bluuebunny/crossref_metadata_2025 huggingface dataset:
Prophylactic cranial irradiation (PCI) significantly decreases risk of brain metastases in patients with bulky, higher stage small-cell urothelial cancer.
Authors: Choi Seungtaek , Campbell Matthew T , Shah Amishi Yogesh , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Nguyen Quynh , Siefker-Radtke Arlene O.
Published: March 2019

486

Background: Patients with bulky, higher-stage small cell urothelial cancer (≥T3b, N+, and/or M+) have a high risk of developing brain metastases. Siefker-Radtke et al reported a 50% risk of brain metastases in this patient population. Therefore, a prospective trial evaluating the potential benefit of PCI was undertaken. Methods: Thirty patients with stage ≥T3b, N+, and/or M+ disease (without brain metastases on MRI) were treated between 12/2008 and 5/2018 with PCI. Patients were treated to a total dose of 30 Gy in 2 Gy fractions over 3 weeks. The patient had baseline brain MRI and mini-mental status exam (MMSE) before the treatment began. After treatment, patients underwent MRI and MMSE every 3-4 months for one year and every 6 months thereafter. If the patients did not have M+ disease at diagnosis, they were also treated with neoadjuvant chemotherapy (usually consisting of cisplatin/etoposide alternating with Adriamycin/ifosfamide), followed by a radical cystectomy. The PCI was either given between the last cycle of chemotherapy and surgery or after the surgery. Both acute and chronic toxicity from PCI were measured using CTCAE 3.0. Change in the MMSE after PCI was evaluated using a t-test. Results: Twenty-nine patients were evaluable. Twenty-four patients had ≥T3b and/or N+ disease and 5 patients had M1 disease. Median follow-up was 22 months (range 8-103 months). Four patients have developed brain metastases with a median time of 11.5 months after PCI (range 3-23 months). Two of these patients have died. Nine other patients have died from progressive systemic disease, but they did not have evidence of brain metastases. PCI was well-tolerated, with no grade ≥2 toxicity seen. Acute grade 1 toxicity seen included headache, nausea, and dermatitis. MMSE were available for 19 patients with a median follow-up of 13 months (range 3-87 months). There was no significant change in the MMSE scores after the PCI when compared to baseline (p = 0.61). Conclusions: In this study, PCI decreased the risk of developing brain metastases in patients with bulky, higher-stage small cell urothelial cancer from 50% (historical) to 13.8% without significant toxicity. Clinical trial information: NCT00756639.
The impact of pathologic downstaging with neoadjuvant chemotherapy on survival of patients with muscle-invasive bladder cancer.
Authors: Martini Alberto , Heard John R , Waingankar Nikhil , Jia Rachel , Sfakianos John P. , Galsky Matthew
Published: March 2019

491

Background: Achieving a pathologic complete response (pCR) with neoadjuvat chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been correlated with improved survival. Such findings have served as justification for using pCR as an intermediate endpoint for clinical trials and perpetuated the notion that NAC only benefits patients achieving a pCR. The impact of downstaging (pDS) on outcomes of patients with MIBC treated with NAC has been underexplored. Methods: The National Cancer Database (NCDB) was queried to identify patients with MIBC (cT2-4N0M) treated with platinum-based NAC. A multivariable Cox model including either pDS or pCR and adjusted for potential confounders was generated and c-indices were computed to evaluate whether the inclusion of pDS or pCR was more informative in predicting overall survival (OS). Results: Overall 2,010 patients from NCDB met inclusion criteria. The median follow-up for survivors was 36 months with a 5-year OS of 47% (95% CI 44, 50%). Overall, 694 (43.5%) patients achieved pDS; 139, 201, 291, 49 and 14 downstaged of 1, 2, 3, 4 and 5 categories, respectively. The 5-year OS rate for patients who achieved pDS was 70%. A pCR was achieved by 306 (15%) of the patients, the 5-year OS rate in this group was 84%. In the NCDB, pDS and pCR emerged as predictors of OS: HR:0.36 (95% CI: 0.30,0.44, p<0.001) and 0.25 (95% CI: 0.18,0.25, p<0.001), respectively. The cindex of the model including pDS was 72 vs. 70 of the model with pCR. Conclusions: pDS represents a more informative endpoint in predicting OS with respect to pCR in patients receiving NAC for MIBC.
Pretrial outlining quality assurance in PIVITOLBoost.
Authors: Evans Elin , Mayles Helen , Naismith Olivia Frances , Hall Emma , Tree Alison , Staffurth John , Syndikus Isabel
Published: March 2019

50

Background: PIVOTALBoost is a Phase III randomised controlled trial (CRUK/16/018) of radiotherapy to prostate and pelvic nodes versus prostate alone with or without prostate boost. To minimise impact of target volume delineation (TVD) variation on trial outcome, pre-trial radiotherapy quality assurance (RTQA) was implemented to identify and correct potential variations. Methods: Participating centres offering a prostate boost submitted two pre-accrual outlining benchmark cases: one with a central zone boost (GTVpb) only and another with GTVpb (peripheral zone), CTVp/psv and CTVn. A detailed outlining protocol and diagnostic information were provided to centres. Submitted outlines were compared to consensus volumes created by the trial management group (TMG). The TMG deemed the volumes acceptable or as having acceptable or unacceptable variation. Detailed feedback was provided for each submission. Unacceptable variations required resubmission. Results: 32 investigators submitted pre-trial outlines. GTVpb was the most incorrectly outlined volume; 22 (69%) outliners had unacceptable errors for case 2 GTVpb, 17 (53%) for case 1 GTVpb. Most common GTVpb error was inferior extent of lesion followed by incorrect lesion outlined. 12 (38%) of outliners had unacceptable errors for CTVp/psv, most commonly due to delineation at the prostate apex. 8 (25%) outliners had unacceptable CTVn mostly due to incorrect vessel delineation. Of 26 (81%) outliners required to resubmit at least 1 case, 3(12%) required a second resubmission due to unacceptable errors on first resubmission. Conclusions: The majority of pre-trial outlining submissions had unacceptable errors requiring resubmission of at least one case. This was predominantly due to boost delineation error which is a relatively new skill for prostate clinical oncologists in the UK. This suggests robust on-trial RTQA is imperative to minimise further variation. Clinical trial information: ISRCTN80146950.
Penile squamous cell carcinoma is genomically similar to other HPV-driven tumors.
Authors: Chahoud Jad , McCormick Barrett Z. , Netto Frederico , Rao Priya , Pickering Curtis R. , Pettaway Curtis Alvin
Published: March 2019

