX4; p = 0.0444). DNA damage gene mutations were found in 8/10 (80%) metastatic tumor specimens and 14/24 (58%) primary tumors. Conclusions: Overall, in this mRCC cohort, neither TMB nor PD-L1 correlated with patient outcomes or with ICI response. Furthermore, high TMB was not significantly associated with PD-L1 expression within the samples. The higher frequency of mutations in DNA repair genes in the DC group suggests potential use as a predictive signature for ICI response, warranting future prospective studies. Further studies with matched primary-metastatic samples would be beneficial to determine if DNA repair mutations occur more frequently in metastatic versus primary tumor specimens.
Clinical activity of ipilimumab plus nivolumab (Ipi/Nivo) in patients (pts) with metastatic non-clear cell renal cell carcinoma (nccRCC).
Authors: Gupta Ruby , Ornstein Moshe Chaim , Gul Anita , Allman Kimberly D , Ball Jessica , Wood Laura S. , Garcia Jorge A. , VonMerveldt Dendra , Hammers Hans J. , Rini Brian I.
Published: May 2019

e16084

Background: Ipi/Nivo is a standard of care for pts with metastatic clear cell RCC. The clinical activity of Ipi/Nivo in patients with metastatic nccRCC remains poorly defined. Methods: Metastatic nccRCC pts who were treated with Ipi/Nivo at Cleveland Clinic or UT Southwestern were retrospectively reviewed. Ipi/Nivo was administered as per CHECKMATE 214. Computed tomography imaging was obtained at baseline and every 12 weeks to assess disease response per RECIST 1.1 criteria. Baseline pt characteristics, outcome to therapy and adverse effects as per CTCAE v5.0 were collected. Results: Eighteen pts with metastatic nccRCC histology who were treated with Ipi/Nivo were identified. The median age was 60 years (range, 32-81). Non clear cell histologies included adenocarcinoma of renal origin not otherwise specified (2), unclassified (3), papillary (6), chromophobe (5), translocation (1) and medullary histology (1). ECOG PS was 0 (7 pts); 1 (9 pts) and 2 (2 pts). Fourteen patients were male and four female. IMDC risk group at the time of initiation of Ipi/Nivo was favorable (2 pts), intermediate (14 pts) and poor (2 pt). Fourteen pts received Ipi/ Nivo as first line treatment, two pts received Ipi/Nivo after prior TKI and two pts received Ipi/ Nivo as third line treatment after prior chemotherapy and nivolumab monotherapy. In total, fourteen pts had restaging scans with four pts demonstrating partial response (PR 28%), two with stable disease (SD 14%) and eight with progressive disease (PD 58%). Four pts died (22%) – three from the disease and one from treatment related complication (encephalitis).Four pts experienced diarrhea- three pts (grade 2) and one pt ( grade 3) , three developed hepatotoxicity- one pt (grade 2) and two pts (grade 3), one pt each developed hypophysitis (grade 3), fatigue (grade 2) , rash (grade 2) and encephalitis (grade 3). All 100% pts required steroids, one each got infliximab and Mycophenolate Mofetil. . All 100% pts required steroids, one each got infliximab and Mycophenolate Mofetil. Conclusions: Ipi/Nivo is feasible and safe in patients with metastatic nccRCC with preliminary evidence of anti-tumor activity
Efficacy of receptor tyrosine kinase inhibitors (RTKIs) and immunotherapy (PD-1/PD-L1) for treatment of osseous vs. soft tissue metastases of renal cell carcinoma (RCC).
Authors: Tai Katherine Yuxi , El Abiad Jad , Morris Carol , Levin Adam , Markowski Mark Christopher
Published: May 2019

