bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and prevalence of cancer-susceptibility germline mutations (Mts) in patients (Pts) with advanced renal cell carcinoma (aRCC).
Authors: Carlo Maria Isabel , Mukherjee Semanti , Kemel Yelena , Zhang Liying , Mandelker Diana , Vijai Joseph , Coskey Devyn Taylor , Pradhan Nisha , Hyman David Michael , Hakimi A. Ari , Coleman Jonathan , Lee Chung-Han , Feldman Darren R. , Voss Martin Henner , Offit Kenneth , Robson Mark E. , Motzer Robert J. 
Published: September 2018

4524 Background: About 5% of RCC is thought to be familial, but recent studies suggest this may be an underestimate (Int. J. Cancer;100:476). We studied the prevalence of germline cancer-susceptibility mts in pts with aRCC. Methods: Pts with aRCC (stage III or IV), unselected for suspicion of an inherited cancer syndrome, were offered germline testing for 76 cancer-associated genes between 10/2015 and 12/2016. Germline sequencing was done as part of MSK-IMPACT, a matched tumor-normal next-generation sequencing platform. Results: 203/213 pts accepted testing (median age 55, range 13-55) of whom 73% had clear cell RCC (ccRCC), 92% had metastases, 20% were early onset (≤46 yrs at diagnosis), 9% had a family history of RCC, 6% multifocal RCC at diagnosis, and 15% ≥2 primary malignancies. Pathogenic/likely pathogenic mts were found in 35 pts (17%): 12 (6%) with mts in genes associated with familial RCC; 10 (5%) mts in high/moderate penetrance genes not linked to RCC (Table).13 (6%) had mts in genes of low/uncertain penetrance or for autosomal recessive disease. Mts were present in 15% of ccRCC and 19% of non-ccRCC. Mts were not more common in pts with early onset, family history, multifocal RCC, or ≥2 malignancies (p>0.1 for each by Fisher’s exact test). Notably, 4/12 pts with mts in familial RCC genes did not meet the American College of Medical Genetics (ACMG) criteria for testing (1 each VHL, BAP1, SDHA, FH). Prevalence of CHEK2 mts was compared to population databases (ExAC); CHEK2 conferred a relative risk of 10.9 (p< 0. 002; CI=3.9-24.7) for RCC. Conclusions: 17% of aRCC pts had a germline mutation in a cancer-associated gene of which 33% of the high penetrance RCC germline mts were not identified using standard clinical criteria, providing rationale for broad testing. Once the increased risk is confirmed, CHEK2 should be included in RCC genetic testing. [Table: see text]
Phase I/II trial of cetuximab with 5-fluorouracil and mitomycin C concurrent with radiotherapy in patients with muscle invasive bladder cancer.
Authors: Hussain Syed A. , Buckley Laura , Kaur Baljit , Hendron Carey , Zarkar Anjali , Ford Daniel , Viney Richard , Syndikus Isabel , Malik Zafar , Eswar Chinnamani , Desai Amisha , Southgate Elizabeth , Mangar Stephen , Van Der Voet Johannes , Lydon Anna , James Nicholas D. 
