bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of resection of the primary in metastatic well/intermediate-differentiated neuroendocrine tumor (NET).
Authors: Shaib Walid Labib , Penely Mckenna , Zakka Katerina Mary , Jiang Renjian , Akce Mehmet , Wu Christina , Behera Madhusmita , Maithel Shishir K. , Sarmiento Juan , Alese Olatunji B. , El-Rayes Bassel F.
Published: May 2019

e15693

Background: Resection of the primary tumor in metastatic neuroendocrine tumor (NET) is controversial. The aim of this study is to evaluate survival outcomes and identify prognostic variables of surgical resection of the primary tumor in metastatic NET patients. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Chi-square and ANOVA tests were done to identify factors associated with surgical modality. Univariate and multivariate cox proportional hazards models were used for association between patient characteristics and survival. Kaplan-Meier curves were generated and log-rank tests conducted to compare the survival difference of patient characteristics. Results: A total of 2,361 patients between 18 and 90 years of age with stage IV well/intermediate-differentiated NET were identified. The mean age was 62.1 years (SD±13), with an equal male to female ratio (50.0%). Majority of NET primaries were in the small intestine (33.0%), pancreas (26.3%), and lung (24.4%). The majority were well differentiated tumors (69.6%) and 42.5% of patients underwent surgery at the primary site. On multivariate analysis total surgical resection of the primary (HR 0.44; 0.22-0.90; p < 0.001), female sex, year of diagnosis 2010-2014, negative surgical margin, Charlson-Deyo score < 2, and age < 51 years at diagnosis were associated with better overall survival (OS). Conclusions: Resection of the primary in stage IV well/intermediate-differentiated NET was associated with improved 5-year OS compared to patients with no surgery in small intestine (60.1% vs 44.2%), lung (70.0% vs 20.2%), and pancreas tumors (59.3% vs 30.6%).
Geographic and demographic disparities in neuroendocrine tumors (NETs): A population-based study.
Authors: Gosain Rohit , Ball Somedeb , Rana Navpreet Kaur , Groman Adrienne , Gage-Bouchard Elizabeth , Dasari Arvind , Mukherjee Sarbajit
Published: May 2019

e15694

Background: The incidence and prevalence of Neuroendocrine Tumors (NETs) are rapidly rising. There are very few studies investigating the role of sociodemographic factors on NETs. The aim of our study was to identify the disparities in the NET population. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database, and studied NETs patient population from 1973 to 2015. Univariate and multivariate analyses were performed to evaluate patients’ disease-specific survival (DSS) and overall survival (OS). Different socio-demographic factors including location of residence: urban area (UA) versus rural area (RA), gender, race, insurance status and marital status were included in the analysis. Results: A total of 53,522[ RA: N = 9,053; UA: N = 43,981] patients were included in the analysis. The incidence of NETs was found to be rising in both RA and UA but more rapidly in UA. RA was associated with more advanced stage at presentation in comparison to UA (p < 0.001). Cause-specific mortality remained higher in RA than UA throughout the study period. In the multivariate model, RA had a trend towards poorer DSS (HR:1.03, p = 0.399) and a worse OS compared to UA (HR = 1.06, p = 0.0003). Blacks had a poorer OS compared to non-Hispanic Whites (HR = 1.16, p < 0.001). Multivariate analysis showed significantly worse DSS and OS in uninsured, single and male patients compared to insured, married and female patients respectively. Conclusions: Our study identified sociodemographic disparities on NET outcomes. Access to healthcare could be a potential contributing factor although differences in environmental exposure, health behavior and tumor biology could also be responsible. Further population-based studies are required to address these disparities.
Prognostic value of the volume time index (VTI) ratio for patients with appendiceal cancer with peritoneal carcinomatosis treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).
Authors: Karpes Josh , Dotta Daniel , Fisher Oliver , Shamavonian Raphael , Alzahrani Nayef , Morris David L.
Published: May 2019

