bluuebunny/crossref_metadata_2025 huggingface dataset:
Histology and stage at presentation among patients with rare pancreatic tumors: An exploratory analysis of the SEER database.
Authors: Subramoney Jay , Delgado David J. , Nguyen Victoria , Denneny Rachel Gray , George Brandon , Mitchell Edith P.
Published: May 2019

e15774

Background: Rare pancreatic tumors account for approximately 15% of all pancreatic cancers (PCs) and 8,300 new cases diagnosed within the United States annually, while 85% of PCs diagnosed are classified as adenocarcinomas. Comparatively little research exists to analyze differences in diagnosis between rare PCs and the more common adenocarcinoma given greater clinical interest in the latter. The purpose of this study was to analyze the relationship between PC histology and stage at presentation with a focus on rare histologies. Methods: This study employed a retrospective cohort model using the NCI’s Surveillance, Epidemiology, and End Results (SEER) 1990-2015 database. We included patients diagnosed with PC aged 18+, with the comparator group being patients diagnosed with adenocarcinoma, and “rare” tumors defined as one of the following histologies: ductal, carcinoid, mucinous adenocarcinoma, and undetermined neoplasm. Stage was dichotomized (locoregional versus distant). Multivariable logistic regression was used to describe the association between tumor histology with initial stage at diagnosis, controlling for patient and tumor characteristics. Results: 90,764 PC patients were analyzed: 66.3% adenocarcinoma, 9.6% ductal carcinomas, 4.5% carcinoid, 3.8% mucinous, and 15.8% undetermined neoplasm. 54.7% of all cases were distantly metastasized at diagnosis. In multivariable analysis, pancreatic cancer patients with mucinous histology had greater odds of presenting at late-stage compared to those with adenocarcinoma: OR = 1.41, 95% CI = [1.31, 1.52]. Carcinoid and undetermined neoplasm odds for late stage presentation were not significant compared to adenocarcinoma: OR = 0.99, 95% CI = [0.92, 1.07] and OR = 1.01, 95% Cl = [0.97, 1.05] respectively. Ductal carcinoma was less likely than adenocarcinoma to present with late stage: OR = 0.38, CI = [0.36, 0.40]. Conclusions: We observed that mucinous histology had greater odds of late-stage diagnosis compared to those with adenocarcinoma. Patients with ductal carcinoma was less likely than those with adenocarcinoma to present with late stage. Further investigation is needed to explore the reasons for these differences.
Impact of KRAS mutations in clinical features and survival in pancreatic cancer patients: A single institution experience.
Authors: Saavedra Elizabeth Inga , Gomez Maria Auxiliadora , Cano Maria Teresa , Perdomo Eduardo , Toledano Marta , Aranda Enrique
Published: May 2019

e15779

Background: Pancreatic cancer (PC) is currently one of the most lethal tumors. In recent years, although improvements have been developed in the detection and treatment of this disease, the 5-year survival is less than 10%. KRAS plays a key role in ras/mitogen-activated protein kinase signaling. Somatic mutation in KRAS mutations have been shown to be early events in the carcinogenesis of PC. KRAS mutations as a prognostic factor for PC remains inconclusive. Methods: We performed a retrospective study of our patients (pts) to demonstrate the impact of KRAS mutations in clinical features and survival in real-life clinical practice. This was an observational study of all patients with histological confirmed PC referred to Medical Oncology between April 2017 to December 2018 and followed until February 2019. KRAS mutations were analyzed by sequencing codons 12, 13, and 61 in diagnostic tumor tissues from formalin fixed paraffin embedded tissue using PCR and liquid biopsy test (BEAMing technology). Categorical variables were statistically analyzed with Fisher’s exact test and continuous variables with T-student for differences between both groups. Survival was analyzed by Kaplan–Meier estimation and log-rank testing while Cox regression was used to estimed hazard ratios. Results: Our study cohort was 64 pts. 43% of pts died, the most die at home (25%). Median follow-up was 552 days (18 months). Metastatic pts had an expected overall survival (OS) of 376 days, locally advanced 525 days and localized stage 592 days but not statistically significant difference (p = 0.11). Wild-type pts had an expected OS of 559 days and KRAS mutated 389 days with statistically significant difference. (p = 0.032). Conclusions: KRAS mutations are associated with a poorer survival in patients with pancreatic cancer in all stages. These results suggest that KRAS mutations may be an important biomarker in determining response and prognosis in patients with high risk and in developing specific treatments for these patients in clinical applications.[Table: see text]
A retrospective analysis of antibiotics usage and effect on overall survival and progressive free survival in patients with metastatic pancreatic cancer.
Authors: Mohindroo Chirayu , Rogers Jane E. , Hasanov Merve , Mizrahi Jonathan , Overman Michael J. , Varadhachary Gauri Rajani , Wolff Robert A. , Javle Milind M. , Fogelman David R. , Pant Shubham , McAllister Florencia
Published: May 2019