Published: September 2018

4527 Background: This phase I/II trial assessed the safety, feasibility and efficacy of cetuximab (Cet) in combination with 5-fluorouracil (5FU) and mitomycin C (MMC) with concurrent radiotherapy (RT) for the treatment of muscle invasive bladder cancer (MIBC). BC2001 trial has previously reported significant improvement in locoregional control in patients (pts) with MIBC who were randomised to synchronous chemo-RT compared to RT alone (James, Hussain, Hall et al NEJM 2012). Results for phase I have been reported previously. This abstract reports the combined results of phases I/II. Methods: From September 2012 to October 2016, 33 pts were recruited (7 pts to phase I from 2 UK centres and 26 patients to phase II from 5 UK centres). Pts received loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2 for 7 weeks, continuous infusion 5FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC 12mg/m2on day 1 in combination with radical RT 64 Gy in 32 fractions. Neoadjuvant chemotherapy was mandatory in phase I but optional in phase II. Primary outcomes in phase I were feasibility and toxicity. Primary outcome in phase II was 3 month pathological complete response (CR) rate, secondary outcomes included toxicity, progression free survival (PFS) and overall survival (OS). Results: Median age of pts was 70 (range 46.9-85.6). Treatment completion rates in phase I were RT 100%, 5FU 100 %, MMC 100%, Cet 96%. Of the 28 analysable pts, phase II primary outcome data was available for 25 pts at the time of analysis with a 3 month pathological CR rate of 88%. 5 local progressions and 4 deaths were reported. 12 pts suffered at least one SAE. Grade 4 toxicities observed were dyspnoea, atrial fibrillation, interstitial pneumonitis, sepsis, thromboembolism, neutropenia and palpitations. The commonest grade 3 toxicities were skin rash, diarrhoea, low platelet count, low white blood cell count, fever and haematuria. The most common grade 1 and 2 toxicities were diarrhoea and skin rash. Data on PFS and OS will be presented. Conclusions: It was feasible and safe to add cetuximab to full dose chemo-RT with 5FU/MMC. The CR rate is encouraging and further randomised studies with this combination are warranted. Clinical trial information: ISRCTN80733590.
Atezolizumab (atezo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Safety analysis from an expanded access study.
Authors: Bellmunt Joaquim , Pal Sumanta K. , Zheng Hanzhe , Tayama Darren , Chang Dannis , Hoffman-Censits Jean H. 
Published: September 2018

4532 Background: A majority of mUC pts progress on standard platinum-based chemo regimens. Atezo (anti–PD-L1) was approved in the US for mUC in the post-platinum setting. Here we report the preliminary safety results from an expanded access program conducted to grant access to atezo, prior to commercial availability, to a broader range of mUC pts than are typically eligible for Phase I-III studies. Methods: From Nov 2015-Aug 2016, this study (NCT02589717) enrolled mUC pts who progressed during or following platinum. Atezo was given 1200 mg IV q3w, and pts could be treated post RECIST v1.1 PD until lack of clinical benefit (per investigator). Safety and clinical activity were key endpoints. PD-L1 expression on immune cells (IC) was assessed with the VENTANA SP142 IHC assay on the first 73 pts prior to protocol amendment omitting this requirement. This study was ended early following FDA approval of atezo. Results: 218 pts were enrolled at 36 sites in the US, with 214 treated pts comprising the safety/efficacy population (Table). Median treatment duration was 9 wks (range 3-26), corresponding to a median of 3 doses of atezo (range 1-8). Overall, 89% of pts had an AE. Treatment-related AEs (TRAEs) occurred in 46% (any Gr) and 7% (Gr3-4) of pts; 2 treatment-related Gr 5 AEs were seen (ileus; acute respiratory failure). TRAEs ≥ 5% were fatigue, decreased appetite and anemia. TRAEs leading to dose interruption or discontinuation occurred in 11% and 6% of pts, respectively. Investigator-assessed RECIST v1.1 ORR was 15% (95% CI: 9, 23), and disease control rate (ORR + SD) was 49% (95% CI: 40, 59). Additional clinical data will be reported. Conclusions: In this expanded access study, atezo was administered to > 200 mUC pts. Overall, atezo was safe and tolerable, supporting its use in a wider platinum-based population. Clinical trial information: NCT02589717. [Table: see text]
Spectrum of tumor mutational load (TML) in genitourinary cancers (GU CA).