e16094

Background: Checkpoint inhibitors and RTKIs have changed the standard of care in metastatic RCC. However, anecdotal evidence suggests these therapies may be less effective for treating bone metastases than soft tissue metastases. Our study aimed to evaluate this potential difference in treatment response between osseous and visceral metastases. Methods: Our institutional Cancer Registry database was queried for RCC patients treated at Johns Hopkins Hospital from 1997-2017 (n = 2212). 68 patients were identified with measurable bone and soft tissue metastatic disease who were treated with RTKIs and/or PD-1 inhibitors over the study period. The extent of metastasis was quantified at the time of therapy initiation, 3 mos., 6 mos., and 1 yr. Changes in disease status from baseline were categorized as partial response (PR), complete response (CR), stable (S), mixed (M) or progressive disease (PD) based upon RECISTv1.1 and MDA criteria for soft tissue and bone metastases, respectively. These categories were further organized into Controlled Disease (PR, CR, S) or Evidence of Progression (M, PD) in order to generate a generalized linear effects model with visceral response as the independent variable and bone response as the dependent. Results: Visceral response correlates with bone response at 3 (p = 0.005, n = 76) and 6 months (p = 0.017, n = 48). At 3 mos. 46 patients were treated with RTKI and 30 with PD-1. At 6 mos. 31 patients were treated with RTKI and 17 with PD-1. Of patients with controlled visceral disease, only 19% had progression in bone at 3 mos. (32% at 6 mos.). Of patients with progression in soft tissue, 42% had controlled bone disease at 3 mos. (41% at 6 mos.). Conclusions: This suggests that, contrary to anecdotal reports of a divergent response to biologic therapy, osseous metastases do not appear to respond worse than soft tissue metastases upon treatment with these agents. [Table: see text]
Leveraging a robust patient-derived xenograft platform to characterize predictors for engraftment and oncologic outcomes in renal cell carcinoma patients.
Authors: Singla Nirmish , Woolford Layton , Stevens Christina , Tcheuyap Vanina , Onabolu Oreoluwa , Xie Zhiqun , McKay Renee , Wang Tao , Christie Alana , Gahan Jeffrey , Bagrodia Aditya , Raj Ganesh , Sagalowsky Arthur I. , Lotan Yair , Cadeddu Jeffrey A , Margulis Vitaly , Kapur Payal , Brugarolas James
Published: May 2019

e16100

Background: Patient-derived xenograft (PDX) models of renal cell carcinoma (RCC) preserve the biological features of patient tumors, providing a platform for biomarker identification and preclinical drug testing. We sought to identify predictors of successful tumor engraftment and evaluate the prognostic value of engraftment in patients with RCC using a robust murine PDX platform. Methods: 1,200 specimens derived from nephrectomy, thrombectomy, metastasectomy, or biopsy were orthotopically (renally) implanted into NOD/SCID mice between 2008-2018. Non-RCC pathology was excluded. Stable engraftment was defined by successful passage of tumor tissue at least twice with histologic confirmation. Clinicopathologic characteristics were stratified by engraftment status, and multivariate (MVA) logistic regression was used to identify predictors of engraftment. Kaplan-Meier and Cox regression analyses were used to assess the prognostic value of engraftment on patient overall (OS) and disease-free (DFS) survival. Results: 1,003 independent PDX lines derived from 770 RCC patients were included. 157 (15.6%) lines successfully engrafted and exhibited higher tumor grade, stage, size, and presence of sarcomatoid or rhabdoid components. 79.3% of all tumors were of clear cell histology, and histologic distribution did not vary by engraftment status. We have completed whole exome sequencing and RNAseq on 197 and 213 PDX lines, respectively, and downstream analyses will be reported. On MVA, sarcomatoid (OR 5.71, p < 0.001), rhabdoid (OR 2.79, p = 0.046), and advanced stage (OR 1.72, p = 0.049) were significant predictors for engraftment, while high grade and metastatic tumor source were significant only on UVA. Engraftment was associated with poor OS (HR 2.11, p < 0.001) and DFS (HR 1.85, p = 0.020) in patients after controlling for sarcomatoid, rhabdoid, grade, stage, and age on MVA. Conclusions: Aggressive RCC biology correlates with successful engraftment in PDX models. Engraftment remains independently predictive of OS and DFS even after controlling for adverse pathologic features. Engraftment in mice may illuminate aspects of tumor biology not captured by clinicopathologic variables and provide insight into novel determinants of tumor aggressiveness and metastasis.
Pathologic response and surgical outcomes in patients undergoing nephrectomy after receipt of immune checkpoint inhibitors for renal cell carcinoma.
Authors: Margulis Vitaly , Singla Nirmish , Elias Roy , Ghandour Rashed , Freifeld Yuval N , Bowman I. Alex , Woldu Solomon L. , Gahan Jeffrey , Bagrodia Aditya , Brugarolas James , Hammers Hans J.
Published: May 2019

e16102

Background: With the approval of immune checkpoint inhibitors (ICI) for metastatic renal cell carcinoma (RCC), the role, timing, and safety of surgically excising the primary tumor remain unclear. We sought to evaluate the safety and feasibility of nephrectomy following receipt of ICI for RCC. Methods: We reviewed our experience of RCC patients who underwent nephrectomy from 2016-2018 following exposure to nivolumab or combination ipilimumab/nivolumab. Demographics, IMDC risk score, and pathology were collected. Surgical outcomes including operative time (OT), estimated blood loss (EBL), hospital length of stay (LOS), readmission rates, and 30- and 90-day complication rates were analyzed using descriptive statistics. Results: 11 nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. 6 patients received 1-4 cycles of ipilimumab/nivolumab, while 5 received 2-12 infusions of nivolumab preoperatively. One patient with non-metastatic, synchronous bilateral renal masses underwent staged left radical nephrectomy and right partial nephrectomy. 5 surgeries were performed laparoscopically, and 4 patients underwent thrombectomy. IMDC score for metastatic patients was intermediate (7/9) or poor (2/9). One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 mL, and 4 days, respectively. Four patients experienced any complication, including 3 that were addressed with a single interventional radiology procedure. One patient died of progressive disease > 3 months after surgery, and one patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients. Conclusions: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. As multimodal management in the era of ICI continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants attention.
Overall survival with or without brain metastases from diagnosis of metastatic renal cell carcinoma.
Authors: Bowman I. Alex , Christie Alana , Le Tri Cao , Bent Alisha , Brugarolas James
Published: May 2019