e15704

Background: Completeness of cytoreduction score (CC-score) and tumour volume (as expressed by the peritoneal cancer index (PCI)) have been demonstrated as important post-operative prognostic factors in those patients with appendix cancer with peritoneal metastases undergoing CRS/HIPEC. A previous analysis included a pre-operative factor and demonstrated the tumour marker to volume index (CA19-9/PCI) in patients who had low grade appendiceal cancer with peritoneal metastases was an independent prognostic factor for overall survival (OS). This analysis aims to evaluate VTI as a prognostic factor in low- and high-grade appendix neoplasms with peritoneal dissemination managed with CRS/HIPEC. Methods: A retrospective cohort study of all patients diagnosed with appendiceal cancer with peritoneal dissemination managed with CRS/IPC from 1996 to 2017 was performed by analysing the survival effect of the ratio of tumour volume to the time between initial tumour resection and CRS/HIPEC. VTI was stratified into low versus high groups, and tumour grade was divided into low grade: diffuse peritoneal adenomucinosis (DPAM); and high grade: peritoneal mucinous carcinomatosis (PMCA). Results: Two hundred and sixty-four patients were included. For both DPAM and PMCA, there was no statistically significant difference in overall survival between patients with a low versus high VTI. For both low and high VTI in DPAM, the median survival was not reached, p= 0.586. For PMCA, those with a low VTI had an overall survival of 63 months (95%CI 48-NR), versus those with a high VTI 69 months (95%CI 45-NR), p= 0.97. There was no statistically significant difference in the median recurrence free survival (RFS) between low and high VTI for both DPAM and PMCA. Conclusions: The volume to time ratio for appendix cancer with peritoneal dissemination was not an independent prognostic indicator for overall survival in patients undergoing CRS/HIPEC, suggesting that this index is not a valuable pre-operative planning tool.
Real-world assessment of healthcare costs for patients with metastatic pancreatic cancer following first-line chemotherapy initiation.
Authors: Bullock Andrea J. , Rowan Christopher G , Hill Nina , Yeganegi Homa , Chiorean E. Gabriela
Published: May 2019

e15710

Background: Nab-paclitaxel-gemcitabine (AG) and FOLFIRINOX (FFX) are commonly used regimens for the treatment of metastatic pancreatic cancer (mPDA). This descriptive study aimed to report total healthcare costs following first line (1L) exposure to AG/FFX among patients with mPDA. Methods: Retrospective cohorts of 1L AG and FFX initiators with mPDA were constructed from the MarketScan database (study period 2014-2017). The index date was the date of 1L AG or FFX initiation. Included patients had continuous insurance enrollment. Total healthcare costs (outpatient, inpatient, emergency department, chemotherapy, pharmacy) were assessed at 0-1, 0-3, 0-6, and 0-12 months post-index among patients who remained uncensored (using the last claim date) through the last month of each follow-up interval. Results: 2199 patients initiated AG (N=1352) or FFX (N=847) as their 1L regimen. Compared with AG initiators, FFX patients were younger (59 vs 63 years) and had better baseline health status (FFX/AG): diabetes 43%/57%; cerebrovascular disease 21%/27%. Median time to censoring was 5.4 (AG) and 7.2 (FFX) months. Median treatment duration was 2.1 (AG) and 2.3 (FFX) months. FFX costs were higher than AG costs during each follow-up interval, with the cost differential increasing over time (Table). Conclusions: Higher total healthcare costs were observed for patients with mPDA who initiated 1L FFX compared with 1L AG. Further research using comparative methodology is warranted to fully elucidate these findings and understand cost drivers. [Table: see text]
Sequential assessments of KRAS-mutated circulating tumor DNA in longitudinal monitoring enable the prediction of prognosis and therapeutic responses in patients with pancreatic cancer.
Authors: Watanabe Fumiaki , Suzuki Koichi , Tamaki Sawako , Ishikawa Hideki , Kakizawa Nao , Noda Hiroshi , Rikiyama Toshiki
Published: May 2019

