bluuebunny/crossref_metadata_2025 huggingface dataset:
Next-generation sequencing (NGS) in advanced pancreatic adenocarcinoma (PA): A Brazilian experience.
Authors: Moreira Raphael Brandao , Alessandretti Matheus Bongers , Lino Aline Da Rocha , Martins Junior Rodnei Merlrina , Amarante Marcus Paulo Fernandes , Gomes Jessica Ribeiro , Sousa Tarcia Tarciane Soares de , Abrahao Carina Mina , Kawamura Haddad Carolina , Peixoto Renata D'Alpino , Maluf Fernando C. , Buzaid Antonio C. , Cruz Marcelo Rocha ,   COAEM
Published: February 2017

315

Background: Metastatic PA is a lethal malignancy with poor prognosis and limited therapeutic options. We hypothesized that a comprehensive next-generation sequencing (NGS) assay could identify novel therapy targets not routinely explored in PA patients. Methods: We included patients with advanced pancreatic adenocarcinoma (PA) with accessible lesion for biopsy. Paraffin-embedded tumor tissues were evaluated by the method of NGS (Foundation Medicine, Cambridge, MA, USA). Hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥ 50 ng of DNA extracted from 10 PA specimens and sequenced to high, uniform coverage. Genomic alterations (GAs), were characterized and reported for each patient sample. Actionable GAs were defined as those identifying anti-cancer targeted therapies either available on the market or in registered clinical trials. Results: A total of 10 PA patients were included. Median age was 56 years (range 31-79). All cases harbored at least one GA with a mean of 2.7 actionable GAs per tumor. The most common actionable GAs were KRAS (90%), PTCH1 (20%), STK11 (10%) and GNAS (10%). KRAS mutations potentially treatable with MEK-inhibitor were identified in 9 patients. However, none of them received a MEK-inhibitor. Activating STK11 point mutations not detectable by IHC/FISH, potentially targetable with m-Tor inhibitor therapies were identified in 1 patient, who received everolimus and had a long-lasting (> 6 months) partial response. Conclusions: NGS of PA was able to reveal genomic alterations that may be potentially responsive to available targeted therapy. We are just at the dawn of exploring this strategy and NGS can effectively contribute for increasing the understanding of the disease.
Aurora kinase A inhibition in combination with proapoptotic BH3-mimetic for treatment of pancreatic cancer.
Authors: Kim Edward Jae-hoon , Chinn Danielle C. , Semrad Thomas John , Mack Philip C.
Published: February 2017

316

Background: BH3-mimetics were designed to inhibit the anti-apoptotic members of the Bcl-2 family of proteins. BH3-mimetics in clinical development do not inhibit the Bcl-2 protein Mcl1, which is often active in pancreatic cancer. However, Mcl1 level can be decreased by mitotic arrest. Therefore, drugs that cause mitotic arrest may augment apoptosis induced by BH3-mimetics. Aurora Kinase A (AKA), also commonly overexpressed in pancreatic cancer, regulates mitotic spindle assembly and centrosome maturation and its inhibition leads to M-phase arrest. We hypothesized that inhibiting AKA would increase sensitivity of pancreatic cancer cells to BH3-mimetic-induced apoptosis. Methods: Pancreatic cancer cell lines (AsPC-1, PANC-1, MIA PaCa-2, HPAF-II) were evaluated for AKA protein expression by Western blot (WB). Baseline cell cycle distribution was evaluated by flow cytometry. All four cell lines were treated with a BH3-mimetic (ABT-263) alone, an AKA inhibitor (MLN8237) alone, or the combination in comparison to untreated controls. Cell viability was measured using the Celltiter-Fluor assay. Apoptosis was evaluated by WB for cleaved PARP and caspase 3. Percentage of cells undergoing apoptosis was quantitated using flow cytometry of annexin V and propidium iodide stained cells. Results: AKA expression varied between cell lines but correlated with percentage of cells in G2/M. Level of AKA expression did not appear to correlate with response to MLN8237. However, MLN8237 did induce mitotic arrest resulting in an increase in the G2/M fraction. Cell viability assays revealed limited sensitivity to MLN8237 or ABT-263 alone. MIA PaCa-2 cells were the most sensitive to MLN8237 with IC50 ~0.09µM and HPAF-II cells were the most sensitive to ABT-263 with IC50 0.6µM. MLN8237 lowered the IC50of ABT-263 in all 4 cell lines. Chou-Talalay plots exhibited a combination index < 1 in each cell line, confirming synergy. WB for cleaved PARP and caspase 3 showed increased apoptosis with the combination. The percentage of cells undergoing apoptosis also increased with the combination in each cell line. Conclusions: Inhibition of AKA synergistically augments BH3-mimetic-induced apoptosis in pancreatic cancer cells.
Discrepancies between two staging systems (European-ENETS versus. American-AJCC) of neuroendocrine neoplasms of the pancreas: A study of 77 cases.
Authors: Cienfuegos Javier A. , Salguero Joseba , Nuñez Jorge , Rotellar Fernando , Marti-Cruchaga Pablo , Zozaya Gabriel , Pardo Fernando
Published: February 2017