e15781

Background: Recent studies have shown that the pancreatic ductal adenocarcinoma (PDAC)-associated gut microbiome can play a major in modulating responses to therapies. Antibiotics (ATB) can potentially alter the tumor and gut microbiota diversity and composition leading to modified responses to chemotherapeutic/immune therapy regimens and hence the survival. Methods: We retrospectively analyzed the clinical data of 148 patients (pts) with documented metastatic PDAC seen at MD Anderson Cancer (MDACC) from 2009 to 2017. Along with demographic and chemotherapy regimen details the duration, type and reason for antibiotic consumption for more than 3 days were recorded. Overall survival (OS) and Progression free survival (PFS) were calculated. Log-rank test and Gehan-Breslow-Wilcoxon test were used to check the statistical significance for OS and PFS. Confounding variables were also accounted. Results: We analyzed the data of 148 metastatic pancreatic cancer pts[mean age 62.73, 50.67% males 49.32% females, 75.6% white] out of which 135 patients received antibiotics. The infectious sources consisted of intraabdominal (n = 68), urinary (n = 36), respiratory (n = 57), skin/soft tissue infections (n = 26), blood related (n = 24), and others (n = 76). Beta lactams (n = 96) and Quinolones (n = 96) were the most commonly prescribed antibiotics. When comparing outcomes, we found out that the median OS for pts taking macrolides (n = 24) was 541 days compared to 341 days for pts not taking macrolides (n = 144) (HR = 0.6384, p value = 0.0191) . Median PFS for pts taking macrolides was 178 days versus 124 days in those not taking macrolides (HR = 0.6331, p value = 0.0188). The potential confounders were having a respiratory infection or the type of chemotherapy regimen. Conclusions: Macrolide consumption for > 3 days leads to a prolonged OS and PFS. Consistent with the preclinical evidence our data suggests a potential role for some antibiotics in modulating PDAC-associated gut microbiome. Hence, having implications on the survival of PDAC pts. [Table: see text]
Effect of targeting CD40 for DC vaccination in pancreatic adenocarcinoma.
Authors: Lau Sai Ping , van Montfoort Nadine , Kinderman Priscilla , Lukkes Melanie , Dumas Jasper , van Nimwegen Menno , Mustafa Dana , Vroman Heleen , van Hall Thorbald , van der Burg Sjoerd H. , Aerts Joachim G.J.V. , Dammeijer Floris , van Eijck Casper H.J.
Published: May 2019

e15783

Background: Although immunotherapy yields striking results in various malignancies, results in pancreatic cancer have been disappointing. Both a highly immunosuppressive tumor microenvironment and a dense desmoplastic stroma have been found to prohibit proper T-cell infiltration in these tumors, thereby preventing immunotherapy efficacy. We hypothesize that a rational and translational multistep approach is needed to sensitize pancreatic cancer to immunotherapy. In an aggressive murine pancreatic ductal adenocarcinoma model, we assessed the effectiveness of dendritic cell (DC) vaccination in combination with αCD40 treatment, as these treatments are known to induce effector T cells and degrade stroma, respectively. Methods: Immune competent C57BL/6 mice were inoculated subcutaneously with pancreatic tumor cells (KPC3). Mice with established tumors were vaccinated with tumor-loaded monocyte derived DCs and consequently treated with αCD40 agonistic antibodies. Tumor sizes were monitored over time. Immune responses were determined by flow cytometry of cells in peripheral blood, spleen and tumor. NanoString Technologies were applied on tumor samples. Results: A significant delay in tumor growth was found in the combination therapy arm compared to untreated mice and mice treated with DCs or αCD40 alone. Monotherapy had no effect on tumor growth. Survival of mice treated with the combination therapy was also improved compared to untreated mice or mice treated with monotherapy (P < 0.001). Interim blood analysis showed significant increases in frequencies of activated and proliferating T cells in treated animals and those cells also displayed an effector memory phenotype. This was more pronounced for CD4 T cells in mice treated with DCs while αCD40 therapy induced a confined response in CD8 T cells. Increased frequencies of tumor infiltrating lymphocytes were found in all treated mice compared to untreated mice. mRNA expression analysis indicated less exhausted phenotype of intratumoral lymphoid cells in mice treated with DCs and αCD40 compared to monotherapy DCs or αCD40. Conclusions: These results demonstrate the potency of this novel form of combination immunotherapy and reveals a mechanistic insight into the requirements of effective immunotherapy in pancreatic cancer.
Modified FOLFIRINOX as a second-line treatment in pancreatic adenocarcinoma patients with poor performance status.
Authors: Das Adarsh , Dean Andrew Peter , Higgs Domenic
Published: May 2019

e15796

Background: FOLFIRINOX is well known to be a highly effective treatment in pancreatic cancer for young patients with good performance status. As the original ACCORD study was carried out with patient’s performance status 0 or 1, many oncologists feel uncertain administering modified dose FOLFIRINOX (m-FOLFIRINOX) as a second-line therapy. We have previously reported our experience in 35 patients (aged 27 – 85) where we concluded that m-FOLFIRINOX can be administered safely with appropriate dose reductions. More recently, the systematic review and meta-analysis by Tong et al. concluded that m-FOLFIRINOX is a good choice of therapy even for those with poor performance status. This retrospective analysis assessed the efficacy of m-FOLFIRINOX in second-line treatment of pancreatic adenocarcinoma. Methods: Using an electronic database, patients with either locally advanced or metastatic pancreatic adenocarcinoma were identified who had received first-line gemcitabine plus nab-paclitaxel, followed by second-line m-FOLFIRINOX between January 2013 and July 2018. All patients had an ECOG performance status of 2 or less. Overall survival (OS) was estimated by the Kaplan-Meier method. Results: Fifty-two patients were identified, with 65% of the patients having metastatic pancreatic disease. Median age of patients was 75 (range, 27 – 86). Dose intensity of m-FOLFIRINOX was 65% for oxaliplatin, 68% for irinotecan, 18% for bolus 5-fluorouracil (5-FU) and 68% for infusional 5-FU. From diagnosis, the median OS of all patients was 45.0 months (95% CI, 25.0 – 63.0). The median OS of the locally advanced and metastatic pancreatic adenocarcinoma was 63.0 months (95% CI, 45.0 – 70.0) and 22.5 months (95% CI, 18.0, 38.0), respectively. Conclusions: Our study demonstrates the safety and efficacy of m-FOLFIRINOX as a second-line therapy after gemcitabine plus nab-paclitaxel failure. These findings correlate with the findings of Tong et al.’s findings of the benefits of m-FOLFIRINOX for advanced pancreatic cancer in patients with poor performance status.
Pilot study of [18F] fluorodexoyglucose positron emission tomography-magnetic resonance imaging (FDG-PET-MRI) for staging of muscle-invasive bladder cancer.
Authors: Eulitt Patrick , Altun Ersan , Sheikh Arif , Wong Terence Z. , Woods Michael , Rose Tracy L , Wallen Eric , Pruthi Raj , Smith Angela , Nielsen Matthew Edward , Whang Young E. , Kim William Y. , Godley Paul Alphonso , Basch Ethan M. , David Grace , Ramirez Juanita , Deal Allison Mary , Lee Joseph , Milowsky Matthew I.
Published: May 2019