e15712

Background: Liquid biopsy enables the detection of circulating tumor DNA (ctDNA) levels, including KRAS-mutated ctDNA, which is considered a predictive biomarker for pancreatic cancer. This study aimed to evaluate the significance of sequential KRAS ctDNA assessments in longitudinal monitoring. Methods: A total of 422 blood samples were collected from 78 patients undergoing treatments for localized and metastatic pancreatic ductal adenocarcinoma. KRAS ctDNA levels was determined by droplet digital polymerase chain reaction. Longitudinal monitoring of KRAS ctDNA was performed to assess its significance for predicting recurrence and prognosis and evaluating therapeutic responses to chemotherapy. Results: In 39 patients who underwent surgery for potentially resectable tumors, sequential assessments of KRAS ctDNA in longitudinal monitoring was significantly associated with prognosis ( P < 0.001). In 39 patients who did not undergo surgery, sequential assessments of KRAS ctDNA was a predictive factor for prognosis ( P = 0.005). Multivariate analysis revealed that detection of KRAS ctDNA in longitudinal monitoring was the only independent prognostic factor regardless of tumor resection ( P< 0.001). Longitudinal monitoring revealed the significance of sequential assessments of KRAS ctDNA within a short period. The presence of KRAS ctDNA in sequential assessments within 1 year after surgery showed significant association with prognosis irrespective of recurrence ( P< 0.001). The presence of KRAS ctDNA in sequential assessments within 6 months was significantly correlated with therapeutic responses in the first line chemotherapy ( P< 0.001). Conclusions: Our study showed for the first time that sequential assessments of KRAS ctDNA levels within a short period enabled the prediction of prognosis and therapeutic response in patients with pancreatic cancer.
Serum microRNA signatures for the detection of pancreatobiliary cancer.
Authors: Mitsunaga Shuichi , Nomura Shogo , Hara Kazuo , Takayama Yukiko , Ueno Makoto , Hanada Keiji , Miki Ikuya , Takahashi Shinichiro , Kuwahara Takamichi , Nomoto Tomohiro , Sudo Tamotsu , Myomoto Akira , Sudo Hiroko , Takizawa Satoko , Kojima Motohiro
Published: May 2019

e15718

Background: The diagnostic value of serum microRNAs (miRNA) in a highly sensitive microarray for pancreatobiliary cancer (PBca) has been demonstrated. This study attempted to build and validate a signature comprised of multiple serum miRNA markers for discriminating PBca from healthy controls. Methods: A multicenter prospective study on the diagnostic performance of serum miRNAs was conducted. The patients (pts) with treatment-naïve PBca and healthy participants aged ≥60 years were enrolled. Clinical data and sera were collected. Target population was randomly divided to training or validation cohort with an allocation ratio of 2:1. Twenty-nine serum miRNA markers on the microarray data were analyzed. Using any combinations of the markers, a Fisher’s linear discriminant analysis was performed, and the resulting sensitivity, specificity and AUC of ROC curve to discriminate PBca from healthy controls were calculated for each combination. Marker combinations with a sensitivity/specificity (SN/SP) of ≥80%/90% and high AUC in comparison with AUC of CA19-9 were defined as the diagnostic miRNA signature, which were selected in the training cohort. Next, the signatures were screened out which showed a good reproducibility in the validation cohort. As an independent external cohort, PBca pts and healthy with pooled frozen sera were enrolled and the identified miRNA signatures were further validated. Results: Total of 546 participants (80 healthy and 223 PBca in training set, 40 healthy and 104 PBca in validation set, 49 healthy and 50 PBca in external validation set) were analyzed in this study. Four serum miRNA combinations were identified as the diagnostic miRNA signature. In the training set, four miRNA signatures, consisted of 10 miRNAs, were developed. For the best-performed miRNA signature, the SN/SP and AUC in the validation and external validation cohorts were 84/90% and 0.95 (CA19-9: 73/95% and 0.88) and 84/90% and 0.93 (CA19-9: 80/94% and 0.87), respectively. Conclusions: The diagnostic serum miRNA signatures for PBca were identified in this study.
Adjuvant FOLFOX + nab-paclitaxel (FOLFOX-A)for pancreatic cancer, BrUOG 278: A Brown University oncology research group phase II study.
Authors: Safran Howard , Charpentier Kevin , Breakstone Rimini , Vatkevich John , Hamel Celine , Kolvek Taylor , Kastura Michaela , Bartley Carolyn , Baekey John , Robison Jordan , Beard Rachel , Leonard Kara Lynne , Rossiter Rachael , Rosati Kayla
Published: May 2019

