bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional personalized oncology to determine drug sensitivity in cholangiocarcinoma.
Authors: Zarrinpar Ali , Kim Un Bi , Grandori Carla , Schaub Franz , Rosati Rachele
Published: May 2019

e15672

Background: Rare tumors, such as cholangiocarcinoma (CC), have no established treatment protocols, forcing clinicians to select therapies based on educated guesses or small case series. Genomic tumor analyses fail to identify options for most patients. Here, we show the feasibility of using a high-throughput functional assay to test targeted drug libraries on individual patient-derived tumor organoids from CC to yield experimentally-validated therapeutic options. Methods: Three consecutive patients with CC who were undergoing a standard of care biopsy or resection were enrolled in an IRB-approved study. Patient characteristics, demographics, tumor pathology, including Next Generation Sequencing (NGS) data and organoid-derived drug recommendations are shown in the Table. Specimen (~ 200 mg of tumor) was shipped on ice overnight to SEngine Precision Medicine for tumor-derived organoid culture and sensitivity analysis. Organoids were evaluated using a multi-dose response to each drug in a library of 120 FDA-approved and investigational drugs and compared those responses to all prior patients. This established both functional sensitivity and the uniqueness of each patient’s response. Results: We tested operational logistics, tumor growth rates, and chemosensitivity reporting timelines. This has allowed us to: 1) operationalize the expansion process, 2) quantify turn-around time, and 3) identify any technical or logistic barriers. All specimens resulted in adequate growth for sensitivity characterization. None of the NGS studies resulted in recommendations for sensitivity to targeted chemotherapy. Conversely, tumor organoid assays rapidly identified selective, personalized drugs. Conclusions: We have shown the feasibility of this approach in CC. Our preliminary results will inform the design of a future prospective clinical trial to establish and validate this method to select personalized cancer treatments for rare malignancies.[Table: see text]
Retrospective analysis of outcomes with different adjuvant treatments in cholangiocarcinoma: An NCDB review.
Authors: Mamadgi Jyothika , Babar Laila , Lundeen Kristina , Abel Stephen , Verma Vivek , Wegner Rodney E , Raj Moses S.
Published: May 2019

e15677

Background: Annually approximately 5000 cases of cholangiocarcinoma are reported in the US. Of these, less than 40% are treated surgically with a curative intent. Post resection, local and distant recurrence rates are as high as 35% within two years. Positive surgical margins, with either Microscopic (R1) or Macroscopic (R2) disease, confer a higher risk of recurrence. We aim to analyze survival outcomes for different adjuvant treatment strategies in patients with R1/R2 resection. Methods: We queried the NCDB from 2004-2015 for patients with non-metastatic cholangiocarcinoma, who had an R1/R2 resection status post surgery. We then stratified these patients into three arms based on the adjuvant treatment they received: combined chemotherapy and radiation (CRT) vs chemotherapy (CTH) vs observation (OBS). Mean overall survival (OS) was compared for these three groups. OS was calculated from the date of diagnosis to the date of last contact or death using Kaplan Meier curves to present the cumulative probability of survival, with log-rank statistics to assess significance. Results: We identified 522 patients who met our inclusion criteria. Of these, 178 received CRT adjuvantly, 171 CTH, and 173 were observed. The OS in these arms was 42 vs 32 vs 30 months respectively (pooled p < 0.04). As compared to CRT, the hazard ratio was 1.4 (95% CI 1.07-1.72) for CTH and 1.6 (95% CI of 1.2-2.1) for OBS arm. At one year, 83% vs 41% vs 20% of the patients were alive in the respective cohorts and at 5 years, the OS rates were 56% vs 25% vs 13% respectively. Conclusions: Our data demonstrates that combined chemotherapy and radiation is superior to either chemotherapy increase in overall survival for CRT when compared to CHT and observation alone.
Chronotherapeutic regimen with liposomal cisplatin for systemic treatment of primary liver cancer.
Authors: Tavartkiladze Levan , Tavartkiladze Alexandre , Sordia Teimuraz , Gvajaia Ani
Published: May 2019

e15678

Background: Primary liver cancer (HCC) treatment is one of the priority issues of clinical oncology due to inefficiency and quantitative lack of medicines. The goal of our research was to perform treatment of Primary Liver Cancer, based on chronobiological mechanisms, assessment of treatment efficiency and advantage over the standard regimen. Methods: A total of 21 patients with HCC participated in the study. The treatment was performed by Liposomal Cisplatin. Assessment of cancer cells sensitivity to platinum group medicines was performed using RT-PCR method by expression of DNA methyltransferase I gene. During 24 hours, with 2-hour intervals, circulating tumor cells (CTC) were taken from peripheral venous blood. At the end, in all samples circadian regimens of DNA methyltransferase I gene expression were studied. According to obtained results, the circadian peak of gene expression was registered at 02:00-04:30 am time interval. Results: According to the study design of the 21 patients 12 ones received treatment based on chronotherapy regimens (investigated group, infusions were made at 02:00-04:30 am), 9 patients received treatment with standard regimen (control group, infusion was performed at 10:00-12:00 am). Infusions were performed according to the protocol with 1 week intervals for 9 weeks (a single infusion dose 150mg/m2). The treatment efficiency was evaluated 9 weeks later by the following parameters: AFP serum level and computer tomography of the liver. Results of the study demonstrated significant differences in treatment efficacy. During chemotherapy performed in chronotherapy regimen in patient's blood plasma, the AFP concentration decreased on average by 36.5% compared to the initial value, however in the control group the AFP concentration decreased on average by 13.7%. By CT positive dynamics was detected in both groups, but with significant advantage in case of chronotherapy regimen, size reduction of tumor growth by 27.1% on average was associated with fibrous transformation and prominent decrease of vascularization was found. In the control group, size reduction of the tumour growth was seen, however only by 6.3% on average. Patients clinical condition as well as CBC data differed with significant prevailing in case of chronotherapy. Conclusions: Obtained results confirm high clinical significance of chronobiological features of gene expression in antitumour therapy as well as importance of the development of new, up-to-date protocols for HCC – highly aggressive tumour therapy based on chronotherapy principles.
The impact of sorafenib on the treatment and survival of advanced hepatocellular carcinoma (HCC): Analysis of the National Cancer Database (NCDB) from 2004 to 2014.
Authors: Opneja Aman , Cioffi Gino , Alahmadi Asrar , Patil Nirav , Bajor David Lawrence , Saltzman Joel N. , Barnholtz-Sloan Jill , Lee Richard T.
Published: May 2019

