bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploiting DNA repair alterations in metastatic pancreatic cancer (mPAC): Is MGMT methylation a new therapeutic target?
Authors: Niger Monica , Morano Federica , Manglaviti Sara , Raimondi Alessandra , Perrone Federica , Tamborini Elena , Marcuzzo Matteo , Nichetti Federico , Peverelli Giorgia , Pagani Filippo , Randon Giovanni , Ottini Arianna , Torchio Martina , Prisciandaro Michele , Antista Maria , Pietrantonio Filippo , Pusceddu Sara , Pruneri Giancarlo , Di Bartolomeo Maria , De Braud Filippo G. 
Published: May 2019

e15770 Background: Metastatic pancreatic cancer (mPAC) has a poor prognosis, with few therapeutic options and an overall survival (OS) at 5 years < 5%. O6-methylguanine-DNA methyltransferase ( MGMT) is a key DNA repair gene, responsible of alkyl groups’ elimination from the O6-position of guanine. Its promoter methylation results in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). Of note, both reductions in MGMT expression and MGMT promoter methylation are described in a variety of gastrointestinal malignancies, including colorectal cancer (CRC). Here we present data on MGMT methylation tested in mPAC pts treated at our center. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI). Furthermore, the exploratory analysis of MGMT status was performed via methyl specific PCR (EZ DNA Methylation-Gold™ KIT) to assess promoter methylation, and immunohistochemistry (IHC) was done to assess protein expression. Results: Archived FFPE tissue sections obtained from 60 pts treated at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to December 2018 were analyzed. 47 samples (78%) had adequate tissue for extended analyses. As expected, 44 (93%) pts had KRAS mutations, while ATM, CDKN2A mutations and microsatellite instability (MSI) were found in 3 pts (6%), respectively. MGMT promoter methylation was identified in 14 pts (29%), with low/negative MGMT protein expression in 7 (14%). Interestingly, amongst MGMT methylated pts, there were 3 (21%) BRCA1/2 somatic mutant and 1 (7%) MSI, suggesting possible genomic instability. Conclusions: MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in metastatic CRC, with phase II studies showing a response rate of 10% in chemorefractory pts with MGMT methylation treated with TMZ. In our single center experience, MGMT methylation was found in 29% of patients with mPAC. This data warrant further prospective confirmation, but there is definitely a growing interest in the role of MGMT methylation as a predictive and prognostic biomarker in mPAC.
The effect of antibiotic use on survival of patients with resected pancreatic ductal adenocarcinoma.
Authors: Hasanov Merve , Mohindroo Chirayu , Rogers Jane , Prakash Laura , Overman Michael J. , Varadhachary Gauri Rajani , Wolff Robert A. , Javle Milind M. , Fogelman David R. , Pant Shubham , Katz Matthew H. G. , Kim Michael Paul , Tzeng Ching-Wei David , McAllister Florencia 
Published: May 2019

e15773 Background: Recent studies showed that gut microbial dysbiosis can affect carcinogenesis and tumor responses to therapies. Antibiotics, key pharmacologic agents that modulate microbiota diversity and bacterial strains, can lead to dysbiosis. Recent studies have postulated a tumor promoting effect for some pancreatic ductal adenocarcinoma (PDAC)-associated gut bacteria. However, the effects of antibiotic use on PDAC patients outcome is yet to be discovered. Methods: We examined a total of 342 patients who were diagnosed with PDAC between 2003-2015 and underwent primary tumor resection. Antibiotic exposure was defined as the use of antibiotics for ≥7 days between diagnosis and surgery. We collected data on patient demographics, presurgical antibiotic use, duration, type and reason, disease and therapy characteristics, and prognostic parameters. We analyzed and compared the objective responses, progression free survival (PFS) and overall survival (OS). Results: From a total 342 patients with resected PDAC, 147 patients (43%) used antibiotics for ≥7 days duration during the presurgical period. The most frequently used antibiotics were quinolones (80.4%), beta-lactams (38.2%), nitroimidazoles (23%), glycopeptides (15.3%), tetracyclines (8.6%), and macrolides (6.7%). The median OS for patients with antibiotic use was 1007 vs. 940 days for those without antibiotic use (p = 0.57). The median PFS was 374 for patients with antibiotic use and 313 days for those without antibiotic use (p = 0.51). The effect of individual antibiotics was examined and statistical analysis was done for possible confounding factors including disease stage, treatment type, and the reason for antibiotic use. Tetracyclines use was found to be significantly associated with worse survival on resected PDAC patients and was not affected by confounding factors such as skin infections. The median OS of patients who had tetracycline for ≥7 days was 687 vs. 1004 days for those not exposed to this antibiotic (HR 1.836; p = 0.015). Although not statistically significant, PFS was shorter with tetracycline use. Conclusions: We conducted the first retrospective, single-center cohort study on resected PDAC patients examining the potential influence of antibiotic use on survival. Tetracycline use in resectable PDAC patients is associated with clinically significant decreased PFS and statistically significant worse OS. Further multicenter studies with larger population would be necessary to confirm these findings that could help clinical practice for infectious treatment in PDAC patients.
Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer.
Authors: Seery Tara Elisabeth , Kistler Mira , Sender Leonard S. , Lee John H. , Shinde Arvind Manohar , Annamalai Anand , Soon-Shiong Patrick 
Published: May 2019