e15733

Background: Adjuvant FOLFIRINOX increases survival in pancreatic cancer but is associated with significant toxicity. The Brown University Oncology Research Group (BrUOG) developed the FOLFOX-A regimen in a phase I study in advanced pancreatic cancer (Am J Clin Oncol, 2016). Phase II studies (BrUOG 292 and BrUOG 318) have shown substantial activity in patients with metastatic and locally advanced disease. Highly active regimens have the potential to improve survival in the adjuvant setting. The primary objective of BrUOG 295 was to determine the feasibility of administering 10 cycles of FOLFOX-A. Secondary objectives were toxicity and disease free survival. Methods: Patients received oxaliplatin, 85mg/m2 day 1, nab-paclitaxel, 150mg/m2 and leucovorin 400mg/m2 day 1 and fluorouracil 2400mg/m2 by continuous IV infusion over 46 hours. Myeloid growth factor support was optional. Cycles were repeated every 14 days for up to 10. Oxaliplatin was dose reduced to 68mg/m2 for grade 2 neurotoxicity. CTCAE version 4 toxicity scales were utilized. Results: The study reached its initial accrual goal of 25 patients. The median age was 60 (43-69). Twenty-one patients were node +. Twelve of the first 20 patients have received 10 cycles of FOLFOX-A and 17 of the first 20 patients received > 8 cycles. The most common grade >3 toxicities were neutropenia grade 3 (N = 3), grade 4 (N = 3) and fatigue grade 3 (n = 13). One patient had grade 3 neuropathy. Conclusions: Adjuvant FOLFOX-A is well tolerated with low incidences of grade 3 neuropathy and gastrointestinal toxicity. Toxicity, feasibility and disease free survival will be updated at the May 2019 BrUOG DSMB meeting. Clinical trial information: NCT02022033.
Relapse-free survival (RFS) after surgical resection to predict survival after relapse (SAR) and overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDA).
Authors: Rodriguez-Pascual Jesus , Alvarez-Gallego Rafael , Munoz Cesar , Ugidos Lisardo , Sanz Enrique , Ceniceros Lucia , Rivas Maria , Torres Esther , Cardenas Jose M , Cubillo Gracián Antonio
Published: May 2019