e15682

Background: HCC is a common cause of mortality in the U.S. among men and women (5thand 7th, respectively) with overall five-year survival of ~18%. Sorafenib was the only FDA approved therapy for advanced HCC from 2007 until 2018. This study analyzes trends in the treatment and survival of advanced HCC before and after sorafenib approval. Methods: Adult patients ( > 18 years) with diagnosis of HCC treated with only chemotherapy from 2004 – 2014 were identified in NCDB database. Comparisons were made between 3 time frames: 2004 – 2007 (pre-sorafenib), 2008 – 2011 (early sorafenib) and 2012 – 2014 (late sorafenib). Patients treated with single or multi-agent chemotherapy were analyzed. Cox proportional hazards models were used for univariate and multivariable analyses. Kaplan-Meier method was used for survival analysis. Results: The NCDB contained 33,136 patients with HCC diagnosed between 2004 – 2014 and treated with chemotherapy alone. Patients were generally men (77.4%), over the age of 50 years (92.4%), with an elevated AFP at diagnosis (64.4%), and had limited co-morbidities (76.0%, Charlson/Deyo score of 0-1). The T-stages were T1 (26.3%), T2 (20.5%), T3 (25.6%), and T4 (16.2%). The number and proportion of patients treated with single agent chemotherapy increased significantly during the study period: 2,733 (45.3%) pre-sorafenib, 9,723 (72.7%) early sorafenib, and 13,502 (86.1%) late sorafenib. The proportion of all HCC patients in the NCDB receiving only chemotherapy increased from 17.2% to 26.4% to 28.3% across the 3 time frames. The survival of patients with advanced HCC treated only with chemotherapy improved significantly in the early and late sorafenib cohorts compared to the pre-sorafenib cohort (10.3 months (95% CI: 9.8-10.6) vs. 12.3 months (12.0-12.7) vs. 15.5 months (15.1-15.9), p-value < 0.001). Age > 70 years, male sex, higher Charlson/Deyo score ( > 1), elevated AFP at diagnosis, and higher T-stage were associated with worse survival (p value < 0.001). Conclusions: The approval of sorafenib has dramatically increased the use of chemotherapy for the treatment of advanced HCC and has resulted in a significant survival advantage.
Combinational strategies of immunotherapy for hepatocellular carcinoma: One institutional experience in Taiwan.
Authors: Chen Jo-Pai , Hsueh Fu-Jen , Lu Wei-Chen , Ma Wei-li , Wu Hsu , Kuo Sung Hsin
Published: May 2019

e15684

Background: Nivolumab in CheckMate40 study for advanced HCC has brought ORR 15 to 20% and DCR 55%. Our goup found lymph node or lung metastasis responded better and increased PDL1 expression in tumor-infiltrating immune cells after sorafenib (by Lu in AACR & Liver Cancer 2018), suggesting sequential or combination use of sorafenib and immunotherapy. In the 1st line setting, bevacizumab and atezolizumab has brought encouraging response, even with extrahepatic spread and/or macrovascular invasion. Methods: From early 2016 till now, 28 advanced HCC patients had received immunotherapy-containing regimens in Yun-Lin Branch of National Taiwan University Hospital. We have reviewed basic characteristics and regimens to find out their outcomes and responders characters. Results: In 28 patients (1 sorafenib-naive); 14 hepatitis B & 10 hepatitis C; intrahepatic lesions only 25%, lymph node and/or lung metastasis 11%, fulminant spread 64%. The ORR was 25% and DCR was 53.6%. In 5 pembrolizumab users, 1 stable disease; 2 with 200 mg & 3 with 2 mg/kg triweekly; 1(hepatitis B with fulminant metastasis) to fatal liver rupture after bevacizumab and pembrolizumab. In 23 nivolumab users, ORR was 30%; dosage ranging from 0.3 to 3 mg/kg (56.5%) biweekly; 16 combined with metronomic chemotherapy, 10 with bevacizumab, 10 with chemotherap, 7 with bevacizumab and chemotherapy; 1 (failing sorafenib, TACE, & regorafenib) experienced liver necrosis to fatal liver failure after bevacizumab and nivolumab. 7 patients with partial response. Conclusions: In our institution, nivolumab combined with metronomic chemotherapy, low dose bevacizumab or sorafenib, or chemotherapy and even several combination regimens could produce favorable benefits and toxicity profiles in advanced HCCs regardless of viral etiology, even in heavily-treated and fulminant status. Possible combinational strategies of immunotherapy need to be developed with more rationales and biomarkers investigation.[Table: see text]
Predictors of mortality following cardiac surgery for carcinoid heart disease.
Authors: Iliescu Cezar , Balanescu Dinu Valentin , Hassan Saamir , Lopez-Mattei Juan , Palaskas Nicolas , Dasari Arvind , Halperin Daniel M. , Yao James C. , Kar Biswajit , Gregoric Igor , Nathan Sriram , Durand Jean-Bernard , Karimzad Kaveh , Kim Peter Y. , Iliescu Gloria , Balanescu Serban Mihai , Marmagkiolis Konstantinos , Donisan Teodora
Published: May 2019

