bluuebunny/crossref_metadata_2025 huggingface dataset:
Spanish registry and screening program for families at high risk of pancreatic adenocarcinoma.
Authors: Guillen-Ponce Carmen , Mocci Evelina , Marquez Mirari , Earl Julie , Guerrero Carmen T , Salazar Maria Teresa , Calcedo Maria Celia , Real Francisco X , Malats Nuria , Carrato Alfredo
Published: February 2017

192

Background: 5-10% of pancreatic cancer (PC) cases show familial aggregation. 20% of these correspond to syndromes: Peutz Jeghers, hereditary pancreatitis, familial multiple melanoma, breast and ovarian cancer (HBOC) and others. Familial pancreatic cancer (FPC) is defined as: ≥2 first degree relatives with PC and with no other known syndromes. FPC seems to have autosomal dominant inheritance, but the genetic cause is unknown.

Methods: The objectives are: 1) To develop the first FPC Spanish Registry, connecting different groups interested in this disease 2) To study inheritance, phenotypic and molecular characteristics of the FPC, and families with early PC 3) To establish a strategy for early detection of PC in high-risk individuals and to implement it 4) To characterize preneoplastic lesions and diagnosed PC by monitoring high-risk individuals. 16 Spanish hospitals are participating. This study has two components: 1) Cohort to identify families with FPC and hereditary PC. Sources for the families are the PanGen-ES Study, a case-control study of PC which identifies families through a questionnaire on family history of cancer, and Genetic Counseling Units, 2) Cohort of high-risk families. The latter will be followed up by endoscopic ultrasound (EUS) and CT ± abdominal magnetic resonance imaging. In addition, circulating tumor cells (CTC) in peripheral blood will be determined.

Results: The assessment of family history of the 421 cases included in the PanGen Study has identified 32 (7.6%) families with FPC and 52 patients with PC ≤ 50 years (12.4%). In addition, the 190 families presenting PC aggregation with other neoplasms are being further evaluated. At this time we have obtained clinical data and blood samples to carry out molecular studies of 23 individuals: 17 belonging to 3 families with FPC, and 6 members of 2 families with an HBOC with some cases of pancreatic cancer. 18 relatives at risk began a follow-up with EUS and CT, with no detection of any suspicious pancreatic lesion; also CTC have not been detected.

Conclusions: This initiative will permit to know more about FPC and will serve to evaluate protocols and PC markers in screening the high-risk population, and promote connections with other international groups.
Endobiliary jumbo forceps biopsy as a technique for diagnosing bile duct malignancies.
Authors: Hsu Michael H. , Tummuru Rajeev , Patil Abhitabh
Published: February 2017

197

Background: Pancreaticobiliary cancers are difficult to diagnose early and have a high associated mortality. Current methods of obtaining pathologic specimens from a biliary stricture include fine-needle aspiration, brush cytology, and endobiliary forceps biopsy. Among these forceps biopsy is the best, but is frequently limited by its low sensitivity (56%). The goal of this study is to evaluate the diagnostic yield and safety of jumbo forceps biopsies taken from the bile duct.

Methods: All patients who presented to a single, tertiary academic referral center from July 2009 to July 2010 with a non-anastomotic biliary stricture were studied. This resulted in 9 patients with common bile duct strictures – 3 male and 6 female (ages 29-83, mean 61). All subjects underwent ERCP by the same gastroenterologist with endobiliary jumbo forceps biopsy using the Boston Scientific Radial Jaw 4 jumbo biopsy forceps. Specimens obtained were compared to available specimens obtained via fine needle aspiration, cytologic brushing or surgical resection. Patients with benign results were followed clinically for 1 year.

Results: Three patients had benign biliary strictures as determined by clinical follow-up or surgical resection specimen. Jumbo forceps biopsy diagnosed a benign entity in 100% of these cases. Among the remaining 6 patients with malignant strictures, jumbo biopsy diagnosed a malignancy in 83% of cases. Tissue obtained was deemed adequate for histologic evaluation in 8 of 9 patients. The exception was recognized at the time of the procedure and was attributed to the technical inability to adequately open the biopsy forceps within the bile duct. Of the technically successful cases, 100% yielded an accurate histologic diagnosis as determined by concordant alternative sampling or clinical follow-up. In the 90 days following jumbo forceps biopsy, there were no adverse events such as bleeding, cholangitis, pancreatitis, perforation, peritonitis, or need for hospitalization.

Conclusions: In our limited study, the use of jumbo forceps biopsies is safe and, when technically feasible, has a very high yield in evaluating biliary strictures. Larger studies are needed to confirm our findings.
Acquired resistance to combination therapy with lapatinib and MEK 1/2 inhibitor GSK1120212 in an in vivo murine model of pancreatic cancer.
Authors: Lindberg James M. , Walters Dustin M , Adair Sara J , Cowan Catharine R , Stokes Jayme B , Borgman Cheryl A , Stelow Edward B , Lowrey Bryce T , Chopivsky Maria E , Parsons J Thomas , Bauer Todd W.
Published: February 2017

208

Background: Mutations of the oncogene KRAS and activation of cell-surface receptor tyrosine kinases are important and preserved mechanisms of tumorgenicity in pancreatic cancer. Dual inhibition of the downstream KRAS effector MEK 1/2 and tyrosine kinases EGFR and Her2 results in effective inhibition of patient-derived tumor growth in a murine orthotopic transplantation model. Because combinatorial therapies are moving rapidly into clinical trials, we sought to develop a model of acquired tumor resistance to this combination therapy.