e16002

Background: Standard of care imaging for staging MIBC is computed tomography (CT) abdomen and pelvis despite poor diagnostic accuracy. The addition of FDG-PET to evaluate biologic activity has been shown to improve detection of metastatic bladder cancer. Better soft tissue characterization with MRI may improve detection of local disease. We hypothesized that simultaneous acquisition of FDG-PET and MRI images (PET-MRI) would allow for more accurate preoperative staging in patients with MIBC. Methods: 21 patients with MIBC and planned radical cystectomy with lymph node dissection were enrolled. Four radiologists (2 senior, 2 junior) with expertise in MRI and PET independently reviewed MRI and FDG-PET scans, respectively, to determine: 1) extent of the primary bladder tumor; and 2) involvement of local lymph nodes and distant sites of disease. Combined radiologist reads were performed (senior MRI and junior PET and vice versa). Imaging results were compared to surgical pathology. Results: 18 patients were included in the final analysis (3 PET-MRI scans excluded due to technical pitfalls with image acquisition). Final pathology revealed 10 patients (56%) with muscle invasion and only 2 patients (11%) with lymph node involvement. Combined analyses of PET-MRI accurately detected the extent of the primary tumor (sensitivity 0.84, specificity 0.50, PPV 0.70, NPV 0.70), but was less accurate for the detection of lymph node involvement (sensitivity 0.00, specificity 1.00, no calculable PPV, NPV 0.91). Senior MRI radiologist had improved PPV and NPV for extent of primary tumor compared to junior MRI radiologist (PPV 0.71 vs 0.56, NPV 0.83 vs. 0.50), and senior PET radiologist had improved PPV with similar NPV for extent of primary tumor (PPV 1.00 vs 0.78, NPV 0.50 vs 0.55). No patient was determined to have distant metastatic disease. Conclusions: To our knowledge, this is the first study exploring the use of PET-MRI for staging MIBC. This novel imaging modality demonstrated promise in detecting the extent of the primary tumor. Further investigation of FDG-PET-MRI is needed to better determine its potential utility in staging MIBC.
Carboplatin-based chemotherapy (C) versus immunotherapy (IO) in metastatic urothelial carcinoma (mUC).
Authors: Feld Emily , Harton Joanna , Meropol Neal J. , Adamson Blythe J.S. , Parikh Ravi Bharat , Galsky Matt D. , Cohen Aaron B. , Narayan Vivek , Christodouleas John Paul , Vaughn David J. , Hubbard Rebecca A. , Mamtani Ronac
Published: May 2019

e16003

Background: There are limited data comparing first-line (1L) C versus IO in cisplatin-ineligible mUC patients. The primary evidence guiding treatment decisions was a May 2018 Food and Drug Administration (FDA) safety alert based on early review of two ongoing phase III trials, reporting shorter survival in PD-L1 negative patients receiving IO relative to chemotherapy. Final results from these trials are unknown and may not be applicable to a real-world cohort. Methods: We conducted a retrospective cohort study of mUC patients receiving 1L C or IO from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record-derived database. The primary outcome was overall survival (OS) from start of 1L treatment to date of death. We compared 12- and 36-month OS, and hazard ratios before and after 12 months. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier (KM) and Cox multivariable regression model estimates of comparative-effectiveness. Results: Of 2,243 patients, 562 received IO and 1,681 received C. Baseline characteristics were balanced between groups, with few exceptions (Table). In the first 12 months, IO was associated with an increased hazard of death compared to C (HR 1.38, 95% CI 1.16-1.66). Among patients who survived one year, survival was improved with IO compared to C (HR 0.50, 95% CI 0.27-0.92). Conclusions: In routine clinical practice, 1L IO was associated with inferior 12-month OS relative to C, but superior OS beyond 12 months. Clinicians and patients should carefully consider how to balance the early benefit of C against the late benefit of IO. Currently pending trial results will contribute additional evidence to inform treatment decision making. [Table: see text]
Two sequential dose-dense regimens of CGP, followed by MVAC in patients with metastatic urothelial carcinoma (mUC): A single institution, explorative trial.
Authors: Donini Maddalena , Brighenti Matteo , Giganti Maria Olga , Panni Stefano , Perrucci Bruno , Pizzo Claudio , Gerevini Fabiana , Foramitti Marina , Marchi Gianluca , Potenzoni Michele , Prati Andrea , Quarta Matteo , Benecchi Luigi , del Boca Carlo , Passalacqua Rodolfo ,   MEDeA MEDicina e Arte, Onlus Cremona
Published: May 2019

e16023

Background: Currently, cisplatin, gemcitabine, paclitaxel (CGP) and MVAC are the most active chemotherapy regimens in mUC. We tested the hypothesis that two sequential non-cross-resistant, dose-dense (DD) regimens may target different cancer cells, avoid drug resistance, and improve response rate. Methods: This is a single institution, explorative trial. The aim is to evaluate the incremental benefit of the two regimens in terms of complete response and long term survival. We treat all consecutive, chemo-naïve mUC patients with 4 cycles of CGP dose-dense every 14 days followed by 4 cycles of MVAC every 14 days. In all cycles we used Pegfilgrastim 6 mg on day 3. Pts were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for 2 years and 6 months thereafter. Results: From 2007 to 2018, 67 consecutive pts were included. Male were 82%; median age 66 years (33-83); Bajorin risk factors was 0 in 31%, 1 in 52%, 2 in 16%. The majority of pts were hospitalized for three days during chemotherapy and received hydration and supportive therapy. After the first 4 cycles of CGP, we observed 7% CR, 46% PR, 31% SD, and 12% PD. After the 4 sequential cycles of MVAC DD we observed a global 25% of CR, 33% PR, 10% SD, and 24% PD. Median TTP was 8.2 months (95% CI, 7.3-10.1) and median OS was 18 months (95% CI, 10.8-26.1). 5 pts are still alive after more than 30 months and maintaining complete response. Main grade 3–4 toxicity included anemia 27%, asthenia 23%, neutropenia 19% (febrile 7%), thrombocytopenia 13%. Conclusions: The sequential use of these two DD regimens is active and leads to an increased number of complete response and possible longer survival. A randomized trial is needed to confirm our results.
Does neutrophil to lymphocyte ratio correlate with toxicities and outcome of patients with genitourinary cancers treated with checkpoint inhibitors?
Authors: Maruzzo Marco , Pierantoni Francesco , Basso Umberto , Deppieri Filippo Maria , Dionese Michele , Lamberti Evelina , Gardiman Marina , Pizzirani Enrico , Gardi Mario , Porreca Angelo , Zattoni Filiberto , Zagonel Vittorina
Published: May 2019