e15692

Background: Carcinoid Heart Disease (CHD) complicates 50% of carcinoid syndrome cases and represents a major cause of mortality in these patients. Surgery continues to be the only strategy to improve survival in CHD. We aimed to evaluate predictors of mortality following surgery for CHD. Methods: We retrospectively analyzed patients with CHD and a history of valve surgery presenting at a tertiary cancer center between November 2005 and March 2018. Data regarding symptoms, clinical findings, and CHD treatment were collected. Overall survival (OS, time interval from heart surgery to death) was calculated. Univariate Cox proportional hazards regression analyses were conducted to identify variables that were associated with OS. Results: We identified 25 patients with CHD who underwent surgical replacement with bioprosthetic valves: 10 (40%) the tricuspid valve (TV), 11 (44%) TV and pulmonary valve (PV), 3 (12%) TV, PV, and aortic valve, and 1 (4%) all 4 valves. Among them, 19 (76%) survived at least 12 months after the surgery. Clinical factors associated with decreased OS are presented in Table 1. Conclusions: OS following surgery is dictated by the severity of CHD at the time of surgery. Worse outcomes are predicted by a history of congestive heart failure, the number of symptoms, and ascites. Better selection criteria are needed in order to choose the candidates for surgery who will benefit the most. [Table: see text]
Circulating tumor DNA analysis of neuroendocrine tumors.
Authors: Starr Jason Scott , Mody Kabir , Roberts Ali , Kasi Pashtoon Murtaza
Published: May 2019

e15698

Background: Neuroendocrine tumors (NETs) and carcinomas (NECs) are a diverse group of tumors with an equally diverse biology and clinical behavior. Data on tissue-based genomic profiling of NETs exists, however, there is limited data using circulating tumor DNA (ctDNA) technology. We sought out to characterize NETs via ctDNA to identify genomic alterations. Methods: 27 patients with metastatic NET/NEC with 32 total plasma samples were analyzed using Guardant360 ctDNA assay. Breakdown of NET/NEC by location: 14 pancreatic NET (pNET), 11 NEC, 1 small bowel NET, 1 lung NET. The ctDNA test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: Of the 27 patients, 19 (70%) had a detectable genomic alteration. The detectable (non-synonymous) alterations are as follows: TP53 (n = 14, 70%), NF1 (n = 8, 40%), EGFR (n = 5, 25%), BRCA2 (n = 4, 20%), KRAS (n = 4, 20%), ARID1A (n = 3, 15%), CDK6 (n = 3, 15%), ALK (n = 3, 15%), MET (n = 2, 10%), PTEN (n = 2, 10%), BRAF (n = 2, 10%), MTOR (n = 2, 10%) AKT1 (n = 1), BRCA1 (n = 1), CCND2 (n = 1), CCNE1 (n = 1), CTNNB1 (n = 1), ESR1 (n = 1), FGFR2 (n = 1), HRAS (n = 1), IDH1 (n = 1), KIT (n = 1), MYC (n = 1), NOTCH1 (n = 1), NRAS (n = 1), PDGFRA (n = 1), RAF1 (n = 1), RB1 (n = 1), SMAD4 (n = 1), STK11 (n = 1), TSC1 (n = 1), ERBB2 (n = 1), PIK3CA (n = 1). Conclusions: This experience highlights the feasibility of ctDNA to help identify genomic alterations in this patient population. Further studies incorporating ctDNA testing in this patient population are warranted.
Predictors of post-operative mortality following pancreatectomy: A contemporary nationwide analysis.
Authors: Hasan Shaakir , Abel Stephen , Verma Vivek , Schiffman Suzanne , Thakkar Shyam , Kulkarni Abhijit , Williams Harry Kenneth , Monga Dulabh , Finley Gene Grant , Kirichenko Alexander , Horne Zachary D. , Wegner Rodney E
Published: May 2019

e15706

Background: To date, the only curative option for pancreatic cancer is surgical resection, which only 15-20% of patients are eligible for at diagnosis. The conventional operation is a pancreaticoduodenectomy which carries a mortality risk of 3-7%. We used the National Cancer Database (NCDB) to examine surgical outcomes following pancreatectomy. Methods: We queried the NCDB from 2004-2015 for patients with stage I-III adenocarcinoma of the pancreas treated surgically. Outcomes reported were 30 and 90 day mortality, readmission within 30 days, and prolonged hospital stay. Prolonged hospital stay was defined as 17 days and 8 cases per year was used to define high volume centers. Multivariable logistic regression was used to identify predictors of all outcomes. Propensity matching was conducted to account for indication bias. Results: We identified 24,798 patients meeting eligibility criteria. The median patient age was 66 (40-90). The majority of patients were stage T3 (47%) N0 (65%) with pancreatic head lesions (83%). Fifty-seven percent of patients were treated with a Whipple procedure. Most patients (83%) were treated with surgery up front. Overall unadjusted risk of 30 day and 90 mortality ranged from 1.32-2.54% and 4.1-7.12%, respectively, depending on extent of surgery. On multivariable analysis predictors of 30 day mortality included preoperative therapy, increased age, higher comorbidity score, lower income, type of surgery, and treatment at a low volume center. Ninety day mortality was associated with preoperative therapy, increased age, increased comorbidity score, higher T stage, more extensive surgery, and treatment at a low volume center. Multivariable analysis revealed increased comorbidity score, treatment at an academic facility, and non-partial pancreatectomy as predictive of readmission. Prolonged hospital stay was associated with increasing age, decreased education, lower income, non-Caucasian race, more extensive surgery, and more remote year of treatment. Propensity matched Kaplan-Meier analysis showed improved survival with treatment at high volume centers, median survival of 23 months compared to 21 months (p = 0.0026). Conclusions: In the largest population based series to date, the 30 day mortality rates remain acceptably low with an increase seen at 90 days. The predictors of post-operative mortality seen here (age, comorbidity score, extent of surgery, and center volume) highlight the need for appropriate patient selection and physician experience to help achieve the best possible perioperative outcomes.
Nab-paclitaxel plus gemcitabine versus FOLFIRINOX in the first-line chemotherapy for patients with advanced pancreatic ductal adenocarcinoma: A national cohort (Comunica-TTD working group).
Authors: Longo Federico , Castillo Trujillo Oscar Alfredo , Serrano Domingo Juan José , Huertas Roberto Martin , Corral de la Fuente Elena , San Juan del Moral Alberto , Portela Jaime , Cano Juana Maria , Reguera Puertas Pablo , Rodríguez Garrote Mercedes , Izquierdo Manuel Marta , Jiménez-Fonseca Paula , Carrato Alfredo , Aranda Enrique
Published: May 2019

