bluuebunny/crossref_metadata_2025 huggingface dataset:
ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma.
Authors: Laforest Anais , Aparicio Thomas , Zaanan Aziz , pittella Silva Fabio , Didelot Audrey , Desbeaux Aurelien , Le Corre Delphine , Benhaim Leonor , Pallier Karine , Aust Daniela Ellen , Pistorius Steffen , Blons Helene , Svrcek Magali , Laurent-Puig Pierre
Published: February 2017

205

Background: Small bowel adenocarcinoma (SBA) is an aggressive tumor responsible for poor outcomes with an expected median OS at 5 years inferior to 30%. Because of its low incidence, few prospective studies have been performed leading to insufficient knowledge and absence of standard of care. Aiming to better understand the small bowel carcinogenesis process we screened for somatic mutations a large data set of patients in more than 740 mutational hotspots among 46 genes. Methods: In total, 83 SBA cases were selected from 2 European databases. The sequencing was performed using the Ion 316 Chip. We additionally looked into MSI status and ERBB2 expression (immunochemistry and FISH). Results: Tumors were mostly located in the duodenum (47%) and stage ≥ 3 (63%). Among the 46 genes investigated, 8 were mutated in more than 5% of the cases: KRAS, TP53, APC, SMAD4, PIK3CA, ERBB2, BRAF, and FBXW7. Compelling mutations (7 cases) and amplifications (3 cases) 12% of the patients had an ERBB2 alteration. In this group, ERBB2 alterations were positively associated with dMMR status (p=0.006) and APC mutations (p=0.02) but negatively associated with p53 mutations (p=0.038). Interestingly, ERBB2 mutations were mainly detected within tumors derived from the foregut while ERBB2 amplifications were limited those derived from the midgut. Conclusions: This study describes the first large screening of somatic mutations in SBA using next generation sequencing. ERBB2 mutation was revealed to be one of the most frequent alterations in SBA with a distribution dependent on tumor location. In most cases patients harbored the same p.L755S-ERBB2 mutation. In clinical practice, this study may suggest that more than 10% of the patients with SBA could be treated using anti-ERBB2-targeted agents.[Table: see text]
A phase II trial of low-dose multiagent chemotherapy with gemcitabine, docetaxel, capecitabine, and cisplatin (GTX-C) in patients with metastatic pancreatic cancer.
Authors: Le Dung T. , Laheru Daniel A. , Purtell Katrina , Uram Jennifer N. , Wang Hao , Lawrence Susie , Foreman Ellen-Lilly , David Jacob Joseph , Parkinson Rose , Savage Dionne T , Donehower Ross C. , Rasheed Zeshaan , Zheng Lei , Azad Nilofer Saba , Cosgrove David , De Jesus-Acosta Ana , Browner Ilene , Diaz Luis A.
Published: February 2017

213

Background: Multiagent chemotherapy with three agents has been shown to delay the emergence of resistance and extend survival in patients with metastatic pancreatic adenocarcinoma. Four drug regimens, even at low doses, may further improve survival by simultaneously targeting multiple non-redundant oncogenic pathways. Methods: A phase II study of GTX-C (capecitabine 500 mg bid on days 1-14, and the combination of gemcitabine 500 mg/m2 (10 mg/m2/min), docetaxel 20 mg/m2 and cisplatin 20 mg/m2 on days 4 and 11) was initiated in newly diagnosed untreated metastatic pancreatic cancer patients. The primary endpoint was progression-free survival rate at 6 months; the regimen would be considered active if the 6-month PFS rate was >75% and inactive if < 50%. Results: Twenty-nine patients were enrolled and 10 patients remain on GTX-C treatment at the time of this report. All patients were ECOG 0 or 1. Eighty-six percent of patients had evidence of liver metastases and 25% had biliary stents in place at time of study enrollment. Median CA19-9 was 6,159 U/mL (37-154,323 U/mL). Median length of follow-up was 9.0 months. Grade 3/4 related adverse events included: nausea/vomiting (7%), transaminitis (10%), anemia (14%), thrombocytopenia (24%), and neutropenia (55%). However, febrile neutropenia occurred in only 3 patients (10%) and not until cycles 6, 14, and 15. PFS rate at 6 months was 76.4% (95% CI: 54.6% - 88.7%). The partial response (PR) rate was 50%, stable disease (SD) rate was 39% and the disease control rate (DCR) was 89%. CA19-9 declines of >80% occurred in 77% of patients with measurable levels. Estimated median PFS was 8.4 months (95% CI: 6.1-10.6 months) and OS was 13.9 months (95% CI: 10.0-17.2 months) at the time of this submission. Updated results will be reported at GI ASCO 2014. Conclusions: GTX-C is highly active and well-tolerated in patients with metastatic pancreatic cancer and should be tested in a larger, comparative study. Clinical trial information: NCT01459614.
The effect and mechanism of M402 on gemcitabine uptake into pancreatic tumors.
Authors: Schultes Birgit Corinna , Chu Chia Lin , Long Alison , Sun Elaine , Kurtagic Elma , Beccati Daniela , Pradines Joel , Miller Paul , Ryan David P. , Flaherty Keith , Roach James , Kaundinya Ganesh Venkataraman
Published: February 2017