e16032

Background: Few data are available concerning the role of neutrophil and lymphocyte counts in predicting toxicities and outcome in patients (pts) with genitourinary cancer treated with recent immunotherapy. Methods: We retrospectively reviewed the clinical charts of all pts with metastatic renal cell (RCC) or urothelial cancer (UC) treated at our Institute with immunotherapy(Nivolumab with or without Ipilimumab, Atezolizumab, Durvalumab, Pembrolizumab), having at least one response assessment after starting treatment. Results: We identified 117 pts treated from May 2015 onwards, median age: 68 years (range 39-84), 72% males, 53% with UC. Incidence of G3/4 toxicities was 17%, while 23.9% of pts needed an high dose steroid treatment because of immune-related toxicities (IrT). Median PFS and OS were 7.0 and 24.1 months, respectively for RCC, and 2.8 and 7.1 months, respectively for UC. 56 pts had progressive disease at best response. Baseline value of neutrophils or lymphocytes does not correlate with IrT (t test, p = 0.399, p = 0.728, respectively). In the IrT events, no significant increase of lymphocytes was detected (p = 0.160). The incidence of a IrT which needed steroid treatment positively impact in PFS (p = 0.03) but not in OS (p = 0.74). The use of steroid therapy was not associated with a different outcome in terms of OS (p = 0.49 for UC and p = 0.18 for RCC) and associated with a better PFS in RCC (p = 0.018). Steroid use was associated with the probability of non-progressive disease at first assessment (Chi-squared test, p = 0.015). In our cohort, baseline neutrophil to lymphocyte ratio (NLR) ≥ 3 correlate with a shorter PFS and OS in UC (p = 0.026 and p = 0.003 respectively), while it does not in RCC (p = 0.104 and p = 0.678 respectively). In our cohort, baseline neutrophil to lymphocyte ratio (NLR) ≥ 3 correlate with a shorter PFS and OS in UC (p = 0.026 and p = 0.003 respectively), while it does not in RCC (p = 0.104 and p = 0.678 respectively). In UC, the positivization of NLR after 2 cycles predicts a shorter PFS for UC (p = 0.008) and a trend for OS. Conclusions: In our retrospective single-center experience, NLR confirms its role in UC even in a cohort treated with immunotherapy and its variation predicts shorter outcome, while neutrophils or lymphocytes do not relate with IrT. The use of steroid for IrT is safe since it does not impact on survival and is associated with a higher probability of non-progressive disease at first assessment.
Trend in the use of neo-adjuvant chemotherapy for the management of muscle invasive bladder cancer at a major tertiary care hospital in Pakistan.
Authors: Jabbar Adnan Abdul , Maqbool Muhammad Asad , Mirza Muhammad Bilal
Published: May 2019

e16033

Background: Although the use of Neoadjuvant Chemotherapy (NAC) has now become the standard of care for Muscle Invasive Bladder Cancer (MIBC) in the world, most patients in lower- middle-income countries (LMIC), like Pakistan, are still undergoing upfront surgery despite being ideal candidates for chemotherapy. Multi-disciplinary tumor boards have been critical in the change of this trend in the developed world. We aimed to assess the trends in the use of NAC for patients with muscle invasive bladder cancer before undergoing definitive surgery. Methods: We included patients who underwent surgery for ≥ cT2 MIBC without distant metastasis between 2011 and 2015 at a tertiary care hospital in Karachi, Pakistan. We retrospectively assessed the trends in NAC compared to upfront surgery in these patients. Results: Among the 171 patients included in our study, only 4 (2.34%) received NAC, whereas the other 167 (97.67%) underwent upfront surgery without NAC. Out of the 90 patients who underwent surgery for MIBC between 2011 and 2013, none of them received NAC and underwent upfront surgery. Among the 81 patients with MIBC in 2014 and 2015, 4 patients received NAC before surgery whereas the other 77 underwent upfront surgery. Conclusions: The adoption of NAC for MIBC remains a challenge in lower- middle-income countries such as Pakistan. Introduction of a multidisciplinary tumor board in our hospital since 2014 has shown a slight change in this trend. Better communication between different departments remains the key in significantly changing the trend of a much desired standard of care.
Pretreatment eosinophil counts (PEC) in metastatic urothelial carcinoma (mUC) treated with anti-PD1/PD-L1 checkpoint inhibitors (CPI).
Authors: Mota Jose Mauricio , Teo Min Yuen , Whiting Karissa , Ostrovnaya Irina , Li Han , Lee Chung-Han , Funt Samuel Aaron , Callahan Margaret K. , Iyer Gopa , Bajorin Dean F. , Rosenberg Jonathan E.
Published: May 2019