Methods: Patient-derived pancreatic tumor xenografts MAD 09-366 (KRAS mut), MAD 08-608 (KRAS mut) and MAD 08-738 (KRAS wt) were implanted orthotopically in nude mice and treated with combination lapatinib (EGFR/Her2 inhibitor) and GSK1120212 (MEK1/2 inhibitor) and tumor volume was measured by MRI. Following 4-6wks of treatment, tumors were reimplanted in second and third generation mice and retreated. Tumors were evaluated by phospho-RTK and phospho-MAPKinase array.

Results: Acquired resistance developed in all three tumor xenografts. Treated tumors demonstrated a relative volume decrease in the original (F0) generation. All second re-implantation (F2) tumors, demonstrated relative tumor volume increases despite treatment. A comparison of pre-treatment mean tumor volumes showed a significant decrease in tumor size from the F0 to F2 generations suggesting selection for slower growing tumors. Array data demonstrated increased activation of FGFR1, VEGFR1/3, GSK-3β, p38, and Akt in resistant tumors as compared to their pre-treatment controls. These may represent mechanisms of tumor resistance and warrant further investigation.

Conclusions: Repeated tumor exposure in vivo to combination treatment with GSK1120212 and lapatinib was used to develop a preclinical, orthotopic murine model of acquired drug resistance in patient-derived pancreatic cancers. This model provides the opportunity to define the mechanism of resistance in an appropriate tumor microenvironment and to develop alternative strategies for treating tumors resistant to this and other emerging therapies.
Metabolomic signature of esophageal cancer.
Authors: Davis Vanessa Wylie , Schiller Dan E. , Sawyer Michael B.
Published: February 2017

21

Background: Esophageal cancer is a pervasive malignancy, and early detection combined with newer therapeutic targets could alter the landscape of this condition. Metabolomic profiling offers one such innovative opportunity. We applied metabolomic techniques to identify urinary metabolites uniquely associated with this condition.

Methods: Urine samples from patients with histologically confirmed esophageal cancer (n=66) and healthy volunteers (n=25) were collected and examined using 1H-NMR spectroscopy. Targeted profiling of spectra using Chenomx NMR Suite 7.0 software permitted detection and quantification of 66 distinct metabolites. Unsupervised (principal component analysis, PCA) and supervised (partial least-squares discriminant analysis, PLS-DA) multivariate pattern recognition techniques were applied to discriminate between sample spectra of esophageal cancer patients and healthy volunteers using SIMCA-P (version 11, Umetrics, Umeå, Sweden).

Results: Significant differences were found when comparing concentrations of 59 metabolites in urines of healthy volunteers and esophageal cancer patients. Those metabolites contributing most class discriminating information included choline, urea, 2-aminobutyrate, and 3-hydoxybutyrate. Clear distinctions between patients with esophageal cancer and healthy controls were noted when PLS-DA was applied to the data set. Model parameters for both goodness of fit R2, and predictive capability Q2, were high (R2 = 0.867; Q2 = 0.732). Model validity was tested using response permutation and results were suggestive of excellent predictive power (see Figure).

Conclusions: Urinary metabolomics identified a discrete signature associated with esophageal cancer compared to healthy controls. This profile has the potential to aid in diagnosis and development of new therapeutic targets.
Association of DNA repair inhibition and radiofrequency ablation in the treatment of xenografted colorectal cancer.
Authors: Devun Flavien , Biau Julian , Sun Jian-sheng , Denys Alban , Dutreix Marie
Published: February 2017

215

Background: Most of the patients with advanced colorectal cancer will develop liver metastasis, even after primary tumor resection. Although surgical resection remains the gold standard treatment of hepatic metastases, only few patients are eligible to curative resection. Radiofrequency ablation (RFA) is the most common curative alternative. Dbait are new molecules that inhibit DNA double-strand breaks repair. In vitro, Dbait has shown to increase cell death after hyperthermia. Here, we have assessed the combination of Dbait and RFA in the treatment of human colorectal cancer model xenografted in nude mice.

Methods: 98 mice were flank-grafted with HT29 (human colon adenocarcinoma). When tumor reached 500 mm3, mice were sham treated (n=19), treated by Dbait via local injections (n=20), treated by RFA using an incomplete ablation scheme (n=20) or treated by combination of Dbait and RFA (n=39 separated in two Dbait regimens). After RFA, 39 mice were sacrificed for blinded pathological study, and 59 others were followed for survival analysis.

Results: Mice treated by RFA-Dbait had significantly longer survival as compared to RFA alone (median survival: 56 vs 39 days, p<0.05) while RFA improved survival as compared to controls (median survival: 39 vs 28 days, p<0.05). Pathological studies of tumor slice have demonstrated significant decrease of tumor area and cancer cell viability in the RFA-Dbait group.

Conclusions: While the implication of DNA repair activity in heat sensitivity remains unclear, our results show that the addition of Dbait to RFA enhances the antitumor response in this model and provide an experimental basis for the use of Dbait as an additional therapy to RFA.

[Table: see text]
Resistance development after long-term sorafenib exposure in hepatocellular cancer cell lines and risk of rebound growth and epithelial to mesenchymal transition.
Authors: Verslype Chris , van Malenstein Hannah , Dekervel Jeroen , Windmolders Petra , Libbrecht Louis , van Eijsden Rudy , Nevens Frederik , van Pelt Jos
Published: February 2017

216

Background: Sorafenib, a multi tyrosine kinase inhibitor, is the first line treatment in patients with advanced hepatocellular carcinoma (HCC). It leads to a survival benefit but treatment with sorafenib is hampered by two phenomena: patients can develop important side-effects and eventually all patients show progression. We aimed to determine the effects of long-term exposure to sorafenib and its withdrawal in vitro.

Methods: We developed sorafenib resistant liver cancer cell lines (HepG2, WRL-68 and Huh-7) by slowly increasing sorafenib concentrations. XTT- and BrdU-assay were used to study the effect of sorafenib withdrawal on proliferation and metabolism. Morphological changes were examined with immuocytochemistry, gene expression changes with RT-PCR and the invasive potential with matrigel invasion chambers. Microarray was performed on resistant HepG2 cells.