505

Background: PSCC is rare with limited treatment options for advanced disease. There have been no published genome-wide studies on the genetic alterations of PSCCs or on the differences between HPV (+) and HPV (−) PSCCs. We report the largest WES analysis of PSCC. Methods: We identified 34 pts diagnosed with PSCC, at MD Anderson, with primary tumors or metastatic lesions sufficient for WES. Patients, tumor and surgical characteristics were available through the MD Anderson prospective registry. Genomic DNAs from both Fresh frozen macrodissected tumors and paired-normal penile tissues were analyzed by WES. Results: Patients clinical characteristics are summarized in table 1. Eight of the most frequently mutated PSCC genes (NOTCH1 (35%), TP53 (35%), CDKN2A (24%), PIK3CA (21%), CASP8 (21%), FAT1 (18%), FBXW7 (15%) and EP300 (12%)) were significantly mutated in other SCC tumor types. Importantly, 8/8 and 5/8 genes were significant in head and neck SCC and cervical SCC, respectively, including 3 (CASP8, FXBW7, and EP300) genes that are only significant in these tumor types. TP53 mutations were associated with HPV (-) PSCC and were absent in HPV (+) SCC (P= 0.03). EP300 mutations were associated with advanced primary tumor stage. Of note we did not identify unique mutations associated with lymph node status. Conclusions: This is the largest systematic analyses of PSCC genomics uncovering the involvement of multiple cancer genes that are likely to be contributing to tumor development including; TP53, squamous differentiation, cell cycle, and chromatin regulation. PSCC are genomically similar to other HPV related SCC, and provide a therapeutic rationale for considering strategies successful in HPV related cancers. [Table: see text]
Comprehensive analysis of metastatic seminoma germ cell tumors shows divergent expression of immune-related pathways.
Authors: Nestler Tim , Haidl Friederike , Wittersheim Maike , Dalvi Priya , Paffenholz Pia , Wagener-Ryczek Svenja , Pfister David J. K. P. , Hellmich Martin , Büttner Reinhard , Odenthal Margarete , Heidenreich Axel
Published: March 2019

506

Background: Not much is known about the molecular mechanisms resulting in tumor progression and finally leading to metastasis in testicular germ cell tumor (TGCT). Only a few studies in some other tumor types have identified a limited set of genes, related to invasion, progression or metastases to be distinctly upregulated at the invasive tumor front in metastasized patients. However, systematic investigations are missing. Therefore, regional differences in the TGCT subtype seminomas were investigated to achieve a better understanding of the mechanisms involved in the metastatic process. Methods: Formalin-fixed paraffin embedded (FFPE) tissue samples of patients with clinical stage I disease, no adjuvant therapy and a relapse-free survival of at 2 years (n = 21), and patients showing metastasis (n = 14) were selected for the study. The tumor front (TF) and tumor center (TC) regions of each patient were determined and separately collected using laser capture microdissection. RNA was extracted and a multiplex gene expression analysis was performed on all TF and TC samples using nCounter technology of Nanostring. A panel of 770 transcripts was analyzed using the PanCancer Progression panel. Different bioinformatics tools were employed for analyzing the expression data. Results: Differential gene expression patterns were observed in the metastatic and non-metastatic patients, with respect to both the tumor front and tumor center regions. Ingenuity pathway analysis on the differentially expressed genes showed enrichment of tumor functions like migration, invasion, and angiogenesis at the TF as compared to the TC. Remarkably, prominent inflammatory and cancer related pathways such as IL-6 signaling, acute phase response signaling, NF-κB signaling and, dendritic cell maturation were significantly upregulated in the metastatic versus non-metastatic tumors (z-score > ± 2 and p-value < 0.05). Conclusions: This is the first study showing tumor heterogeneity in TGCTs. Evidently, IL-6 signalling was the most significantly upregulated pathway in the metastatic versus the non-metastatic patients, that could serve as a therapeutic target for personalized therapy.
Whole genome and transcriptome analysis (WGTA) of metastatic adrenocortical carcinoma (mACC).
Authors: Lavoie Jean-Michel , Csizmok Veronika , Wang Gang , Williamson Laura , Marra Marco A. , Laskin Janessa J. , Jones Steven J. M. , Renouf Daniel John , Kollmannsberger Christian K.
Published: March 2019