e16035

Background: Eosinophils may influence anti-tumor immunity, having been associated with outcomes in CPI-treated melanoma. We sought to examine the association between PEC and outcomes of CPI-treated mUC. Methods: Independent CPI-treated cohorts were identified: discovery (n = 60, Teo et al JCO 2018) and validation (n = 111, non-overlapping CPI-treated mUC patients [pts] from 2014-19). Uni- and multivariate analyses were performed using Cox proportional hazard models to evaluate prognostic value of PEC on (i) overall survival (OS) and (ii) time on treatment (ToT). A platinum-treated metastatic cohort (n = 81, Teo et al, CCR 2017) was used as non-CPI comparator. Results: The cohorts showed comparable OS and pts characteristics, except higher proportion of females and lower neutrophil at baseline (Neut) in the validation cohort. In the discovery cohort, PEC as a continuous variable showed a significant positive association with OS (HR 0.01, 95% CI 0.00-0.29, P = .009). PEC of 100 cells/µL was set as the optimal cut-off point (Eos-L: < 100 cells/µL, n = 9; Eos-H: ≥100 cells/µL, n = 51). Eos-L showed inferior outcomes (OS: HR 3.98, 95%CI 1.85-8.56, P < .001; ToT: HR 2.45, 95%CI 1.17-5.10, P = .017). Similar association was seen in the validation cohort (Eos-L, n = 17; Eos-H, n = 94; OS: HR 2.51, 95%CI 1.31-4.80, P = .006; ToT: HR 2.22, 95%CI 1.29 - 3.80, P = .004). A multivariate model adjusting for other prognostic variables was created (table). In the chemotherapy cohort, continuous Eos or Eos-L was not associated with OS/ToT, with or without adjusting for known prognostic factors (P > 0.5). Conclusions: The association between Eos-L and shorter OS in CPI- but not chemotherapy-treated cohorts might represent a potential negative predictive biomarker for CPI in mUC. [Table: see text]
Different expression and prognostic implications of PD-L1 in tumor cells and immune cells with the SP263 monoclonal antibody in Chinese urothelial carcinoma patients.
Authors: Zhong Qiaofeng , Zhou Ai-Ping , Shou Jianzhong , Ying Jianming , Shi Yuankai , Yu Yue , Ling Yun , Shen Zhirong , Zhang Yun
Published: May 2019

e16040

Background: PD-L1 is expressed on tumor cells (TC) and tumor immune cell (IC) infiltrates. The aim of this study was to explore the expression and the clinical implications of PD-L1 in TC and IC with the SP263 monoclonal antibody and the correlation with clinicopathological features and survival prognosis in urothelial carcinoma(UC) patients. Methods: Formalin-fixed paraffin embedded tumor specimens were collected from 172 patients with UC who received nephroureterectomy or cystoscope biopsy in our center from 2009 to 2016. Tumor samples were evaluated for PD-L1 membrane expression by immunohistochemistry (IHC) using VENTANA PD-L1 (SP263) Assay performed on the automated BenchMark ULTRA platform. PD-L1 expression status was determined by PD-L1 membranous staining at any intensity on TC or IC.PD-L1 is defined as positive if either ≥25% TC or ≥25% IC express membranous PD-L1.Data was analyzed by SPSS software. Results: Among 162 patients, TC and IC infiltrate PD-L1 positivity were detected in 16 (9.9%) and 45 cases (27.8%), respectively. The PD-L1 positivity of TC in female (19.4%) was higher than that in male (7.1%), P = 0.029, and so was in the patients with lymph node metastasis (20.7%) than those without metastatic lymph node (7.5%) , P = 0.031.While these correlation were not observed with PD-L1 positivity in IC. PD-L1 positivity both in TC and IC were not related to age, smoking history, specimen type , tumor size , histology grade, pT, pN stage (P > 0.05) .With a median follow-up of 60.9 months, patients with positive PD-L1 expression in IC have more favorable DFS (NR vs 26.3 months, P = 0.032) and OS (NR vs 71.2 months, P = 0.001) than those with negative PD-L1 expression in IC. More significant differences in DFS (NR vs 18 months, P = 0.002) and OS (NR vs 29.8months,P < 0.001) were observed in patients with T2-4 and PD-L1 positive expression. However, We did not find a statistically correlation between PD-L1 positivity in TC and prognostic outcomes. Univariate and multivariate analyses revealed that patients with PD-L1 positive expression in TC had poorer DFS (HR = 2.573; 95% CI, 1.246–5.313;P = 0.011). Whereas positive PD-L1 expression in IC independently correlated with better OS (HR = 0.303; 95% CI, 0.137–0.671;P = 0.003). Conclusions: PD-L1 positivity in IC is higher than TC in urothelial tumor. Positive PD-L1 expression in IC is associated with better OS and DFS while no correlation between PD-L1 positivity in TC and outcome was observed.
Management of stage I seminomatous germ-cell cancer (SGCC): Results from 4 different risk-adapted strategies in a single institution.
Authors: Riudavets Mariona , Anguera Georgia , Camacho Daniela , Bujosa Aida , Terés Raul , Borrell Maria , Gallardo Pablo , Martin Berta , Molto Consolacion , del Carpio Luis , Martin Cristina , Sancho Gemma , Algaba Ferran , Palou Joan , Maroto Pablo
Published: May 2019

e16047

Background: Management of stage I SGCC depends on pathological findings after orchiectomy. Four risk-adapted strategies were sequentially applied in a single institution during a 24-year (yr) period according to national guidelines. Here, we compare treatment burden and outcomes of each of them. Methods: From 1/1994 to 1/2018, 208 patients with stage I SGCC were prospectively included in 4 cohorts. Those without risk criteria underwent close surveillance. Patients received active treatment as follow: Group 1: 1994-1999, only patients with T > pT1 received 2 cycles of carboplatin (CBDCA AUC7 x2); Group 2: 1999-2003, patients received CBDCA AUC7 x2 if either tumor size > 4cm or rete testis invasion; Group 3 : 2004-2009, CBDCA AUC7 x2 if both tumor size > 4cm and rete testis invasion were present; Group 4 : ≥2010, CBDCA AUC7 x1 if either tumor size > 4cm or rete testis invasion. Kaplan Meier and log-rank tests were used to evaluate disease-free survival (DFS), Kruskal-Wallis test to compare amount of chemotherapy received per patient. Results: At a median follow-up of 108 months [range 3-423], 19 (9.1%) relapses had occurred. Global 3 and 5-yr DFS were 92.3% and 90%. All relapsing patients were rendered disease-free with 4 cycles of cisplatin (CDDP) - etoposide. Table 1 summarizes results by cohort: Conclusions: A risk-adapted program provided an overall specific survival of 100%. A clinically significant difference in RR was observed when 1 or 2 courses of CBDCA were given. In our series and considering treatment burden, vascular invasion was a better criteria for patient selection to adjuvant chemotherapy, showing a similar DFS but a lower no of total platinum cycles per patient.[Table: see text]
Site, age, and gender distribution of extra-gonadal germ cell tumors in the US from 1973 to 2015.
Authors: Pan Elizabeth , Ihenacho Ugonna , Cortesssis Victoria , Barakzai Syem , Hu James S
Published: May 2019

