bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostication by multigene proliferative marker panel compared with Ki-67 in small-intestinal NENs.
Authors: Lawrence Ben , Schimmack Simon , Svejda Bernhard , Drozdov Ignat , Alaimo Daniele , Kenney Barton , Kidd Mark , Modlin Irvin M 
Published: February 2017

242 Background: Ki-67 is the major proliferative marker in clinical use to determine neuroendocrine neoplasm (NEN) prognosis. Ki-67 is unable to predict the outcome of SI-NENs, as the majority have a low (≤2) Ki-67%. Therefore, we aimed to identify a sensitive panel of proliferative markers using qRT-PCR to more accurately define the proliferation of these slow growing tumors. Methods: We identified genes with a mechanistic function in cell cycle progression that were over-expressed in RNA microarrays of SI-NENs (n=8) compared to adjacent normal tissue (n=4) (dCHIP, annotation databases). Timing of marker gene expression (qRT-PCR) in proliferating cell-cycle phases (S, G2, M) was determined in flow-sorted SI-NEN cell lines (KRJ-1, H-STS) after propidium iodide staining. RNA expression of candidate proliferative markers was then investigated using an in vivo model and two independent tumor datasets, and transcript level compared to Ki-67% protein expression (immunohistochemical staining). Results: Twenty genes with a mechanistic role in proliferation were identified and 17 confirmed to be expressed in proliferating cell cycle phases. Each tumor expressed a unique profile of the 17 proliferative markers. Both Ki-67 protein and Ki-67 RNA transcript levels failed to differentiate in vivo SI-NEN models or patient samples despite variable proliferative capacity (e.g., WDNETs versus WDNECs). Although most tumors showed low levels of Ki-67 expression, the tumors expressed high levels of select alternative proliferative markers. Hierarchical clustering provided a novel and clinically meaningful prognostic classification. Conclusions: Proliferation of individual SI-NENs is regulated by unique combinations of multiple genes with a mechanistic role in cell-cycle progression. Regulation of proliferation in SI-NENs is therefore complex and cannot accurately be defined by Ki-67 as a single marker. A panel of proliferative RNA markers has potential to significantly improve prognostication in patients with SI-NENs.
Novel small-molecule CRM-1 inhibitor for GI cancer therapy.
Authors: Azmi Asfar S. , Kauffman Michael , McCauley Dilara , Shacham Sharon , Mohammad Ramzi M 
Published: February 2017

245 Background: Pancreatic (PC) and Colon (CC) cancer remain deadly diseases despite the advent of novel targeted and cytotoxic therapies. Therefore, identification of new targets and development of novel agents against these targets are urgently needed. CRM-1 is a nuclear export protein encoded by the XPO1 (exportin 1) gene that mediates leucine-rich nuclear export signal ( NES )-dependent protein export. Elevated CRM-1 expression has been correlated with poor prognosis in PC and CC making it an attractive therapeutic target. Methods: Using structure based drug design, we have identified novel, irreversible small molecule inhibitors of CRM-1 that lock target proteins, including TSP, in the nucleus. Normal cells undergo cell cycle arrest, but most cancer cells initiate apoptosis. Thus, the drugs selectively kill cancer cells with minimal toxicity to normal tissue and possess clinically acceptable pharmacokinetic parameters. In this report, using multiple molecular biological techniques, we have evaluated the role of CRM-1 inhibition on nuclear localization and apoptosis by PAR-4. Results: The most potent small molecule CRM-1 inhibitor (KPT-185) induced growth inhibition and apoptosis in a panel of PC and CC cell lines with IC50’s <150 nM. Western blot and confocal microscopy analyses demonstrated that KPT-185 treatment resulted in TSP and PAR-4 nuclear localization (a pre-requisite for PAR-4 mediated apoptosis). Most significantly, siRNA knockdown of PAR-4 abrogated the apoptotic potential of KPT-185 in BxPC-3 and Colo-357 (PC) and HCT-116 and HT-29 (CC) cell lines, confirming that this was indeed a PAR-4 dependent apoptotic mechanism. KPT-185 showed synergistically enhanced apoptosis when combined with oxaliplatin in all the tested cell lines. Human genomic expression microarray profiling using HT-12 arrays are underway. Additionally, animal xenograft studies involving single agent KPT-185 and combination with oxaliplatin are currently ongoing. Conclusions: This is the first report demonstrating CRM-1 as a potential therapeutic target in both PC and CC, perhaps by enhancing PAR-4 function. The drugs KPT-185 and related CRM1-inhibitors warrant further clinical investigations for this deadly malignancy.
Apricot-P: A randomized placebo-controlled phase II study of COX-2 inhibitor apricoxib or placebo in combination with gemcitabine and erlotinib in advanced or metastatic adenocarcinoma of the pancreas.
Authors: Modiano Manuel , Keogh George P. , Manges Robert , Stella Philip J. , Milne Ginger , Looper Ella , Zaknoen Sara L. 
Published: February 2017