509

Background: mACC is a rare disease, and no standard treatments exist beyond cytotoxic chemotherapy and mitotane. Recurrent molecular changes have been described, but their clinical significance is still poorly understood, and whether they can guide treatment is unknown. Methods: The genomic and transcriptomic profiles of 6 pts with mACC were analyzed as part of a prospective molecular profiling clinical trial. Findings were correlated with histopathological and clinical data. Results: Whole genome sequencing of six ACC tumors and matched normal tissues was performed; whole-transcriptome sequencing was performed on five of the six tumors. All cases met Weiss criteria for ACC (including 1 pt with oncocytic ACC). Profiling revealed gain of function variations in CTNBB1 gene in 3 cases (p.S45A, p.S45P and homozygous deletion of exons 2 and 3). A stop-gained mutation (Q167*) and a homozygous copy loss of TP53 gene was observed in 2 cases; mutations of CTNBB1 and TP53 co-occurred in one case. Variations in other DNA repair genes included BRCA2 E790* stop-gained mutation and a structural variation in RAD52. Copy number amplification was observed for KDM5A (2/6) and RAD52 (2/6), while NF1 (1/6), CDKN2A (1/6), CDKN2B (1/6) and RB1 (2/6) were subjected to homozygous copy losses. Average ploidy models: one diploid, 4 triploid and one tetraploid case; whole chromosome copy losses and gains were seen in all samples. Three cases showed high homologous repair deficiency scores; associated with respectively, an in-frame deletion of V613 in ATM, a TP53 homozygous loss, and a structural variant of RAD52. All six cases exhibit signature 3 or signature 8. At last follow-up, 2 pts remained alive. Treatments included cytotoxic chemotherapy, mitotane, streptozotocin, sunitinib, avelumab with a SMAC mimetic, a TTK inhibitor on the basis of a CTNNB1 mutation, and temozolomide with olaparib on the basis of ATM loss. Conclusions: Our findings recapitulate published data on the molecular profile of mACC and support previous findings of large scale chromosomal variation. We identify new potential drivers in chromatin remodelling, cell cycle, and DNA damage repair genes. (NCT02155621, NCT02022098, NCT02792465).
Predicting overall survival (OS) in patients (pts) with penile squamous cell carcinoma (PSCC) undergoing regional lymph node dissection (LND) ± multimodal therapy.
Authors: Necchi Andrea , Mariani Luigi , Zhu Yao , Ye Ding-Wei , Lo Vullo Salvatore , Ornellas Antonio Augusto , Watkin Nick , Ager Michael , Hakenberg Oliver W , Heidenreich Axel , Raggi Daniele , Catanzaro Mario , Salvioni Roberto , Chipollini Juan , Azizi Mounsif , Spiess Philippe E.
Published: March 2019

512

Background: Advances in prognostic allocation of pts with PSCC receiving regional LND are needed, along with an assessment of the role of perioperative treatments. Methods: An international, multicenter, retrospective database was queried for all pts with PSCC who had received inguinal ± pelvic LND from 1980 to 2017. We classified or re-classified pts according to the 2009 TNM classification system. The primary endpoint was OS. Survival analysis methods were adopted for the purpose of detecting and modeling putative prognostic factors, and develop a prognostic stratification tool. The analysis was performed in two steps: first, we modeled outcome data and covariates by resorting to a random forest (RF) method (an “ensemble” machine-learning approach, with an ad hoc approach incorporating missing data imputation). Second, data was modeled using Cox proportional hazard regression. In addition, a Cox model was fit including pre-specified variables that were deemed to be clinically relevant. Results: There were 743 pts who received LND at seven referral centers from Europe, the USA, Brazil, and China. Of these pts, 689 were analyzed: 86 (12.5%) received neoadjuvant chemotherapy (NAC); 171 (24.8%) received adjuvant chemotherapy (AC), and 74 (10.7%) received adjuvant radiotherapy. The variables significantly associated with OS were age (p < 0.001), the pathologically involved/total removed LN ratio (p < 0.001), pN stage (overall p < 0.001) and NAC (HR: 1.58, 95%CI: 1.10-2.26, p = 0.013). NAC and AC were ineffective or detrimental in N1-2 patients, whereas they provided OS improvements in N3 patients. OS improvement reached statistical significance for AC in pelvic LN-positive pts (p = 0.046). Finally, we developed a nomogram predicting 12- and 24-month OS based on pre-specified variables (c-index: 0.75). The study is limited by its retrospective nature. Conclusions: We propose a post-treatment prognostic tool that can be offered as an aid to physicians to enhance decision-making, clinical research, and patient counseling after LND in PSCC. Administration of NAC and AC should be restricted to N3 patients.
Risk factors for venous thromboembolism (VTE) during chemotherapy in patients with germ cell tumors (GCT).
Authors: Griswold Cassia R , Bailey Erin B. , Mauser Jessica Campaign , Boucher Kenneth M. , Agarwal Neeraj , Gupta Sumati , Maughan Benjamin Louis
Published: March 2019

520

Background: The Khorana score is the primary tool utilized to predict VTE risk in patients with cancer. This score incorporates primary cancer site, pretreatment hematologic parameters, and body mass index. GCT are considered high-risk for VTE. However, risk factors for VTE not included in the Khorana Score have been reported for GCT including retroperitoneal lymph node (RPLN) size, elevated LDH, and poor risk disease. Methods: A retrospective chart review was conducted to correlate known VTE risk factors with VTE incidence in male patients with GCT undergoing first-line chemotherapy. Variables included venous access type, RPLN size, LDH, chemotherapy regimen, procedure history, cancer stage and histology, Khorana risk factors, and pertinent demographics. VTE and superficial vein thrombosis (SVT) events that occurred within 1 month prior through 6 months after start of chemotherapy were recorded. Fisher’s Exact test was used for univariate analysis and logistic regression for multivariate analysis of the relationship between predictors and thrombosis. P-values are two-sided at an alpha level of 0.05. Results: 47 patients with GCT were identified. 12 VTE occurred (overall incidence 25.5%), 11 in patients with central lines (39.3% incidence) and 1 with a peripheral line (5.3% incidence). SVT were observed in 5 patients with peripheral lines compared to 1 patient with a central line (26.3% vs. 3.6%). Central line access was the primary variable associated with VTE risk in both univariate and multivariate analysis (p=0.01 and p=0.03, respectively). Conclusions: Venous access type is a significant but modifiable factor that can be targeted to reduce VTE risk. Due to small sample size there is limited statistical power to detect potentially meaningful differences in known risk factors. If validated, these results may identify specific patients to be treated with prophylactic anticoagulation. [Table: see text]
Patient-reported psychosocial distress in adolescents and young adults with germ cell tumors.
Authors: Soleimani Maryam , Ho Cheryl , Kollmannsberger Christian K. , Bates Alan , Leung Bonnie
Published: March 2019