e15787 Background: Pancreatic cancer has multiple mechanisms to prevent immune recognition that lead to the creation of an immune suppressive tumor microenvironment. We hypothesize that sustained response against pancreatic cancer requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low-dose chemotherapy, SBRT, cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with recurrent metastatic pancreatic cancer was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral CEA vaccine, yeast Ras vaccine, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 12 subjects with 3rd-line or greater metastatic pancreatic cancer were treated. All treatment was administered in an outpatient setting. AEs were primarily hematologic and managed by planned chemo dose reduction. Grade ≥3 TRAEs were observed in 9 out of 12 subjects, predominately chemotherapy-related neutropenia. 9 out of 12 subjects (75%) had a best response of stable disease (≥ 8 weeks). Median PFS is 7.1 months (4.4 – 8.8) and median OS is 8.2 months (5.7 – 9.7) with 1 subject continuing treatment. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting. Preliminary OS of 8.2 months is encouraging for this heavily-pretreated population. Clinical trial information: NCT03586869.
Gemcitabine and nab-paclitaxel retreatment as a third-line therapy following second-line FOLFIRINOX for advanced pancreatic adenocarcinoma.
Authors: Dean Andrew Peter , Das Adarsh , McNulty Meabh , Higgs Domenic 
Published: May 2019

e15794 Background: First-line and second line treatment for advanced pancreatic adenocarcinoma typically involves therapy with gemcitabine plus nab-paclitaxel, FOLFIRINOX or as per the recent phase III trial (NAPOLI-1), the combination of nal-irinotecan with 5-fluorouracil and leucovorin. Despite these advances, there remains minimal amount of data regarding the options for, or efficacy of, third-line treatment in these patients. We have previously reported our experience of twenty patients who received effective third-line therapy with gemcitabine plus nab-paclitaxel retreatment after receiving FOLFIRINOX as second-line treatment. This retrospective analysis assessed the updated data of the use of gemcitabine plus nab-paclitaxel as a third-line treatment option in a single hospital setting. Methods: We conducted a retrospective analysis using an electronic database of patients with locally advanced or metastatic pancreatic adenocarcinoma who received first-line gemcitabine and nab-paclitaxel, second line FOLFIRINOX and third-line retreatment with gemcitabine and nab-paclitaxel between January 2013 and December 2018. All patients had an ECOG performance status of 2 or less. Overall survival (OS) was estimated by the Kaplan-Meier method. Results: Twenty-six patients were reviewed. Median age of 73 (range, 45 – 81). 73% of the studied patients had locally advanced cancer at diagnosis. The median OS from diagnosis was 39.0 months (95% CI, 34.0 – 66.0). The median OS from third-line re-initiation of gemcitabine plus nab-paclitaxel was 18.0 months (95% CI, 9.0 – 32.0). Conclusions: This is one of the first retrospective studies to show the efficacy of third-line treatment with gemcitabine plus nab-paclitaxel in advanced pancreatic cancer. It demonstrated that retreatment with gemcitabine plus nab-paclitaxel is feasible, tolerable and effective in patients with a good performance status. We suggest a formal phase 3 study to confirm our data and potentially establish a formal new standard of care for third line chemotherapy in this previously disadvantaged group.
Single-arm phase I/II study of the safety and efficacy of OncoTherad immunomodulator in patients BCG-refractory or relapsed non-muscle invasive bladder cancer.
Authors: Fávaro Wagner José , Iantas Sonia Regina , Gonçalves Juliana Mattoso , Socca Eduardo Augusto Rabelo , Duran Nelson , Billis Athanase , Alonso João Carlos Cardoso 
Published: May 2019