253 Background: Apricoxib is an oral, selective inhibitor of COX-2. COX-2 and EGFR signaling regulate the dominant ERK/MAPK, AKT and ß-catenin pathways in pancreatic cancer; combinations of COX-2 and EGFR inhibitors are of particular interest in this disease. ß-catenin activity is implicated in gemcitabine resistance. In addition, apricoxib has been demonstrated to potently reverse EMT in xenograft models of pancreatic cancer. In a completed Phase II study NSCLC patients were selected based on a decrease in PGEM, a urinary biomarker of COX-2 activity. As pancreatic cancer patients overwhelmingly over express COX-2 PGEM was measured for the purpose of secondary analysis in this study. Methods: Pts with locally advanced or metastatic adenocarcinoma of the pancreas were treated with erlotinib 100 mg PO daily and apricoxib/placebo 400mg PO daily and gemcitabine per previously published schedule (Burris JCO 2007). The primary objective PFS. Results: 109 patients were randomized (70 AP/GE:39 P/GE). Characteristics were balanced between the arms, 63% had elevated baseline PGEM. Most common adverse events included; rash (69%), diarrhea (59%), nausea (59%) and fatigue (57%). Drug-related SAEs included GI bleeding, MI and CVA and were more numerous on the apricoxib arm. The primary study endpoint was not met, HR 0.7; 95% CI (NA, 1.2). Trends in OS favoring the addition of apricoxib were demonstrated in 2 subgroups; elevated baseline PGEM and pts with a ≥ 50% drop from baseline PGEM. Conclusions: This study is the first randomized placebo controlled trial combining chemotherapy with COX-2 inhibition and EGFR kinase inhibition. The apricoxib containing arm had increased GI toxicity including GI hemorrhage. Although the primary endpoint was not met, overall survival in patients with a PGEM response to COX-2 inhibition favored addition of apricoxib. Further study in a biomarker selected population is warranted. [Table: see text]
Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET).
Authors: Hobday Timothy J. , Qin Rui , Reidy Diane Lauren , Moore Malcolm J , Strosberg Jonathan R. , Kaubisch Andreas , Shah Manisha H. , Kindler Hedy Lee , Lenz Heinz-Josef , Chen Helen X. , Erlichman Charles 
Published: February 2017

260 Background: Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib in PNET noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 patients, with interim analysis after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. Results: Confirmed PR was documented in 11 of the first 25 (44%) evaluable patients. 20 of 25 (80%) patients were progression-free at 6 months. Both endpoints exceeded pre-defined criteria to continue enrollment. For 35 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were leukopenia (12%), hypertension (12%), hyperglycemia (12%), mucositis (9%), and fatigue (9%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 44%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing. Supported by NCI N01 Contracts: 662205, 62203, 62208, 62209, 62206, 62204, 62207, 62201.
Investigation of the HDAC inhibitor resminostat in patients with sorafenib-resistant hepatocellular carcinoma (HCC): Clinical data from the phase I/II SHELTER study.
Authors: Bitzer Michael , Horger Marius , Ganten Tom M , Siveke Jens T , Woerns Marcus A , Dollinger Matthias M. , Gerken Guido , Scheulen Max E. , Wege Henning , Giannini Edoardo G , Montesarchio Vincenzo , Mais Anna , Jankowsky Rüdiger , Hauns Bernhard , Hentsch Bernd , Lauer Ulrich ,   SHELTER Study Group
Published: February 2017