521

Background: Germ cell tumours are the most common cancer of male adolescents and young adults (AYA, age 18-39). Men in this age group have been healthy much of their lives, and are at a stage of personal and professional growth, consequently a diagnosis of cancer can cause significant psychosocial distress. We evaluated patient reported psychosocial distress and hypothesized that AYA compared to older patients experienced more anxiety and distress in emotional, practical and physical domains. Methods: All patients referred to BC Cancer complete the Psychosocial Screen for Cancer (PSSCAN-R) at first consultation. This is a validated screening questionnaire for distress. Components include a screen for subclinical/clinical symptoms of depression and anxiety and the Canadian Problem Checklist (CPC) with 6 domains of concern: emotional, informational, practical, spiritual, social/family and physical. Results: Data was collected for 349 patients from 2011-2015. Baseline characteristics: 227 (65%) AYA, median age 33 (range 18-83), 41 (11%) metastatic disease at diagnosis. The top 3 AYA concerns were work/school (38.3%), financial (34.8%), frustration and anger (26%). AYA patients scored positive for subclinical/clinical anxiety more commonly than their older counterparts (39.4% vs. 27.9%, p = 0.028). AYA patients with subclinical/clinical anxiety symptoms experienced more fears and worries (41.5%), concerns regarding work/school (38%), lack of understanding of their disease (37.9%), finances (35.3%) and frustration and anger (26.3%) than AYA patients who do not express anxiety symptoms. Conclusions: The results of this study indicate that AYA with testicular cancer have unique needs and experience significantly more self-reported anxiety symptoms with emotional, informational, and practical concerns. Programs tailored to address needs of AYA patients may help reduce anxiety and improve the cancer experience. The results of this study are valuable to stakeholders for allocation of resources to address psychosocial parameters of distress in this patient group.
Survival and toxicity outcomes in patients age 40 or older with relapsed metastatic germ cell tumors (mGCT) treated with high-dose chemotherapy (HDCT) and autologous peripheral-blood stem cell transplant (PBSCT).
Authors: Adra Nabil , Albany Costantine , Abonour Rafat , Abu Zaid Mohammad Issam , Pereira Dannillo , Althouse Sandra K. , Sullivan Cheryl K , Hanna Nasser H. , Einhorn Lawrence H.
Published: March 2019

522

Background: HDCT plus PBSCT is effective salvage therapy for relapsed mGCT but has potential toxicity which can be more pronounced in older patients. We report survival and toxicity outcomes in pts with relapsed mGCT age ≥ 40 at time of HDCT. Methods: 440 consecutive pts with relapsed mGCT were treated with HDCT and PBSCT with tandem cycles at Indiana University (IU) between 2004-2017 per our previous reported regimen (N Engl J Med 2007; 357: 340-8). Kaplan-Meier methods were used for progression free survival (PFS) analysis. Results: 110 pts were age ≥ 40 while 330 pts were age < 40. Among pts age ≥ 40, median AFP was 6.6 (range, 1-2,709) and median hCG was 5.3 (range, 1-42, 453). Of the 110 pts age ≥ 40, 75 had complete remission without relapse during a median follow-up of 23 months. There were 3 treatment-related deaths. Conclusions: HDCT plus PBSCT is safe and effective salvage therapy in pts age ≥ 40 with relapsed mGCT. [Table: see text]
Genomic features of metastatic testicular sex cord stromal tumors.
Authors: Necchi Andrea , Bratslavsky Gennady , Pinkhasov Rubin , Shapiro Oleg , Gay Laurie M. , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Nho Nhu Thi , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Ali Siraj Mahamed , Chung Jon , Reddy Venkataprasanth P. , Miller Vincent A. , Schrock Alexa Betzig , Ross Jeffrey S. , Liu Nick , Jacob Joseph
Published: March 2019

532

Background: Metastatic testicular sex cord stromal tumors of the testis (MSCST) comprise an extremely uncommon form of genitourinary malignancy. In a comparative genomic study, we performed comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) in MSCST and to enable the search for potential therapy targets. Methods: The MSCST were classified as metastatic Leydig Cell Tumors (LCT), Sertoli Cell Tumors (SCT) and Undifferentiated (USCST). In this study, 10 cases of LCT, 6 cases of SCT and 3 cases of USCST underwent hybrid-capture based CGP to evaluate all classes of genomic alterations. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: All patients had clinically advanced recurrent and/or metastatic disease. The primary testis tumor was used for sequencing in 6 MSCST (32%) and a metastatic site in 9 (68%) of the MSCST. In 10 (91%) of 11 MSCST positively stained by IHC for inhibin expression. The overall frequencies of GA were similar in all LCT, SCT and UTST ranging from 3.0 to 3.5 GA/tumor. The most frequent untargetable GA found in all MSCST cases included CTNNB1 and CDKN2A/B, both ranging from 20-33% of cases. Targetable GA were uncommon in all MSCST sub-groups but several tumors featured potential for cell cycle inhibitors ( CDK4 in LCT), MTOR inhibitors ( RICTOR, NF2 and PTEN in all 3 tumor types), hedgehog inhibitors ( PTCH1 in LCT) and PARP inhibitors ( BAP1 in SCT). No MSI-High status was identified in any MSCST. The TMB was also low in all MSCST groups. Conclusions: Although the 3 subgroups of testicular MSCST feature defining histopathologic features, these tumors have similar genomic signatures on CGP. The low levels of GA per tumor, infrequent tumor aneuploidy, absence of MSI-High status and low TMB all indicate that testicular MSCST are genetically stable. However, rare cases of testicular MSCST reveal GA linked to potential targeted therapy benefits on CGP linked to dysregulation of multiple biologic pathways. In contrast, the lack of MSI-High status and overall low TMB in testicular MSCST indicates a likely lack of benefit for immunotherapies for these rare forms of malignancy.
Safety and efficacy of nivolumab in metastatic renal cell carcinoma (mRCC): Final analysis from the NIVOREN GETUG AFU 26 study.
Authors: Albiges Laurence , Negrier Sylvie , Dalban Cécile , Chevreau Christine , Gravis Gwenaelle , Oudard Stephane , Laguerre Brigitte , Barthelemy Philippe , Borchiellini Delphine , Gross-Goupil Marine , Geoffrois Lionnel , Rolland Frederic , Thiery-Vuillemin Antoine , Joly Florence , Ladoire Sylvain , Tantot Florence , Escudier Bernard ,   GETUG
Published: March 2019