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Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which has been attributed to high interstitial pressure and poor drug delivery. In nonclinical studies, M402 affected multiple growth factors, adhesion molecules, and chemokines, inhibiting tumor progression, metastasis, and angiogenesis by clearing heparin-binding factors from the tumor microenvironment. We hypothesized that M402 could modulate tumor-stroma interactions in an orthotopic pancreatic cancer model (rich in desmoplasia), decreasing the fibrotic response and in turn increasing tumor perfusion and drug delivery. Methods: Capan-2 human PDAC cells were injected into the pancreata of nude mice. M402 (40 mg/kg/day, s.c.) or saline began Week 5. Gemcitabine (GEM; 30 mg/kg, i.p. biweekly) started Week 7. At different time points, primary tumors were analyzed for mRNA arrays, immunohistochemistry (ECM components, CD31), and functional tumor vasculature. GEM tumor uptake was evaluated by quantifying the incorporation of dFdC into tumor DNA by LC-MS/MS. M402 tumor uptake was visualized using HyLite-750-labeled drug in a Xenogen system. Results: M402 readily targeted pancreatic tumors with long residence time. Alone and particularly in combination with GEM, M402 significantly reduced tumor size and fibrosis, which was accompanied by down-regulation of SHH, PDGF, and TGF-β signaling in stromal cells. Tumors treated with M402 or M402+GEM showed perfusion and microvessel penetration into the tumor centers while vehicle or GEM treated tumors exhibited limited tortuous vessels surrounding the tumor rim. This translated into increased GEM incorporation into the tumor DNA when mice were pre-treated with M402 vs. saline (10.9±5.5 vs. 6.7±1.8 pg of dFdC/µg dG, respectively; p=0.037). Conclusions: M402 appears to inhibit stromal activation within the tumor microenvironment. Reduction in desmoplasia led to improved tumor perfusion, delivery of GEM, and tumor shrinkage. These and other promising nonclinical data support the rationale for the ongoing Phase 1/2 study evaluating the safety and tolerability of M402 in combination with nab-paclitaxel and GEM in patients with metastatic pancreatic cancer.
Functional BRM promoter polymorphisms, pancreatic adenocarcinoma risk, and survival.
Authors: Segedi Maja , Anderson Laura N , Espin-Garcia Osvaldo , Borgida Ayelet , Bianco Teresa , Cheng Dangxiao , Chen Zhuo , Patel Devalben , Brown M Catherine , Hung Rayjean J , Cotterchio Michelle , Gallinger Steven , Xu Wei , Reisman David , Liu Geoffrey , Cleary Sean P.
Published: February 2017

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Background: Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM -1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex (PMID:23524580). BRM suppression can be reversed pharmacologically (PMID: 21478905). Our group and others have reported associations with lung, head and neck, and hepatocellular cancer risk (PMIDs: 21478907, 23322154, 23359823). We have also reported associations with lung and esophageal cancer prognosis (ASCO 2013; abstr 11057 and 4077). In this analysis, we assessed risk and survival associations with pancreatic cancer. Methods: A population-based case-control study was conducted in Ontario with 623 histologically-confirmed pancreatic adenocarcinoma cases and 1192 age/gender distribution-matched controls (PMID: 23908141). Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Results: Median age was 65 years; 52% were male; 53% had received a curative resection; Stage I (8%), II (55%), III (14%), IV (23%); 79% received chemotherapy; 83% had died. In the risk analysis, the adjusted odds ratios were 1.01 (95%CI:0.1-2.0) and 0.96 (95%CI:0.7-1.3) for the homozygous variants of BRM-741 and BRM-1321, respectively, when each was compared to wildtype; adjusted odds ratio of double-homozygotes was 1.11 (95%CI:0.80-1.53) when compared to the double-wildtype. In contrast for the survival analysis, the hazard ratios (adjusted for age, stage, receipt of curative surgery, receipt of chemotherapy, and packyears) were 2.19 (95%CI: 1.9-2.5) for BRM-741 and 1.94 (95%CI: 1.7-2.2) for BRM-1321, per each unit increase in variant alleles. Compared with the double-wildtype, the adjusted hazard ratio for carrying no, one, and two homozygous (double-homozygous) variants were 2.14 (95%CI:1.6-2.8), 4.17 (95%CI:3.0-5.7), and 8.03 (95%CI: 5.7-11.4), respectively. Conclusions: Two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.
Phase II study of induction therapy with gemcitabine and nab-paclitaxel followed by consolidation with mFOLFIRINOX in patients with metastatic pancreatic cancer.
Authors: Ramanathan Ramesh K. , Lee Peter , Seng John E. , Anthony Stephen Patrick , Rosen Peter J. , Mena Raul R. , Picozzi Vincent J. , Sachdev Jasgit C. , Larson Tim , Korn Ronald , Jameson Gayle S. , Stoll Amy C. , Von Hoff Daniel D. , Leach Joseph W.
Published: February 2017

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Background: FOLFIRINOX or NabP-Gem are now standard mPC regimens.The optimal sequence is not known.This phase II study evaluated the feasibility of NabP-Gem followed by FOLFIRINOX. Methods: Eligible pts had evidence of untreated mPC, ECOG 0-1 and adequate organ function. Pts received Nab-P (125 mg/m2) and Gem (1000 mg/ m2) weekly x 3 (Induction ) every 4 weeks for upto 6 cycles. FOLFIRINOX, q2 weeks (Consolidation regimen) was initiated after 6 cycles of the Induction regimen, or earlier in case of progression, and given for a maximum of 6 months (12 cycles). mFOLFIRINOX (NEJM, 364:1817-25: 2011) has been modified with growth factor prophylaxis and omission of bolus 5FU. One endpoint is to increase 1 year survival to > 70%, (n=30, 95% CI is +/- 20%). Results: Accrual goals have been met (n=31). The M/F ratio is 55%/45%, median is 66 years. In 23 pts with elevated baseline CA19-9 levels treated with NabP-Gem, 83% had a > 90% decrease. The response rate with the NabP-Gem regimen is 43%. Selected therapy related Grade > 3 adverse events during the course of both NabP-Gem and FOLFIRINOX therapy are: neutropenia (39%), fatigue (32%), anemia (19%), thrombocytopenia (16%), thromboembolic events (3%), peripheral neuropathy (16%), leukopenia (16%), nausea (3%), vomiting (3%), diarrhea (7%), and neutropenic fever (3%). During the course of NabP-Gem, 14 dose reductions and four dose delays were seen. Two pts had early progression at cycle 4 or less and were switched to the Consolidation regimen. Seventy one % (22/31) of pts went on to receive FOLFIRINOX (4 pts still on study), 4 received FOLFIRI, and one pt received FOLFOX as Consolidation therapy. One-year survival is projected to be 50-60%. Conclusions: The induction NabP-Gem regimen shows evidence of substantial activity similar to published reports (JCO.29:4548-54: 2011). The induction-consolidation strategy is feasible in selected patients. Cumulative side effects predominantly fatigue and neuropathy will require appropriate dose reductions or treatment breaks. (Supported by the Seena Magowitz foundation). Clinical trial information: NCT01488552.
In vitro chemotherapy profiling of well-differentiated midgut neuroendocrine tumors (NETs) based on individual patient tumor biomarkers analysis.
Authors: Wang Yi-Zarn , Carrasquillo Jean P. , Carimi Alexis , McCord Elizabeth , Chester Maria M. , Ramirez Robert , Boudreaux J Philip , Woltering Eugene , Raines Daniel , Anthony Lowell Brian
Published: February 2017