e16000 Background: There is no effective intravesical second-line therapy for high-grade non-muscle-invasive bladder cancer (HGNMIBC) when Bacillus Calmette-Guerin (BCG) fails. In this scenario, a new perspective is represented by OncoTherad immunomodulator. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein, developed by University of Campinas/ Brazil, which exhibits antitumor properties. The aims of the study were to evaluate the efficacy and safety of OncoTherad immunomodulator for BCG-refractory or relapsed HGNMIBC. Methods: We carried out a prospective, single-center (Municipal Hospital of Paulinia, São Paulo, Brazil), single-arm phase I/II study in 15 (10 male, 5 female) consecutive patients with HGNMIBC-refractory or relapsed (≥ 1 previous course of BCG intravesical therapy). Patients with muscle-invasive disease were excluded. OncoTherad regimen consisted of an induction course of 6 weekly intravesical instillations followed by a maintenance course of 1 monthly instillation until completing 1 year of treatment. Follow-up was performed with systematic mapping biopsies of the bladder, cystoscopy, ultrasound and urinary cytology. The primary endpoint was recurrence-free survival (RFS) rate, and secondary endpoint was safety response. The recurrence was defined as histology proven tumor recurrence (any grade), and monitored at 3-month intervals. Results: The median age and follow-up were 71 years and 14.0 months, respectively. A 14-months RFS rate in all patients was 86.7%. Only 2 patients (13.3%) showed recurrence during follow-up, however these patients showed incipient malignant lesions (downstaging of pT1G3 to pTaG1). Regarding toxicity, we reported moderate adverse systemic event of hypersensitivity to OncoTherad in 2 patients (13.3%), and minimal local side effects (dysuria and cystitis)in 6 patients (40.0%). Conclusions: In conclusion, OncoTherad seems a safe and effective treatment option for BCG-refractory or relapsed HGNMIBC patients and may provide benefit for preventing tumor recurrence. We report a RFS rate of 86.7% (14.0 months), potentially avoiding or postponing the need for radical surgery in these patients. Clinical trial information: CAAE: 93619718.7.0000.5404.
Mutational analysis using next-generation DNA sequencing in platinum-resistant muscle-invasive bladder cancer.
Authors: Samiei Arash , Tayshetye Pritam , Sanguino Angela , Miller Ralph , Lyne John , Cohen Jeffrey , Mao Shifeng 
Published: May 2019