542

Background: NIVOREN GETUG AFU 26 study, is a French multicenter prospective study to evaluate safety and efficacy of Nivolumab (N) in a broad “real world setting” in mRCC after failure of 1 or 2 tyrosine kinase inhibitors. Methods: Between February 2016 and June 2017, 729 pts have been enrolled across 27 institutions. Primary objective of the trial was safety assessed by grade ≥ 3 treatment related adverse event (TRAE). Results: Overall, 720 patients treated with N were included in this final analysis. All pts had clear cell mRCC. Median age was 64 years old, 77.4% were male, 84.7% had prior nephrectomy. ECOG PS was >1 in 15.0%, 21.3% pts had received prior everolimus, 22.4% pts had received more than 2 previous lines, IMDC risk groups were 18.3%/56.2%/25.5% for good/intermediate and poor risk respectively. Brain Metastasis at screening was noted in 83 (12.3%) pts. With a median follow up of 20.9 months (mo), median duration of treatment was 5.2 mo (0.5; 28.1) with 15% of pts still on therapy. Median PFS was 3.2 IC 95% [2.9; 4.6] mo. At the time of this analysis, 316 pts have died and 12 mo OS rate was 69% IC 95% [66; 73]. Objective response rate was 20.8% (1.2% CR, 19.6%PR). Stable disease was seen in 31.6% and PD in 47.6%. Noteworthy, 46.1% of pts were treated beyond progression. Overall, 123 pts (17.1%) have presented at least one grade ≥ 3 TRAE, including asthenia (2.4%), metabolic disorders (2.1%), gastro-intestinal disorders (1 .9%), musculoskeletal (1.7%), renal disorders (1.3%), hematologic (1.3%). 6 patients have developed grade 5 toxicity (2 cardiac failure, 1 macrophage activation syndrom, 1 Cerebral hemorrhage, 1 unknown). Treatment discontinuation due to any grade TRAE occurred in 54 pts (7.5%). Interestingly, pts with grade ≥ 3 TRAE had longer PFS than pts without grade ≥ 3 TRAE (HR 0.69 [0.55-0.87]). Conclusions: We report the primary objective analysis of the largest prospective real world setting study of N in mRCC. NIVOREN study demonstrates that N safety and efficacy in a “real world” prospective study are similar to the pivotal study. Grade ≥ 3 TRAE was associated with longer PFS. Clinical trial information: NCT03013335.
Subgroup analysis from JAVELIN Renal 101: Outcomes for avelumab plus axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).
Authors: Choueiri Toni K. , Motzer Robert J. , Campbell Matthew T. , Alekseev Boris Y. , Uemura Motohide , Kollmannsberger Christian K. , Gravis Gwenaelle , Bjarnason Georg A. , Gurney Howard , Chung Jinsoo , Haanen John B. A. G. , Rini Brian I. , Larkin James M. G. , Schmidinger Manuela , Nole Franco , Chudnovsky Aleksander , Huang Bo , Hariharan Subramanian , di Pietro Alessandra , Albiges Laurence
Published: March 2019

544

Background: In the ongoing phase 3 JAVELIN Renal 101 trial, progression-free survival (PFS) was longer (median, 13.8 vs 8.4 mo; hazard ratio, 0.69; p=0.0001) and the objective response rate (ORR) was higher (51% vs 26%) with A + Ax vs S in patients with previously untreated aRCC. Here we report outcomes from an analysis of several prespecified subgroups. Methods: Patients were randomized 1:1 to receive A (10 mg/kg) IV every 2 weeks + Ax (5 mg) PO twice daily or S (50 mg) PO once daily for 4 wk (6-wk cycle). Primary and key secondary endpoints were PFS per independent review committee (IRC; RECIST v1.1) and OS in patients with PD-L1+ tumors (≥1% of immune cells) and in patients irrespective of PD-L1 expression; other secondary endpoints included OR per IRC (RECIST v1.1). Results: A total of 886 patients were randomized; 560 (63%) had PD-L1+ tumors. At data cut-off (Jun 2018), median follow-up was 12.0 vs 11.5 mo for A + Ax vs S groups. The table shows PFS and ORR by MSKCC and IMDC risk groups (F, favorable; I, intermediate; P, poor) and PD-L1 subgroup. Similar results for prognostic risk were seen in patients with PD-L1+ tumors. Outcome data (including PFS2) for additional clinical subgroups by baseline demographics and features will be presented. Clinical trial information: NCT02684006. Conclusions: A + Ax demonstrated PFS and OR benefit across all prognostic risk groups and PD-L1 subgroups vs S in aRCC.[Table: see text]
Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab (N+I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Tannir Nizar M. , Frontera Osvaldo Arén , Hammers Hans J. , Carducci Michael Anthony , McDermott David F. , Salman Pamela , Escudier Bernard , Beuselinck Benoit , Amin Asim , Porta Camillo , George Saby , Bracarda Sergio , Tykodi Scott S. , Powles Thomas , Rini Brian I. , Tomita Yoshihiko , McHenry M. Brent , Mekan Sabeen Fatima , Motzer Robert J.
Published: March 2019

