bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of the combination chemotherapy with 5-fluorouracil and oxaliplatin in metastatic gastric or colorectal cancer patients more than age of 80.
Authors: Lim Kyu-Hyoung , Lee Hui-Young , Park Sung Bae , Song Seo-Young 
Published: February 2017

136 Background: The combination chemotherapy of 5-fluorouracil (5-FU) and Oxaliplatin is usually used in gastric cancer (GC) and colorectal cancer (CRC). The safety and efficacy of the combination chemotherapy in patients over 80-years old has not been established yet. The purpose of this study was to assess the clinical outcomes and tolerability in the combination with 5-FU, leucovorin and oxaliplatin as first-line treatment in extremely elderly patients with GC or CRC. Methods: Eligibility included: 1) more than 80-years old, 2) metastatic gastric or colorectal cancer 3) chemotherapy-naive, 4) ECOG PS 0-1, 5) adequate organ function. Patients received the combination chemotherapy of 5-FU, leucovorin and oxaliplatin. Response evaluation was done every 8 weeks with RECIST criteria and toxicity was evaluated with NCI-CTCAE. Results: Between Sep 2008 and Nov 2014, 28 patients were reviewed and composed of equal numbers of GC and CRC. The median age was 82.2 years (80.0-85.6yrs) in GC and 81.1 years (80.0-89.3) in CRC, respectively. Total administrated cycles were 89 with median cycles of 5 in GC and 112 with median cycles of 11 in CRC. The median progression-free survival (PFS) and overall survival (OS) in GC were 5.4 months and 6.6 months, as compared with 7.3 months and 8.1 months, respectively. There were no significant difference in PFS (p = 0.94) and OS (p = 0.28) between GC and CRC. Overall survival rates at 1 year were 35.7% and 42.9%, respectively. After disease progression, salvage chemotherapy in GC and CRC was administrated in 1 and 7 patients, respectively. Common grade 3/4 hematology toxicities in both group were neutropenia, anemia. Frequent non-hematological toxicities were anorexia (60%), neuropathy (40%) and mucositis (25%), which were grade 1/2. Conclusions: The combination chemotherapy of 5-fluorouracil (5-FU) and Oxaliplatin has limited effect on improvement of OS in metastatic gastric or colorectal cancer patients more than age of 80. Further studies on the role of chemotherapy in these extremely elderly patients are needed.
FPA144-001: A first in human study of FPA 144, an ADCC-enhanced, FGFR2b isoform-selective monoclonal antibody in patients with advanced solid tumors.
Authors: Bendell Johanna C. , Rogers Seema , Xiang Hong , Pierce Kristen L. , Krishnan Kartik , Sikorski Robert S. , Hambleton Julie , Rasco Drew W. 
Published: February 2017

140 Background: FPA144 is a humanized monoclonal IgG1 antibody directed against the 2b Isoform of thefibroblast growth factor receptor (FGFR2b) that has been glycoengineered to enhance ADCC. Amplification of FGFR2 is found in a number of tumors, including 3 – 9% of gastric cancer, and is associated with poor prognosis. FPA144-001 is a phase 1 study in two parts: Part 1 will evaluate the safety and pharmacokinetics (PK) of FPA144 in patients with solid tumors; Part 2 will evaluate efficacy in gastric cancer patients whose tumors overexpress FGFR2b, as determined by a proprietary test. Here we present early safety and PK results from solid tumor patients treated with FPA144. Methods: A standard 3+3 design was used to assess safety, tolerability and PK of escalating doses of FPA144 in patients with advanced solid tumors (Part 1A) or recurrent/metastatic gastric cancer (Part 1B). Tumor testing for FGFR2gene amplification or FGFR2b overexpression was conducted centrally by a proprietary assay consisting of both FISH and IHC. Results: At the time of data analysis, enrollment of FPA144-001 through the 6mg/kg q2w cohort had been completed. In Part 1A, 13 patients with 8 different tumor types have been enrolled. Patients have been treated for an average of 4 cycles (range 1 – 10, median 2) or 101 days (range 28 – 287, median 43). Nine patients have discontinued the study for progressive disease or lack of clinical benefit; all others continue on study treatment. No dose-limiting toxicities have been observed, and no patients have withdrawn due to an adverse drug reaction. Upper respiratory infection, alopecia and fatigue are the AEs reported in more than one patient; one SAE of dyspnea and pyrexia not related to drug has been reported. PK analysis demonstrates non-linear clearance in doses up to 3mg/kg, likely due to receptor-mediated clearance. Conclusions: FPA144 is a glycoengineered monoclonal antibody directed against FGFR2b that is being developed for the treatment of patients with tumors that overexpress FGFR2b. FPA144 has been safely administered at doses up to 6mg/kg q2w; dose escalation continues. Updated safety, PK and anti-tumor activity will be presented. Clinical trial information: NCT02318329.
Bone loss and vitamin D deficiency post gastrectomy for gastro-esophageal malignancy.
Authors: Virik Kiran , Wilson Robert 
Published: February 2017