e16006 Background: Platinum-resistant muscle-invasive bladder cancer (prMIBC) is the main cause of bladder cancer mortality. Recent advances in next-generation DNA sequencing (NGS) has allowed characterization of the molecular landscape of MIBC. Yet, the correlation between the molecular alteration and the poor outcome of prMIBC is still lacking. This study aims to explore the potential genetic alterations in this group of patients. Methods: A retrospective study of prMIBC patients that had NGS molecular profiling at a single center from November 2014 to October 2018 was conducted. The prMIBC was defined as patients who had a significant residual disease or disease progression following cisplatin-based chemotherapy in a neoadjuvant or metastatic disease setting. NGS was performed on formalin-fixed paraffin-embedded tissue samples through commercial companies. Results: A total of 17 prMIBC with the median age of 65 [51-74] years old were included in this study. At the end of the study, 8 patients were alive and 9 deceased. A total of 58 mutations were identified. 7 of the 58 genes were mutated in ≥20% of cases: TP53 (65%), TERT promoter -124C > T (59%), ARID1A (35%), CDKN2A/B (30%), RB1 (24%), PIK3CA (24%), and FLCN (20%). Less frequent mutations (12% each) include MDM2, AKT2, KDM6A, SMARCA4, FGF3, FGF4, BRCA2, STAG2, and CCNE1 genes. Analysis of the mutations revealed key pathways including TP53/cell cycle pathway altered in 82%, PI-3K/mTOR pathway in 71%, Telomere regulation in 59%, SWI/SNF complex in 35% and histone modification in 24% of cases. Conclusions: Among patients with prMIBC, mutations in the p53/cell cycle pathway are the most common findings. Genetic alteration involving the PI-3K/mTOR pathway is frequently associated with prMIBC, which could provide an important lead for a predictive model and targeted intervention. Interestingly, the TERT promoter -124C > T mutation is a very common molecular alteration in prMIBC that has not been reported before. Telomere regulation may play a role in contributing to platinum-resistance in bladder cancer. Further elucidation of the molecular landscape in prMIBC on a larger scale would help to establish a molecular model to predict platinum-response in MIBC.
Patient (pt) characteristics, treatment patterns, outcomes and prognostic factors in plasmacytoid urothelial carcinoma (PUC).
Authors: Diamantopoulos Leonidas Nikolaos , Khaki Ali Raza , Vakar-Lopez Funda , Tretiakova Maria S. , Gore John L. , Schade George R , Psutka Sarah P. , Hsieh Andrew Caleb , Lee John Kyung , Yezefski Todd , Schweizer Michael Thomas , Cheng Heather H. , Yu Evan Y. , Grivas Petros , Montgomery Robert B. , Wright Jonathan L. 
Published: May 2019

e16007 Background: PUC is uncommon and highly aggressive, with limited data on treatment patterns, outcomes and prognostic factors. We hypothesized that PUC is associated with clinical under-staging, poor outcomes and lack of chemotherapy (CT) response. Methods: We conducted a retrospective review of pts with UC and plasmacytoid component (PUC), seen in our institution (2000 - 2018). Demographic and clinicopathologic data, treatment modalities, pathologic complete/partial response (pCR, pPR) to neoadjuvant CT (NAC), and overall survival (OS) from diagnosis and surgery (Sx) were captured. T-test, chi-square, and Cox-regression were used to explore potential prognostic associations. OS was estimated with KM method. Results: We identified 63 consecutive pts (51 men) with available data for analysis. Median age at diagnosis was 67 (44-89). During initial diagnostic workup, 32 (51%) pts had extravesical disease (cT3:24, cT4:8) and 23 (36.5%) hydronephrosis at imaging. Overall, 39 (62%) pts underwent Sx with curative intent, 25 (39.6%) were pre-treated with cisplatin-based NAC; adjuvant CT was given to 15 (24%). The remaining pts pursued bladder-sparing and/or palliative approaches. At time of Sx, 17/39 (43.6%) pts had pathologic upstaging, 10 (25.6%) had positive margins and 19 (48.7%) pN+ stage. In the NAC pt subset (25 pts), 5 (20%) had progression on scans, 19 (76%) had Sx; 2 pts had pCR (10.5%), 1 had pPR, 6 (31.5%) had pathologic upstaging. In the entire cohort, median follow-up was 8 months. Median OS was 20.7 months from diagnosis and 23.6 months from Sx. NAC was not significantly associated with longer OS (from Sx) (HR 1.53, 95%CI 0.16-15, p = 0.715) and the same was true for adjuvant CT (HR 0.64, 95%CI 0.1-4, p = 0.630). 15/39 pts recurred after Sx (38.4%), with 9/15 (60%) having peritoneal/retroperitoneal involvement. Conclusions: PUC frequently presented with advanced stage at diagnosis and demonstrated poor NAC response, frequent upstaging, positive margins and pN+ stage at Sx. More than half of patients who recurred after Sx, presented with (retro)peritoneal disease. Studies evaluating molecular biomarkers and drivers in PUC, and prospective clinical trials are being pursued.
Identifying predictors of pathologic complete response to neoadjuvant chemotherapy for muscle invasive bladder cancer.
Authors: Harzstark Andrea , Merchant Maqdooda 
Published: May 2019