Authors: Hussain Muhammad Azam , Heath Elisabeth I. , Somer Bradley G. , Arguello David , Johnston Curtis , Drabick Joseph J. , Joshi Monika 
Published: September 2018

4535 Background: Immunotherapy (IO) is now standard of care for bladder and kidney cancer (CA) and is investigational in other GU CA such as prostate and germ cell CA. Tumor mutational load (TML) has correlated with response to IO in several tumor types. Herein, we explore TML across different histological subtypes in GU CA. In addition, we also assess the correlation between TML and PD-L1 status. Methods: 544 GU specimens were identified: bladder, 145; kidney, 164; prostate, 221; penile, 2; testicular, 12. TML was calculated using somatic non-synonymous missense mutations from a 592-gene panel (Illumina NextSeq). A high TML was > 17 mutations/MB. PD-L1 (SP142) was done depending tumor availability. Results: High TML was more prevalent in bladder CA (14.5%, 21/145) compared to other GU CA. Urothelial carcinomas had a noticeably high TML while squamous histology had a pronounced PD-L1 expression (Figure 1). A comparison of TML-high (n=15) versus TML-low (n=76) urothelial bladder CA showed the following differences (Figure 2). TML was rare in kidney CA (1.8%, 1/57); PD-L1 was high in sarcomatoid (33.3%, 5/15), CDC/RMC (28.6%, 2/7). Prostate adenocarcinoma had few TML-high (2.3%, 5/219) or PD-L1 expressing tumors (1.4%, 3/208). Tumors of penile or testicular origin lacked high TML and PD-L1 expression. No correlation was found between a high TML and PD-L1 expression. Conclusions: TML varied considerably amongst GU CA. As in other CA, TML-high scores did not predict PD-L1 expression and vice versa. Comprehension of the underlying biology may assist in determining which CA may respond better to IO. [Table: see text] [Table: see text]
Randomized study of intravesical chemotherapy using pirarubicin in patients with non-muscle-invasive bladder cancer in Japan: Comparing one immediate postoperative intravesical chemotherapy with short-term adjuvant intravesical chemotherapy after TURBT: Subanalysis in patients with intermediate risk.
Authors: Naya Yoshio , Mikami Kazuya , Takaha Natsuki , Okihara Koji , Miki Tsuneharu , Ukimura Osamu 
Published: September 2018

4536 Background: The objective is to evaluate the efficacy defining of 2-year tumor recurrence free rate of intravesical chemotherapy using pirarubicin (THP) for patients with intermediate risk. Methods: Between October 2010 and January 2015, 206 patients were enrolled in this study and finally 113 were randomized to one immediate postoperative intravesical instillation of THP 30mg (Group A), or additional intravesical instillation of THP 30mg weekly for 8 weeks after single postoperative instillation (Group B). The recurrent risk was stratified using EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2009 update. Of 113, 100 with intermediate risk were analyzed in this study. The patients were examined by cystoscopy and urine cytology every 3 months after trans urethral resection to determine bladder tumor recurrence. The primary endpoint was 2 year-recurrence-free survival rates. A statistical analysis was performed by SAS (SAS Institute Inc., Cary, USA). Results: The 2-year recurrence free survival rates were 66.2% in Group A and 86.1% in Group B, respectively (log rank test, p = 0.0043). In patients with recurrence score between 5 and 9, the 2-year recurrence free survival was 92.3% in Group B and 22.2% in Group A (log rank test, p = 0.0013). Cox regression analysis revealed that only additional instillation of THP was significant independent factor for recurrence free rate in patients with intermediate risk. There was no patient with progression during this period. Frequent adverse effects were frequent urination and micturition pain without severe adverse effect (Grade 3 or more). Limitation of this study is a failure to enroll sufficient number for statistical analysis. Conclusions: Additional instillation of THP 30mg weekly for 8 weeks reduced the risk of tumor recurrence without severe toxicity in NMIBC patients with intermediate recurrent risk.
Intra-patient heterogeneity in urothelial cancer (UC) circulating tumor cells (CTC) and PDL1 expression to identify biomarkers of response and new therapeutic targets: A pilot study.