e15707

Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a five-year overall survival (OS) of less than 5%. Folfirinox and Nab-Paclitaxel plus Gemcitabine (NabPacGem) are the most active treatments in the first-line (1L). The decision to use Folfirinox or NabPacGem is a matter of debate. Methods: A retrospective cohort of advanced PDAC patients treated from January 2011 to May 2018 in four Spanish institutions was analyzed. The principal objective was to compare OS among patients receiving Folfirinox versus NabPacGem in 1L. Progression-free survival (PFS) was a secondary objective. Results: Characteristics of 251 patients included: median age 66.6 years; male 54.4%; stage IV at diagnosis 66.7%; ECOG 0/1/2 18/70/12%; treated with Folfirinox 18.3% and NabPacGem 81.7%. Patients treated with Folfirinox versus NabPacGem were younger (median age 58.3 vs. 67.9; p<0.001) and had lower ECOG (0/1/2 of 46/54/0% vs. 13/71/16%; p<0.001). Univariate analysis: median PFS 5.8 months (95%CI, 4.3 – 7.3) for Folfirinox and 4.2 months (95%CI, 3.7 – 5.2) for NabPacGem, HR=1.53 (95%CI, 1.1 – 2.1; p=0.012); median OS 12.7 months (95%CI, 8.4 – 14.3) for Folfirinox and 7.6 months (95%CI, 5.8 – 8.8) for NabPacGem, HR=1.38 (95%CI, 0.96 – 1.98; p=0.081). Multivariate Cox analysis (including type of treatment, ECOG and age) showed that ECOG was the only variable associated with PFS and OS (Table). Conclusions: In our study, advanced PDAC patients treated with Folfirinox were younger and had a better performance status than those treated with NabPacGem. We found no differences in survival between both treatments when adjusting by ECOG and age.[Table: see text]
Immune landscape of neoadjuvant/preoperative chemoradiotherapy in pancreatic cancer.
Authors: Nakajima Kosei , Ino Yoshinori , Hiraoka Nobuyosh
Published: May 2019

e15709

Background: Neoadjuvant/preoperative chemoradiotherapy in pancreatic cancer has been implicated to induce a local anti-tumor immunity, however the molecular mechanism remains a conundrum. Methods: Two patients’ cohort samples with/without preoperative chemoradiotherapy were used (n = 26 and n = 20, respectively). The treatment-driven immune microenvironment changes were analyzed by stratified bioinformatic approaches i.e. heat map analysis of immune-related genes selected by Gene Ontology, GSEA with Immunologic Signature data base, and Ingenuity Pathway Analysis (IPA). The results were further validated by immunohistochemical approaches. Results: Preoperative treatment induced 212 genes including DC-SIGN (CD209) and 13 immune-associated pathways such as TCR signaling, with an increasing shift of CD8 T-cell population by upregulation of MAL (T-cell differentiation protein). Consistently, immunohistochemical findings showed that the accumulation of DC-SIGN (+) dendritic cells and MAL (+) lymphocytes were significantly increased in patients with preoperative therapy. Conclusions: Preoperative chemoradiotherapy induces a shift toward CD8 T-cell generation mediated by DC-SIGN (+) dendritic cells and MAL (+) lymphocytes, leading to enhance anti-tumor immunity.
Remnant pancreatic volume to predict short-term and long-term outcomes in patients with resected pancreatic cancer.
Authors: Miyamoto Ryoichi , Oshiro Yukio , Ohkohchi Nobuhiro
Published: May 2019

e15713

Background: Remnant pancreatic volume (RPV) is a well-known marker for short-term outcomes in patients with resectable pancreatic cancer. However, in terms of the long-term outcomes, the significance of the RPV remains unclear. Here, we addressed whether the RPV is a predictor of long-term outcomes in pancreatic cancer patients by comparing various cancer-, patient-, and surgery-related prognostic factors and systemic inflammatory response markers in a retrospective cohort. Methods: The RPV was measured on the 3D image, revealing the actual pancreatic parenchymal remnant volume. Ninety-one patients who underwent pancreaticoduodenectomy (PD) were retrospectively enrolled. We divided the cohort into high- and low-RPV groups based on a cut-off value ( > 35.5 cm3, n = 66 and ≤ 35.5 cm3, n = 25, respectively). The patient characteristics, perioperative outcomes and median survival times (MSTs) were respectively compared between the two groups. Using multivariate analysis, the RPV and other well-known prognostic factors were independently assessed. Results: A significant difference in the RPV value was observed with respect to the incidence of postoperative pancreatic fistula (high, 18 [55%] vs. low, 9 [16%], p < 0.001). The MSTs (days) were significantly different between the two groups (high, 823 vs. low, 482, p = 0.001). Multivariate analysis identified the RPV (≤ 31.5 cm3) (hazard ratio [HR], 2.015; p = 0.011), lymph node metastasis (HR, 8.415; p = 0.002), adjuvant chemotherapy (HR, 5.352; p < 0.001), presence of stage III/IV disease (HR, 2.352; p = 0.029), and pathological fibrosis (HR, 1.771; p = 0.031) as independent prognostic factors. Conclusions: The present study suggests that the RPV is an additional useful predictor of both long-term and short-term outcomes in pancreatic cancer patients after PD.
Treatment response and survival in patients with pancreatic adenocarcinoma receiving neoadjuvant chemotherapy or chemoradiation.
Authors: Khattab Ahmed , Patruni Sunita , Abel Stephen , Hasan Shaakir , Finley Gene Grant , Monga Dulabh K. , Wegner Rodney E , Verma Vivek
Published: May 2019