e16051

Background: Germ cell tumors (GCT) commonly arise in post pubertal gonads where they are influenced by sexually dimorphic hormone signaling. More rarely, extra-gonadal GCTs (EGGCTs) arise in midline sites, coinciding with the route of primordial germ cell migration. EGGCTs are proposed to arise from cells not completing this migration. We characterized the incidence of EGGCTs according to patient and tumor features in an attempt to elucidate tumor origins. Methods: In Surveillance, Epidemiology, and End Results (SEER) Program SEER*Stat Database SEER 9 Regs Research Data, 1973-2015, primary EGGCT cases were identified by ICD-O-3 histologic types (seminoma: 9060-9062, 9064; non-seminoma 9065-9101) grouped into central nervous system (CNS), mediastinum, and other EGGCT sites. Age-specific incidences for males and females were divided into adolescents and young adults (AYA) defined by the National Cancer Institute as 15-39 years of age, and younger childhood and older adult groups. Results: In AYAs and older adults, age-adjusted incidence of males exceeded that of females at all sites (p≤0.006, all comparisons) (Table). Male incidence was highest in AYAs (all EGGCT, 4.35/1,000,000 person-years (Mpy); mediastinum, 2.17/Mpy; other 0.68/Mpy). Female incidence was highest in childhood (CNS, 0.86/Mpy; mediastinum, 0.14/Mpy; other 0.64/Mp-y). Conclusions: Patterns of EGGCT incidence differ substantially between sexes. Permissive extra-gonadal sites of males or male-predominant exposures may explain higher incidence in males. Alternatively, EGGCT precursor cells may have sex-specific features affecting malignant potential. [Table: see text]
Impact of cannabis (CA) use on chemotherapy (C) treatment and tumor characteristics of patients (pts) with testicular germ cell tumor (TGCT): Experience of the Centre Léon Bérard (CLB).
Authors: Arnaud-Coffin Patrick , Moriceau Guillaume , Lorcet Marianne , Couillet Audrey , Boyle Helen Jane , Flechon Aude
Published: May 2019

e16054

Background: TGCT are the most frequent cancers in men aged 15-45. This population is increasingly exposed to CA that is illegal in France. Its consequences on treatment and prognosis remain unknown. Methods: The use and the quantity of CA were evaluated for all pts treated by C for a TGCT in the CLB from 01/2016 to 06/2018. Tobacco (T) and alcohol (A) co-addictions were also analyzed. All pts had before starting C pulmonary test with diffusing capacity of the lung for carbon monoxyde (DLCO) evaluation. We searched a link between the use of toxics, contraindication to Bleomycin (B) due to decreased DLCO and tumor characteristics: stage and IGCCCG prognostic groups. Results: One hundred and thirty two pts with a median age of 33.5 years (interval: 17-65) received C for TGCT mainly for NSGCT (n = 97, 73%). Nine pts (7%) were treated in the adjuvant setting (1: 6 or 2 BEP: 3). In metastatic pts, 79 (60%), 30 (23%) and 14 (10%) were considered as good, intermediate and poor prognosis (PG) according to IGCCCG respectively. BEP was given for 3 cycles to 63 pts and 4 to29 and 6 pts received a dose dense regimen according to GETUG13. Eleven pts didn’t received B (5: 4EP, 6: 4VIP) because of DLCO alteration before the beginning of C. Eleven pts treated with B switched to a regimen without B due to a decrease of the DLCO during treatment. CA use was frequent (n = 20, 15%) with 8 pts (6%) having a regular CA consumption (median 5 joints/d). Seventy eight pts (59%) were regular T smokers. Co-addictions for CA consumers were frequent (90% for T and 50% for A). T and CA smokers had more DLCO alteration leading to B contraindication (p = 0.01 and p = 0.04). A quarter (n = 5) of pts using CA didn’t received B, and only 1 pt who didn’t receive B was not a smoker (T and CA). The use of CA was associated with PG, OR 5.46 (CI 95%: 1.35-21.2; p = 008). We could not observe a relationship between relapse and the use of CA (p = 0.34) because of the small number of relapses (n = 8). Half (n = 10) of CA consumers were single men and 25% (n = 5) were unemployed. Conclusions: The use of CA is significantly associated with PG and with a reduction of B use due to adecreased DLCO. The impact of CA intoxication is negative on the quality of treatment (because of more contraindications to B). The association with PG remains unclear, but may be related to social isolation.
Outcome of patients with stage 2 or stage 3 seminoma treated with 3 cycles of cisplatin-etoposide chemotherapy (EP120): Updated data from a single center retrospective study.
Authors: Gardiner Claudia , Hutton Paul , Jafri Mariam , Porfiri Emilio
Published: May 2019