262 Background: Resminostat (4SC-201), an oral pan-HDAC inhibitor, is in clinical development in a variety of cancer indications. The SHELTER study aims to evaluate safety, tolerability and efficacy in HCC patients (pts) exhibiting progressive disease under sorafenib first-line therapy. Methods: Pts with advanced HCC, (BCLC B or C) are included in a multi-center, open-label, two-arm parallel group trial. Radiologic progression under sorafenib is determined acc. to RECIST by central review prior to study entry. For Arm A, dose escalation of resminostat and sorafenib is performed to determine the MTD. Resminostat is administered orally once-daily in a “5+9” schedule, consisting of 5 consecutive treatment days followed by a 9-day rest period resulting in 14 day cycles on dose levels of 200 (DL1), 400 (DL2) and 600 mg (DL3+4), either combined with continuously taken sorafenib at 400 (DL1-3) or 800 mg (DL4) (Arm A), or as resminostat monotherapy (600 mg, Arm B). Primary objective is to determine progression-free survival after 12 weeks (w) (6 cycles). Secondary objectives include safety, tolerability, tumor response, TTP, OS, PK, biomarkers. Results: To date, 39 pts were treated with 600 mg resminostat alone or on DL1-4 in combination with sorafenib. Up to now, no DLT occurred in 5 pts treated on DL4. Most frequently AE observed include CTC grade 1-2 gastrointestinal complaints such as nausea and vomiting and skin disorders like rash, pruritus and HFSR. CTC Grade 3-4 toxicity documented in SAE reports consisted mainly of no-hematological events and was mostly related to the tumor disease. Interim results revealed that 15 out of 27 pts (56%) assessed after 6 w of treatment, and 11 out of 24 pts after 12 w displayed SD. In one patient treated on DL2, SD persisted for more than 1 year along with good long-term tolerability. Conclusions: Preliminary clinical data show a favorable drug profile of resminostat either in mono or in combination treatment with sorafenib. No DLT was observed on the highest DL of the combination therapy up to now. Initial data on toxicity and therapeutic activity to overcome resistance to sorafenib are promising and will be updated for the meeting.
Radiofrequency ablation versus hepatic resection as an initial treatment for solitary small-sized hepatocellular carcinoma.
Authors: Imai Katsunori , Beppu Toru , Chikamoto Akira , Doi, Koichi , Okabe Hirohisa , Nitta Hidetoshi , Hayashi Hiromitsu , Ishiko Takatoshi , Takamori Hiroshi , Baba Hideo 
Published: February 2017

290 Background: Nowadays Radiofrequency ablation (RFA) is a popular method and demonstrates favorable results for the treatment of small-sized hepatocellular carcinoma (HCC). However, whether RFA is as effective as hepatic resection (HR) for long-term outcomes remains controversial. The aim of this study is to compare HR and RFA with regard to survival and recurrence for the establishment of treatment strategy of small-sized HCC. Methods: A total of 183 patients with solitary small-sized (≤3cm) HCC were enrolled in this study: 101 patients underwent HR and 82 underwent RFA as an initial treatment. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups and in subgroup analyses. Results: Patients who underwent RFA had less platelet count (HR: 15.3±7.0, RFA: 9.8±3.6, P<0.01), and more advancer Child-Pugh class (A/B = HR: 97/4, RFA: 61/22, P<0.01). The 5-year OS and DFS were significantly higher in the HR group compared with the RFA group (OS: 90% vs 59%, P<0.01, DFS: 45% vs 27%, P<0.01, respectively). In multivariate analyses, treatment modality (HR or RFA) and gender were indipendent predicting factors for DFS (RR: 1.85, P=0.05, and RR: 2.15, P=0.01, respectively). In subgroup analyses of HCC <2cm, there was no significant difference in OS and DFS between the two group (5-year OS: 90% vs 74%, P=0.40, 5-year DFS: 43% vs 28%, P=0.24, respectively), despite the differences in liver functional reserve. However, HR was superior to RFA for OS and DFS in subgroup ≥2cm (5-year OS: 85% vs 32%, P<0.01, 5-year DFS: 40% vs 23%, P<0.01). In the subgroup analyses treated by RFA, GPT >35mIU/ml and tumor ≥2cm were significant predicting factors for DFS (RR: 2.34, P=0.01, and RR: 2.09, P=0.02, respectively). For OS, tumor ≥2cm was the only prognostic factor (RR: 2.9, P=0.04). Conclusions: RFA might be as effective as HR for the treatment of solitary HCC <2cm. However, in the patients with HCC ≥2cm, HR provides a better OS and DFS than RFA.
Early experience with robotic radiosurgery for local control of liver metastasis.
Authors: Kwiatt Michael , Spitz Francis R. , LaCouture Tamara A. 
Published: February 2017