Authors: Arafat Waddah , Stahlfeld Charlotte , Sperger Jamie M , Heninger Erika , Gopalakrishnan Dharmesh , Barata Pedro C. , Lamenza Marcelo , Devonshire Sarah , Hoxha Nita , Profusek Pam , Rini Brian I. , Ornstein Moshe Chaim , Garcia Jorge A. , Kyriakopoulos Christos , Lang Joshua Michael , Grivas Petros 
Published: September 2018

4537 Background: Recent use of immune checkpoint inhibitors (CI) has improved overall survival (OS) in a subset of patients (pts) with metastatic UC. Intra-patient tumoral heterogeneity and epithelial-to-mesenchymal transition has been hypothesized as a driver of treatment resistance to both chemotherapy and CI in UC. There is a critical need to evaluate heterogeneity in UC for biomarkers of treatment response and new therapeutic targets. Trop2 is hypothesized to play a role in UC progression and is the target of a new antibody-drug conjugate, IMMU-132 that is being tested in UC trials. We report the phenotypic comparison of PDL1 expression among CTC subpopulations in UC pts. Methods: Peripheral blood samples were collected from pts with UC treated at Cleveland Clinic and U. of Wisconsin. Immunomagnetic capture and CTC enumeration using both EpCAM and Trop2 from matched blood samples was performed in the VERSA platform. Protein expression for PDL1 in these CTC populations was quantified. Longitudinal analysis of UC pts treated with chemotherapy or CI is ongoing. Results: CTC were captured using EpCAM and Trop2 in all 10 pts in our initial cohort. The frequency of Trop2 CTC was higher than EpCAM CTC with a mean of 248 Trop2 CTC (range 2-1885) compared to 76 EpCAM CTC (range 1-632). PDL1 expression was more frequent in Trop2 CTC than EpCAM CTC. In two pts progressing on Atezolizumab, Trop2 CTC had a higher frequency of PDL1 expression compared to EpCAM CTC (85% vs 2% in pt 1 and 2% vs 0% in pt 2). In pts followed longitudinally, Trop2 CTC dropped from 1885 to 1 in a pt with response to Atezolizumab and PDL1+ CTC declined from 4 to 0. After 1 cycle of Carbo/Gem in another pt, EpCAM CTC declined from 46 to 3 while Trop2 CTC from 116 to 47. Conclusions: This is the first report of CTC heterogeneity in pts with UC identifying high frequency of Trop2 CTCs with variable expression of PDL1 across different pts. Early results from longitudinal analysis suggest CTC as potential predictive / pharmacodynamic biomarkers of treatment response. Prospective data validation in larger cohort is ongoing, while IMMU-132 clinical trials in UC may provide context for future validation.
Effectiveness of the Moreau strain of Bacillus Calmette-Guerin (BCG) for nonmuscle invasive bladder cancer.
Authors: Chade Daher Cezar , Machado Andre , Waksman Ricardo , Garcia Guilherme , Esteves Paulo , Adonias Sanarelly , Botelho Luis , Cordeiro Mauricio , Murta Claudio , Ribeiro-Filho Leopoldo , Sarkis Alvaro , Bastos Diogo Assed , Dzik Carlos , Srougi Miguel , Nahas William Carlos 
Published: September 2018

4539 Background: Intravesical instillation therapy of Bacillus Calmette-Guerin (BCG) for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) after complete transurethral resection has been widely shown to be more effective than any other adjuvant treatment. However, there are several different BCG strains not appropriately evaluated in clinical setting, but in current use. BCG Moreau is by far the most utilized strain in Brazil and has been recently introduced to the European market to cover the issue of BCG shortage, but there is insufficient data regarding its oncologic efficacy. Methods: We retrospectively analyzed 336 consecutive patients, who received adjuvant intravesical instillation therapy with BCG Moreau for intermediate- and high-risk NMIBC between January 2005 and February 2015 at a single institution. The end points of this study were time to first recurrence and progression to muscle-invasive disease. Results: Median age was 62 years (interquartile range 54-76, mean 64.3 years). In addition to induction BCG therapy, 228 (67.9%) patients received maintenance BCG. However, 35 (15.4%) patients interrupted maintenance BCG due to toxicity. Overall, after at least a complete induction BCG therapy, 87 (25.9%) patients presented with disease recurrence and 33 (9.8%) patients had disease progression. When analyzing on patients who received BCG maintenance in addition to induction therapy, 31 (13.6%) patients had disease recurrence and 10 (4.4%) had disease progression. The 5-year recurrence-free survival and progression-free survival rate was 69.8% (95% CI 52.8-77.2) and 86.2% (95% CI 69.9-93.2), respectively. Conclusions: BCG Moreau has shown to be safe and effective as adjuvant intravesical treatment in intermediate and high-risk NMIBC patients. Since results are comparable to other strains, wider use of BCG Moreau may be encouraged and prospective clinical trials stimulated for higher level of evidence.