Results: HepG2 cells (6µM), WRL-68 cells (6µM) and Huh-7 cells (5µM) became resistant to sorafenib. Resistance was confirmed with a shift of the IC50 to ±16µM and ongoing phosphorylation of ERK during sorafenib exposure. All three resistant cell types showed significant increased proliferation and metabolic activity after withdrawal of sorafenib. The HepG2 resistant cells have undergone an epithelial to mesenchymal transition (EMT) with loss of E-cadherin and high expression of vimentin. The cells that displayed EMT became spindle shaped and were highly invasive. Furthermore, gene expression profiling confirmed EMT changes in a large set of EMT-related genes. Considering drug metabolism, the HepG2 sorafenib resistant cells showed a downregulation of UDP glucuronosyltransferases (UGT) and cytochromes P450, such as CYP3A4. There was a strong downregulation of different ABC-transporters, although breast cancer resistance protein (ABCG2) was upregulated.

Conclusions: Long-term treatment with sorafenib can lead to the development of resistant cells, even with an aggressive phenotype because the cells can undergo EMT. Furthermore we demonstrated that abrogation of treatment leads to rebound growth, suggesting the importance of aggressive management of side-effects.
The role of circumferential resection margin in esophageal cancer: Does it influence local recurrence and survival?
Authors: Kutup Asad , Ghadban Tarik , Vashist Yogesh Kumar , Bogoevski Dean , Izbicki Jakob Robert
Published: February 2017

23

Background: Established independent prognostic factors after resection are tumor stage, tumor grade, nodal involvement, lymph node ratio and tumor infiltration of the proximal or distal resection margin in esophageal cancer. In a few series the clinical and prognostic significance of the CRM involvement have been investigated, showing conflicting results in esophageal cancer. The purpose of this study was to analyze the significance of microscopic tumor involvement of the CRM on long-term survival and local recurrence (LR) following esophagectomy in T3 esophageal cancer.

Methods: Between 1993 and 2008, 146 patients, with T3 esophageal tumors had undergone potentially curative transthoracic esophagectomy (TTE) with radical lymphadenectomy of the upper abdomen and mediastinum or transhiatal esophagectomy (THE) with microscopically tumor free proximal and distal resection margins. Surgical specimen were recorded as CRM positive (CRM+) if the distance from the CRM was measured microscopically 1mm or less; otherwise it was graded as CRM negative (CRM-). None of these patients had a neoadjuvant therapy.

Results: In the whole study population, median survival for CRM-- and CRM+ patients was 13 and 15 months, respectively (p=.933). LR occurred in 48 patients (32.9%). Of these, 19 (39.6%) had a positive CRM and 29 patients (60.4%) a negative CRM. Of the remaining 98 patients (67.1%) without LR, in 40 patients (40.8%) CRM was positive, while 58 patients (59.2%) had a negative CRM (p=.887). The grading and tumor localization had no significant influence on the LR (p=.181 and .163). The TTE group included 104 patients, in 68 patients (65.4%) of them CRM was negative, in 36 (34.6%) CRM was positive. The THE group included 42 patients, in 19 patients (45.2%) CRM was negative, whereas in 23 patients (54.8%) CRM was positive, respectively (p=.025). CRM involvement had no statistical significant impact on LR or metastatic relapse in either node negative tumors (p=.384) or node positive tumors (p=.653).

Conclusions: After TTE a positive CRM was less seen without statistifical influence on median survival time. This study has shown that the presence of microscopic tumor of the CRM is not a significant prognostic variable.
Use of global histone modifications to predict response to gemcitabine in patients with pancreatic cancer.
Authors: Watanabe Takuo , Morinaga Soichiro , Akaike Makoto , Numata Masakatsu , Tamagawa Hiroshi , Yamamoto Naoto , Shiozawa Manabu , Ohkawa Shinichi , Yoichi Kameda , Nakamura Yoshiyasu , Masuda Munetaka , Miyagi Yohei
Published: February 2017

232

Background: Epigenetic alternations such as DNA methylation and histone modification play important roles in carcinogenesis. It has been recently suggested that global histone modification pattern are independent predictors of cancer outcomes. We studied the prognostic and predictive value of five histone modifications in pancreatic cancer.

Methods: Double 2-mm core tissue microarrays were made from 61 paraffin-embedded pancreatic cancer samples and examined by immunohistochemistry for histone H3 lysine 9 dimethylation (H3K9me2), and acetylation (H3K9ac), histone H3 lysine 4 dimethylation (H3K4me2), and trimethylation (H3K4me3), and histone H3 lysine 18 acetylation (H3K18ac). Positive tumor staining for each histone modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic features and clinical outcomes.

Results: The high expression group of H3K4me3 was related to the well and moderately differentiated histological type (p=0.012) and the low expression of H3K4me2 was related to the presence of preineural invasion (p=0.007). The high expression of H3K9ac was related to the presence of lymph node metastasis (p=0.041). In the subgroup of patients receiving gemcitabine chemotheraphy, low levels of H3K4me2 were significantly associated with worse disease free survival (p=0.0239). Univariate and multivariate hazards models also indicated that low levels of H3K4me2 was significant independent predictor of disease-free survival (p=0.007).

Conclusions: H3K4me2 is considered to be useful predictor of response to gemcitabine in patients with pancreatic cancer.
A phase I/IIA safety study of NPC-1C: A novel, therapeutic antibody to treat pancreas and colorectal cancers.
Authors: Morse Michael , Diaz Luis A. , Azad Nilofer Saba , Laheru Dan , Haley Sherri , Sleer Leanne Sophia , Arlen Philip M.
Published: February 2017

233

Background: NPC-1C (NEO-101; ensituximab) is a chimeric monoclonal antibody being developed as a novel biological treatment for pancreatic and colorectal cancers. This antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C target appears to be a variant of MUC5AC that is expressed specifically by human colon and pancreatic tumors with only occasional minimal cross-reactivity to certain GI tract tissues.