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Background: Midgut neuroendocrine tumors (NETs) are rare malignancies with indolent clinical courses. In general, they are well differentiated with most tumor cells in the G0 phase of the cell cycle, consistent with the poor response rate of NETs to chemotherapy in vivo. We hypothesize that insults, such as surgery, can drive NET cells from G0 into S phase and that biomarker analysis of individual patient tumors harvested and grown in the lab will provide useful practical guide for future intra and post operative adjuvant therapy. Methods: 97 well-differentiated midgut NET patients underwent cytoreductive surgery at our institution between 5/2012 and 10/2012. 148 surgical specimens were collected and submitted to a single commercial lab for processing. Primary tumors, lymph nodes and liver metastases were harvested and cultured. Their RNAs were then extracted to analyze the expressivity a total of 88 different biomarkers. Based on our patients specific tumor biomarker expressivity and known correlations between 36 anti-neoplastic agents with their linked biomarkers, recommendations were reported as clinically benefit or lacking such benefit. Results: A total of 148 specimens from 97 patients were tested. In four of the 97 patients, no clinically beneficial chemotherapy agent could be identified. Among the remaining 93 patients, the top three agents that are most likely to be clinically beneficial are: Fluorouracil, Cisplatin and Carboplatin. These were reported to be clinically beneficial in 135/148 (91.2%), 103/148 (69.6%), and 103/148 (69.6%) patients respectively. Conclusions: Midgut NETs are slow growing tumors which are chemotherapeutically inert owing to the fact that most of the tumor cells are in G0 cell cycle. Surgical insult drives NET cells into active synthetic phase where they begin to express biomarkers specific to their tumor cells. Analysis of these biomarkers guides further potential beneficial therapy based on the current known associations among biomarkers and chemotherapy agents. These results must then be compared and confirmed against a direct in-vitro chemo sensitivity assessment conducted simultaneously on the same patients.
Association of long-term regular aspirin use with reduction of gastric cancer risk: A nationwide cohort study.
Authors: Kim Young-Il , Kim So Young , Park Jong-Hyock , Cho Soo-Jeong , Lee Jun Ho , Kim Young Woo , Choi Il Ju
Published: February 2017

24

Background: Aspirin use has been associated with a decreased incidence and mortality of various gastrointestinal malignancies. In this study, we evaluated the association between aspirin use and gastric cancer risk. Methods: We randomly selected 200,000 patients with hypertension or type 2 diabetes from the Korean National Health Insurance claim database at 2004. Of these, 3,907 patients who used aspirin regularly (aspirin users) and 7,808 patients who did not use aspirin (aspirin non-users) were selected by 1:2 frequency matching (age, sex, co-morbid illnesses, and starting time of follow-up), and assessed gastric cancer incidence during the followed-up periods from January 2004 to December 2010. Results: In the matched cohort, the incidence rates of gastric cancer were 0.8% (31/3,907) in aspirin users and 1.1% (86/7,808) in aspirin non-users, but the cumulative incidence rates were not significantly different between aspirin users and non-users (P=0.11, log-rank test). Although there was no statistical significance, a multivariate analysis showed that aspirin use was associated with reduced gastric cancer risk (adjusted hazard ratio [AHR], 0.71; 95% confidential interval [CI], 0.47–1.08; P=0.11). However, duration of aspirin use was significantly associated with the reduction of gastric cancer risk (overall AHR, 0.85; 95% CI 0.73–1.00, P=0.04), especially in patients that used aspirin for more than 3 years (AHR, 0.40; 95% CI, 0.16–0.98; P=0.04). Conclusions: Long-term regular aspiri n use is significantly associated with reduced gastric cancer risk.
Phase II trial of temozolomide and veliparib combination therapy for sorafenib-refractory advanced hepatocellular carcinoma (HCC).
Authors: He Aiwu Ruth , Tesfaye Anteneh , Smith Daniel , Marshall John , Pishvaian Michael J. , Smaglo Brandon George , Weiner Louis M. , Dorsch-Vogel Karen , Wang Hongkun
Published: February 2017