e15735

Background: We aimed to evaluate the clinical relevance of RFS after local PDA resection as a prognostic factor in terms of SAR and OS. Methods: Patients diagnosed with local PDA who had undergone surgical resection in 4 hospitals from Spain were identified. Disease location, demographic, pathologic, treatment during recurrence and mortality information was retrospectively collected. RFS was measured from date of surgery until recurrence and censored at death or last follow-up. SAR was measured from relapse, until death or last follow-up. We defined patients presenting an RFS value of 6 months or more, or less than 6 months as High-RFS and Low-RFS respectively. Results: Of 93 patients with resected PDA, 51 (54.8%) were male and 42 (45.2%) female. The median age was 65.2 years. 62 (66.7%) tumors were localized in the head. There were 5 (5.4%), 17 (18.3%) and 69 (74.1%) stage I, II and III respectively. 53 (57%) patients had undergone cephalic (Whipple), 20 (21.5%) distal and 20 (21,5%) total pancreatectomy. 48 (51.6%) patients received radiotherapy and 86 (92.5%) received chemotherapy in the neoadjuvant and/or adjuvant setting. Median RFS was 12.3 months. In the metastatic setting, the most frequent chemotherapy combination was gemcitabine plus nab-paclitaxel. 43(46,2%) of patients received second line chemotherapy. Median OS and median SAR were 25,9 and 10,1 months respectively. Kaplan-Meier survival analysis showed that PDA cancer patients with Low-RFS have a poorer clinical outcome than those with High-RFS (median OS 48.26 months, CI 95% 39,3-57,1 for High-RFS; 19.2 months CI 95% 15.7-22-8 for Low-RFS; p = 0.0001). On multivariate Cox regression analysis, age, initial stage I-II, adjuvant chemotherapy utilization and High-RFS were independent prognostic factors for OS and SAR rate. Conclusions: RFS was strongly correlated and discriminated PDA patients with better SAR and OS from the poorer prognosis patients in the ulterior metastatic setting. Prospective studies are needed to confirm this finding.
Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution.
Authors: Hosein Abdel Nasser , Huang Huocong , Wang Zhaoning , Parmar Kamalpreet , Du Wenting , Huang Jonathan , Maitra Anirban , Olson Eric , Verma Udit , Brekken Rolf A.
Published: May 2019

e15739

Background: Pancreatic ductal adenocarcinoma (PDA) is a major cause of cancer-related death with limited therapeutic options available. This highlights the need for improved understanding of the biology of PDA progression. The progression of PDA is a highly complex and dynamic process featuring changes in cancer cells and stromal cells; however, a comprehensive characterization of PDA cancer cell and stromal cell heterogeneity during disease progression is lacking. In this study, we aimed to profile cell populations and understand their phenotypic changes during PDA progression. Methods: We employed single-cell RNA sequencing technology to agnostically profile cell heterogeneity during different stages of PDA progression in genetically engineered mouse models. Results: Our data indicate that an epithelial-to-mesenchymal transition of cancer cells accompanies tumor progression. We also found distinct populations of macrophages with increasing inflammatory features during PDA progression. In addition, we noted the existence of three distinct molecular subtypes of fibroblasts in the normal mouse pancreas, which ultimately gave rise to two distinct populations of fibroblasts in advanced PDA, supporting recent reports on intratumoral fibroblast heterogeneity. Our data also suggest that cancer cells and fibroblasts are dynamically regulated by epigenetic mechanisms. Conclusions: This study systematically outlines the landscape of cellular heterogeneity during the progression of PDA. It strongly improves our understanding of the PDA biology and has the potential to aid in the development of therapeutic strategies against specific cell populations of the disease.
Nab-paclitaxel/S-1(AS) versus nab-paclitaxel/gemcitabine(AG) for first-line chemotherapy in advanced pancreatic ductal adenocarcinoma (aPDAC): A retrospective analysis of efficacy and safety.
Authors: Zong Yuan , Peng Zhi , Lu Ming , Wang Xicheng , Zhou Jun , Shen Lin
Published: May 2019