Methods: A Phase 1/2A open label, multi-center dose escalation clinical trial with NPC-1C is currently accruing subjects with advanced pancreatic and colorectal cancer who are refractory to standard therapy. The primary objectives of the Phase I clinical trial are to determine the safety and tolerability of escalating doses of NPC-1C and to assess pharmacokinetics (PK) and select immune responses to the antibody at each dose level. Secondary objectives are to evaluate evidence of clinical benefit and to explore the immunologic correlates associated with administration of NPC-1C.

Results: Three cohorts of subjects have been treated with NPC-1C at escalating dose levels of 1, 1.5, and 2 mg/kg IV every two weeks. Fourteen patients (9 colon, 5 pancreatic) have enrolled on study. At the 2 mg/kg dose level, at escalating rates of infusion, 3 subjects experienced mild to moderate hemolysis that resolved without intervention. Currently, 5 patients who have received 1.5 mg/kg at a constant rate of infusion have been evaluated, with no dose limiting toxicity. One of 3 patients re-staged thus far in the 1.5 mg/kg cohort showed stable disease on scans after completing the first course of treatment (4 doses). Preliminary data show no host induced antibody responses to the drug.

Conclusions: NPC-1C is tolerated well at the current dose level of 1.5 mg/kg every 2 weeks. If no DLT is experienced by the 6th subject in this cohort, we plan to continue accrual at this dose level to evaluate additional PK data, to assess dosing schedules, and to evaluate objective response rate, progression free survival, and overall survival in the phase 2A portion of this study.
Selection, therapy, and outcome in an unselected population-based study of 604 patients with pancreatic cancer.
Authors: Bjerregaard Jon Kroll , Mortensen Michael Bau , Schønnemann Katrine R. , Pfeiffer Per
Published: February 2017

238

Background: Knowledge of patients (pts) with pancreatic cancer (PC) is often inferred from randomized phase III trials or registry based studies. Information about selection, therapy, and outcome is however often limited by availability of data in registries or lack of generalizability due to strict inclusion criteria in phase III studies. We wanted to investigate therapy choices and survival in a complete population of pts with PC.

Methods: During 2007-2009 all cases of PC in the Region of Southern Denmark (RSD) (pop: 1,200,000) was retrieved from the Danish Cancer Registry. Concurrently we established a registry at the regional PC cancer center, recording clinical variables. The two registries were merged and dis-concordant cases were all examined. Information about hematology, liver function, performance status and therapy was retrieved from patient charts. Patients with neuroendocrine or acinar cell carcinomas were excluded from outcome analysis.

Results: 618 cases of PC were retrieved from the Danish Cancer Registry. After examining dis-concordant pairs and histology 64 cases were removed and 25 added resulting in a total of 579 eligible pts with PC. Based on therapy delivered pts were divided in four groups (Table 1). Sixty-five pts had an initial resection of their tumor, 191 pts were treated with either chemotherapy or chemo-radiotherapy (CT/CRT), 56 pts were evaluated for CT/CRT, but was in too poor performance status or progressed/died before therapy; finally 268 pts were never evaluated for CT/CRT and never received tumor directed therapy. Of the total population 3% participated in clinical trials.

Conclusions: Survival of un-selected patients appears to be similar to trial patients, and has improved compared to other registry based studies. However the majority of pts with PC do not receive cancer directed therapy. Improving the outcome of PC pts as a whole requires research into the large group of untreated pts.

[Table: see text]
Resource utilization among neuroendocrine tumor patients in the United States.
Authors: Casciano Roman , Chulikavit Maruit , Parikh Rohan , Stern Lee , Liu Zhimei , Wang Xufang , Strosberg Jonathan R.
Published: February 2017

251

Background: Neuroendocrine Tumors (NET) constitute over 100,000 prevalent cases in the United States (US), with predicted increase of incidence in the future. Advanced NET is associated with significant morbidity and mortality. Resource use was assessed for managing advanced NET.

Methods: As part of a global study, an online survey was administered to US physicians to quantify resource use among advanced pancreatic (pNET) and lung/gastrointestinal (GI) NET patients. The study collected resource use data (treatments, visits with survey and other physicians, surgery and hospitalizations) for baseline (diagnosis to 1st disease progression [DP]), 1st and 2nd DP periods. DP was defined as measurable/radiographic evidence of tumor progression. As patients with 2nd DP were likely to be less, resources were estimated in a hypothetical scenario.

Results: 55 US physicians provided data on 110 NET patients (36.4% pNET, 63.6% Lung/GI NET). Average follow up in baseline was 14.0 and 13.3 months for pNET and Lung/GI NET, respectively; in 1st DP period, it was 5.7 and 7.9 months, respectively. For 2nd DP, it was assumed to be 12 months. Table 1 shows resource use for baseline and 1st DP. Increased use of chemotherapy, somatostatin analogs, hospitalization and other physician visits was observed during 1st DP, especially for pNET patients. Targeted therapy use was minimal at baseline and 1st DP; however it may increase in 2nd DP.

Conclusions: Among advanced NET patients, resource use is generally high and there appears to be increase in resource use upon DP, especially in patients with pNET.