240

Background: The combination of the imidazotetrazine derivative temozolomide (TMZ) and poly(ADP-ribose) polymerase inhibitor veliparib (ABT-888) has shown in vivo activity against a variety of tumor types through the alkylating effects of TMZ and DNA repair inhibition by ABT-888. To date, no studies have examined the combination of TMZ and ABT-888 in treating advanced HCC refractory to sorafenib. Methods: This is a single arm Phase II trial. Eligible HCC patients have Child Pugh A/B cirrhosis and have failed prior treatment with sorafenib either through intolerance or disease progression. All patients have received ABT-888 40 mg daily on days 1-7 and Temozolomide 150 mg/m2 daily on days 1-5 in 28 day cycles for a maximum of 6 cycles. Tumor response is analyzed every 2 cycles using RECIST criteria. The primary endpoint is time to disease progression. The trial is being conducted using a modified Simon’s two-stage design optimal design as implemented by Hanfelt, et al. Results: The trial is currently in Simon Stage 1 with 16 patients recruited: 9 patients have stopped the study due to disease progression, 3 patients are still on protocol, and 4 patients stopped the study for reasons other than disease progression. 7 patients had disease progression at two months, 1 patient had cancer progression at 4 months, and 1 patient had disease progression at 16 months. Median time to progression in these 9 patients was 56 days (range 42-486 days). The four patients that stopped the study prematurely were for the following reasons: hiccups/dehydration, Mallory-Weiss tear secondary to refractory nausea, intraperitoneal bleeding from exophytic HCC lesion, and development of hepatorenal syndrome in a paracentesis-dependent patient. The most common grade 3 toxicities in this cohort so far have been nausea/vomiting (in 2 subjects), and anemia/thrombocytopenia (in 2 subjects). Defects in DNA repair pathways are being tested from the liver biopsy in the patient who had response to TMZ and ABT-888 for 16 months. Conclusions: The combination of TMZ and ABT-888 is fairly tolerated in patients with advanced HCC. So far, the treatment did not show activities in majority of patients with advanced HCC. Clinical trial information: NCT01205828.
Angiogenesis genotyping, LDH serum levels, and treatment efficacy for advanced hepatocellular carcinoma patients receiving sorafenib.
Authors: Faloppi Luca , Scartozzi Mario , Bianconi Maristella , Loretelli Cristian , Svegliati Baroni Gianluca , Toniutto Pierluigi , De Minicis Samuele , Bitetto Davide , Mandolesi Alessandra , Giampieri Riccardo , Del Prete Michela , Bittoni Alessandro , Bearzi Italo , Benedetti Antonio , Cascinu Stefano
Published: February 2017

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Background: Previous reports suggested that angiogenesis genotyping predicts clinical outcome for HCC patients receiving sorafenib. However gene profiling techniques may not be available in the clinical practice, thus resulting in lack of selection. LDH serum levels, a marker of tumour-driven hypoxia and angiogenesis, demonstrated to play a prognostic role in patients undergoing anti-angiogenetic therapy in different tumour types. Our study evaluated whether angiogenesis genotyping correlates with LDH levels in HCC patients receiving sorafenib with the final aim to provide clinicians with a readily available marker for the clinical management of these patients. Methods: 82 HCC patients treated with sorafenib were included. Tumour samples were tested for VEGF-A/C and VEGFR-1/2/3 SNPs. The LDH cut off value (407 U/l) was set after ROC analysis. Patients were divided into two groups according to the LDH pre-treatment levels and subsequently classified for LDH pre- and post-treatment variations (increased vs. decreased). Results: In patients with LDH values ≤ or > 407 U/l mPFS and mOS were respectively 6.7 vs. 1.9 months (p=0.0006) and 13.2 vs. 4.9 months (p=0.0002). Patients with decreased LDH values after treatment experienced an improved mPFS and mOS compared to those with increased LDH levels (mPFS: 6.8 vs. 2.9 months, p=0.0087, mOS: 21 vs. 8.6 months, p=0.0035). As previously reported VEGF-A (rs2010963) and VEGF-C (rs4604006) genotyping predicted improved clinical outcome and in the present series also significantly correlated with low LDH pre-treatment levels (respectively: p=0.027; p=0.016) and with decreased LDH levels after treatment (respectively: p=0.012; p=0.015). Conclusions: VEGF-A (rs2010963) and VEGF-C (rs4604006), low LDH pre-treatment levels and decreased LDH levels after treatment seem to be concordant in determining clinical outcome in this setting. Our observations suggest that these genotypes are likely to affect tumour angiogenesis with subsequent LDH levels modifications as a result of sorafenib treatment. We believe that these findings may be relevant for a better prognostic stratification of advanced HCC patients receiving sorafenib.
Effect of inflammation-associated cytokines of biliary tract cancer on chemoresistance and therapeutic implications.
Authors: Kobayashi Shogo , Nagano Hiroaki , Yamada Daisaku , Ishii Hideshi , Tomimaru Yoshito , Hama Naoki , Wada Hiroshi , Kawamoto Koichi , Eguchi Hidetoshi , Doki Yuichiro , Mori Masaki
Published: February 2017

247

Background: Biliary tract cancer (BTC) is well-known to be commonly suffered from inflammations; cholangitis and/or liver abscess. The author previously showed interleukin-6 (IL-6) worked on anti-apoptotic process in BTC. Herein, we focused on inflammation-associated cytokines including not only IL-6 but also transforming growth factor-beta 1 (TGF-β1), and investigated the working processes, their relationship to chemoresistance, and therapeutic implications. Methods: We employed resected specimens and BTC cell lines. We evaluated IL-6/TGF-β1 expression, invasion, endothelial-mesenchymal transition (EMT), and chemoresistance to gemcitabine, with or without silencing of PI3K/Akt, MAPK, STAT, and Smad pathways. Results: Resected specimens expressed IL6 and TGF-β1 staining at the invasion front by immunohistochemical staining. In BTC cell lines, spontaneous expression of IL-6/TGF-β1 was related to malignant potencies such as EMT and chemoresistance. Rh IL-6/TGF-β1 induced invasion, EMT, and chemoresistance. Smad4 among cell signaling pathways functioned in a dominant manner; inhibition of Smad4 pathway reduced invasion, and reversed EMT and chemoresistance, in both rh IL-6/TGF-β1-treated cells, and we confirmed these results using SMAD4 siRNA. And, our established gemcitabine-resistant cells expressed high level of IL-6/TGF-β1, and promoted EMT. Inhibition of Smad4 also reversed chemoresistance in gemcitabine-resistant cells. We confirmed N-cadherin and Smad4 expression at the invasion front by immunohistochemistry. Conclusions: IL-6 and TGF-β1 resulted in chemoresistance, and inhibition of Smad4 would reverse chemoresistance in BTC.
Quality indicator for esophagogastroduodenoscopy in screening gastric cancer.
Authors: Lee Yong Chan , Park Chan Hyuk , Chung Hyun Soo , Lee Hyuk , Park Jun Chul , Lee Sang Kil
Published: February 2017

