bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]