e15715

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Neoadjuvant chemotherapy (NeoChT) and chemoradiation (NeoCRT) have emerged as strategies to optimize resection, but data investigating predictors of treatment response and the overall survival (OS) impact are not well characterized. To investigate the effects of NeoChT/NeoCRT on primary tumor/nodal downstaging and OS, we analyzed the national cancer database (NCDB). Methods: We queried the NCDB for patients with PDAC receiving NeoChT/NeoCRT. Patients were classified as responders (T and/or N downstage), nonresponders (mixed/no response) and progressors (T and/or N upstage). Multivariable logistic regression identified predictors of response. Univariable and multivariable analyses identified characteristics predictive of OS. Results: 2,028 patients with PDAC receiving NeoChT/NeoCRT were analyzed. Univariable analysis of responders (n = 790) vs. nonresponders/progressors (n = 1,238) demonstrated a significant difference in median OS at 29.1 months vs. 25.3 months and 3-year overall survival of 40% vs. 34% [p = 0.006; HR: 0.95 (95% CI: 0.84-1.08)] respectively. When compared independently to both responders and nonresponders, progressors had a significantly decreased 3-year OS at 31% vs 40% and 37% respectively [p = 0.003; HR: 0.82 (95% CI: 0.70-0.96)]. Predictors of response on multivariable logistic regression included receipt of multiagent chemotherapy and receipt of NeoCRT. Only NeoCRT predicted for pathologic complete response (pCR). Multivariable analysis of patients with pCR demonstrated a trend towards increased OS (p = .08). Conclusions: Our results suggest that both response and progression following neoadjuvant therapy may predict for longer and shorter OS respectively. Randomized, prospective studies are needed to further validate these findings. [Table: see text]
Change in body composition and survival in patients with pancreatic cancer.
Authors: Krishnan Mridula , Yu Lei , Dasgupta Aneesha , Mullen Nicholas J , Osayande Ferdinand , Berim Lyudmyla Derby , Alam Morshed , Yu Fang , Oliveto Jennifer , Klute Kelsey , Singh Pankaj K.
Published: May 2019

e15716

Background: The incidence of pancreatic ductal adenocarcinoma (PDAC) is on the rise and continues to have a poor overall survival despite aggressive available treatment strategies. Sarcopenia is prevalent in PDAC patients and is likely caused by both disease and treatment. We hypothesized that ongoing muscle loss during treatment with chemotherapy would be associated with shorter progression-free survival (PFS) and overall survival (OS). Methods: We measured skeletal muscle index at L3 vertebra on baseline follow-up scans in patients with PDAC treated with chemotherapy at our institution. Patients were categorized by percent SMI lost over an 8-week period (<10%, 10-20%, ≥20% loss). We compared PFS and OS between the groups. Results: We included 162 patients with stage I-IV pancreatic cancer. Baseline characteristics are listed in the Table. SMI loss was associated with shortened PFS and OS (p=0.009, p=0.032 respectively) via log-rank test for trend. Even after adjusting for confounders (age, gender, resection status, stage, baseline sarcopenia, treatment and therapy), the relative risk of death (2.0; 95% CI=1.10-3.64, p=0.023), and progression (1.83; 95% CI =1.08-3.10, p =0.024) were higher in those who lost ≥20% SMI. There was no significant association between BMI change or fat change with the survival outcomes. Conclusions: The loss of skeletal muscle during the first 8 weeks of chemotherapy is associated with shortened survival outcomes and is independent of stage and resection status in patients receiving chemotherapy for PDAC. Future studies should seek to understand mechanisms of muscle loss by both tumor and chemotherapy to improve survival in patients with PDAC. Baseline characteristics. [Table: see text]
Effect of neoadjuvant chemotherapy using gemcitabine and S1 before surgery for pancreatic cancer on quality of life.
Authors: Sato Naoko , Motoi Fuyuhiko , Iseki Masahiro , Kawaguchi Kei , Sato Fumiko , Katayose Yu , Unno Michiaki
Published: May 2019

e15719

Background: To improve the poor prognosis of patients with pancreatic cancer, we examined the effect of 6 months of neoadjuvant chemotherapy (NAC) using gemcitabine and S1 before surgery and found significantly prolonged survival. Clinical use of this treatment is expected in the future. However, preoperative NAC may increase the physical burden on patients as well as their psychological burden due to the longer waiting time. Thus, it is necessary to confirm that the treatment does not reduce quality of life (QOL). Methods: In this observational study of patients who underwent resection after this NAC, a QOL questionnaire survey was administered preoperatively and at postoperative months 3, 6, and 12, to consenting patients from those enrolled in randomized controlled trials (RCTs). The intervention group (planned surgery and NAC) had added pre- and post-treatment QOL surveys. We used the Short Form 36 Health Survey version 2 (SF-36v2 Standard, Japanese) to measure health-related QOL. Overall differences among the groups were evaluated by paired t test and two- and three-way ANOVA. All statistical analyses were performed using SPSS (ver. 21) software. Results: In total, 55 patients (mean age 66.0 years), about 15% of those enrolled in the RCTs, responded to the questionnaire (NAC group, n = 22; control group, n = 33). QOL was not significantly reduced in the NAC group pre- and post-treatment ( p= 0.19-0.96). Notably, there were no significant differences in post-treatment QOL, with improvement in the Physical Functioning (75.9→79.4), Bodily Pain (70.5→72.5), Vitality (59.6→59.9), and Mental Health (66.5→69.7) SF-36 domains compared with before preoperative treatment. This suggests that patients had good preoperative physical and mental QOL. QOL at each time point did not differ significantly in the 8 domains with or without NAC; the Mental component summary score was significantly higher in the NAC group compared with the control group at 3 months (54.9 vs 49.3, p= 0.04). NAC and QOL did not differ significantly by time, sex, and operation type. Conclusions: NAC using gemcitabine and S1 before surgery for pancreatic cancer does not reduce QOL. Improved prognosis can be expected with no adverse effect on QOL.
Effect of irreversible electroporation (IRE) combined with chemotherapy (C) on survival in locally advanced pancreatic cancer (LAPC) patients (pts).
Authors: Karamouzis Michalis , Oikonomou Dimitrios , Dimitrokallis Nikolaos , Papamichael Demetris , Kountourakis Pantelis , Astras George , Moris Demetrios , Davakis Spyridon , Papalampros Alexandros , Petrou Athanasios S , Felekouras Evangelos
Published: May 2019