547

Background: N+I showed superior OS v S in ITT (IMDC any risk) and intermediate/poor-risk (I/P) pts with aRCC in CheckMate 214 at 17.5 mo min follow-up. Methods: Pts with clear cell aRCC were randomized 1:1 to N3 mg/kg + I1 mg/kg Q3W×4 and then N3 mg/kg Q2W, or S 50 mg daily for 4 wk on, 2 wk off. Co-primary endpoints were OS, RECISTv1.1 ORR and PFS per IRRC in I/P pts. PFS and ORR were assessed by investigator (inv) at 30 mo. Results: At 30 mo min follow-up, OS remains significantly improved in ITT and I/P pts with N+I v S; the HR for OS in favorable (fav) risk pts has improved for N+I v the previous analysis (1.22 [95% CI 0.73–2.04] v 1.45 [99.8% CI 0.51‒4.12]). Per previous IRRC ORR (N+I, 42% [95% CI 37‒47]; S, 27% [95% CI 22‒31]), ORR per inv was higher with N+I v S in ITT and I/P pts. ORR CIs overlapped in fav pts, CR was doubled with N+I v S. Increasing PFS benefit with N+I v S is emerging in ITT and I/P pts; PFS CIs between arms remain overlapping in fav pts (Table). 15% v 9% of N+I and S ITT pts remain on therapy, and 48% v 61% have received 2nd-line systemic therapy; 39% of S pts received subsequent immune-checkpoint inhibitor therapy. Among pts who were alive with CR, 50% v 10% remain on treatment with N+I (n = 56) v S (n = 10). 5 N+I and 7 S additional pts developed Gr 3–4 drug-related AEs; 1 N+I and 3 S additional pts had AEs leading to discontinuation. No new drug-related deaths occurred. Conclusions: At 30 mo min follow-up, OS and ORR remain improved with N+I v S in ITT and I/P CheckMate 214 pts. No new safety signals emerged with longer follow-up. Clinical trial information: NCT02231749. [Table: see text]
Genomic analysis of mitochondrial mutations in chromophobe renal cell carcinoma by using low-depth whole genome sequencing.
Authors: Kang Minyong , Shin Yong Ho , Joung Jae Young , Seo Seong Il
Published: March 2019

553

Background: Mitochondria have a circular genome that is independent of the nuclear genome of the nucleus. Mutations of mitochondrial DNA rarely occur during tumorigenesis. Chromophobe renal cell carcinoma (chRCCC) is a type of kidney tumor characterized by a morphologic abnormality of mitochondria. However, there is still little research on the existence of mitochondrial mutation in chRCC and how it plays a role in tumorigenesis. Here, we investigated the mutation patterns of mitochondria genome in chRCC using low-depth sequencing technique. Methods: We evaluated 17 patients with chRCC who underwent radical nephrectomy from December 2010 to January 2017. Mitochondrial genomic analysis was performed by low-depth sequencing. Varscan and MToolBox analysis programs were used to search for mutations. Germline mutation information reported in MtDB, Phylotree, and Mitomap databases was used to allocate patient haplogroups and exclude germline mutations. Results: Whole genome sequencing of 17 chRCC tissues at an average depth of 1x based on whole genome revealed that the mitochondrial genome was sequenced to an average of 630x. A total of 1,206 Haplotype frequency > 0.25 mutations were found, of which 30 were mutations not reported in the database. Seven of them were identified as synonymous mutations (average of 0.41 and 41% per tumor), and three were truncating mutations (average of 0.18 per tumor; 18%). Truncating mutations were specifically identified as two frameshift indel and one stop gain mutation. Conclusions: In summary, our study showed that the frequency of truncating mutation of mitochondrial DNA was higher in chRCC compared to other solid tumors which have a low frequency of 1-2%. This finding suggests that dysfunctional mitochondria may play an oncogenic role in tumorigenesis of chRCC, while other tumors are predicted to undergo negative selection of mitochondrial truncating mutations during tumorigenesis. Based on these results, we are performing prospective study for evaluating mutational characteristics and associated morphological changes of mitochondria under electron microscopy.
Thick perirenal fat predicts the growth pattern of renal cell carcinoma.
Authors: Kashiwagi Eiji , Imada Kenjiro , Shiota Masaki , Takeuchi Ario , Inokuchi Junichi , Tatsugami Katsunori , Eto Masatoshi
Published: March 2019