295 Background: Liver toxicity limits radiation therapy for liver metastasis; however, robotic radiosurgery delivers effective doses with limited toxicities. Robotic radiosurgery may be an effective treatment for liver metastases in patients with lesions not amenable to surgical resection. Methods: We conducted a retrospective study of patients treated with robotic radiosurgery for liver metastasis at our institution from June 2008 and June 2010. Medical records were reviewed and all cases discussed in multi-disciplinary conference. Preradiosurgery and follow-up abdominal computed tomography (CT) scans reviewed for treatment response. Our primary endpoint was local recurrence, defined as increased enhancement or tumor progression within the treatment field on follow-up CT scan. Results: Thirty-three patients had 37 liver metastasis treated with robotic radiosurgery (17 colorectal, 4 ovarian, 4 breast, 3 melanoma, 2 liver, 2 lung, 1 gastric, 1 cholangiocarcinoma, 1 pancreas, 1 anal, 1 bladder). Eighteen of 33 patients (54.5%) had isolated liver metastasis. Prior to radiosurgery 27 of 33 patients (81.8%) had undergone surgical resection of primary tumor, 26 of 33 patients (78.8%) were treated with chemotherapy for metastatic disease, and 15 of 33 patients (45.5%) had non-liver radiation therapy. Median time from primary diagnosis to radiosurgery treatment was 33.3 months (5.7 to 320 months). Patients received median radiation dose of 30 Gy (22.5 to 42) over 3 to 5 fractions. Median follow up was 8.1 months (1.2 to 23.5). There were no cases of liver failure. Sixteen patients had disease progression outside the treatment field (15 liver, 6 systemic) with a median time to progression of 4.6 months (0.9 to 17.6). Five lesions (13.5%) had in field progression with a median time to progression of 10 months (2.6 to 13.1). Seventeen patients (51.5%) died during follow-up. Conclusions: Robotic radiosurgery offers a potential local therapy for patients with metastatic liver disease with limited toxicity. Longer follow-up and more patients are required to better assess its safety. Robotic radiosurgery may fill a role for patients with lesions not amenable to traditional ablative and surgical techniques.
Second interim analysis of the Global Investigation of Therapeutic Decisions in Unresectable HCC and of Its Treatment with Sorafenib (GIDEON): Sorafenib dosing and safety in U.S. patients.
Authors: El-Khoueiry Anthony B. , Piperdi Bilal , Goldenberg Alec , Cohn Allen Lee , Geschwind Jeff H. , Marrero Jorge A. , Sanyal Arun , Venook Alan Paul 
Published: February 2017

302 Background: Sorafenib (SOR) is the first systemic therapy to improve survival in patients (pts) with advanced hepatocellular carcinoma (HCC). GIDEON is a global, prospective, noninterventional study to evaluate SOR safety in pts with unresectable HCC in real-life practice. We present results from the second interim analysis, describing SOR dosing in US pts. Methods: From Jan 2009 – Nov 2010, 326 pts were enrolled in 92 US centers and followed ≥4 months, with 313 pts evaluable for safety. Demographics, initial dose, treatment duration (TD), dose modifications (mods), treatment interruptions (TIs), and adverse events (AEs) were analyzed in pts with complete data available. Results: Initial SOR dose was 400 mg/d in 106 pts (34%) and 800 mg/d in 177 pts (57%). Thirty (10%) pts received alternate doses or had incomplete data. Most pts were male (400 mg/d: 75%; 800 mg/d: 80%). Age distribution was similar between groups (400 mg/d: 59% <65 yr and 41% >65 yr; 800 mg/d: 64% <65 yr and 36% >65 yr). In 400 mg/d vs 800 mg/d groups respectively, ECOG PS was 0/1/2 in 19%/49%/16% vs 34%/35%/12%, and Child-Pugh (CP) status was A/B/C in 32%/35%/7% (26% unevaluable) vs 42%/29%/6% (21% unevaluable). Median TD was 9.8 wks (<4 wks in 22%, >4-12 wks in 40%, and >12 wks in 39%) in the 400 mg/d group and 13.2 wks (<4 wks in 17%, >4-12 wks in 29%, and >12 wks in 53%) in the 800 mg/d group. Dose mods and TIs occurred in 49% (37% due to AE) and 35%, and 57% (36% due to AE) and 38% of 400 mg/d vs 800 mg/d pts, respectively. See table for safety data. Conclusions: While statistical comparisons were not made, PS or CP status may impact initial SOR dose selection. Other baseline characteristics did not affect this decision. Frequencies of dose mods, TIs, and AEs were similar between dosing groups. Limitations of an observational study must be considered. Clinical judgment remains important in choosing initial SOR dose. [Table: see text]
Primary small cell carcinoma of the esophagus: Retropective analysis of the Veterans Affairs Cancer Registry.
Authors: Abu Hazeem Mahmoud , Thota Ramya , Subbiah Shanmuga 
Published: February 2017