[Table: see text]
Are we justified in excluding combined hepatocellular-cholangiocarcinoma from transplantation?
Authors: Groeschl Ryan T. , Pappas Sam G , Christians Kathleen K. , Tsai Susan , Quebbeman Edward J , Gamblin T. Clark , Turaga Kiran
Published: February 2017

256

Background: Although transplantation has shown remarkable survival benefit for patients with hepatocellular carcinoma (HCC), there is limited data to support or refute the treatment of combined hepatocellular-cholangiocarcinoma (cHCC-CC) with transplantation. We hypothesized that patients with mixed histology had a lower overall survival than HCC after liver transplantation.

Methods: Patients with localized HCC and cHCC-CC treated with surgical resection (SR) or transplant (TP) were identified using the Surveillance, Epidemiology, and End Results (SEER) Database (1973-2007). Survival was analyzed using the Kaplan-Meier model. Prognostic factors were examined with Cox regression analyses.

Results: We identified 3378 (1447 [43%] TP and 1931 [57%] SR) patients with HCC, and 54 (19 [35%] TP and 35 [65%] SR) patients with cHCC-CC. Cohorts were similar with respect to age, gender, race, and tumor size. Median overall survival (OS) was 68 months (95% confidence interval (CI): 64-75) for HCC and 36 months (95% CI: 19-89) months for cHCC-CC (p = 0.01). Patients undergoing SR of HCC and cHCC-CC had similar 3-year OS (55% vs. 46%, p=0.4). Overall 3-year survival of patients undergoing TP was significantly longer for HCC (78%) than for cHCC-CC (48%, p=0.01). After adjusting for age at diagnosis and gender, multivariate modeling revealed an increased hazard ratio for patients undergoing TP with a mixed histology: HR 2.5 (95% CI: 1.2-5.1, p=0.01).

Conclusions: Patients undergoing transplantation with localized cHCC-CC have a shorter overall survival than patients with HCC. In an era of organ shortage, this may justify excluding patients with cHCC-CC from transplantation. Our data is limited by the lack of tumor and host-specific factors, and prospective validation of this conclusion is warranted.
Screening for somatic mutations in esophageal squamous cell carcinoma using OncoMap 4.0.
Authors: Maeng Chi Hoon , Lu Shan , Park Se Hoon , Hummelen Paul Van , MacConaill Laura E. , Kim Kyoung Mee , Lee Jeeyun
Published: February 2017

27

Background: Analysis of gene mutations in tumor specimens is essential to treat cancers with molecular target agents. Given the high incidence of metastatic esophageal squamous cell carcinoma in East Asia, we screened for the presence of somatic mutations using OncoMap 4.0 with the aim of establishing novel treatment strategy.

Methods: We analyzed 87 tissue specimens obtained from 80 patients who were pathologically confirmed of esophageal squamous cell carcinoma and received 5-fluoropyrimidine/platinum-based chemotherapy. OncoMap 4.0 is designed to interrogate >700 mutations in 113 genes. Tumor specimens were prepared from primary cancer sites in 70 patients and from metastatic sites in 17 patients. In order to test the concordance between primary and metastatic sites from the patient for mutations, we analyzed 7 paired (primary-metastatic) specimens. All specimens were formalin-fixed paraffin embedded tissues and tumor content was > 70%.

Results: In total, we have detected 23 mutations out of 87 specimens tested. The most frequent mutation was PIK3CA mutation (four E545K, five H1047R and one H1047L) (N=10, 11.5%) followed by MLH1 V384D (N=7,8.0%), TP53(R306, R175H and R273C)(N=3, 3.5%), BRAF V600E (N=1, 1.2%), CTNNB1 D32N (N=1, 1.2%), and EGFR P733L (N=1, 1.2%). Distributions of somatic mutations were not different according to anatomic sites of esophageal cancer (cervical/upper, mid, lower). In addition, there was no difference in mutations between primary-metastasis paired samples.

Conclusions: PIK3CA and BRAF mutations can be new targets for novel molecular agents to treat esophageal squamous cell carcinoma.
North Central Cancer Treatment Group phase II study of panitumumab (Pmab), chemotherapy, and external beam radiation (Chemo-RT) in patients with locally advanced (LA) pancreatic cancer.
Authors: Kim George P. , Foster Nathan R. , Haddock Michael G. , Bollinger John William , Dakhil Shaker R. , Behrens Robert J. , Flynn Patrick J. , Steen Preston D. , Bury Martin Joseph , Stella Philip J. , Alberts Steven R.
Published: February 2017

271

Background: Epidermal growth factor inhibitors show some benefit in the treatment of advanced pancreatic cancer. A trial to evaluate the incorporation of Pmab into a conventional multimodality regimen and continuation as maintenance therapy was conducted in pts with LA disease.

Methods: Pts with ECOG PS 0-1, preserved organ function and tumor encompassed within standard radiation fields were eligible. Pmab 6 mg/kg on days 1, 15, 29 and continuous infusion 5-FU 225 mg/m2/d or capecitabine 825 mg/m2 were given with RT. Pts then received weekly gemcitabine 1000 mg/m2 and Pmab on days 1, 15 for three 4-week cycles. Maintenance Pmab was then continued for additional 6 months. RT consisted of 45 Gy to the tumor and regional nodes with a 5.4 Gy boost using conformal techniques. Primary endpoint of one-year survival (OS) with secondary endpoints progression-free survival (PFS), confirmed tumor response, and adverse events (at least possibly related) are reported.

Results: 51 pts (23 M: 28 F) were enrolled with a median age of 65 (range: 43-84). Twenty-two pts (43%) received at least 1 cycle of post-chemo-RT, while 29 patients only received chemo-RT. All 51 pts have ended treatment with pts going off study because of: progression (39%), adverse events (27%), refusal (25%), and other reasons (8%). Frequently occurring maximum grade 3/4 AEs across the entire treatment course (chemo-RT + post-chemo-RT chemo) are shown below. With a median follow-up of 12.3 months, survival at 12 months is 50.2% (95% CI: 37.9-66.5%), median survival 12.1 mos (95% CI: 6.8-15.9) and median PFS 7.4 mos (95% CI: 3.7-8.6). Confirmed response rate was 5.9% (1-CR, 2-PR).