e15743

Background: AG significantly improved PFS and OS compared with gemcitabine monotherapy in patients (pts) with metastatic PDAC, but the confirmed ORR was limited to 23% with increased grade 3 or 4 myelosuppression. In GEST and JASPAC01 studies, S-1 showed non-inferior or superior activity to gemcitabine in advanced and postoperative PDAC. S-1 also developed less hematologic adverse events especially in neutropenia and was a convenient oral alternative. Two single-arm phase II trials in China demonstrated high ORR of 50.0-53.1% with AS. We investigated the efficacy and safety of first-line chemotherapy with AS versus AG in pts with aPDAC. Methods: A retrospective review was conducted of aPDAC pts treated with first-line AS and AG in GI dpt. Of PUCH between 11/2013 and 12/2018. Pts received 125mg/m2 nab-paclitaxel intravenously (IV) on day1, and 80-100mg S-1 orally per day on day1-7 every two weeks in AS cohort, while pts received 125mg/m2 nab-paclitaxel IV on day1,8, and 1000mg/m2 gemcitabine IV on day1,8 every three weeks in AG cohort. ORR, ORR of primary lesion, DCR, PFS, OS and safety were analysed between two cohorts. Survival outcomes were evaluated by Kaplan-Meier method and compared with the log-rank test. A Cox proportional hazard model was made to determine independent predictors of survival. Results: A total of 70 pts (45 in AS cohort, 25 in AG cohort) with locally advanced (4%) and metastatic (96%) PDACs were identified. 75% were male and the median age was 65(range 36-72). Among intention-to-treat population, the ORR and DCR were 40.0% vs 32.0% (p = 0.70) and 75.6% vs 64.0% (p = 0.57) in AS and AG cohort, respectively. The ORR of primary lesion was 31.1% with AS vs 20.0% with AG (p = 0.73). With the median follow-up of 9.8 months(range 2.3-22.2), the median PFS and OS were 4.7m vs 6.7m (HR, 1.2; 95% CI, 0.6 to 2.4; p = 0.62) and 10.3m vs 11.3m (HR, 0.9; 95% CI, 0.5 to 1.8; p = 0.78) in AS and AG cohort, respectively. Grade 3/4 toxicities occurred in 31.1% AS vs 36.0% AG (p = 0.59). Most G3/4 toxicities were: leukopenia/neutropenia (26.7% vs 20.0%), febrile neutropenia (2.2% vs 8.0%), thrombocytopenia (0 vs 12%), fatigue (4.4% vs 12%), peripheral neuropathy (0 vs 8.0%). In multivariate analysis, liver metastasis was the only independent predictor of poor OS (HR 0.3, 95%CI 0.1-0.8, p = 0.014). Conclusions: AS was a comparable and convenient alternative with manageable toxicities in aPDAC. There was a trend towards improved ORR of primary lesion compared with AG.
Combination therapy of dendritic cell vaccination plus chemotherapy in pancreatic cancer.
Authors: Chiriva-Internati Maurizio , Mirandola Leonardo , Bresalier Robert , Dahlbeck Scott , Figueroa Jose A. , Nguyen Diane Duyen Thuy
Published: May 2019