e16015 Background: Pathologic complete response (pCR) to neoadjuvant chemotherapy is associated with improved outcome in patients (pts) with muscle invasive and/or lymph node positive (LN+) bladder cancer. Although molecular predictors are currently being evaluated, limited information is available regarding purely clinical parameters offering predictive information regarding pCR to neoadjuvant chemotherapy. Methods: We identified 189 unique pts within Kaiser Permanente Northern California diagnosed with bladder cancer during 1/1/10 through 12/31/17 who underwent chemotherapy with neoadjuvant intent with a plan for subsequent radical cystectomy. All pts had disease that was ≥cT2 and/or ≥cN1 and M0. Fourteen variables were examined for their association with pCR at radical cystectomy, using bivariate analysis and multivariate models. Results: Of the 189 pts in our cohort, 141 (74.6%) were male, 162 (85.7%) were white and the mean age was 66.4 years. 76 (40.2%) pts achieved pCR; of these, 59 (77.6%) had pre-treatment hemoglobin (hg) ≥ 13 g/dL (p = 0.0087), 69 (90.8%) did not have hydronephrosis (p < 0.0001), 66 (86.8%) had no lymphovascular invasion (LVI) on transurethral resection of bladder tumor (TURBT) (p = 0.0506) and 69 (90.8%) had cT2 disease at time of diagnosis (p < 0.0001). Logistic regression analysis showed that pCR was associated with hg ≥ 13 (OR 2.736, 95% CI 1.188-6.657), absence of hydronephrosis (OR 4.672, 95% CI 1.820-13.554), age ≤ 75 years (OR 3.410, 95% CI 1.263-10.057), absence of LVI on TURBT (OR 2.592, 95% CI 1.055-6.829), and clinical stage T2 vs. ≥T3 and/or N+ (OR 6.480, 95% CI 2.645-17.858). There was no statistically significant relationship between pCR and the following variables: cumulative cisplatin dose, split dose chemotherapy, chemotherapy regimen, history of tobacco use, race, gender, Charlson comorbidity score, baseline alkaline phosphatase, and percentage body weight loss during therapy. Conclusions: Pathologic CR was predicted by Hg < 13 g/dL, absence of hydronephrosis, age ≤ 75 yrs, absence of LVI on TURBT specimen, and stage at diagnosis. These factors may influence selection of pts with muscle invasive and/or LN+ bladder cancer for neoadjuvant chemotherapy.
Circulating tumor DNA in patients with metastatic urothelial cancer: concordance of genomic findings with matched tissue biopsies.
Authors: Lavoie Jean-Michel , Vandekerkhove Gillian , Annala Matti , Sundahl Nora , Sano Takeshi , Struss Werner J. , Todenhöfer Tilman , Ost Piet , Chi Kim N. , Black Peter C. , Eigl Bernhard J. , Wyatt Alexander William 
Published: May 2019

e16036 Background: Patients (pts) with metastatic urothelial cancer (mUC) now have access to many different treatment options. This creates an incentive for molecular profiling of their tumors, with the aim of developing biomarkers. Genomic profiling may leverage the presence of circulating tumor DNA (ctDNA), but it has not been shown whether this recapitulates the findings from tissue samples. Methods: Whole blood samples were collected for next-generation sequencing of leukocyte and cell-free DNA (cfDNA). Deep targeted sequencing was performed across a UC-specific custom 50-gene panel (median depth of 986x). Matched archival tissue was profiled using the same assay for 65 pts. Results: Between 11/2011 and 12/2017, 90 pts developed mUC (87 evaluable). Baseline characteristics: median age 67, 83% male, 14% upper-tract disease, 17% stage IV at initial presentation. Treatments delivered: 76% platinum-based chemotherapy, 47% PD-1/PD-L1 inhibitor. At a median follow-up of 12.8 mo., 45% remain alive. We found ctDNA fractions above 2% in at least one blood collection in 81% of cases. For 17 pts, matched metastatic biopsies and cfDNA collection were available; in those cases 82% of coding somatic mutations identified in tissue were independently detected in cfDNA. Half of discordant findings could be attributed to low ctDNA fraction. Most (89%) mutations detected in primary tissue (cystectomy or nephrectomy) were present in later cfDNA collections. ctDNA detected mutations in TP53 and ARID1A in 64% and 29% of pts, respectively. A tumor mutation burden ≥25 mutation per Mb was observed in 27% of cases. Conclusions: There is a high concordance between genomic findings from ctDNA and matched tissue of pts with mUC. This supports the use of liquid biopsies to study potential biomarkers in this disease.