318

Background: Pancreatic neuroendocrine tumors (pNETs) comprise a spectrum of neoplasm with variable biological behaviour and heterogeneous prognosis. The European Neuroendocrine Tumor Society (ENETS) and the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) TNM staging systems have been recently published. The aim of this study was to evaluate the consistency of both staging systems on outcomes for patients with pNETs. Methods: A retrospective clinico-pathological study of 77 consecutive patients with pNETs who were surgically treated from 1993 to 2014 was carried out. Results: The male to female ratio was 1.0 (38 men, 39 women); 56 tumors were non-functionating and 21 functionating. Most of the tumors were G1 (57) and 20 were classified as G2-G3. The AJCC/UICC stage was IA in 29 patients, IB in 14, IIA in 10, IIB in 7 and IV in 17. Meanwhile, according with the ENETS staging system was: stage I in 30, IIa in 14, IIb in 3, IIIa in 6, IIIb in 7 and IV in 17. We found 18 (23.3%) cases of ENETS - AJCC/UICC discrepancies regarding the primary tumor. They included 6 cases (33%) disagreement between IIA (T3 N0 M0) and IIIa (T4 N0 M0); and 7 cases (38.8%) between IIB (T1-T3 N1 M0) and IIIb (anyT N1 M0). Conclusions: The AJCC and ENETS TNM classification staging for pNETs provide meaninful prognostic value of long-term survival por patients with pNETs. The T staging discrepancies between AJCC/UICC and ENETS are relative frequent and should be strictly recognized.
A pilot study of molecularly tailored therapy for patients with metastatic pancreatic cancer (MPC).
Authors: Pishvaian Michael J. , Wang Hongkun , He Aiwu Ruth , Ley Lisa , Dorsch-Vogel Karen , Hartley Marion L. , Carney Erin , Weiner Louis M. , Smaglo Brandon George , Brody Jonathan Robert , Marshall John
Published: February 2017

329

Background: We have entered an era where multiple chemotherapeutic (chemo) agents can be utilized in the treatment (Tx) of patients (pts) with MPC. However, there are no methods for selecting the optimal regimen for any individual pt, and pure empiricism has not proven to be an optimal strategy. Molecular profiling is now widely used, albeit without evidence-based studies linking molecular profiles to Tx choices. Methods: We initiated a pilot study to assess the feasibility of following a simple algorithm, basing Tx on 3 published predictive markers of response to chemo: RRM1 (for gemcitabine); ERCC1 (for platinums); and TS (for 5FU). Pts with untreated, biopsiable MPC were eligible. Tissue biopsies were analyzed by Caris, and the results used to assign pts to 1 of 7 doublet regimens. Our 1o objective was to provide preliminary data to inform a larger, randomized trial. Key 2o objectives included assessment of the response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Between 12-2012 and 08-2014, 26 pts were enrolled. Eleven failed screening primarily due to inadequate tumor tissue availability (and pts not wanting to wait for a 2ndbiopsy). Of the 15 pts profiled, 6 different doublets were assigned, reflecting the breadth of profile results. Three pts were not evaluable for response by the date of this abstract. Of the 12 pts who received Tx, the RR was 9%, but the DCR rate was 82%. The median PFS and OS were 5.9 and 10.4 months, respectively. Conclusions: The incorporation of chemo biomarkers is feasible and resulted in a promising PFS and OS for pts with MPC. Our pilot experience suggests that there may be value to assessing a pt’s tumor molecular profile to select Tx. Expansion of this experience into a randomized trial of profile-directed Tx vs. Tx based on the physician’s discretion would not only be realistic, but could be critical to realizing the full, clinically meaningful benefit of molecular profiling. We do however caution that biomarker-directed Tx can be challenging in untreated pts, where initiation of Tx is time critical, and delays due to inadequate tumor samples may be untenable. Thus, a randomized trial in the second line setting may be more appropriate. Clinical trial information: NCT01888978.
Phase II randomized trial of MEK inhibitor pimasertib or placebo combined with gemcitabine in the first-line treatment of metastatic pancreatic cancer.
Authors: Van Cutsem Eric , Hidalgo Manuel , Bazin Igor , Canon Jean-Luc , Poddubskaya Elena , Manojlovic Nebojsa , Milella Michele , Radenkovic Dejan , Verslype Chris , Guo Wei , Damstrup Lars , Hammel Pascal
Published: February 2017

344

Background: In metastatic pancreatic cancer (mPaCa), KRAS mutations lead to constitutive activation of the MAPK pathway in the vast majority of cases. Pimasertib (Pim) is a selective, non-competitive MEK 1/2 inhibitor with potent antitumor activity in preclinical models with constitutive MAPK activation. Methods: Following a phase I, dose-finding part to the trial, 88 patients (pts) with mPaCa were randomized 1:1 to receive Pim 60 mg BID (A, 44 pts) or placebo (B, 44 pts) in combination with weekly gemcitabine (Gem) 1000 mg/m2(7 of 8 wks in cycle 1, then 3 of 4 wks in subsequent cycles), in a phase II setting (NCT01016483). The primary endpoint was progression-free survival (PFS). Response rate (RR), overall survival (OS) and safety were secondary endpoints. Biomarker analysis was an exploratory endpoint. Results: Pt characteristics were balanced (median age 63.5 yrs, males 56%, stage IV at initial diagnosis 75%) except for PS 0, which was more frequent in arm A (59 vs 41%). Time on treatment was longer in arm B (10.6 vs 8.0 wks). A higher proportion of pts in arm A discontinued treatment during the first 4 wks (31 vs 19%), predominantly due to adverse events (AEs) and PD. Median PFS was 3.7 mo in arm A and 2.8 mo in arm B (HR=0.883, 95% CI: 0.549–1.42; p=0.608). No statistically significant differences were observed between arms for OS (median 7.3 mo in arm A vs 8.3 mo in arm B) and RECIST 1.0 RR (9.1% in both arms). Grade ≥3 thrombocytopenia (20.0 vs 0%), vomiting (15.6 vs 4.8%), fatigue (15.6 vs 7.1%), stomatitis (13.3 vs 0%) and diarrhea (11.1 vs 2.4%) were more common in arm A. Typical allosteric MEK inhibitor-related AEs, such as all grade retinal detachment (24.4%) and creatine phosphokinase elevation (20.0%), were observed almost exclusively in arm A. KRAS mutational status did not influence PFS or OS. Conclusions: The primary study endpoint was not met; secondary endpoints did not suggest clinically meaningful differences between arms, except for selected toxicities observed more frequently with the combination of Gem and Pim. The outcome does not support further development of this combination in the first-line setting in mPaCa. Pim is currently in development in other solid tumors. Clinical trial information: NCT01016483.
Large-scale analysis for treatment strategy according to genetic alterations of KRAS and DPC4 (SMAD4) genes in pancreatic ductal adenocarcinoma.
Authors: Shin Sang Hyun , Kim Song Cheol , Song Ki Byung , Lee Jae Hoon , Hwang Dae Wook , Lee Dong Joo , Lee Jung Woo , Kim Hyoung Eun , Jun Eunsung , Park Kwang-Min , Lee Young-Joo
Published: February 2017