32 Background: Small cell carcinoma (SCC) of the esophagus is a rare aggressive and rapidly fatal neoplasm, often diagnosed in late stages. Hence no prospective studies evaluating the most effective treatment strategies have been done. We aim to describe the clinicopathological features and treatment outcomes of this rare entity. Methods: Retrospective analysis of 49 patients diagnosed with SCC of the esophagus from 1995 to 2009 was done via the Veteran's Affairs Central Cancer Registry. Demographics, staging, treatment, and outcomes data was recorded. Staging was classified as limited (no distant metastasis) or extensive stage (metastatic disease). Results: Out of 10,540 patients with esophageal cancer, 49 were diagnosed with SCC (0.005%) and were mainly located in the middle and lower thirds of the esophagus (84%). Median age of diagnosis was 64.1 yrs (range: 26-90). 19 patients had limited disease, 26 patients had extensive disease and four patients who were not staged adequately were excluded. Patients received a variety of treatments (Table) with different survival outcomes. Limited stage SCC patients had a median survival of 6.3 mos with patients who received combined modality therapy showing a trend towards improved outcomes. Extensive stage patients who received no therapy had very poor outcomes compared to patients who received any therapy. Conclusions: SCC of esophagus should be considered a systemic disease and like pulmonary SCC, it is an aggressive tumor associated with a poor prognosis. Patient numbers are too low to draw definitive conclusions regarding choice of therapy. Extensive disease patients benefit from chemotherapy and combined modality therapy should be considered in limited stage disease. [Table: see text]
Phase I/II study of E7080 (lenvatinib), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): Initial assessment of response rate.
Authors: Okita Kiwamu , Kumada Hiromitsu , Ikeda Kenji , Kudo Masatoshi , Kawazoe Seiji , Osaki Yukio , Ikeda Masafumi , Tamai Toshiyuki , Suzuki Takuya 
Published: February 2017

320 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. Maximum tolerated dose (MTD) of lenvatinib for solid tumor pts was determined to be 25 mg once daily dosing (qd), and MTD for HCC pts with Child-Pugh A was determined to be 12 mg qd. A preliminary assessment of response rate is presented in this report. Methods: Between July 9, 2010 and June 22, 2011, 46 pts with advanced HCC with Child-Pugh A were enrolled in Japan (n=43) and Korea (n=3). Pts may have received up to one prior treatment regimen including sorafenib. Pts were treated with a starting dose of lenvatinib 12 mg once daily in 28 day cycles until disease progression or development of unmanageable toxicities. Response rate was assessed by RECIST 1.1 (modified to evaluate viable lesions). Results: The first 42 consecutively enrolled pts (med age: 67; M: 76%, F: 24%) were evaluable for response and form the basis of this report. 45% had extra hepatic spread, 24% received prior chemotherapy and 91% had prior locoregional therapy. 19% were withdrawn from therapy due to adverse event. The most common toxicities were hypertension 71% (Gr 3: 48%), anorexia 50% (Gr 3: 2.4%), proteinuria 45% (Gr 3: 14%), palmar-plantar erythrodysaesthesia syndrome 43% (Gr 3: 4.8%), fatigue 43% (Gr 3: 0%), and thrombocytopenia 33% (Gr 3: 19%). No pts experienced Gr 4 toxicity. Confirmed Partial Responses (PRs) were observed in 14 pts (RR: 33%, 95% CI: 20-50) based on investigator assessment. Updated efficacy including median Time to Progression and survival data will be reported. Conclusions: Lenvatinib 12 mg qd when administered to advanced HCC pts with Child-Pugh A is associated with manageable toxicity. The preliminary assessment of efficacy on the basis of overall response rate suggests that lenvatinib may represent a new potential therapeutic agent for advanced HCC pts. Further assessment of safety and efficacy is ongoing.