Activity of RX-3117, an oral antimetabolite nucleoside, in subjects with metastatic bladder cancer resistant to gemcitabine: Preliminary results of a phase Ia/IIb study.
Authors: Gong Jun , Chung Vincent M. , Picus Joel , Tagawa Scott T. , Gupta Sumati , Poore Julie , Peterson Christine , Benaim Ely , Pal Sumanta K. 
Published: September 2018

4544 Background: RX-3117 is an oral small molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Preliminary data from an analysis of a phase 1b/2a clinical study of RX3117 in metastatic bladder cancer is described. Methods: This phase 1b/2a study (NCT02030067) was designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle in a 2-stage design. Eligible subjects (aged ≥ 18 years) were those with relapsed/refractory metastatic bladder cancer with any number of prior therapies. Prior therapy with platinum-based chemotherapy was required. The primary endpoint was to assess the efficacy and safety of RX-3117 in metastatic bladder cancer, with secondary aims of evaluating PFS and CBR. Results: With 9 subjects enrolled, median age was 66 years, ECOG PS was 0-1. All subjects had received gemcitabine/cisplatin in the perioperative or metastatic setting, and 4 subjects had received 3 or more prior therapies. The most frequent related adverse events were anemia, mild-moderate fatigue, vomiting and diarrhea. No dose limiting toxicities were observed. PFS and CBR will be presented at the meeting, as 5 subjects continue to receive therapy at the time of this submission. One subject continues on treatment at 139 days with persistent stable disease. Molecular profiling of his bladder tumor showed alterations in ARID1A, FBXW7, FGFR3, NF1, and TERT. The patient previously responded to an FGFR3 inhibitor but progressed after 9 months, with ctDNA assessments showing incurrence of TP53 alteration. Clinical benefit with RX-3117 was achieved in spite of incurrence of this alteration. Conclusions: RX-3117 demonstrated an excellent safety profile, and prolonged stable disease was seen in 1 subject who failed prior cisplatin/gemcitabine and FGFR3 inhibition. Activity persisted despite development a putative resistance alteration detected by ctDNA. Clinical trial information: NCT02030067.
Life expectancy 20 years after cisplatin-based treatment for testicular cancer (TC).
Authors: Lubberts Sjoukje , Kruyt Lara M. , Steggink Lars Christiaan , Steursma Gerrie , Nuver Janine , Oosting Sjoukje , van Ginkel Robert J. , de Jong Igle J. , Eulenburg Christine , Lefrandt Joop D. , Meijer Coby , Sluiter Wim J. , Gietema Jourik A. 