361

Background: To investigate correlation of genetic alterations of pancreatic ductal adenocarcinoma (PDAC) with patients’ survival, recurrence patterns, and treatment for recurrent disease. Methods: We reviewed genetic alterations of major 4 genes (K-ras, DPC4, p53, and c-erbB-2) in 699 patients who underwent surgical resection, and correlated with clinical outcomes. Results: Median survival of all patients was 21.7 months, and 5-year survival rate was 20.4%. Alterational rates of each gene were as follows: K-ras, 48.3%; DPC4, 68.1%; p53, 40.8%; c-erbB-2, 14.0%. Mutation of K-ras and inactivation of DPC4 genes were associated with shorter patients’ survival in univariate analysis. In multivariate analysis, mutation of K-ras gene was independently correlated with patients’ survival (especially, GAT and TGT subtypes). Inactivated DPC4 gene had no independent correlation with overall survival, but it was strongly associated with distant metastasis following pancreatectomy. Survival after recurrence (SAR) was evaluated in subdivided groups according to DPC4 gene function (intact or loss)/recurrence patterns (locoregional or distant)/treatment options (local control or systemic therapy). In these 8 groups, patients in intact/locoregional/local control group showed the longest survival (24.2 months of median SAR), and intact/locoregional/systemic therapy and loss/distant/systemic therapy groups were associated with much shorter survival (9.5 and 9.2 months of median SAR, respectively). Conclusions: Assessment of genetic features of PDAC may assist in deciding targeted surveillance or treatment for primary as well as recurrent PDAC, and further studies for therapeutic strategies according to genetic analyses should be devised.
Comparative efficacy of sorafenib dose in patients with advanced hepatocellular carcinoma (HCC) with varying liver dysfunction.
Authors: Patel Sukeshi R. , Al-Rajabi Raed Moh'd Taiseer , Ketchum Norma , Lu Ting-Wei , Pollock Brad H. , Michalek Joel , Mahalingam Devalingam
Published: February 2017

369

Background: Sorafenib (SOR) is the only FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). In clinical practice, there are limited efficacy data related to dose modifications, which are often required. Given the high prevalence of HCC in South Texas, we assessed the efficacy and safety of SOR therapy in relation to dose and Child Pugh score (CP). Methods: Retrospective analysis of HCC patients (pts) receiving SOR from 2008-2013. Median progression-free survival (mPFS) and median overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). A proportional hazards regression model was used to assess the significance of SOR (low, high) by CP (A, B) interaction. Results: 107 pts were included. Median age 57 (41-93). Males 83%. Hispanic 72%, White 24%. ECOG PS 0–1 93%. Causes of cirrhosis: Hepatitis C 67%, Hepatitis B 5%, EtOH 60%. Portal vein thrombosis 33%, extrahepatic disease 39%. CP (available for 106 pts): A 57%, B 43%. mOS was 10.2 months (mo) (95% CI: 7.8-13.5); mPFS was 5.2 mo (95% Cl: 3.8-7.2). In subgroup analysis, mOS for 800 mg/day was 12.8 mo vs 6.6 mo for 400 mg/day (HR 0.59, p=0.04). mPFS for 800 mg/day was 5.9 mo vs 3.5 mo for 400 mg/day (HR 0.66, p=0.07). In CP A pts, higher SOR dose did not improve survival; however, in CP B pts, there were statistically significant improvements in mPFS and mOS (Table). The effect of dosage varied significantly with CP category (A, B) for both OS (p=0.002) and PFS (p=0.03). Conclusions: Historically, CP B advanced HCC pts have worse survival and tolerability to higher doses of SOR when compared to CP A. Our study suggests CP B pts should be considered for SOR 800 mg/day to improve survival with optimal management of toxicity but warrants further prospective studies. [Table: see text]
Predicting overall survival for patients with periampullary carcinoma.
Authors: Yeung Vincent , Gong Yutao , Yu Jialu , Yu Yan , Lu Bo , Palmer Joshua David , Burkhart Rick , Leiby Benjamin E , Siow vei Shaun , Lavu Harish , Rosato Ernest , Winter Jordan Michael , Lewis Nancy , Sama Ashwin Reddy , Mitchell Edith P. , Anne Pramila R. , Xiao Ying , Hurwitz Mark , Yeo Charles , Bar-Ad Voichita
Published: February 2017