25

Background: The national gastric cancer screening program including endoscopy has been introduced in Korea in which the high incidence of gastric cancer have been reported. The good quality indicators of screening endoscopy for gastric cancer are mandatory to improve the detection rate. However, most quality indicators were focused on the standardization of an endoscopy unit rather than the individual assessment of endoscopists for cancer screening ability. We aimed to identify quality-assessment indicators associated with screening gastric cancer. Methods: The database records for 54,889 subjects who underwent esophagogastroduodenoscopy (EGD) for screening purpose at the Yonsei University Severance Hospital Health Promotion Center, Seoul, Korea between February 2006 and July 2013 were analyzed. All the endoscopists (n=66) involved in this study were experienced endoscopists who performed 1,000 or more EGDs. The detection rate of early gastric neoplasm according to endoscopists were assessed. The detection rates of various gastric lesions other than gastric epithelial neoplasms were also analyzed. The scoring formula for predicting the qualified endoscopists was proposed and analyzed. Results: Of the enrolled subjects, mean age was 48 years and the percentage of males was 59.7%. The percentage of gastric dysplasia, early gastric cancer, and advanced gastric cancer was 0.18%, 0.10%, and 0.04%, respectively. Most frequently detected lesions were gastric erosions (22.30%) followed by atrophic gastritis and intestinal metaplasia. In multivariate analysis, the detection rates of gastric subepithelial lesion or gastric diverticulum were independent associate factors with early gastric neoplasm detection. Cochran-Armitage trend test confirmed that higher quality score group was associated with significant higher early gastric neoplasm detection rate. Conclusions: The detection rates of gastric subepithelial lesion or gastric diverticulum are well correlated with early gastric neoplasm detection. the proposed quality score formula can be a good indicator assessing endoscopist's ability to detect early gastric neoplasm.
Metabolic landscape using 18F-FDG PET and its clinical significances in advanced biliary tract cancer.
Authors: Cho Kyoung - Min , Kim Tae Yong , Oh Do-Youn , Lee Kyung-Hun , Han Sae-Won , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue
Published: February 2017

252

Background: Metabolic landscape evaluated by 18F-FDG positron emission tomography (PET) in advanced biliary tract cancer (BTC) has not been studied. Furthermore, the clinical meanings of metabolic features have rarely been reported. We evaluated the metabolic features using 18F-FDG PET and its clinical significances in advanced BTC. Methods: We consecutively enrolled advanced BTC patientswho underwent PET prior to palliative chemotherapy between 2003 and 2013. We retrospectively evaluated the findings of PET such as SUVmax, lesion numbers, involved organ and pathologic findings and other clinical factors including response to chemotherapy, progression-free survival (PFS) and overall survival (OS). Results: A total of 106 patients were enrolled (intrahepatic cholangiocarcinoma (ICC):53, extrahepatic BTC :7, gallbladder cancer (GB Ca) :30, and ampulla of vater cancer (AoV Ca): 16 patients) ECOG PS 0-1 in 89 and PS 2 in11 patients. 52.8 % of patients received gemcitabine-based chemotherapy and 47.1% of patients received 5-FU-based chemotherapy. The SUVmax was median 7.8 (range 0-44). Fifty-four percent of patients showed higher SUVmax in metastatic lesion than primary site. The SUVmax was different according to primary origin (ICC: 9.10, extrahepatic BTC: 5.90, GB Ca : 9.10, AoV Ca :6.37, p=0.008) and histologic differentiation (well-differentiated: 4.95, moderately-differentiated :6.60, poorly-differentiated :14.50, p=0.004) Patients with a SUVmax of >7.5 had more poorly differentiated histology and more PET uptake-lesions (p < 0.05) than those with a SUVmax of <7.5. The OS and PFS of all patients were 8.3 (95% CI: 5.7 – 10.8 ) and 4.9 months (95% CI: 3.4 – 6.3), respectively. Patients with a SUVmax of <7.5 had a significantly longer OS (11.4 vs. 7.4 months, p = 0.007) and PFS (6.6 vs. 4.3 months, p = 0.024) than those with a SUVmax of >7.5. In multivariate analysis, SUVmax was also a significant prognostic factor for OS (p=0.012) and PFS (p=0.039). Conclusions: Metabolic landscapes of advanced BTC are different according to primary origin and histology. This metabolic feature such as SUVmax could be a potential prognostic factor for OS and PFS in advanced BTC.
Efficacy of platinum chemotherapy agents in the adjuvant setting for adenosquamous carcinoma of the pancreas.
Authors: Wild Aaron Tyler , Dholakia Avani Satish , Fan Katherine Yu-Ting , Kumar Rachit , Laheru Daniel A. , Zheng Lei , De Jesus-Acosta Ana , Ellsworth Susannah G. , Hacker-Prietz Amy , Voong K Ranh , Hruban Ralph H. , Tran Phuoc T. , Pawlik Timothy M. , Wolfgang Christopher Lee , Herman Joseph M.
Published: February 2017