e16061

Background: Metastatic seminoma is eminently treatable with platinum-based chemotherapy with either 3 cycles of BEP—bleomycin (B), etoposide (E) and cisplatin (P)—or 4 cycles of EP, achieving remission in more than 95% of the patients. However, bleomycin has a substantial toxicity profile and can cause life-threatening lung toxicity. Whether similar cure rates can be achieved without exposing patients to bleomycin is still undetermined. We describe our 19-year experience of treating patients with stage 2 or stage 3 seminoma with 3 cycles of EP chemotherapy. Methods: Patients who received 3 cycles of EP120 chemotherapy (50mg/m2 cisplatin day 1 and 2 and 120mg/m2 etoposide days 1, 2 and 3 every 3 weeks for 3 cycles) for stage 2 or stage 3 seminoma between 01/03/2000 and 31/05/2015 were identified. Data were retrospectively collected on stage, prognostic group, previous adjuvant treatment, serological and radiological response, time to relapse and subsequent management, progression-free survival (PFS) and overall survival (OS). Results: We identified 115 patients who received EP120 for seminoma and who met the inclusion criteria. Median age was 40 years (range 17-72). All patients were in the good-prognosis group. 103 patients (90%) were diagnosed with stage 2 seminoma, 12 patients (10%) with stage 3 (3 patients stage 3a and 9 stage 3b). 97 patients (84%) presented with stage 2 or 3 seminoma and 18 patients (16%) had progressed to stage 2 or 3 following adjuvant radiotherapy or adjuvant carboplatin chemotherapy for stage 1 disease. Seven patients (6%) with stage 2 seminoma relapsed after EP120 chemotherapy: 2 patients ≤3 months and 5 patients ≥ 3 months. None of the patients with stage 3 disease has relapsed so far. Of the 7 patients who relapsed, 2 received radiotherapy, 4 received TIP (paclitaxel, ifosfamide, cisplatin) chemotherapy and 1 received a combination of TIP chemotherapy and radiotherapy. All patients who relapsed after EP120 are currently in remission. Two of the 115 patients (1.7%) died whilst in remission and of unrelated causes. The 5-year PFS was 94% and the OS was 98%. Conclusions: Our data suggest that patients treated with 3 cycles of EP120 had survival rates similar to patients treated with more aggressive chemotherapy regimens.
Cost-effectiveness of pazopanib as first-line treatment of metastatic renal cell carcinoma from National Health Service United Kingdom perspective.
Authors: Ratto Barbara Elizabeth , Khare Ankur , Gudala Kapil , Gunda Praveen
Published: May 2019

e16088

Background: Recently, several therapies have been approved for treatment of metastatic renal cell carcinoma (mRCC) in the United Kingdom (UK); however, there is scarcity of comparative evidence to assist treatment decisions. We evaluated the cost-effectiveness of pazopanib as first-line treatment of mRCC from a UK National Health Service perspective. Methods: A partitioned-survival analysis model with 3 health states (alive with no progression, alive with progression, or dead) was used to evaluate the cost-effectiveness of pazopanib compared to sunitinib, tivozanib and cabozantinib in treatment-naive mRCC patients with treatment cycle length of 1 week and time horizon of 10 years. The model was populated with clinical effectiveness data obtained from network meta-analysis of pivotal trials and data on costs and utilities collected from UK-specific resources. The key model outcomes were quality-adjusted life years (QALY) and incremental cost-effectiveness ratio (ICER). Probabilistic and one-way sensitivity analyses were performed to test the uncertainty regarding model results. Results: Base-case analysis found that pazopanib was dominant (i.e. less costly and more effective) compared to sunitinib and tivozanib. Pazopanib had lower total costs (£69,861 vs £71,398 and £73,530) and higher QALYs (1.901 vs 1.835 and 1.669, respectively) compared to sunitinib and tivozanib. When compared with cabozantinib, pazopanib was found to be less costly (£174,735 vs £69,861) and less effective (total QALYs, 2.213 vs 1.901, respectively). Results of the probabilistic sensitivity analysis showed that at a willingness-to-pay (WTP) threshold of £30,000 per QALY, the probability of pazopanib being cost-effective was highest as compared to all comparators (84% vs sunitinib, 98% vs tivozanib and 100% vs cabozantinib). One-way sensitivity analysis revealed that effectiveness inputs, time horizon and others are model influencers. Conclusions: Based on a WTP threshold of £30,000/QALY gained, pazopanib is the most cost-effective treatment option compared to sunitinib, tivozanib and cabozantinib, for mRCC patients in UK.
A prospective, open label, multicenter, randomized phase II trial: Sequential therapy with bevacizumab, RAd001 (everolimus) and axitinib in metastatic renal cell carcinoma (mRCC) (BERAT study).
Authors: Grünwald Viktor , Bergmann Lothar , Goebell Peter J. , Strauss Arne , Meiler Johannes , Hartmann Arndt , Bedke Jens
Published: May 2019