Conclusions: The addition of Pmab to a conventional chemo-RT regimen provides benefit in terms of median survival. This is similar to reports of other EGFR inhibitors in LA disease. Adverse events, especially during the chemo-RT portion, were considerable and affected administration of subsequent systemic maintenance therapy.

[Table: see text]
Multicenter retrospective analysis of systemic chemotherapy in poorly differentiated neuroendocrine carcinoma of the digestive system.
Authors: Yamaguchi Tomohiro , Machida Nozomu , Kasuga Akiyoshi , Takahashi Hideaki , Sudo Kentaro , Nishina Tomohiro , Tobimatsu Kazutoshi , Ishido Kenji , Furuse Junji , Boku Narikazu
Published: February 2017

274

Background: Poorly differentiated neuroendocrine carcinoma (PDNEC) is a rare and aggressive disease. No standard regimen has yet been established for advanced PDNEC, although regimens for small-cell lung carcinoma such as irinotecan + cisplatin (IP) or etoposide + cisplatin (EP), are usually adopted. The aim of this study was to investigate the outcomes according to the patient’s characteristics and treatment regimens for patients with PDNEC of the digestive system.

Methods: Data was collected from the medical records of patients at 23 hospitals. The selection criteria were as follows: 1) histologically proven PDNEC, small cell carcinoma, mixed endocrine-exocrine carcinoma with a PDNEC component, or histologically proven neuroendocrine tumor with rapidly progressive clinical course; 2) primary tumor arising from the gastrointestinal tract (GI) or the hepato-biliary-pancreatic system (HBP); and 3) inoperable or recurrent disease treated with systemic chemotherapy between April 2000 and March 2011.

Results: There were 258 patients (pts). The median age was 62.5 years (range, 26-81); male/female, 182/76 pts; the primary site was the esophagus/stomach/small bowel/colorectum/hepato-biliary system/pancreas in 85/70/6/31/31/35 pts. According to these primary sites, the median overall survival period (mOS) was 13.4/13.3/29.7/7.6/7.9/8.5 months, respectively. The most commonly used regimen was IP (160 pts, 62%), followed by EP (46 pts, 18%). For the patients treated with IP/EP, the response rates (RR) were 50%/27%, the progression free survival periods (mPFS) were 5.2/4.0 months, and mOS were 13.0/7.3 months. The subgroup outcome data for patients with HBP or GI cancers are shown in Table. A multivariate analysis demonstrated that a primary HBP cancer (HR=1.96, p=0.002), and a poor PS (HR=2.33, p=0.01) were independent unfavorable prognostic factors.

Conclusions: PDNEC of the HBP has a poorer prognosis than GI. IP was the most commonly selected treatment regimen, and seemed to have a favorable treatment outcome.

[Table: see text]
Effect of bevacizumab on sinusoidal injury in patients receiving oxaliplatin-based chemotherapy and liver damage after massive hepatectomy in rats.
Authors: Shimada Mitsuo , Utsunomiya Toru , Hanaoka Jun , Mori Hiroki , Ikemoto Tetsuya , Imura Satoru , Morine Yuji , Miyatani Tomohiko , Sato Hirohiko , Kurita Nobuhiro
Published: February 2017

276

Background: The aim of this study was to clarify impact of bevacizumab (Bev) on both hepatic sinusoidal injury after oxaliplatin (L-OHP)-based chemotherapy for metastatic colorectal cancer, and on liver regeneration after massive hepatectomy (Hx).

Methods:  Fourteen patients who underwent Hx after receiving L-OHP-based chemotherapy for liver metastases from colorectal cancer were divided into two groups (Bev group (n=8) and No-Bev group (n=7)). Histology of non-cancerous liver tissue, blood chemistry such as hyaluronic acid (HA), spleen size, and postoperative complications were compared between the two groups.  Male Wister rats that underwent 90%-Hx were divided into two groups (Control group (n=7) and Bev group (n=7), in which Bev was injected intraperitoneally (5mg/kg) 7days before Hx). The following parameters were compared; blood chemistry, liver weight to body weight (Lw/Bw) ratio, and cytokines in liver tissues by RT-PCR, and survival rate.

Results:  Incidence of sinusoidal dilatation in Bev group was lower than that in No-Bev group (25% vs. 67%). Serum HA before Hx in Bev group (28 ng/ml).was lower than that in No-Bev group (155ng/ml). Spleen size in Bev group (174 ml) tended to be smaller than that in No-Bev group (252 ml). No significant postoperative complication was observed in Bev group, while 4 out of 7 patients had complications in No-Bev group.  Liver damage such as ALT in Bev group (1471 IU/L) was smaller than that in Control group (2287 IU/L). Regeneration rate (Lw/Bw ratio) in Bev group was greater than that in Control group (0.80 vs. 0.67). Expression levels of IL-1β, MMP2 and MMP9 in Bev group tended to be lower than those in Control group. Survival rate at 72 hours after Hx in Bev group (83%) tended to be better than that in Control group (50%).