376

Background: The purpose of this study was to develop a model predicting the overall survival of patients with peri-ampullary cancer (PAC) following resection, with or without adjuvant therapy. This will help guide physicians in providing optimal post-operative care. Methods: Patients treated between 2006-2012 in our institutional pancreatic tumor registry were analyzed. All patients underwent pancreaticoduodenectomy for PAC. 334 patients had adequate records for analysis and were used to develop a multivariate model based on Cox regression. The variables used in our analysis were age, gender, T-stage, tumor differentiation, positive lymph node ratio (# positive/total), positive resection margins, chemotherapy, radiation therapy (RT), and tumor histology. Multivariate Cox hazards regression tested significance. Model performance was evaluated by the concordance index (c-index). Results: Median age of the cohort was 65 years. 54% of the patients were male. Median follow-up time was 16 months. Median overall survival was 19 months. T-stages were as follows: 7% T1, 9% T2, 77% T3, and 8% T4. 27% of the patients had a positive tumor margin, 68% of patients had positive lymph node spread. 81% of the patients had tubular adenocarcinoma, 9% ampullary adenocarcinoma, 5% cholangiocarcinoma, and 4% duodenal carcinoma. T-stage, tumor differentiation, tumor histology, positive lymph node (PLN) ratio, and adjuvant chemotherapy had a statistically significant association with overall survival (Table 1). The model performance c-index was evaluated as 0.630 with 95% CI as [0.571, 0.690], from a bootstrapping internal validation test on 3-year-survival. Conclusions: This model shows promise in predicting survival following resection for patients with PAC. More patient cases and further analysis of additional factors including specific RT related parameters and specific chemotherapy regimen are needed for development of a more robust model. [Table: see text]
Improvement in survival of advanced hepatocellular carcinoma patients: Results of an updated period analysis of SEER database.
Authors: Shah Binay Kumar , Bhandari Amit , Ghimire Krishna Bilas , Manandhar Sajani
Published: February 2017

383

Background: Sorafenib was approved by FDA for treatment of advanced unresectable hepatocellular carcinoma (HCC) patients in November 2007. In this study, we update survival trends in advanced HCC using Surveillance, Epidemiology, and End Results (SEER) data. Methods: We selected patients with advanced HCC diagnosed from January 2001 to December 2010 from SEER 18 registries. We excluded diagnosed at autopsy, from death certificate only, or those without survival date. We calculated 1- and 2- year relative survival rates in pre-sorafenib (2001-2007) and post-sorafenib (2008-2010) era by age, sex and ethnicity among using SEER*stat software. Results: The total number of advanced HCC patients during 2001-2010, 2001-2007 and 2008-2010 were 5,092, 2,747 and 2,345 respectively. The 1- and 2- year survival rates of patients improved significantly from pre-sorafenib era to post-sorafenib era (1 year RS: 17.20±0.7% to 19.90±0.80%, Z=2.63; 2 year RS: 8.00±0.5% to 8.7±0.60%, Z=2.31). Survival rates of male patients improved significantly in post-sorafenib era (1 year RS: 16.4±0.80 to 19.4±0.90%, Z=2.18; 1 year RS: 7.4±0.60% to 8.6±0.70%, Z=2.18). There was no improvement in survival rates of female patients. Similarly, younger patients had improvement in survival rates in post-sorafenib era compared to pre-sorafenib era (1 year Z value 2.46; 2 year Z value 2.23). There was no improvement in survival rates of older patients. Conclusions: Since FDA approval of sorafenib, survival rates of patients with advanced hepatocellular carcinoma have improved. The improvement in survival rates is limited to males and younger patients
Radiosensensitivity index prognostic for survival with adjuvant radiation in resectable pancreatic cancer.
Authors: Strom Tobin Joel Crill , Hoffe Sarah E. , Coppala Domenico , Springett Gregory M. , Malafa Mokenge Peter , Eschrich Steven A. , Torres-Roca Javier , Shridhar Ravi
Published: February 2017

398

Background: Adjuvant radiation therapy (RT) for resectable pancreatic cancer remains controversial. We evaluated whether a previously validated molecular signature of tumor radiosensitivity (RSI) is prognostic for survival in pancreatic cancer. Methods: We identified patients treated with upfront surgery between 2006 and 2012. Briefly, RSI score is derived from the expression of 10 specific genes and a linear regression algorithm modeled on SF2 of 48 cancer cells (RSI, high index = radioresistant). We assessed the relative radiosensitivity of pancreatic cancers compared with other common cancers and then tested the association of RSI with overall survival (OS). Results: Compared with other common cancers such as lung, breast, and prostate, pancreatic cancers were more radioresistant as a group (p<0.0001). We identified 80 patients who underwent upfront surgery with both RSI and clinical outcome available (49 RT, 31 no RT). Median follow-up among surviving patients was 4.1 years. Median OS for radiosensitive tumors (RS), defined by lower ½ RSI, was 2.7 years compared with 1.5 years for radioresistant (RR) tumors (p=0.35). Among the high-risk pancreatic cohort, (positive margins, positive lymph nodes, or a post-operative CA 19-9 >90), irradiated patients with RS tumors had a trend toward improved OS (3y OS: 38% vs. 8%; p=0.07), while there was no difference in OS between RS and RR patients who weren’t treated with RT (p=0.79). When RSI was integrated, high-risk-RS patients had similar OS compared with low-risk-RR patients (3y OS: 38% vs. 50%; p=0.29). When low-risk-RR and high-risk-RS were combined into a single intermediate-risk group, RSI score added substantial prognostic value to OS outcomes on univariate (3 y OS: 78%, 42%, and 8%, for low-risk-RS, intermediate-risk group, and high-risk-RR, respectively; p=0.001) and multivariate analysis (intermediate-risk HR: 4.3, 1.0-18.6; p=0.053; high-risk HR: 9.9, 2.2-45.1; p=0.003). Conclusions: Patients with pancreatic tumors have relatively radioresistant tumors. Integrating RSI with standard prognostic variables refines the classification of resected pancreatic cancer patients.
Effect of body mass index on outcomes in biliary tract cancer.
Authors: Doherty Mark , McNamara Mairead Geraldine , Aneja Priya , Le Lisa W , Cleary Sean P. , Horgan Anne M. , Knox Jennifer J.
Published: February 2017