e16097

Background: Inhibitors of the vascular endothelial growth factor (VEGF), its receptor (Ri) or mammalian target of rapamycin (mTORi) are components of systemic treatment in metastatic renal cell carcinoma (mRCC) and are applied in sequence. We compared the efficacy of VEGFRi and mTORi in 2nd line after failure of bevacizumab/interferon in a phase II trial. Methods: Key inclusion criteria were: measurable mRCC (all histologies), ECOG 0-1, IMDC risk: good or intermediate, adequate organ function. Tumor status was assessed in week 11 and q12 wks., thereafter. Measures of Health-related quality of life (HR-QoL) utilized FKSI-10 and was assessed in week 4, 10 and q12 wks., thereafter. 1st line consisted of bevacizumab 10mg/kg q2wks. + interferon 9*106 IE 3x/week (BEV/IFN). Upon progression or intolerance, patients were re-screened and randomized between VEGFRi (axitinib 5 mg BID, dose-escalation permitted; sunitinib 50 mg OD, 4-2 regimen) and everolimus (EVE) treatment (10 mg OD). Cross-over occurred at time of progression or intolerance. Improvement of 2nd line PFS-rate at 6 mo. from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, ORR, OS, safety and HR-QoL. Results: Between November 2012 and June 2015 a total of 22 of 100 patients were included and at that time stopped for poor accrual. 10 pts. (46%) were randomized to receive 2nd line treatment with everolimus (n = 5) or VEGFRi (n = 5). At study entry (2/10) 20% had nephrectomy. ECOG 0 was recorded in 20% (EVE) and 60% (VEGFRi), respectively. Objective response rate (ORR) to 1st line BEV/IFN was 20%. In 2nd line treatment all patients experienced adverse events (AE). Grade ≥3 AEs occurred in 2/5 (40%) (EVE) and 4/5 (80%) (VEGFRi) pts., respectively. SAEs occurred in 3/5 (60%) in each arm. ORR was 1/5 (20%) for axitinib and 0/5 (0%) for EVE. PFS rate at 180 days was 20% in each arm. Median PFS was 3.7 (EVE) and 2.2 mo. (VEGFRi) HR 1.0 (95%CI 0.26-3.85; p = 0.997). OS was comparable between arms HR 1.12 (95%CI 0.27-4.61; P = 0.872). 7 pts. crossed over to 3rd line treatment. Conclusions: The small number of pts. randomized to EVE or VEGFRi is a major limitation of our trial, but may mirror the current change of treatment reality. However, no significant difference was detected for the PFS rate at 6 mo., indicating the limited activity of EVE or VEGFRi in 2nd line treatment. Clinical trial information: NCT01731158.
Deep learning segmentation of kidneys with renal cell carcinoma.
Authors: Yin Kevin , Liu Chengfeng , Bardis Michelle , Martin Jeremy , Liu Hannah , Ushinsky Alexander , Glavis-Bloom Justin , Chantaduly Chanon , Chow Daniel S. , Houshyar Roozbeh , Chang Peter
Published: May 2019

e16098

Background: Renal cell carcinoma (RCC) is the most common kidney malignancy and the eighth most common cancer overall, with more than 60,000 new cases and nearly 15,000 deaths in the United States each year. The majority of RCC is asymptomatic and detected incidentally on computed tomography (CT) scans performed for other indications. Multiple prior studies have highlighted the potential for a lesion to be missed or mischaracterized. Artificial intelligence (AI), the mimicking of human cognition by computers, has promise for improving radiological accuracy. Convolutional neural networks (CNNs), a type of AI, apply a feed-forward design to an artificial neural network. Multi-layered CNNs thus have application in biomedical imaging and radiology. In this study we describe an approach for automatic localization and segmentation of the kidneys on contrast enhanced CT scan. Methods: This IRB approved retrospective study included patients who were diagnosed with RCC and had an abdominal CT scan with IV contrast from 2011 to 2019. For each abdominal CT scan, the kidneys and any renal lesions were manually segmented by a board-certified abdominal radiologist on the coronal post-contrast phase of the CT scan. Two CNNs were developed and trained to segment the kidneys automatically. Initially, the CNN implemented a regression algorithm that predicted a 3D bounding box around each kidney. Subsequently, the second CNN used a 3D/3D U-Net algorithm that received the bounding cube as its input and outlined the kidney as an output. After training, the CNN algorithms were assessed by a Sørensen-Dice coefficient. Results: The first CNN that predicted a 3D bounding box around each kidney was trained on 127 abdominal CT exams. The second CNN that segmented the kidneys with RCC was trained on 259 bounding boxes that encompassed the kidneys. The Sørensen–Dice coefficient for segmentation of the kidneys with RCC was 0.92. Conclusions: These results demonstrate that two CNNs can be used in succession to segment the kidneys with RCC on a coronal CT image with high accuracy. Moreover, as the subjects included patients with RCC, medical renal disease, and cystic renal disease, the outcome further supports the role of CNN in evaluation of complex cases rather than pristine training sets. Future work will focus on segmentation of RCC lesions.
Detection of circulating tumor DNA in patients with metastatic clear cell renal cell carcinoma.
Authors: Nappi Lucia , Bacon Jack , Annala Matti , Soleimani Maryam , Lavoie Jean-Michel , Chi Kim N. , Wyatt Alexander William , Kollmannsberger Christian K.
Published: May 2019

e16105

Background: Clear cell renal cell carcinoma (ccRCC) represents the most common presentation of kidney cancer. Patient outcomes have significantly improved with the approval of several targeted agents over the past decade. However, the lack of predictive biomarkers has hampered treatment optimization. Circulating tumor DNA (ctDNA) has emerged as an effective, minimally-invasive alternative to tissue for profiling the tumor genome in other tumors. Methods: Blood samples were collected from patients (pts) with metastatic ccRCC for next-generation sequencing of cell free DNA and germline DNA. Targeted sequencing was performed using the Roche Human Oncology Design panel of 981 genes to a median depth of 937x unique reads. Matched FFPE tissue was available from 14 pts and profiled using the same assay. Results: Samples from 52 metastatic, treatment-naïve pts were analyzed. Germline mutations were detected in 6/52 (11%) of the pts with the most frequent abnormalities affecting ATM, PALB2, RAD51D, CHEK2, BRCA1. Median ctDNA fraction was 3.9% (2-40%) with a median of 2 mutations/pt. Somatic mutations were detected in 29/52 (56%) of the samples; of those, 15/29 (51%) of pts harbored RCC-related genes mutations, 3/29 (10%) non-coding mutations and 10/29 (34%) alterations in non RCC-associated genes. Median variant allele frequency was 1.9% (1-22%). Consistent with tissue-based reports, VHL, BAP1, PBRM1, and TP53 were the most frequently altered genes. Lastly, 50% of the patient-matched FFPE tissue samples shared a fully concordant mutation profile. Conclusions: We confirmed a high prevalence of germline mutations in pts with ccRCC. The rate of ctDNA detection in metastatic ccRCC appears to be lower than in other metastatic solid tumors. Furthermore, it is not yet clear whether all the detected somatic alterations are strictly ccRCC-ctDNA dependent. Nevertheless, a quarter of pts exhibited clinically-informative ccRCC associated alterations in their liquid biopsy. These findings suggest that ctDNA is a promising tool for genomic profiling in a subset of patients with metastatic ccRCC.