e15723

Background: LAPC represents 40% of PC pts. IRE is a non-thermal ablative technique that can be used in inoperable pts and safely combined with C. Methods: From 2015 to 2018 laparotomic IRE was performed in a total of 34 LAPC pts. The median age was 64.7yrs (range, 46-81yrs) and 15 (44%) were males. The median tumor size was 3.9cm (range, 2-5.2cm) with the majority of tumors located at pancreatic head (26 pts, 76%), followed by body (6 pts, 18%) and tail of pancreas (2 pts, 6%). Induction C was applied in 27 out of 34 pts and in case of disease control IRE was done, while in 7 pts IRE was done without prior C. In the majority of pts C after IRE was also given. Results: Induction C was applied in 27 out to 34 pts (80%) [FOLFIRINOX in 16 pts, nab-paclitaxel-gemcitabine (AG) in 11 pts]. After the completion of 3 cycles of C tumor evaluation showed partial response (PR) in 20 pts and stable disease (SD) in 7 pts. All pts were treated with IRE and 50% of them had a preoperative biliary stent, while 3 pts had metallic stent that was removed before IRE. No IRE-related deaths occurred. Two major complications grade III were reported: pancreatic fistula grade A in 7 pts and 2 pts diagnosed with delayed gastric emptying. There was also one minor complication (wound infection) in 3 pts (9%). Up to 31/12/2018, the median overall survival (OS) of all pts was 24.2 months (mos) (range, 6-36 mos) and median progression free survival (PFS) was 14.6 mos (range, 3-24 mos). The median OS of the pts treated with C-IRE-C was 22.5 mos (range, 13-36 mos) and median PFS 16.9 mos (range, 3-24 mos), while in pts treated with IRE-C only was 15 mos (6-22 mos) and 10.9 mos (range, 5-16 mos), respectively. The group treated with FOLFIRINOX-IRE-C showed median OS 22.5 mos (range, 15-36 mos) and median PFS 17.1 mos (range, 3-24 mos), while the group treated with AG-IRE-C had median OS 19 mos (range, 13-36 mos) and median PFS 15.8 mos (range, 7-24 mos). After IRE, 24 pts (71%) continued with adjuvant C, either FOLFIRINOX 5 pts (15%) or G-based regimen 18 pts (46%) until disease progression or unacceptable toxicity, while 12 pts (35%) have more than 24 mos OS and 3 pts (9%) have reached 36 mos OS and are still alive. Conclusions: The combination of C with IRE is safe and results in survival increase of LAPC pts. Pts treated with the sequence FOLFIRINOX-IRE-C seems to benefit the most.
Main driver genes and BRCA mutation in Chinese patients with pancreatic adenocarcinoma.
Authors: Tian Jiangfang , He Du , Huang Zhixi , Tian Bole , Cao Dan
Published: May 2019

e15741

Background: Data on pathogenic genetic alterations in Chinese patients with pancreatic adenocarcinoma (PAC) are limited. Especially, as BRCA mutations may become potential biomarkers guiding therapy for PAC patients, the prevalence of BRCA mutations in Chinese patients remains largely unknown.We performed the study to analyze genes mutational landscape and determine the prevalence of BRCA mutations in Chinese PAC patients. Methods: We reviewed clinical characteristics and genes mutations of 134 patients with a pathologically confirmed PAC from West China Hospital of Sichuan University between May 2016 and November 2018. All of them underwent gene-testing and genes variant evaluation with a panel of 381 genes by next-generation sequencing (NGS). The test samples were mainly from primary pancreatic lesions, other were from peripheral blood and metastatic sites. All main driver gene mutations and clinical stages were measured to determine associations of driver gene mutations, the number of altered genes, the level of CA199 with clinical stage. Results: Of the 134 patients, 73 (54.5%) were men with a median age of 58 (range from 34 to 82) years. The major driver mutations were KRAS (89.6%), TP53 (71.6%), CDKN2A (26.9%), SMAD4 (18.7%) and ARID1A (10.4%). The majority of patients (76.9%) had 2 genes or more genes mutations, KRAS/TP53 and KRAS/TP53/CDKN2A were the most frequently combinate types. Stages of PAC was relevant to numbers of altered genes (p = 0.040) and the level of CA199 (p = 0.002). Five (3.7%) patients with BRCA mutations were identified, two patients had somatic BRCA2 variants, one patient had somatic BRCA1 mutation and the other two patients had germline BRCA2 mutation. Two patients with germline BRCA2 mutations received olaparib and keep stable disease for 4 months and more than 8 months. Our finding revealed patients with PAC had a low TMB (median 3.81 per Mb (range 0.81-9 per Mb)) and PD-L1 expression (16/36, 44.4%), nearly all of them were MSS (50/51,98.0%), just three patients with dMMR (3/134,2.2%). Conclusions: The PAC patient commonly harbored two or more number of five major driver mutations including KRAS, TP53, CDKN2A, SMAD4 and ARID1A. The frequency of BRCA1/2 mutations in Chinese patients with PAC was 3.7%. Olaparib may be effective for PAC patients with BRCA mutations. The PAC may be poor response to immunotherapy.
Role of neoadjuvant therapy (NAT) in pancreatic adenocarcinoma (PAC): A single center experience.
Authors: Nassabein Rami Mohamad , Richard Corentin , Ayoub Jean-Pierre M. , Aubin Francine , Campeau Marie-Pierre , Delouya Guila , Donath David , Dagenais Michel , Lapointe Real W. , Letourneau Richard , Plasse Marylene , Turcotte Simon , Roy Andre , Vandenbroucke-Menu Franck , Olivié Damien , Routy Bertrand , Tehfe Mustapha
Published: May 2019