399

Background: Biliary Tract Cancer (BTC) is associated with poor outcomes, and prognostic factors are not well documented. Body Mass Index (BMI) has been shown to correlate with survival in colon, breast, lung and prostate cancer. The effect of BMI on survival in patients with BTC is unclear. Greater understanding of prognostic markers in BTC can help with treatment decisions. Methods: Patients treated for BTC in Princess Margaret Cancer Centre between 06/1987 and 08/2014 were included for analysis. Data were collected on clinicopathologic features, BMI, and survival. Patients were separated into two groups by resectability: definitive surgery (DS) or no definitive surgery (NDS). Multivariable proportional hazards regression was used to investigate the association between variables and overall survival (OS) for DS and NDS groups. Results: 902 patients (461 DS, 441 NDS) were included, with median BMI 25.7 (range 15.5-48.7). Median OS was 48.1 months in DS patients and 11 months in NDS patients. 244 NDS patients received palliative chemotherapy (55%). BMI was prognostic for OS in DS patients. In univariate analysis, DS patients with BMI <25 had poorer outcomes than those with BMI ≥25 [HR 1.40, 95% CI 1.08-1.82, p=0.01]. In multivariable analysis, the effect of BMI in DS patients remained significant: BMI <25 was associated with poorer OS [HR 1.36, 95%CI 1.03-1.81, p=0.03]. No significant differences were found in OS in NDS patients according to BMI by univariate [HR 1.04, 95%CI 0.83-1.29, p=0.74] or multivariable analysis. Prognostic factors by multivariable analysis are summarized in the Table. Conclusions: For patients undergoing definitive surgery for BTC, BMI <25 was a poor prognostic marker independent of other known prognostic variables. Other prognostic variables from our dataset match reported literature. This study is limited by its retrospective nature, however BMI may aid patient risk stratification after DS for BTC. [Table: see text]
Surgery and adjuvant therapy in gallbladder cancer: A single-institution experience.
Authors: Kothari Nishi , Kim Richard D. , Springett Gregory M. , Hoffe Sarah E. , Almhanna Khaldoun , Hodul Pamela Joy , Pimiento Jose Mario , Malafa Mokenge Peter , Fulp William J. , Zhao Xiuhua , Shridhar Ravi
Published: February 2017

405

Background: Gallbladder cancer is a highly fatal disease with a high rate of recurrence even when diagnosed at an early stage. Because of its relative rarity, there are currently no established algorithms to guide therapy after cholecystectomy. To explore the value of adjuvant therapy with chemotherapy and radiation, we evaluated patients with resected gallbladder cancer treated at our institution. Methods: Patients diagnosed with gallbladder cancer who underwent cholecystectomy (simple or radical) between 2000 and 2010 were identified using our cancer registry. Retrospective chart review was performed for clinicopathologic data, including age, stage, grade, type of surgery, margin status, and type and duration of adjuvant therapy. The primary endpoint was overall survival (OS). Univariate (UVA) and multivariate (MVA) analysis was performed with Cox logistic regression analyses. Results: We identified 73 patients with a median followup for all patients of 28.2 months. The majority of patients were female (74%) and underwent radical cholecystectomy (64%). Positive margins and adjuvant radiation therapy were documented in 21% and 37%, respectively. The majority of patients did not receive any adjuvant therapy (53.4%). Median OS for all patients was 41.3 months. There was a survival benefit associated with patients undergoing radical cholecystectomy followed by adjuvant radiation (median OS 48.4 months vs. 22.3 months; HR 0.35; 95% CI: 0.13–0.98; p=0.0448) compared to simple cholecystectomy alone. On UVA, increasing age and positive margins were significantly associated with worse OS, while radical cholecystectomy was associated with improved OS. On MVA, increasing age, male gender, poorly differentiated tumor, and positive margins were associated with worse OS, while adjuvant radiation was associated with improved OS (p=0.0113). Conclusions: Our analysis supports the role for adjuvant radiation therapy in resected gallbladder cancer. Multi-institutional prospective studies should be performed to evaluate the optimal treatment strategy. Biomarker analysis might also help determine the subset of patients who would benefit from combined chemoradiation.
BAP1 mutation-associated cholangiocarcinoma: An aggressive disease.
Authors: Anand Deepa , Churi Chaitanya , Rashid Asif , Shroff Rachna T. , Zuo Mingxin , Conrad Claudius , Vauthey Jean-Nicolas , Javle Milind M.
Published: February 2017

420

Background: BRCA-associated protein-1 is a deubiquitylating enzyme encoded by the BAP1 gene, which is commonly mutated in uveal melanoma, mesothelioma and renal cancers. BAP1 mutations predict an aggressive disease course in these tumors. Recent data indicate that BAP1 mutation is also present in cholangiocarcinoma (CCA). The clinical phenotype of CCA with BAP1 mutations has not been defined. We investigated the clinico-pathologic features and treatment outcomes of these patients treated at a single center. Methods: A comprehensive chart review of CCA patients who had undergone genomic testing was performed. Data collected included clinical, pathological, genetic and radiological features and response to therapy. Results: Nine cases of BAP1 mutation associated CCA were diagnosed from January 2009 to May 2014 (Table). Seven patients had intrahepatic CCA and two had extra-hepatic CCA. Tumor size ranged from 6 to 14.7 cm (mean = 8.7 cm). Seven patients had poorly differentiated carcinoma whilst the other two had moderately differentiated tumors. Out of the nine patients, seven had nodal metastases and six had satellite lesions in liver. Six patients had distant metastases at presentation. Sites of metastases were bone, peritoneum, lung and abdominal wall. All nine patients showed progressive disease following primary therapy (primary chemotherapy or neoadjuvant chemotherapy after primary surgery). The average time to tumor progression after first therapy was 3 months. Conclusions: BAP1 mutation in CCA may be associated with an aggressive prognosis and poor response to standard therapies. [Table: see text]
Does the addition of adjuvant intraoperative postdissection tumor bed chemotherapy during GI neuroendocrine tumor debulking benefit patients?
Authors: Wang Yi-Zarn , Chauhan Aman , Ramirez Robert A , Stevens Melissa A , Boudreaux J Philip , Woltering Eugene , Anthony Lowell Brian
Published: February 2017