554

Background: Partial nephrectomy is the standard surgical treatment for T1a renal cell carcinoma (RCC) and select T1b. Among these tumor classes, the tumor location can be divided into inner or outer. However, little attention has been paid to the mechanism of the pattern of RCC growth. In our body, there are two types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is important for energy storage and BAT is important for thermogenesis. BAT expresses uncoupling protein 1 (UCP-1), and mainly located in mediastinal, supraclavicular and perirenal tissues. But no studies have been done to investigate the relationship between RCC and BAT.In this study, we examined the association between adipose tissue, especially around kidney, and the growth pattern of RCC. Methods: We retrospectively reviewed computed tomography scans of 153 patients with stage 1 RCC who underwent radical or partial nephrectomy in our hospital between January 2013 and July 2016. We calculated the visceral/subcutaneous/perirenal fat volumes using SYNAPSE VINCENT. Of the 60 patients, the perirenal fat was immunohistochemically stained for leptin, adiponectin, COX-2 and UCP-1, and the association with outward tumor protrusion was evaluated. Results: Of the 153 cases, 88 had confirmed outward expansion (57.5%), 110 were classed as pT1a (52 and 58 with outer and inner expansion, respectively), 43 were classed as pT1b (36 and 7 with outer and inner expansion, respectively; P < 0.0001). Multivariate Cox model showed a trend toward significance in pT1b (vs. pT1a, OR 6.033, 95% CI = 2.409-15.108, P = 0.0001), perirenal fat percentage > 1.0 (vs. ≤ 1.0, OR 2.596, 95% CI = 1.205-5.591, P = 0.014). as independent predictors for outer protrusion. Immunohistochemical staining was positive for UCP-1 expression in 31 out of 41 outgrowth types (75.6%), and all 19 endogenous types (100%; P = 0.003). Conclusions: Renal cell carcinoma with thick perirenal fat correlates with an increased likelihood of developing outward tumor protrusion; therefore, fat distribution and UCP1 expression may affect the development of renal cell carcinoma.
Sporadic angiomyolipomas (AMLs) growth kinetics while on everolimus (SAGE).
Authors: Geynisman Daniel M. , Kadow Brian T. , Shuch Brian M. , Boorjian Stephen A. , Matin Surena F. , Rampersaud Edward , McClean Daniel , Milestone Barton N , Plimack Elizabeth R. , Zibelman Matthew R. , Kutikov Alexander , Smaldone Marc C. , Chen David , Viterbo Rosalia , Joshi Shreyas , Greenberg Richard E. , Malizzia Lois , McGowan Thomas , Ross Eric A. , Uzzo Robert
Published: March 2019

560

Background: Level I evidence exists demonstrating the efficacy of the mTOR inhibitor everolimus (EVE) in decreasing tumor volume of syndromic angiomyolipomas (AMLs) among patients with Tuberous Sclerosis. No prospective data are available regarding the effect of mTOR inhibition on growth kinetics in patients with sporadic AMLs. Methods: We conducted a multi-institutional, prospective, phase 2 trial with an optimal two-stage Simon design in patients presenting with > 3cm sporadic AMLs who were candidates for surgical or percutaneous intervention. Response was defined as ≥25% volumetric reduction of the AML. Planned enrollment was 43 patients to test the null hypothesis at a 5% level of significance with 80% power. Baseline, 4- and 6-month volumetric analysis was performed by dynamic contrast-enhanced MRI (DCE-MRI). Patients received EVE 10mg for four 28-day cycles, at which point EVE was discontinued in those with < 25% volumetric reduction. Those with ≥ 25% volumetric reduction received two additional cycles of EVE. Dose reductions and interruptions were allowed to 5 mg QOD. Conservative stopping rules were established for toxicity, given the benign nature of AMLs. Results: The early stopping rules for both efficacy and toxicity were invoked. We enrolled 20 patients (median age = 68) from 5 centers with 21 sporadic AMLs. 11/20 (55%) patients completed 4 cycles of EVE, while 7/20 (35%) completed 6 cycles. Median days on treatment was 88 (2 cycles). 4/20 (20%) patients were withdrawn due to toxicity, while 8/20 (40%) withdrew due to personal preference. Dose reductions were required in 6/20 (30%) patients, and 5/20 (25%) patients had grade 3 toxicities which resolved upon discontinuation or dose reduction of EVE. At 4-month MRI, 10/16 (62.5%) patients had a ≥25% reduction in volume (mean = 54.1% decrease). At 6-month MRI, 8/12 (66.6%) patients had a ≥25% reduction in volume (mean = 51.5% decrease). Conclusions: EVE was effective in reducing tumor volume in patients with sporadic AMLs but was associated with a high rate of treatment termination due to patient preference or prespecified AEs. Neoadjuvant EVE may be useful in potentiating surgical resection of large or anatomically complex AMLs. Clinical trial information: NCT02539459.
Treatment-free survival (TFS) after discontinuation of first-line nivolumab (NIVO) plus ipilimumab (IPI) or sunitinib (SUN) in intention-to-treat (ITT) and IMDC favorable-risk patients (pts) with advanced renal cell carcinoma (aRCC) from CheckMate 214.
Authors: McDermott David F. , Rini Brian I. , Motzer Robert J. , Tannir Nizar M. , Escudier Bernard , Kollmannsberger Christian K. , Hammers Hans J. , Porta Camillo , George Saby , Donskov Frede , Gurney Howard , Grimm Marc-Oliver , Harrison Michael Roger , Hutson Thomas E. , Yang Shuo , Johansen Jennifer , Rao Sumati , Mekan Sabeen Fatima , Rael Michael , Powles Thomas
Published: March 2019

564

Background: TFS characterizes the antitumor activity of immuno-oncology agents after treatment discontinuation. In CheckMate 214, pts with IMDC intermediate/poor-risk aRCC who discontinued first-line NIVO+IPI experienced significantly longer TFS than those who discontinued SUN (McDermott et al, ESMO 2018). Here, we continue the analysis of TFS from CheckMate 214 in ITT and IMDC favorable-risk pts. Methods: Pts with previously untreated, predominantly clear cell aRCC were randomized 1:1 to intravenous NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses followed by NIVO 3 mg/kg every 2 weeks, or oral SUN 50 mg daily for 4 weeks on, 2 weeks off (6-week cycles). TFS was defined as the time from protocol therapy cessation to the start of subsequent systemic anticancer therapy or death, whichever occurred first. TFS in pts who discontinued NIVO+IPI or SUN was compared using Kaplan–Meier methods and log-rank tests. This analysis was conducted for all ITT (NIVO+IPI, 550; SUN, 546) and IMDC favorable-risk (NIVO+IPI, 125; SUN, 124) pts in CheckMate 214. Results: Among 463 NIVO+IPI and 477 SUN ITT pts who discontinued protocol therapy, the median TFS was 3.0 months with NIVO+IPI vs 1.3 months with SUN (HR [95% CI]; 0.54 [0.46–0.62]; P<0.0001); the TFS rates 2 years post-discontinuation were 21% vs 7%, respectively. In IMDC favorable-risk pts, 111 and 94 pts discontinued from NIVO+IPI and SUN, respectively. TFS in IMDC favorable-risk pts was also significantly longer with NIVO+IPI vs SUN (median, 6.3 vs 1.1 months; HR [95% CI]; 0.47 [0.34–0.65]; P<0.0001). The TFS rates 2 years post-discontinuation in favorable-risk pts were 29% for NIVO+IPI vs 13% for SUN. Conclusions: Similar to the TFS benefit seen in intermediate/poor-risk pts with aRCC, first-line therapy with NIVO+IPI resulted in reduced need for second-line therapy in ITT and IMDC favorable-risk pts compared with SUN. The durable TFS benefit across risk groups despite discontinuation of therapy provides further evidence of the encouraging benefit-risk profile of NIVO+IPI over SUN in pts with previously untreated aRCC. Clinical trial information: NCT02231749.
Real-world use of sorafenib for advanced renal cell carcinoma patients with cardiovascular disease: Nationwide survey in Japan.
Authors: Inamoto Teruo , Azuma Haruhito , Oya Mototsugu , Hamada Yoko , Akaza Hideyuki
Published: March 2019