e15747

Background: Surgical resection of PAC followed by adjuvant therapy is the standard of care for non-metastatic resectable tumors. Surgical resection with clear margins of borderline (BR) or locally advanced (LA) tumors is either challenging or impossible. Furthermore, there are no clear recommendations concerning NAT for non-upfront resectable PAC. Thus we reviewed our own experience with different NAT modalities for BR and LA PAC. Methods: Medical records of patients identified by Tumor Board as BR or LA PAC and treated with NAT at Centre Hospitalier de l’Université de Montréal (CHUM) were retrospectively reviewed. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test. For both univariate and subgroup analyses, hazard ratio and 95% confidence interval were estimated by Cox proportional hazard regression. Results: Between 2009 and 2017, 90 patients (50 BR, 40 LA) were identified. Chemotherapy, mostly FOLFIRINOX, was the only NAT in 51 patients (56.6%), 23 patients (25.3%) received chemoradiotherapy alone and 16 patients (17.7%) received sequential treatment of both modalities. Tumor resection was achieved in 44 patients, with 32 BR patients (R0: 68.7%) and 12 LA patients (R0: 75%). Median Disease free survival (DFS) of patients that underwent resection was 12.3 months. mPFS was 29 vs 10 months (HR:0.2; p < 0.001) and mOS was 41.7 vs 15.7 months (HR:0.3; p < 0.001) in resected and non-resected patients, respectively. In subgroup analysis, resection statistically improved PFS and OS regardless of age, sex, T stage and type of vessel involvement. Treatment with more than one modality showed better clinical outcomes (PFS and OS) and a non-statistically higher R0 resection rate that was 100% in BR tumors. OS in patients with resected cancers was not reached for the multimodality group, 41.7 months for chemotherapy alone group and 22.4 months in patients treated with chemoradiotherapy group (p = 0.017). Conclusions: In this retrospective single center analysis, NAT with chemotherapy and/or chemoradiotherapy appears to improve patients’ clinical resection results and outcomes. These results validate previous retrospective studies but warrant large prospective trials to define the best NAT.
Comprehensive genomic analysis of metastatic pancreatic ductal adenocarcinoma (mPDAC) reveals a significant proportion of clinical actionable aberrations.
Authors: Lee Michael , Jones Martin R , Williamson Laura , Topham James Thomas , Wong Hui-Li , Addison Sean , Denroche Rob , Jang Gun Ho , Karasinska Joanna , McGhie John Paul , Gill Sharlene , Lim Howard John , Yip Stephen , Knox Jennifer J. , Gallinger Steven , Laskin Janessa J. , Marra Marco A. , Jones Steven J. M. , Schaeffer David F. , Renouf Daniel John
Published: May 2019

e15753

Background: Significant progress has been made in the understanding of the genomic landscape of PDAC, but the clinical utility of these data remains uncertain. Methods: As part of the BC Cancer Personalized Oncogenomics (POG) and PanGen studies (NCT02155621, NCT02869802), whole genome analysis and transcriptome sequencing were performed on fresh biopsy and blood sample from 48 mPDAC patients. Genomic findings informed therapy choices including potential eligibility for the CCTG PM.1 molecular basket trial (NCT03297606). Results: Cohort consists of 54.1% male, average age 57.6, 34/48 had ≥2 lines of treatment. 37/48 biopsies were from liver and 27/48 were collected pre-treatment. 8/48 (16.6%) patients had aberrations with strong evidence of clinical actionability. These include 2 germline BRCA2, 1 germline BRCA1, 1 somatic XRCC2 homozygous deletion with strong COSMIC signature 3, all predictive of platinum sensitivity. Patients with XRCC2 deletion and BRCA1 had over 2 years on FOLFIRINOX. Fusions affecting the NRG1 gene were identified in 3/4 patients with KRAS wildtype tumours, which may confer ERRB inhibitor sensitivity. 2/3 NRG1 fusion patients have thus far been treated with the ERBB inhibitor afatinib with radiographic responses noted in both patients. One patient had mismatch repair deficiency, and a high mutational burden, suggestive of immune checkpoint inhibitor sensitivity. Other possible actionable mutations include CCTG PM.1 trial potential eligibility: 4/48 with high homologous recombination defects and 1 germline ATM mutation loss (PARP inhibitor arm), 1/47 ERBB2 amplification (anti-HER2 arm), 2/47 high expression of FGFR1 (Sunitinib arm) and 1/47 with high FLT4 and IGF1R expression (Axitinib arm). Conclusions: More routine use of comprehensive genomic analysis should be considered in mPDAC given finding of high degree of actionability. Importantly, a significant proportion (16.6%) had findings with strong evidence of clinical impact.
Significant neutrophil accumulation, IL-18 deposition, and active inflammasome in tumor regions of human pancreatic ductal adenocarcinoma.
Authors: Khattab Ahmed , Garciafigueroa Yesica , Phillips Brett , Patruni Sunita , Kamran Amir , Jayakrishnan Thejus , Khatoon Nazia , Mohy-ud-din Nabeeha , Monga Satdarshan P , Miller Stacey , Giannoukakis Nick , Monga Dulabh K.
Published: May 2019