442

Background: Midgut neuroendocrine tumor (NET) patients are often diagnosed at an advanced stage with extensive mesenteric lymph node and liver metastasis. The only treatment for potential cure and durable results is resection with extensive debulking. However, even with the most elegant surgical dissection/resection, macro and microscopic residual disease at the tumor resection bed remains a distinctive possibility. We hypothesize that local application of 5-florouracil (5-FU) within tumor bed would eliminate the microscopic residual disease post operatively. Methods: Surgical records of 188 consecutive patients who underwent extensive cytoreductive surgeries for stage IV, small bowel NETs with boggy mesenteric lymphadenopathy between 2003-2012 were reviewed. 85 Patients who had 5-Florouracil saturated gelfoam strips secured into their mesenteric resection defects served as the study group (n=85) with one hundred three patients who did not receive such intra-operative chemotherapy as the control (n=103). Survival from the time of diagnosis, postoperative morbidity and mortality between the two groups were collected and compared. Results: Mortality rates at immediate, 30, 60 and 90 days post operative period were 3; 0; 1; 0; and 0; 2; 0; 4 respectively for study and control group. Minor complications (Clavien-Dindo Grade I and II) at 30, 60 and 90 day postoperative period were 12; 0; 1 and 12; 5; 5 respectively. Major complications (Grade III and IV) at the same time intervals were 2; 0; 2 and 2; 3; 2 for study and control groups. Most of all, the mean survival from time of histological diagnosis for the study patients was 210 months (17.5 years) as compared to 177 months (14.7 years) for the control group with a difference of 33 months (2.75 years). Conclusions: Intra-operative tumor resection bed chemotherapy is a safe adjuvant without any discernible toxicity. Furthermore, it might provide survival benefit to midgut NET patients with extensive mesenteric lymphadenopathy undergoing extensive cytoreductive surgery without additional procedure related complications.
A tertiary cancer center experience with yttrium-90 radioembolization in hepatocellular carcinoma.
Authors: Schaffer Kerry , Noel Marcus Smith , Hezel Aram F. , Katz Alan W. , Sharma Ashwani , Baran Andrea , Connolly Gregory Clayton , Tejani Mohamedtaki Abdulaziz
Published: February 2017

443

Background: Local-regional radioembolization with Yitrium-90 (Y-90) has become standard practice for patients with hepatocellular carcinoma (HCC) either as a bridge to transplant, or for local disease control. Outcomes data in the United States are limited and here we review our institutional experience with Y-90 radioembolization. Methods: We retrospectively reviewed charts from 70 patients with HCC who were treated with Y-90 from May 2010- January 2014. Clinical variables including Child-Pugh class and CLIP score were extracted from patient records. The Cox proportional hazards model was used to determine prognostic factors, and Kaplan-Meier curves were used to determine PFS and OS. Results: Median age was 61 (range 43-82), 79% Caucasian, 84% male, and 79% Child-Pugh class A. Median progression free survival (PFS) was 8.4 months (95% CI 6-10.7) and overall survival (OS) was 14.2 months (95% CI 9.7-21). Overall survival significantly differed by Child -Pugh score (p= 0.009), CLIP score (p=0.003), and presence of portal vein thrombosis (PVT) (p=0.0384), based on the log-rank test comparing Kaplan-Meier curves. Using univariate Cox proportional hazards models, both elevated baseline AFP, measured on a log scale (HR 1.79, 95% CI 1.32-2.43, p=0.0002) and post Y-90 treatment with sorafenib (HR=2.30, 95% CI 1.07-4.95, p=0.03) were associated with worse mortality. Elevated AFP (HR 2.45, 95% CI 1.73-3.47, p<0.0001) and Child-Pugh score of B (HR 4.83, 95% CI 2.23-10.43, p<0.0001) were associated with worse mortality in a multivariate Cox model adjusting for age and ethnicity. Furthermore, AFP values were significantly higher in the 10 patients who died within 4 months of Y-90 (p=0.001), and significantly lower in 7 patients who eventually received a liver transplant (p=0.0002). Conclusions: In patients undergoing treatment with Y-90 radioembolization, Child-Pugh class, CLIP score, presence of PVT, baseline AFP, and sorafenib post Y-90 were significantly associated with overall survival. Median PFS and OS data in this institutional cohort are encouraging. Further prospective studies on Y-90 treatment for HCC are warranted.
Stereotactic body radiotherapy (SBRT) reirradiation for recurrent pancreas cancer.
Authors: Dagoglu Rabia N , Callery Mark , Moser James , Tseng Jennifer F. , Kent Tara , Bullock Andrea J. , Miksad Rebecca A. , Mancias Joseph Douglas , Mahadevan Anand
Published: February 2017