565

Background: The average age of the patients (pts) with renal cell carcinoma (RCC) are getting older year by year, hence the baseline comorbidity should be considered when pts have tyrosine kinase inhibitor treatments. However, the safety and efficacy data of these agents in pts with cardiovascular disease (CVD) are limited. In this study, we analyzed the data which were prospectively collected practical use of sorafenib amongst all RCC pts in Japan, and investigated whether baseline comorbidity of CVD would provide any affection for the safety and efficacy on sorafenib treatment using propensity-matched analysis. Methods: A total of 3,255 pts with advanced RCC were enrolled and 770 pts selected by propensity score were matched for CVD (n=385) and non-CVD pts (n=385). Dose modification, tumor response, progression free survival (PFS), and adverse events (AEs) were analyzed. Results: After matching the patient’s demographics were well balanced except for BMI (22.47 ± 3.37 vs. 23.13 ± 3.59, p=0.019) between non-CVD and CVD group, respectively. The median starting dose (800mg vs. 800mg), median daily dose (484.8mg vs. 500mg), and median duration of treatment (7.26 months vs. 7.89 months) were not significantly different. Objective response rate (CR+PR) was comparable in both groups (27.1 and 29.4%). The hazard ratio (HR) of overall PFS was similar between two groups (HR: 1.005, 95% CI: 0.838-1.206). When stratified according to IMDC risk classification, the risk of PFS was not significantly different in any IMDC risk groups (favorable; HR: 0.883, 95% CI: 0.600-1.300, intermediate; HR: 1.11, 95% CI: 0.885-1.3920, and poor ; HR 0.972, 95% CI: 0.513-1.842). Safety was analyzed for 766 pts, and any grade AEs observed ≥20% were hand-foot skin reaction (59.5%), hypertension (40.0%), rash (26.9%), lipase/amylase increased (26.5%), and diarrhea (24.2%). The frequency of any grade AEs were similar between the groups, but lipase/ amylase increased was significantly higher in CVD group than that in non-CVD group (p=0.0042). Conclusions: The present study suggests that sorafenib can be used with clinical benefit for RCC pts regardless of baseline cardiovascular comorbidities. Clinical trial information: NCT01411423.
Identification of differentially expressed genes to predict radioresistant prostate carcinomas.
Authors: Nestler Tim , Wittersheim Maike , Hellmich Martin , Pfister David J. K. P. , Odenthal Margarete , Büttner Reinhard , Schäfer Stephan , Heidenreich Axel
Published: March 2019

57

Background: Although relapses after radiotherapy are common in prostate cancer (PCa) patients, there are no clinical models or markers to identify patients at high risk for radioresistance. So far, only in vitro studies and xenograft models have been performed to identify gene expression patterns associated with radioresistance. However, studies which address the protein pattern to predict radioresistance in humans are completely missing. In order to determine potential biomarkers for radioresistance, we compared protein expression profiles of radioresistant PCa patients with PCa of primary prostatectomized patients. Methods: Two study groups consisting of: I) 30 patients who were treated by salvage prostatectomy and II) 94 patients treated by primary prostatectomy were formed. Tissue microarrays were constructed and immunostained for 15 proteins which are suggested to be associated with radioresistance by in vitro findings. Kruskal-Wallis test was used for multiple group comparison and followed by Dunn-Bonferroni-Test to detect intergroup differences. Cohen’s d was used to calculate the intergroup effect size. Results: Most proteins studied did not show any relevant differences between radioresistant PCa and primary PCa, except for two (AR and AKR1C3). On comparing immunostaining patterns between radioresistant PCa and primary PCa separated by Gleason risk groups, we observed only AR (androgen receptor) to be most expressed in radioresistant PCa (89.7%) and, in 87.8% of primary PCa of the high-risk group ( > 7a) (p = 0.851, Cohen’s d = 0.05), while only 67.3% PCa of the low-risk group (≤7a) (p = 0.017, Cohen’s d = 0.55) were positive. Considering the highest Gleason pattern per patient, only AKR1C3 (Aldo-Keto Reductase Family 1 Member C3) was seen to be similarly expressed in radiation-resistant PCa and patients with Gleason patterns 4 and 5 (p = 0.827, Cohen’s d = 0.05 and p = 0.893, Cohen’s d = 0.10) as compared to Gleason pattern 3 (p = 0.20, Cohen’s d = 0.69) in primary PCa. Conclusions: This is the first study evaluating protein expression profiles to predict radioresistance in PCa, where AR and AKR1C3 were identified to be the most promising protein markers.