bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasmacytoid variant urothelial carcinoma: Clinicopathologic outcomes and experience with neoadjuvant chemotherapy.
Authors: Ericson Kyle J , Thomas Lewis , Lee Byron H 
Published: March 2019

483 Background: Plasmacytoid variant histology is a rare variant that is often locally advanced at diagnosis. Data is limited to small series and the ideal treatment remains unknown. Here we report the clinicopathologic features and outcomes of 29 patients with plasmacytoid variant histology, including 12 patients treated with neoadjuvant chemotherapy (NAC) and 4 with adjuvant or salvage immunotherapy. Methods: All cystectomies performed from 2011-2018 at our institution were reviewed. Patients with plasmacytoid features on transurethral resection or cystectomy were included. Categorical variables were compared using chi-squared tests and survival outcomes were analyzed with log-rank analysis. Results: A total of 993 patients underwent cystectomy for malignancy. Of these, 29 patients (2.9%) had plasmacytoid variant features. At cystectomy, 65.5% were ≥ pT3, 48.2% were node positive, and 13.8% had positive soft-tissue margins. Twelve patients died during the observed period (41.4%), with a median time to death of 7.2 months. Among surviving patients, median follow-up was 21.9 months. Of the 4 patients with positive margins, survival was significantly worse than those with negative margins (p<0.005); all 4 died with a median survival of 1.8 months. Cisplatin based NAC was given to 12 patients (41.4%). NAC was not associated with a survival benefit over cystectomy alone (median survival 27.7 and 51.9 months, respectively; p=0.07), complete response (pT0), or organ confined disease (< pT3). Four patients (13.8%) received adjuvant or salvage checkpoint inhibitors; all surviving with a median follow-up of 28.7 months. Conclusions: Consistent with prior reports, plasmacytoid variants were uncommon and locally advanced. While our rate of positive margins was lower than in previous series, patients with positive margins universally did poorly. NAC was not associated with improved survival or pathologic outcomes. Our findings suggest plasmacytoid variants may not respond well to NAC, though no definitive conclusions can be drawn due to the small number of patients and retrospective design.
Contemporary analysis of ureteroenteric strictures after open and robot-assisted radical cystectomy: A population-based study.
Authors: Patel Neal , Alshak Mark , Goh Alvin , Sedrakyan Art , Belarmino Andre , Sun Tianyi , Bochner Bernard H. , Hu Jim C. 
Published: March 2019

484 Background: Robot-assisted radical cystectomy (RARC) has been shown to have comparable oncologic efficacy compared to open radical cystectomy (ORC). We sought to compare the rates of benign strictures after RARC and ORC using a population-based data. Methods: From Surveillance, Epidemiology, and End Results (SEER)-Medicare, we identified 332 RARC and 1449 ORC performed during 2009 and 2014, using International Classification of Diseases-9th edition and Current Procedural Terminology 4th edition to compare the development of ureteroenteric strictures at 6 months, 1 year and 2 years following radical cystectomy. We defined ureteroenteric stricture as the need for procedural intervention, consistent with prior studies. Additionally, we compared the incidence of stricture diagnosis. Multivariable proportional hazards regression was performed to determine factors associated with stricture development. Results: The incidence of ureteroenteric stricture at 6 months and 12 was higher for RARC vs. ORC at 12.1% vs. 7.0% (p<0.01) and 15.0% vs. 9.5% (p=0.01), respectively. However, the RARC vs. ORC stricture incidence at 2 years did not differ significantly at 14.6% vs. 11.4% (p=0.29). Similarly, the stricture diagnosis rates were significantly lower following ORC at 6, 12, and 24 months (p<0.05). In adjusted analysis, RARC (HR 1.70, 95% CI 1.28-2.26) and pre-operative hydronephrosis (HR 1.48, 95% CI 1.15-1.91) were associated with the development of stricture. Conversely, higher hospital volume was associated with a lower risk of stricture (HR 0.43, 95% CI 0.29-0.63). Conclusions: RARC is associated with a higher rate of post-radical cystectomy stricture complication diagnosis and intervention on a population-based level that is mitigated by higher hospital volume. Technical factors are likely responsible and prospective studies are needed to assess the influence of ureteral dissection, tissue handling and perfusion, redundancy, and/or tension on the anastomosis. A significant study limitation is the inability to differentiate extracorporeal versus intracorporeal diversion with our use of administrative data.
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]