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Background: Pancreatic adenosquamous carcinoma (PASC) accounts for only 1-4% of exocrine pancreatic cancers and carries a particularly poor prognosis. This retrospective study was performed to determine whether inclusion of a platinum agent as part of adjuvant therapy is associated with improved survival in patients with PASC. Methods: Records of all patients who underwent pancreatic resection at our institution from 1986-2012 were reviewed to identify those with PASC. Multivariable Cox proportional hazards modeling was used to assess for significant associations between patient characteristics and survival. Results: In total, 62 patients with PASC were identified among 5,627 cases (1.1%). Median age was 68 (interquartile range [IQR], 57-77) and 44% were female. Multivariate analysis revealed that among all patients (n=62) the following factors were independently predictive of survival: lack of adjuvant therapy (hazard ratio [HR]=3.558, p=0.0002), positive margin (HR=3.466, p=0.0003), lymph node involvement (HR=3.482, p=0.004), and age (HR=1.030, p=0.035). Among patients who underwent adjuvant therapy (n=39), those who received a platinum agent as part of the adjuvant therapy regimen experienced a longer median survival of 19.1 months (95% CI, 13.8-24.4) compared to 10.7 months (95% CI, 7.9-13.5) for patients who never received a platinum agent (p=0.011, log-rank test). Given this improvement in survival on univariate analysis, a second multivariable model was constructed to elucidate factors associated with survival among patients who received adjuvant therapy in order to confirm the univariate result while controlling for potential confounding risk factors. Backward elimination performed using this second multivariable model revealed that inclusion of a platinum agent in the adjuvant regimen (median survival HR=0.408, p=0.040) and larger tumor diameter (HR=1.259, p=0.047) were independent predictors of survival for this cohort. Conclusions: Addition of a platinum agent to adjuvant regimens for resected PASC should be considered as a means to improve survival among these high risk patients, though collaborative prospective investigation is needed.
Final result of a phase I study of combination of pasireotide (SOM 230) LAR plus gemcitabine in metastatic pancreatic cancer (MPC).
Authors: Suleiman Yaman , Springett Gregory M. , Siegel Erin M. , Shibata David , Fulp William J. , Kim Richard D.
Published: February 2017

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Background: Pasireotide is a cyclohexapeptide engineered to bind to multiple somatostatin (SST) receptor subtypes (SST 1, 2, 3, and 5) to mimic the action of natural somatostatin with 40-times higher affinity for SST1 and SST5 and 5-times higher affinity for SST3 compared to octreotide and is potent inhibitor of insulin-like growth factor-1 (IGF-1). SST receptors and IGF receptors are highly expressed in pancreatic cancer, therefore potentially making it a valuable target. Methods: A 3+3 dose escalation design was used; patients with previously untreated MPC were eligible for the trial. Patients received GEM 1000 mg/m2(30-min, once-weekly IV infusion for 3 out of 4 weeks) and SOM 230 LAR according to dose escalation. Two dose levels were planned, 40mg IM and 60 mg IM once a month. Cohort was expanded to 10 more patients at the highest tested dose to further access safety and efficacy. IGF-1, IGFBP (insulin-like growth factor binding protein)-1, and IGFBP-3 were measured at baseline and with each restaging. Results: 20 patients enrolled with this study were treated and 16 patients (median age 65.5 years; male/female 6:10) were evaluable for safety and efficacy. No dose limiting toxicities were observed with the two used doses, therefore cohort at 60mg was expanded to 10 patients to assess efficacy. 12 % (2/16) of patients had partial responses (PR), 56% (9/16) had stable disease (SD) as best response. Median PFS was 4.1 months (range 1 to 16 months) and median overall survival was 6.8 months. Most common grade 3 or 4 toxicities were hyperglycemia (n=5), increased bilirubin (n=2), neutropenia (n=1), thrombocytopenia (n=1) and fatigue (n=1). Median baseline IGF-1 level was lower in Pts with stable disease than in progressive disease (63 vs.71 ng/mL), the median drop in the level of IGF-1 between the first cycle and the last cycle was more prominent in the stable disease than progressive disease (16 vs. 28 ng/mL). Conclusions: Pasireotide in combination with gemcitabine was well-tolerated. The disease control rate (56% SD + 12% PR) in patients with MPC. Baseline IGF-1 level may potentially be a prognostic and predictive biomarker for pasireotide. These results are promising and warrant further evaluation. Clinical trial information: NCT01385956.
Phase II study of first-line trebananib plus sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Abou-Alfa Ghassan K. , Blanc Jean-Frédéric , Miles Steven , Ganten Tom M. , Trojan Jorg , Cebon Jonathan S. , Liem Andre K. D. , Lipton Lara Rachel , Gupta Charu , Wu Benjamin , Litten Jason B. , Saltz Leonard
Published: February 2017

286

Background: Trebananib is a first-in-class antiangiogenic therapy that sequesters Ang1 and Ang 2, preventing their interaction with the Tie 2 receptor. A previous study of the combination of trebananib with sorafenib in renal cell carcinoma showed an acceptable toxicity profile. Elevated Ang 2 levels have been associated with a poor prognosis in HCC. We thus evaluated the safety and efficacy of trebananib plus sorafenib in HCC. Methods: Patients with HCC, ECOG ≤ 2, Childs-Pugh A, and adequate organ function received IV trebananib at 10mg/kg weekly (cohort 1) or 15 mg/kg weekly (cohort 2) plus sorafenib 400 mg PO twice daily. Thirty patients were accrued to each cohort to provide a power of 80% with the 1-sided exact test for single proportion at α = 0.20 to show a ≥ 78% PFS rate at 4 months relative to 62% reported in the sorafenib historical control. Secondary endpoints included safety and tolerability, progression free survival, objective response rate, disease control rate, time to progression, and overall survival. Results: See table. Conclusions: Trebananib at 10 mg/kg and 15 mg/kg plus sorafenib were well tolerated in patients with advanced HCC. When compared with historical controls, study results did not show an improvement in PFS rate at four months. Clinical trial information: NCT00872014. [Table: see text]
Pre-90Y hepatic radiotherapy hemoglobin and liver functions to predict overall survival in unresectable, chemotherapy-refractory metastatic colorectal cancer.
Authors: Kennedy Andrew S. , Ball David , Cohen Steven J. , Cohn Michael , Coldwell Douglas M. , Drooz Alain , Ehrenwald Edward , Kanani Samir , Moeslein Fred M , Nutting Charles W. , Putnam Samuel G. , Rose Steven C. , Savin Michael , Schirm Sabine , Sharma Navesh K , Wang Eric
Published: February 2017