Conclusions: Bev could reduce sinusoidal injury in patients with L-OHP-based chemotherapy, furthermore, Bev reduced liver injury and promoted liver regeneration after massive hepatectomy in rats. Those data strongly suggest Bev has beneficial effects for patients receiving L-OHP-based chemotherapy who undergo massive Hx.
Effect of non-anticancer drugs on prognosis of pancreatic cancer (PaC) receiving chemotherapy.
Authors: Nakai Yousuke , Isayama Hiroyuki , Mizuno Suguru , Sasaki Takashi , Kawakubo Kazumichi , Kogure Hirofumi , Yamamoto Natsuyo , Sasahira Naoki , Hirano Kenji , Ijichi Hideaki , Tateishi Keisuke , Tada Minoru , Koike Kazuhiko
Published: February 2017

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Background: Non-anticancer drugs such as metformin or statin are reported to have a potential role in cancer treatment and we previously reported inhibition of renin-angiotensin system (RAS) by angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) lead to better prognosis in PaC receiving gemcitabine (Br J Cancer 103: 1644-8). The relation between diabetes (DM) with its medication and the incidence of PaC has been described but its impact on prognosis is still unclear.

Methods: We retrospectively reviewed 250 pts with advanced PaC receiving chemotherapy with gemcitabine and/or S-1 between June 2001 and April 2011 with a median follow up of 9.9 months (Mo). Univariate and multivariate analyses of progression-free survival (PFS) and overall survival (OS) were performed in pts with and without DM, using age, gender, BMI, PS, stage, protocol, DM with its treatment, hypertension (HT) with its treatment, and use of statin as variables.

Results: DM was diagnosed in 124 pts (49%) and was treated with insulin or insulin analogs (n = 59), sulfonylurea (n = 38), biguanide (n = 8), thiazolidinedione (n = 6), and alpha-glucosidase inhibitor (n = 5). Statin was used in 16 pts with DM and 14 pts without DM. Locally advanced disease (44% vs. 29%) and HT (44% vs. 28%) were more prevalent in pts with DM. PFS (6.3 vs. 4.9 Mo, P = 0.440) and OS (13.3 vs. 10.0 Mo, P = 0.084) was longer in pts with DM, though not significantly. Use of statin in pts with DM was associated with longer PFS (11.6 vs. 6.0 Mo, P = 0.034) and longer OS (25.4 vs. 11.3 Mo, P = 0.006), while PFS and OS did not differ by the use of statin in pts without DM. Multivariate subgroup analysis with and without DM showed metastatic disease (Hazard ratio [HR] 2.11, P = 0.001 and HR 1.57, P = 0.013), PS 0-1 (HR 0.08, P <0.001 and HR 0.21, P <0.001), use of ACEI/ARB (HR 0.60, P = 0.030 and HR 0.46, P = 0.031) as common prognostic factors for OS. Doublet chemotherapy (HR 0.48, P = 0.007) and use of statin (HR 0.40, P = 0.010) were prognostic only in pts with DM, but any medications for DM were not significant prognostic factors.

Conclusions: In our retrospective analysis, use of statin in pts with DM as well as inhibition of RAS was associated with better prognosis in pts with PaC receiving chemotherapy.
Neoadjuvant chemoradiation and intraoperative electron irradiation for locally unresectable/borderline resectable pancreas adenocarcinoma.
Authors: Ashman Jonathan Ben , Moss Adyr A , Callister Matthew D. , Reddy Kunam S , Mulligan David C , Gunderson Leonard L. , Borad Mitesh J.
Published: February 2017

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Background: The use of preoperative therapy for pancreatic cancer remains controversial. This study reviews our experience using neoadjuvant chemotherapy and chemoradiation (CRT) followed by surgery with intraoperative electron irradiation (IOERT) for patients with borderline resectable (BR) or unresectable (UR) tumors.

Methods: A retrospective review identified 48 patients (pts) with primary BR/UR pancreas adenocarcinoma treated with preop CRT with intent to proceed to curative surgery with IOERT. Seventeen patients did not undergo attempted resection and are excluded (disease progression, 12; medically inoperable, 3; declined surgery, 2). Thirty-one patients proceeded to resection attempt and are the subject of this analysis. Kaplan-Meier survival analysis was performed using log rank test for significance. Median follow up was 19 months (mo).

Results: Complete resection (R0) was achieved in 11 pts, R1 in 5, and R2 or not resected (IOERT alone) in 15 patients. Twenty-six pts died (23 of disease, 2 unrelated causes, 1 uncertain). Median overall survival (OS) was 19 mo for all pts. Local progression was detected in only 5 patients (16%) while distant disease developed in 24 (77%). Resection status significantly correlated with OS; R0/R1 patients had a median survival of 23 mo vs. 10 mo for R2/unresected tumors (p = 0.002). Three-year OS was 35% vs. 0%, respectively. Survival was not influenced by tumor location, CA19-9 baseline or response, tumor size, or initial judgment of resectability (BR vs. UR). BR tumors were resectable after neoadjuvant therapy in 9 of 11 patients (R0, 8; R1, 1) while 8 of 20 initially UR tumors underwent resection (R0, 3; R1, 4; R2, 1).

Conclusions: Neoadjuvant therapy combined with IOERT has the possibility to improve patient selection for surgical resection and to optimize local therapy. Although the prognosis for locally advanced pancreatic cancer remains poor, survival was superior among patients for whom R0 or R1 resection was achieved. Distant metastasis remained the dominant pattern of failure, and novel systemic agents are needed. Prospective evaluation of the impact of neoadjuvant chemotherapy, CRT, and IOERT is warranted.
Comparison of hepatic artery embolization and selective internal radiation therapy for metastatic neuroendocrine tumors.
Authors: Engelman Eric Steven , Leon-Ferre Roberto , Naraev Boris , Sharma Nancy , Sun Shiliang , O'Dorisio Thomas M. , Halfdanarson Thorvardur Ragnar
Published: February 2017

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Background: Liver-directed therapies can be beneficial in reducing morbidity and mortality in patients with metastatic neuroendocrine tumors (mNETs). We compared the clinical outcomes of patients treated with hepatic artery embolization/chemoembolization (HA(C)E) or selective internal radiation therapy (SIRT) with SIR-Spheres at our institution over the last ten years.