e16112

Background: Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have historically been associated with a poor prognosis. We have previously reported improved outcomes for RCC patients diagnosed with brain metastases prior to or during 1st line systemic therapy among patients treated with modern systemic and local therapies. Here we report outcomes in all mRCC patients regardless of the timing of BM diagnosis. Methods: A retrospective database of mRCC patients treated at our institution between 2006 and 2015 was compiled and patients with BM identified. Overall survival (OS) was analyzed by the Kaplan-Meier method from the diagnosis of metastatic RCC, according to BM status and by IMDC risk group. Results: 271 patients with mRCC were identified, including 79 (29.2 %) diagnosed with BM. Clear-cell histology was more common among BM (94.2 v 81.0%, p = 0.01), otherwise patient characteristics were similar. BM were diagnosed prior to systemic therapy (44.3%), or after one or more lines of therapy (one 26.6%, two 13.9%, three 5.1%, four 6.3%, five 3.8%). Among BM patients, 54 (68.4%) received local therapy with stereotactic radiosurgery (SRS) and/or surgical resection, 14 (17.7%) received WBRT alone, and 11 (13.9%) had no CNS-directed treatment. Local therapy consisted of SRS in 43 (54.4%) and surgical resection in 18 (22.8%), with some patients receiving both. Medial OS from metastatic diagnosis for those with BM was not significantly different from those without BM (26.4 v 28.7 mo, p = 0.305). This remained true when analyzed according to IMDC risk factors (see table). Conclusions: OS from the diagnosis of metastatic RCC did not significantly differ with or without BM in a cohort treated with modern systemic and CNS-directed therapies regardless of the timing of BM diagnosis or presence of IMDC risk factors. [Table: see text]
Efficacy of bone resorption inhibitors (BRI) + abiraterone acetate + prednisone (AA) vs. AA alone as first-line therapy for men with castration-resistant prostate cancer (CRPC) and bone metastases (BM) in an international multicenter hospital-based registry.
Authors: Francini Edoardo , Montagnani Francesco , Pier Vitale Nuzzo , Alimohamed Nimira S. , Moreno Candilejo Irene , Rosellini Pietro , Gonzalez-Velez Miguel , Rubio Jaime , Zhang Li , Shaw Grace , Crivelli Francesca , Petrioli Roberto , Bengala Carmelo , Francini Guido , Foncillas Jesus Garcia , Bryce Alan Haruo , Sweeney Christopher , Harshman Lauren Christine , Lee-Ying Richard , Heng Daniel Yick Chin
Published: May 2019

e16508

Background: BM in patients (pts) with CRPC correlate with higher mortality and costs. BRI zoledronic acid and denosumab are frequently used for the prevention of skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line treatment for men with metastatic CRPC. We sought to evaluate the impact of BRI on time to first SRE (ttSRE) and OS of pts receiving 1st line therapy AA for CRPC with BM. Methods: We identified a cohort of men starting AA as 1st line therapy for CRPC with BM between 2013-2015 from 7 hospitals’ IRB approved registries. Pts were grouped by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. The endpoints were OS, defined as time from AA start to death or last follow-up visit, and ttSRE. Results: Of the 338 pts included, 256 (76%) received AA alone and 82 (24%) AA+BRI. ECOG PS (PS) was ≥1 for 178 pts (52.7%). No statistically significant difference in ttSRE was found between the 2 cohorts [see Table]. Median follow-up for OS was 25.6 months. Pts receiving concomitant BRI showed a significantly longer OS and a 36% decreased risk of death compared to AA alone (HR = 0.64; 95% CI, 0.64 0.46-0.91; p = 0.012). Notably, OS in the AA alone group was shorter than commonly described. The OS benefit with BRI was greater for men with high volume disease (HV) (HR = 0.42; 95% CI, 0.25-0.71; p = 0.001). On MVA, BRI vs. no BRI, low volume of disease vs. HV, PS 0 vs. ≥1, baseline VAS pain ≤3 vs. > 5, and baseline PSA are independently associated with longer OS. Conclusions: Using a multicenter database, the addition of BRI to 1st line AA for CRPC men with BM and poor prognostic factors did not improve prevention of SRE. However, concomitant use of BRI and AA was associated with a significantly improved OS, particularly in HV. Further research to determine the driving factors is needed. [Table: see text]