Published: September 2018

4550 Background: Four decades have passed since the introduction of cisplatin-based chemotherapy for metastatic TC, providing the opportunity to evaluate very long-term survival. Although 80-90% of the patients are cured, the effect of treatment on residual life span is unknown. Aim of the study was to investigate life expectancy after TC treatment: from prolonging survival after cancer diagnosis, focus shifts to regaining a normal residual life span. Methods: Patients with metastatic TC treated with cisplatin-based chemotherapy > 20 years ago (1977 - 1996) at the University Medical Center Groningen were included. Survival status and cause of death were obtained from medical records, Netherlands Cancer Registry and general practitioners. Events were defined as death due to any cause (overall mortality) and death due to TC or TC treatment complications (TC specific mortality). Standardized mortality ratios (SMR) were calculated as ratio between observed and expected deaths, derived from the age-matched nationwide male population (Dutch Central Office of Statistics). SMRs were calculated for overall mortality, non TC specific mortality (censoring death from TC or treatment-related complications), mortality from cardiovascular disease (censoring death from other causes than cardiovascular disease (ICD-10 I0-I99)) and mortality from secondary malignancies (censoring death from other causes than secondary malignancies (ICD-10 C0-C99 excluding C62: TC)). Results: We included 321 metastatic TC patients with a median age of 28 years (range 16 - 64) at start of chemotherapy. After a median follow-up of 25 years (range 0 - 38) 106 patients died (33%). SMR for overall mortality was 4.0 (95% CI 3.6 - 4.4) and for non TC specific mortality 1.5 (95% CI 1.1 - 1.9). SMR for secondary malignancies was 1.7 (95% CI 1.0 - 2.2) and for cardiovascular diseases 1.5 (95% CI 0.7 - 2.2). Median age at death was 5-10 years lower in TC patients than expected. Conclusions: Twenty years after cisplatin-based chemotherapy, TC patients have a 50% increased risk of dying from non TC causes compared to the general population. These findings suggest that cisplatin-based treatment for TC comes at the expense of about 7.5 life years and induces early aging.
Phase II-study of sequential high-dose-chemotherapy with paclitaxel, ifosfamide, carboplatin, etoposide( P-ICE) in patients with relapsed or refractory germ cell tumors (GCT).
Authors: Kegel Thomas , Cygon Franziska , Meinert Fabian Maximilian , Hammad Khaled , Steinbach Frank , Seseke Florian , Schmoll Hans-Joachim 
Published: September 2018

4552 Background: High-dose chemotherapy (HD-CTx) is an active option for salvage chemotherapy in patients (pts) with refractory or relapsed GCT. All previous trials with HD-CTx used one or two cycles of high dose chemotherapy (CTx) including 2 or a maximum of 3 drugs. Another potentially more active option is the application of four sequential HD-CTx cycles (Schmoll et al, JCO 2003). Methods: We conducted a phase II trial of 1(-2) cycle(s) induction CTx with standard dose P-ICE (Paclitaxel 135mg/m² d1, Ifosfamide 1500mg/m² d1-3, Carboplatin 150mg/m² d1-3, Etoposide 150mg/m² d1-3), followed by 4 sequential cycles of HD-P-ICE (Paclitaxel 200mg/m² d1, Ifosfamide 3300mg/m² d1-3, Carboplatin 330mg/m² d1-3, Etoposide 330mg/m² d1-3). Eligibility criteria: relapse or progression under one or more induction CTx, ECOG PS (0-1), Creatinine-clearance > 30ml/min, adaequate liver function, measurable tumor or at least marker-elevation. Results: 37 pts entered the trial and 33 are evaluable (4 pts never received HD-CTx due to lack of stem cells (3) or medical reasons (1)). Prior CTx:1 (N = 26), 2 (N = 4), 3 (N = 3); primary extragonadal: 6; seminoma/ non-seminoma 5/28; ECOG-PS: 0 (19), 1 (14). Response rate: CR/NED 17 (51.5%), CR/NED/PR-/SD- with marker normalization 21 (63.6%), PD 12 (36.4%). DFS of CR/NED: median 59 (8-105) months; RFS of all favourable responders 60 (8-105) months, PFS total 46 (2-105) months. OS for all pts. 51 (6-105) months, OS Favourable Responders: 65 (23 – 105), Nonfavourable Responders: 11 (6-27) months,. Toxicity was tolerable without treatment related death, with mainly grade 4 bone-marrow toxicity and grade 2 mucositis and/or diarrhea. Conclusions: Sequential HD-CTx with one cycle of SD-P-ICE and four cycles HD-CTx is feasible with acceptable toxicity and favourable efficacy. Sequential HD-CTx using the four most active drugs might be a potentially option for this pts-population due to good tolerability, applicability and interesting long-term outcome. Comparison of the standard approach with 1 to 3 sequential high dose cycles of Carboplatin/Etoposide is ongoing (TIGER-Trial). Clinical trial information: EUDRA-CT: 2006-006004-11.