e15754

Background: Obesity is an established risk factor for cancer and cancer-related mortality. Adipocytes may act as a “damage” signal resulting in the accumulation of innate immune cells, fueling an inflammatory micro-environment. Among the innate immune cells, tumor-associated neutrophils (TANs) are confirmed to accumulate inside the tumor. As obesity is a significant risk factor for a poorer prognosis in pancreatic ductal adenocarcinoma (PDAC), we hypothesize that obesity-driven adipose fuels the progression of PDAC in a TAN and inflammasome-facilitated manner. This may happen through several mechanisms, including genomic instability of aggressive PDAC clonal populations. Methods: Tissue from resected tumors of PDAC patients with a body-mass index (BMI) > 27 (obesity, n = 5) and BMI < 22 (normal, n = 5) were incubated with anti-human IL-18 and CD66b antibodies and detected using Alexa Fluor 488-conjugated donkey anti–mouse and Alexa Fluor 594-conjugated goat anti-rabbit secondary antibodies. Images were acquired in a Zeiss Axioplan microscope workstation and analyzed by ZEN and Metamorph software. Results: We identified the presence of CD66b+ neutrophils and IL-18 in all tissue sections. There is a significantly greater density of CD66b+ neutrophils and IL-18 in the tumor environment when compared to adjacent normal areas and IL-18+ signals appear to be deposited alongside the luminal area in a unique lasso-like pattern. These data suggest an association between BMI and inflammasome accumulation in the tumor environment. There does not appear to be an association between tumor stage and TAN or IL-18 accumulation in the tumor area or the adjacent normal tissue in the tissues. Conclusions: Our data uniquely shows that CD66b+ neutrophils accumulate inside PDAC and this is associated with intra-tumoral active inflammasomes. The novel periductal deposition of IL-18 in the tumor areas may be of mechanistic relevance in understanding how inflammation induces progression of PDAC. A larger cohort of tissues from PDAC obtained from low and high BMI individuals will be needed to test our hypothesis and to begin to decipher the role of obesity on inflammation and PDAC progression.
Development of a radiomics nomogram based on the CE-CT features to predict the survival of upfront resectable patients with pancreatic head cancer and suspected venous invasion.
Authors: Shen Yinan , Tang Tianyu , Bai Xueli , Liang Tingbo
Published: May 2019

e15760

Background: Pancreatic head adenocarcinoma is commonly diagnosed at an advanced stage when adjacent vascular invasion is present. This study aimed to establish a radiomics nomogram by integrating radiomics signature and clinical predictors to estimate overall survival(OS) in patients who underwent attempted curative resectional surgery for pancreatic head cancer with suspected peri-pancreatic venous invasion. Methods: Data on patients with pancreatic head adenocarcinoma and suspected peripancreatic invasion who underwent pancreatic resection with venous reconstruction were retrospectively collected from 2012 to 2016 at two academic institutions. A total of 396 radiomics features were extracted from pretreatment CE-CT images of each patient. Least absolute shrinkage and selection operator (LASSO) regression was applied to select optimal features and generate a radiomics signature. The radiomics nomogram was developed by integrating the radiomics signature and clinical predictors. The performance of radiomics nomogram validated in the cohort of patients of second institution. Results: Radiomics signatures were significantly associated with pancreatic head adenocarcinoma patients' survival time. The radiomics nomogram combined with clinical predictors(CA-199 value, Peripancreatic venous abnormalities and Lymph node staging) provided good predictive accuracy of survival on calibration curves. The C-index of the model in predicting overall survival (OS) was 0.836 for the validation cohort. Conclusions: The nomogram accurately predicted OS in patients with pancreatic head cancer with suspected peripancreatic venous invasion after attempted curative pancreatic resectional surgery. These findings might aid clinicians with treatment decision-making and improve precise medicine.
Comparison of FOLFIRINOX and gemcitabine with nab-paclitaxel in metastatic pancreatic cancer: Using Korean Pancreatic Cancer (K-PaC) Registry.
Authors: Lee Jong-Chan , Shin Dong Woo , Yang Se Yeol , Kim Min Jae , Kim Jaihwan , Woo Sang Myung , Lee Woo Jin , Choi Kui Son , Jung Jae Hyup , Kang Jingu , Hwang Jin-Hyeok
Published: May 2019

e15762

Background: Although FOLFIRINOX and gemcitabine with nab-paclitaxel (GNP) are widely used in metastatic pancreatic cancer (MPC), the multi-center study comparing two regimens is rare. Recently, a multi-center, web-based registry for pancreatic cancer (K-PaC, Korean pancreatic cancer) was firstly launched in South Korea. We aimed to compare the clinical outcomes for FOLFIRINOX and GNP in MPC patients using K-PaC registry. Methods: In the K-PaC registry, we constructed the web-based database of anonymized 3,748 patients with histologically-proven pancreatic ductal adenocarcinoma. For this study, MPC patients who have received first-line FOLFIRINOX or GNP were enrolled. The baseline characteristics, overall survival (OS), grade III-IV toxicity, and other subgroup characteristics were analyzed. Results: From 2011 to 2017, a total of 413 (FOLFIRINOX 231 vs. GNP 182: with the same order below) patients met the eligible criteria. Median age was 63 year (60 vs. 68) and male were 46% (51% vs. 39%). Origins of tumor were head (41%), body (25%), and tail (34%). Major metastatic sites were liver (62%), peritoneum (32%), lung (18%), and others (34%), including multiple metastases. Median OS was 11.6 month (11.3 vs. 12.4, hazard ratio [HR] 0.91, confidence interval [CI] 0.71–1.16). The major hematologic toxicity was 32% of neutropenia (37% vs. 23% with P-value 0.116) and 12% of febrile neutropenia (16% vs. 10% with P-value 0.172). The major non-hematologic toxicity was 33% of fatigue (29% vs. 37% with P-value 0.455) and 28% of vomiting (27% vs. 29% with P-value 0.516). According to metastatic site, median OS by agents (months, FOLFIRINOX vs. GNP) were as follows: 9.5 vs. 10.2 with HR 0.898, CI 0.66–1.22 in liver; 11.8 vs. 12.5 with HR 0.90, CI 0.61–1.33 in lung; 9.1 vs. 12.6 with HR 0.94, HR 0.70–1.19 in peritoneal seeding. According to the sequential treatment, median OS of 1st-line FOLFIRINOX followed by GNP group (n = 53) was 11.2 month and that of 1st-line GNP followed by FOLFIRINOX group (n = 43) was 12.4 month (HR 0.82, CI 0.68–1.18). Conclusions: In this study using K-PaC registry in Korea, FOLFIRINOX and GNP showed comparable efficacy and toxicity. In the subgroup analysis, sequential treatment did not showed significant difference, but GNP showed a better trend in the group of peritoneal seeding.