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Background: After adjuvant or definitive radiation for pancreas cancer, there are limited conventional treatment options for recurrent pancreas cancer. We explored the role of (Stereotactic Body Radiotherapy) SBRT for reirradiation of recurrent pancreas cancer. Methods: Our institutional IRB approved database was retrospectively reviewed. All patients were deemed unresectable and treated with systemic therapy. Fiducial gold markers were used. CT simulation was performed with oral and IV contrast and patients were treated with respiratory motion tracking.The choice of fractionation was based on tumor volume, location of the tumor and prior radiation dose, interval between prior RT, adjacent normal tissue, patients’ performance status and co morbidities. The irradiation dose was prescribed to the isodose line covering at least 95% of the target volume. Maximum point dose to the gastric and duodenal walls was kept at or below prescription dose. Results: This study included 30 patients reirradiated for recurrent pancreas cancer at our center between September 2005 and September 2013. 17 males and 13 females were treated. The median age at the time of reirradiation was 67 years (range 44 to 88 years). Median follow-up was 11 months (4 to 24 months).The median target volume was 41.29cc. The median prescription dose was 25Gy (24-36 Gy) in a median of 5 fractions prescribed to a mean 78% isodose line. The median overall survival was 14 months. The 1 and 2 year local control was 78%. The worst toxicity included 3/30(10%) grade III acute toxicity for pain, bleeding and vomiting. There was 2/30 (7%) Grade III long-term bowel obstructions. Conclusions: Management of locally recurrent pancreatic cancer, particularly after prior radiation therapy, is challenging. We report the utility of SBRT for reirradiation of locally recurrent pancreas cancer after prior radiation, with reasonable local control, modest survival and acceptable toxicity. Future prospective studies are needed to define the role of SBRT reirradiation for local recurrences in the setting of systemic therapy.
Quality of life (QOL) in patients with pancreatic and periampullary adenocarcinoma (PPAC).
Authors: Sheng Jennifer , Wai Christina , Fang Carolyn Y , Devarajan Karthik , Huang Christine , Hoffman John Parker , Denlinger Crystal Shereen
Published: February 2017

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Background: QOL includes perceived well-being, symptom burden, satisfaction, and enjoyment of normal activities. Limited data exist on QOL and long-term treatment effects in PPAC survivors. We evaluated factors that may impact QOL. Methods: Cross-sectional study (survey and chart review) of QOL, fear of recurrence, symptom burden, nutritional factors, and physical activity in disease free stage 0-III PPAC pts who completed treatment ≥ 12 months between 1990-2013. Pts identified via Tumor Registry and institutional database. Survey scales: FACT-Hep, Fear of Cancer Recurrence Inventory (FCRI), FACIT-AD, Hepatobiliary Symptom Index (FHSI-8), Godin Leisure Time Score (GLTS), Cancer Appetite and Symptom Scale (ASQ), and pancreatic enzyme use. Dillman mailed survey method used. Chart review yielded demographics, PPAC stage, therapy received, enzyme use, and comorbidities. Results: Of 90 identified pts, 78 mailed surveys (10 recurred; 2 died). Response rate 77% (n=60). 45 pts returned consent and survey (2 no consent, 6 opt-out, 7 ineligible). Median age at dx 65 yrs (46-87), at survey 70 yrs (51-89). Male 19/Female 26. Stage 0 (5), I (17), II (22), III (1). Median time from dx to survey 2156 days (385-6333), from surgery to survey 2134 days (343-6280). Mean scores (SD): FACT-Hep 144.5 (19.16), FCRI 51.57 (27.0), FACIT-AD 99.13 (14.47), FHSI-8 26.3 (4.15) and ASQ 34.58 (4.61), consistent with published cohorts. Pts insufficiently active with mean GLTS unit 11 (0-140, SD 25.85). Compared to those without, pts with hypertension (n=27) after surgery were less physically active (9.41 vs 13.61, p=0.046) and pts with diabetes (n=23) had poorer physical well-being (23.39 vs 25.13, p=0.017). Overall QOL was not associated with pancreatic enzyme use, time from diagnosis or surgery, primary tumor site, surgery type or physical activity. Conclusions: Despite small sample size, overall QOL, fear of recurrence, hepatobiliary cancer symptoms, and appetite in our cohort appear similar to other PPAC populations. Pts are insufficiently active, with hypertensive pts at higher risk for inactivity and diabetics with poor physical well-being. Additional evaluation of these in larger cohorts of PPAC survivors is warranted.
Role of second-line gemcitabine after FOLFIRINOX failure in advanced pancreatic adenocarcinoma: A retrospective analysis.
Authors: Lino Aline Da Rocha , Martins Junior Rodnei Merlrina , Abrahao Carina Mina , Moreira Raphael Brandao , Sousa Tarcia Tarciane Soares de , Gomes Jessica Ribeiro , Alessandretti Matheus Bongers , Amarante Marcus Paulo Fernandes , Ferrian Andrea Malta , Schutz Fabio Augusto Barros , Kawamura Carolina , Schmerling Rafael , Cruz Marcelo Rocha , Peixoto Renata D'Alpino , Machado Marcel Cerqueira Cesar , Buzaid Antonio C. , Maluf Fernando C.
Published: February 2017

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Background: Cancer of the exocrine pancreas is a highly lethal malignancy. Based on a phase III study, FOLFIRINOX regimen became the standard first-line treatment for patients with good performance status. However, the optimal management strategy for patients who fail initial FOLFIRINOX remains undefined. We aim at reporting our experience with single-agent gemcitabine as a second-line treatment for advanced pancreatic cancer patients who progressed on FOLFIRINOX. Methods: Patients with advanced exocrine pancreatic adenocarcinoma who received gemcitabine (1.000 mg/m² on days 1, 8 and 15 every 4 weeks) until disease progression, as second-line therapy after FOLFIRINOX failure at our institution were retrospectively evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: A total of 20 patients were reviewed. Most of them (60%) had metastatic disease while 40% had locally advanced tumors. Median age was 60 years (range 43–74) and 80% were male. Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 in 65% and 2 or 3 in 35% of the patients. Median time on prior FOLFIRINOX therapy was 5 months. Median PFS and OS with gemcitabine were 2,0 (95% CI 1,2-2,8) and 5,7 months (95% CI 3,9-7,4), respectively. There were no deaths due to the treatment. Conclusions: In this study, gemcitabine was a reasonable second-line treatment option for patients with advanced pancreatic adenocarcinoma. Phase III trials are urgently needed exploring the role of gemcitabine in the second-line setting.
Phase 3 clinical Trial Evaluating 90y glass microspheres in patients with metastatic colorectal carcinoma of the liver who have failed first-line chemotherapy.
Authors: Karpf Maria Angela
Published: February 2017