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Background: Patients with liver metastases from colorectal cancers (mCRC) can benefit from 90Y resin microsphere radioembolization (RE) administered via the hepatic arteries. This study investigated which standard laboratory tests may assist in improving treatment outcomes by identifying potentially correctable pre-radiation abnormalities prior to delivery of RE. Methods: A database containing retrospective review of 606 mCRC patients treated consecutively from July 2002 to December 2011 at 11 US institutions was used. Data collected included background characteristics, prior chemotherapy, surgery/ablation, radiotherapy, vascular procedures, 90Y treatment, subsequent adverse events and survival. Kaplan-Meier estimates compared survival of patients across lines (0–≥4) of chemotherapy. The following values were obtained within 10 days prior to treatment: hemoglobin, albumin, alkaline phosphatase, AST, ALT, total bilirubin and creatinine. CTCAE v3.0 grade was assigned to each parameter and analyzed for impact on survival by line of chemotherapy. Where applicable, Consensus Guidelines were used to establish the abnormal limits for RE. Results: 606 patients (370 Male; 236 Female) were studied with a median follow-up of 8.5 months (IQR 4.3–15.6) after RE. Fewer than 11% of patients were treated outside recommended guidelines, with grade 2 albumin (<3–2.0 g/dL) being the most common (10.5%) at time of RE. Abnormal parameters (grade >0) were associated with statistically significantly decreased median survivals (p<0.05) and this was consistent across most lines of prior chemotherapy. Compared to patients with grade 0, those with grade 2 albumin decreased median survival by 67%; for grade 2 total bilirubin, by 63%; and grade 1 hemoglobin, by 66%. Conclusions: Review of pre-RE laboratory parameters may aid in improving median survivals if correctable grade >0 values are addressed prior to radiation delivery. Hemoglobin <10 g/dL is a well-known negative factor in radiation response and is easily corrected. Improving other parameters is more challenging. These efforts are important in optimizing treatment response to liver radiotherapy.
Streptozocin-based chemotherapy in patients with advanced pancreatic neuroendocrine tumors.
Authors: Pavel Marianne E. , Dilz Lisa-Marie , Denecke Timm , Steffen Ingo , Prasad Vikas , Pape Ulrich-Frank , Pascher Andreas , Heetfeld Maximilian , Wiedenmann Bertram
Published: February 2017

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Background: The role of systemic chemotherapy for advanced pancreatic neuroendocrine tumours (pNETs) is controversially discussed. Objective response rates (RR) with streptozocin(STZ)-based chemotherapy range between 6% and 69%. Novel targeted drugs have recently been approved, however sequence of treatment remains unclear. We aimed to evaluate efficacy of STZ+5-FU chemotherapy in a large pNET cohort. Methods: Clinical data of 95 patients (pts) with advanced pNET who had been treated with STZ+5-FU between Aug 1998 and Sept 2013 were analyzed retrospectively. RR, time to tumour progression (TTP) and overall survival (OS) were assessed. Assessment of RR was judged by tumour board involving an experienced radiologist (TD). Results: Median age at start of chemotherapy was 60 years (range 32-80). 74 pts (77.9%) had non-functional pNETs. In 52 pts (54.7%) STZ+5-FU was 1st line systemic therapy. 11.6% had G1, 78.9% G2 and 6.3% G3 tumours. Baseline progression was evident in 75.8% of cases. Mean number of therapy cycles was 6 (range 1-18). Treatment was discontinued for toxicity in 15.8% of the cases. Partial response was seen in 43.2% of pts, stable disease in 32.6% and disease progression as best response in 18.9% of cases. Overall TTP was 13.7 months and was independent of prior systemic treatment (1st line vs. >1st line, 13.6 vs. 25.3 months, P= 0.54). Functionality had no impact on median TTP. There was no difference between pts with G1 and G2 NET (TTP 21.3 vs. 16.4 months, P=0.78). Median OS was 27.6 months (range 0.8-174 months). In pts with at least two extrapancreatic disease sites (34.7%) median OS was inferior compared to pts with one disease site involvement (37.3 vs. 70.5 months, P=0.02). Conclusions: The combination of STZ and 5FU was associated with a considerable objective response rate in advanced G1/G2 pNETs who had prior disease progression. Efficacy of treatment was not depending on therapy line or grading (G1 vs. G2). Objective response rate is higher than those observed with targeted drugs. This finding along with good tolerability of the treatment strengthens the durable value of this chemotherapy in the era of targeted drugs for the outcome of pts with pNETs.
Associations between K-ras mutation, smoking, and prognosis of pancreatic cancer.
Authors: Saito Kei , Nakai Yousuke , Isayama Hiroyuki , Sasaki Takashi , Takahara Naminatsu , Hamada Tsuyoshi , Miyabayashi Koji , Yamamoto Keisuke , Mizuno Suguru , Mohri Dai , Kogure Hirofumi , Yamamoto Natsuyo , Hirano Kenji , Ijichi Hideaki , Tateishi Keisuke , Tada Minoru , Koike Kazuhiko
Published: February 2017