Methods: Medical records of 42 mNET patients with hepatic metastases treated with either bland hepatic artery embolization (HAE), chemoembolization (HACE), or SIRT at the University of Iowa from 2001 to 2011 were analyzed. Chi-square and Wilcoxon rank-sum tests were performed to compare the groups. Time to progression (TTP) and overall survival (OS) were calculated using Kaplain-Meier analysis.

Results: The tumors were located in the small bowel in 21 patients (50%), pancreas in 8 (19%), lung in 2 (5%), and other locations in 11 patients (26%). Ten patients (24%) had extra-hepatic metastases. 13 patients had HAE, 17 patients had HACE and 12 patients had SIRT. 20 of these patients had a second procedure with 6 receiving SIRT, 9 HAE and 5 HACE. TTP was similar between SIRT (15.1 months) and HAE or HACE (19.6 months) (p= 0.968). There was a trend towards an increased TTP in patients receiving HACE (33.4 months), compared to HAE (12.1 months) or SIRT (15.1 months) (p = 0.512). The overall survival for all patients from the first intervention was 41.9 months.

Conclusions: There appears to be no significant difference in TTP in patients treated with SIRT compared to patients treated with HAE or HACE in this cohort; however, there may be a trend towards a longer time to disease progression in patients treated with chemoembolization compared to the other two modalities. Patients tend to have a prolonged survival after all three liver-directed therapies.
Feasibility and potential benefits of second-line chemotherapy in patients with advanced biliary tract cancer.
Authors: Walter Thomas , Horgan Anne M. , McKeever Elizabeth , Min Trisha , McNamara Mairead , Hedley David W , Serra Stefano , Krzyzanowska Monika K. , Chen Eric Xueyu , Mackay Helen , Feld Ronald , Moore Malcolm J. , Knox Jennifer J.
Published: February 2017

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Background: Chemotherapy is effective in metastatic or unresectable biliary tract cancer (BTC). The benefits of second-line chemotherapy (CT2) are unclear.

Methods: We retrospectively studied all patients (pts) receiving at least one cycle of chemotherapy for advanced BTC at our institution between 1991 and 2011. We analyzed pt and chemotherapy characteristics (type of regimen; tumor response; time to progression (TTP); and overall survival (OS)). The objectives were: 1) to characterize pts eligible for CT2; 2) to evaluate the efficacy of CT2.

Results: 367, 89 (24%), and 24 (6%) pts received CT1, CT2, and CT3, respectively. Primary tumor location was the gallbladder (30%), intraphepatic (16%), perihilar (20%), distal common bile duct (20%), and ampulla of Vater (14%). 88% had a baseline performance status of 0-1 prior to CT1. The regimen and efficacy data of CT1 and CT2 are presented in the Table . On univariate analysis females (p=0.002) and pts with TTP >6 months on CT1 (p=0.016) were the only variables associated with receiving CT2. The only factor associated with disease control (objective response+ stable disease) on CT2 was the regimen type (75% with a doublet versus 46% with monotherapy, p=0.03).

Conclusions: Among patients with advanced BTC treated with chemotherapy, less than 25% received CT2; but responses were seen and were surprisingly high even in this selected population. Pts with a longer TTP on CT1 were more likely to be offered CT2. Better disease control with CT2 occurs with a doublet than single agent, however clearly more effective therapies must be found. Updated data will be presented.

[Table: see text]
Incidence and natural history of bone metastases in neuroendocrine tumors.
Authors: Keiser Jennifer , Nakakura Eric K. , Imhoff Laurel , Mayorga Margaret A. , Bobiak Sarah , Venook Alan Paul , Bergsland Emily K.
Published: February 2017

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Background: Bone metastases (BM) occur in carcinoids and other neuroendocrine tumors (NET), however, a comparative analysis of the incidence and natural history of BM across different NET subtypes has not been performed. We retrospectively characterized BM incidence, complications, and management across five subtypes: carcinoid/unknown primary (CARC), pancreatic NET (PNET), pheochromocytomas/paragangliomas (PHEO), adrenal cortical carcinoma (ACC) and high grade NET (HGNET) using data collected in the context of the NCCN NET Outcomes Database.

Methods: 296 NET patients (pts) presenting at UCSF from 2004 to 2007 were retrospectively identified. Eligibility criteria included presentation on or after Jan 1, 2004, continued management at UCSF within one year of consultation, age over 18, and pathological confirmation of an eligible NET subtype. BM identified radiographically and/or pathologically, and classified as symptomatic (pain, pathologic fracture, or spinal cord compression) or asymptomatic. BM treatments (tx) included radiation, surgery, bisphosphonate and/or denosumab.

Results: BM identified in 36/296 (12%): 29% pts with HGNET (5/17), 10% pts with CARC (12/121), 7.4% pts with PNET (6/81), 17% pt with PHEO (11/66), 18% pt with ACC (2/11). BM occurred in 21 men/15 women; median age 54. 30/36 (83%) had stage IV disease at diagnosis (dx); 69% had BM at dx. 69% pts were eventually symptomatic: bone pain (24/25, 96%), cord compression (3/25, 12%) and/or pathologic fracture (6/25, 24%); 8/25 (32%) had more than one symptom from BM. Median survival from BM: 28 mo (21.1 mo if symptomatic; 34.3 mo if asymptomatic). Overall, 81% (29/36) pt received tx for BM: 53% XRT (19/36), 25% surgery (9/36), 39% bisphosphonate (14/36), and/or 11% denosumab (4/36).

Conclusions: 12% of pts with NET in this database developed BM. Most pts with BM experienced pain. Serious complications such as cord compression and/or pathological fracture occurred in 36% (9/25) suggesting that bisphosphonate and/or denosumab tx may be of value in these patients. Accrual to the database is ongoing.