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Background: Colorectal cancer (CRC) is the third most common cancer in the US. Half of pts diagnosed with CRC develop liver disease. Unresectable liver metastases are responsible for morbidity/mortality. Typically, pts with metastatic CRC receive an oxaliplatin- or irinotecan-based regimen as first-line chemotherapy, +/- bevacizumab. On progression, pts are treated with the regimen they did not receive during first-line chemo. A study to evaluate yttrium 90 glass microspheres (TheraSphere; 90Y) in pts with unresectable mCRC of the liver showed that pts with good performance status, no extrahepatic metastases, and ≤ 25% tumor may benefit most from 90Y. 90Y glass microspheres are approved by FDA under a Humanitarian Device Exemption (HDE). This study will evaluate outcomes in this patient subset when 90Y is added to second-line SOC chemo. The objective is to evaluate efficacy/safety of 90Y in patients with liver mCRC that has progressed after first-line chemo. Methods: Open-label, multi-center, randomized study to evaluate 90Y treatment in ~340 eligible pts, in whom SOC 2nd-line chemo with either an oxaliplatin or irinotecan-based regimen is planned. Eligible pts will be randomized 1:1 to control or treatment. Treatment pts will receive a first cycle of second-line chemo within 21 days of randomization and at least 14 days after the last dose of first-line agents including VEGF inhibitors. 90Y will be administered in place of the second chemotherapy cycle. Control pts will receive planned SOC second-line chemo. Primary endpoint is progression-free survival. Secondary: overall survival, hepatic progression-free survival, time to symptomatic progression, tumor response rate, and adverse events. Pts will have regular study visits as long as they participate, at which time safety/efficacy data will be collected and recorded. Results: NA Conclusions: Given the potential benefit to mCRC pts, this Phase 3 study will evaluate 90Y in the second-line setting in patients who have progressed following SOC first-line chemotherapy. Clinical trial information: NCT01483027.
Living longer with pancreatic cancer: More than FOLFIRINOX?
Authors: Chae Phillip , Punja Punam , Koutlas Nate , Atluri Prashanti
Published: February 2017

476

Background: Effective treatment for uresectable locally advanced pancreatic cancer (LAPC) or metastatic pancreatic cancer is limited and has a poor prognosis with a five year survival rate of 6.7%. FOLFIRINOX has been studied as a neoadjuvant therapy for LAPC and has a response rate of 32%. We set out to investigate which factors, if any, have a meaningful impact on time to disease progression within this cohort of patients. Methods: A retrospective chart review was conducted. All patients who recieved FOLFIRINOX at our institution from 2011-2014 were included. 16 of 19 had unresectable LAPC or metastatic disease at time of diagnosis. A few recieved FOLFIRINOX upon first progression after adjuvant therapy. Results: See Table. Conclusions: Novel approaches are being used to get patients to R0 resection if they have borderline resectable pancreatic cancer or unresectable LAPC consisting of combination chemotherapy followed by radiation. Metastatic patients or unresectable LAPC who do not undergo surgery have limited survival. Reviewing our data we found that the addition of radiation in the metastatic setting may impact time to progression as determined by RECIST criteria. Of the three patients who had the longest time to progression, two were metastatic and both underwent palliative RT to the primary pancreatic lesion. Incorporation of RT to the primary lesion upon completion of FOLFIRINOX therapy should be considered as an innovative approach to increase time to progression and potentially progression free survival and overall survival. Clinical trials randomizing selected patients with metastatic or unresected LAPC to FOLFIRINOX followed by RT versus no RT should be considered. [Table: see text]
Is serum HER2-ECD testing significant for resectable gastric cancer?
Authors: Tanaka Tsutomu , Tajika Masahiro , Ishihara Makoto , Mizuno Nobumasa , Hara Kazuo , Hijioka Susumu , Imaoka Hiroshi , Hashimoto Mitsuyoshi , Yatabe Yasushi , Muro Kei , Yamao Kenji , Niwa Yasumasa
Published: February 2017

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Background: Accurate assessment of human epidermal growth factor receptor (HER) 2 is essential for patients with gastric cancer (GC) who may benefit from therapies targeting this surface receptor such as trastuzumab. The extracellular domain (ECD) of the HER2 protein may be shed into the serum and is detectable using an enzyme-linked immunosorbent assay. Correlations have been reported between raised baseline ECD levels, suggesting that serum ECD levels may be useful in making treatment decisions in patients with HER2 positive GC. We investigated this relationship in patients with resectable GC. Methods: This retrospective study was conducted in 71 patients with resectable GC between Apr. 2009 and May 2012. We assessed HER2 protein overexpression and gene amplification using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 positive was defined as IHC 3+ or IHC 2+/ positive FISH. The serum HER2-ECD level was measured using the blood serum before the surgical treatment. We examined the relationship between serum HER2-ECD level, HER2 expression in resected specimens, depth of invasion of cancer, lymph node metastasis, and clinical stage. Results: Baseline values were available in 71 patients, and of these, 2 (2.8%) had raised levels (> 15 ng/mL). Median serum ECD levels was 11.7 (7.5-17.9) ng/mL. Two patients showing high HER2-ECD without HER2 over-expression. No clear relationship was found between baseline ECD levels and HER2 over-expression. Serum HER2-ECD level was not associated with invasion depth and lymph node metastasis, and clinical stage. Conclusions: There is no significance of serum HER2-ECD testing in resectable gastric cancer.