e15748

Background: Pancreatic cancer is one of the world’s deadliest malignancies with an average 5-year survival rate of only 9%. Fortunately, immunotherapy is providing encouraging results for treatment of this historically resistant malignancy. Kiromic Biopharma is performing a phase I/II dendritic cell vaccine trial for progressive solid malignancies. We present here a notable response to metastatic pancreatic cancer. Methods: The patient is a 73-year-old male with the history of a locally advanced pancreatic cancer treated initially with gemcitabine, concurrent 5FU and radiation therapy, and consolidation 5FU, followed by surgical resection in 2009 . Although the patient did well exceeding typical survival curves, the patient’s cancer became metastatic, requiring multiple lines of chemotherapy including FOLFIRINOX, gemzar and abraxane, and most recently Onivyde and leucovorin/5FU in February - August, 2017 for progressive liver and lung metastases. The patient was then enrolled onto Kiromic Biopharma’s DC vaccination trial in March, 2018. Results: He subsequently received 6 ID autologous dendritic cell vaccinations over 12 weeks, demonstrating a tumor antigen specific immunogenic response by IFN-gamma immunoassay. Total tumor burden (TTB) prior to clinical trial enrollment at the sites of metastatic disease was 2,221mm2, and after completion of the DC vaccination protocol in May, 2018, the TTB increased to 4,466mm2 in June, 2018 (not considered to be pseudo-progression due to a corresponding increase in tumor biomarkers). The patient then received a repeat course of Onivyde and leucovorin/5FU on 8-3-18, completing that course of therapy on 9-14-18, with subsequent TTB decreasing to 2,986 mm2. Conclusions: The sequential combination of dendritic cell vaccine and chemotherapy resulted in a substantial response with a recession in metastatic tumor burden. A CT scan was obtained just 6 days after the 5 week course of Onivyde was completed, and given the optimal immunotherapy window after the DC vaccination, and the repeat of the same chemotherapy regimen, it is unlikely that chemotherapy alone led to such a rapid decrease in the TTB. Metastatic sites were likely populated by chemo resistant clones that survived the August 2017 administration of the Onivyde regimen. Thus, chemo alone would be unlikely to act so quickly. We hypothesize that there was synergistic activity between the DC immunotherapy and the Onivyde/5FU regimen, accounting for the decrease in TTB between May and September, 2018. Clinical trial information: NCT02705703.
Tolerability and safety of a replication-competent adenovirus-mediated double suicide gene therapy (Ad5-yCD/mutTK(SR39)rep-ADP) with chemotherapy in locally advanced pancreatic cancer: Phase 1 trial.
Authors: Lee Jong-Chan , Shin Dong Woo , Yang Se Yeol , Kim Min Jae , Jung Jae Hyup , Kang Jingu , Kim Jaihwan , Hwang Jin-Hyeok
Published: May 2019

e15761

Background: Up to 35% of pancreatic cancers are considered ‘locally advanced’ (LAPC) at the time of diagnosis. Replication-competent adenovirus-mediated double suicide gene therapy (Ad5-yCD/mutTK(SR39)rep-ADP) showed an anti-cancer effect in prostatic cancer patients in previous studies. We aimed to investigate tolerability and safety of Ad5-yCD/mutTK(SR39)rep-ADP in combination with gemcitabine in patients with LAPC. Methods: In this single-center, open label, dose-escalation phase I trial, we recruited adult patients (≥18 years) with newly diagnosed LAPC. Patients with histologically confirmed pancreatic ductal adenocarcinoma with good performance were enrolled. We injected Ad5-yCD/mutTK(SR39)rep-ADP into pancreatic mass with EUS-FNB needle in combination with oral 5-fluorocytosine 500mg qd, oral valgancyclovir 450mg qd, and standard gemcitabine (1000mg/m2, day 1-8-15 infusion every 4 weeks). In the three-stage dose-escalation scheme with traditional 3+3 design, the dose of Ad5-yCD/mutTK(SR39)rep-ADP in each cohort was 1x1011, 2x1011, and 1x1012 vp/mL, respectively. Every patient has been evaluated adenovirus-induced toxicity in 8 weeks and tumor response in 12 weeks. The primary aim is to establish the maximum tolerated dose (MTD) of Ad5-yCD/mutTK(SR39)rep-ADP, as assessed by dose-limiting toxicities (DLT). Results: From 2016 to 2018, we enrolled 11 patients and analyzed nine patients for the final cohort. Two were dropped out by withdrawal of consents. In the first evaluation period (8 weeks), any of patients did not experience dose-related serious adverse event. Only one patients of in 3rd cohort experienced transient grade II fever. In the second evaluation period (12 weeks), two patients showed partial response (PR) and seven showed stable disease (SD). Adenovirus DNA fragments disappeared in median 50 days (range 20 – 139). After the gemcitabine periods, five patients received 2nd-line chemotherapy with FOLFIRINOX, and overall survival was median 14.9 months (range 8.9 – 21.9). Conclusions: In this phase I trial, Ad5-yCD/mutTK(SR39)rep-ADP has been well-tolerated without dose-related severe adverse events, and no MTD reached in locally advanced pancreatic cancer. Phase II clinical trial is needed for evaluating clinical efficacy. Clinical trial information: NCT02894944.
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.