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Background: Smoking is recognized as a risk factor for pancreatic cancer, but its associations with prognosis are not fully elucidated. Smoking was associated with poor outcomes in colon cancer, especially in patients with K-ras mutation (J Clin Oncol. 2013;31:2016-23). Therefore, we conducted this retrospective analysis of the associations of K-ras mutation, smoking and prognosis in patients with pancreatic cancer. Methods: Patients with pancreatic cancer who received surgery or chemotherapy at the University of Tokyo Hospital were retrospectively studied. The prognosis of patients with mutant and wild K-ras were compared. Overall survival was evaluated using Kaplan-Meier methods and compared by long-rank test. Cox regression models were used to calculate hazard ratios (HRs) to evaluate the prognostic factors in patients with pancreatic cancer with mutant K-ras or wild K-ras. Results: Between January 2009 and August 2013, K-ras mutation analysis was evaluated in 187 patients (47 surgical resection and 140 chemotherapy). K-ras mutation was detected in 74.3%. The rates of current-, ex- and never-smokers were 18.2%, 31.6% and 50.3%, respectively. In patients with mutant K-ras, the rate of male gender (46.0% vs. 29.0%), presence of distant metastasis (50.4% vs. 31.3%) and median CA19-9 (374 U/mL vs. 136 U/mL) were significantly higher than that in patients with wild K-ras. The rate of ever smokers (current- and ex-smokers) did not differ significantly (48.2% in mutant K-ras vs. 56.3% in wild K-ras, p=0.403). Median survival time (MST) was 16.7 (95%CI, 11.9-21.8) months in patients with mutant K-ras, compared with 20.3 (95%CI, 15.8-34.6) in patients with wild K-ras (p=0.193). Meanwhile, MST was 22.2 (95%CI, 16.9-27.9) vs. 14.8 (95%CI, 9.1-19.4) months in patients with and without smoking (p=0.024). After adjustment by age, gender, performance status, CA19-9 and treatment, HRs of smoking were 1.96 (95%CI, 1.06-3.68, p=0.032) in patients with mutant K-ras, but the association was not significant in patients with wild-K-ras (HR 1.35 [95%CI, 0.37-5.28], p=0.653). Conclusions: As previously reported in colon cancer, smoking was associated with poor prognosis in pancreatic cancer with K-ras mutation.
Phase I/II trial of gemcitabine (Gem) plus irinotecan (CPT-11) for metastatic pancreatic cancer (MPC).
Authors: Yamai Takuo , Ioka Tatsuya , Sueyoshi Hironari , Takada Ryoji , Fukutake Nobuyasu , Ashida Reiko , Katayama Kazuhiro
Published: February 2017

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Background: Treatment options for patients with metastatic pancreatic cancer are still limited. Recently, new strategies to prolong disease control are reported. We conducted phase I/II trial of GEM+CPT-11 combination chemotherapy for MPC to evaluate the effectiveness and safety. Methods: As phase I study, traditional 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose. Four escalating dose levels of GEM/CPT-11 (800/60 mg/m2, 1000/60 mg/m2, 1000/80 mg/m2, and 1000/100 mg/m2) were studied. As results of this investigation, the recommended phase II dose was GEM 1000 mg/m2 and CPT-11 100 mg/m2, biweekly. Phase II eligibility included naïve MPC, PS0-2, Pathological diagnosis, no refractory ascites and pleural effusion, and adequate organ function. Primary endpoint was overall survival. Results: Eighteen patients were entered phase I study. The DLTs were anorexia, and nausea/vomiting. Severe neutropenia was rare. MTDs were determined GEM 1000 and CPT-11 100 mg/m2. After that, we investigated phase II trial in 40 patients. There were 6 partial response, 14 stable disease, 18 progressive disease and 2 in-evaluable. Response rate was 16%. The median overall survival was 7.5 months; progressive disease 4.0 months. Grade 3 to 4 toxicity included neutropenia (7%), anemia (7%), diarrhea (7%), ALT elevation (10%), pneumonitis(7%). There was no treatment-related death. Conclusions: This combination chemotherapy is not effective as first-line chemotherapy for metastatic pancreatic cancer. But this is safe and generally well tolerated. This chemotherapy could be effective of salvage chemotherapy with low toxicity after standard chemotherapy such as FOLFIRINOX.
Potential factors influencing initial sorafenib dose selection in hepatocellular carcinoma (HCC): U.S. regional analysis of GIDEON.
Authors: Piperdi Bilal , Cohn Allen Lee , El-Khoueiry Anthony B. , Geschwind Jean-Francois , Gholam Pierre Michel , Mantry Parvez , Martin Robert C. G. , McGuire Brendan , Miksad Rebecca A. , Sanyal Arun J. , Venook Alan Paul , Babajanyan Svetlana , Goldenberg Alec
Published: February 2017

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Background: GIDEON is a global, prospective, noninterventional study to evaluate sorafenib (SOR) safety under real-life practice conditions. Here we examine potential factors that may have had an impact on initial SOR dose (ID) selection in the U.S. cohort of GIDEON. Methods: Patients (pts) with unresectable HCC who were candidates for systemic therapy and for whom a decision was made to treat with SOR were eligible for inclusion. ID choice was at physician discretion. Baseline characteristics were analyzed for their potential impact on the choice of ID. Adverse events (AEs) were evaluated by ID. All results are descriptive. Results: 563 pts were valid for safety. 54% of pts received the recommended ID of 800 mg/d, 35% received 400 mg/d, and 11% other (includes 100, 200, 600 mg/d. dose). Among pts who had an ID <800 mg/d, 37% underwent a dose increase to 800 mg/d. ID did not appear to differ by baseline Child-Pugh or its components, BCLC stage, etiology, or body mass index. By ECOG performance status (PS), IDs of 800/<800 mg/day were given as follows: PS ≤1: 55%/45%; PS ≥2: 44%/56%. By age, corresponding values were 57%/42% for <75 yr; 33%/67% for ≥75 yr. The incidence of AEs was similar across dose levels (Table). Conclusions: Baseline liver function, tumor stage, and etiology did not seem to have an influence on ID selection. We observed a trend toward lower ID in pts with age ≥75 yr and PS ≥2. Despite differences in average daily dose and time on drug, the safety profile for each ID was similar and dose adjustments may have contributed. Additional analyses are being evaluated to assess these and other contributing factors. Clinical trial information: NCT00812175. [Table: see text]