165 Background: Metabolic bone disease is a known but incompletely understood consequence of gastrectomy. Post gastrectomy osteoporosis (OP) is multifactorial. Evidence suggests that patients who undergo this surgery require long term bone health assessment and nutritional support. Methods: 30 post gastrectomy patients (2000-2008) from a single centre in Australia were evaluated re bone health post surgery and post nutritional supplementation. Exploratory analysis included: age, gender, pathology, type of surgery, 25 OH-vitamin D, calcium, parathyroid hormone (PTH), bone mineral density (BMD), vertebral XRs, urinary calcium and N telopeptides of type I collagen. Other risk factors evaluated were: smoking, corticosteroid use, alcohol intake, hyperthyroidism, menopausal status, hyperparathyroidism (hPTH), pre-existing bone disease. Results: The median age of the cohort was 67.5 (range 53-83) of whom 22 (73%) were male. Histology showed 16 (53%) gastric adenocarcinoma, 6 (20%) esophageal adenocarcinoma, 2 (7%) GISTs, 5 (17%) gastric/duodenal lymphoma and 1 other category. Similar numbers of patients underwent total (12) and partial/distal gastrectomy (12), with 6 having a subtotal gastrectomy. 22 (73%) had a Roux-en-Y or BR II reconstruction and 8 had a BRI/other. Median time from surgery to first BMD was 54.5 months (range 12-360) with median correlative calcium level 2.24 (range 1.97-2.49), median vitamin D level 43 (range 11-82) and median PTH 6.4 (range 1.8-13.8). Osteoporosis was diagnosed in 14 (47%) of patients, osteopenia in 14 and 2 (7%) patients had a normal BMD. Low vitamin D was seen in 23 (77%) patients, low calcium levels in 5 (17%) and secondary hPTH in 12 (41%). Post nutritional supplementation preliminary results showed 2/23 (9%) had a low vitamin D level, 3/11 (27%) had secondary hPTH, 5/19 (26%) had osteoporosis, 12/19 (63%) had osteopenia and 2/19 had a normal BMD. Analysis of other risk factors is to follow. Conclusions: Poor bone health and vitamin D deficiency is a clinically significant problem post gastrectomy. Patients should undergo long term nutritional and bone health surveillance in addition to their oncological follow up post resection.
Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with advanced gastric or gastroesophageal junction cancer.
Authors: Chung Hyun Cheol , Arkenau Hendrik-Tobias , Wyrwicz Lucjan , Oh Do-Youn , Lee Keun-Wook , Infante Jeffrey R. , Chin Kevin M. , von Heydebreck Anja , Kang Yoon-Koo , Safran Howard 
Published: February 2017

167 Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. We report safety and clinical activity of avelumab in patients (pts) with advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJ) based on level of PD-L1 expression. This phase Ib JAVELIN study (NCT01772004) enrolled pts who had progressed on prior therapy ( ≥ 2L) and pts who had received 1L chemotherapy but had not yet progressed (switch-maintenance [Mn]) Methods: Pts received avelumab 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumours were assessed every 6 wks (RECIST 1.1). Best overall response and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression was assessed by immunohistochemistry using various cutoff criteria Results: As of Feb 13, 2015, 75 pts with GC/GEJ were treated with avelumab (20 pts, 2L; 55 pts, Mn). Treatment-related treatment-emergent AEs (TR-TEAEs) of any grade occurred in 47 pts (62.7%); the most common ( > 10%) was infusion-related reaction (12 [16.0%], all grade 1/2). Nine pts (12.0%) reported a grade ≥ 3 TR-TEAE, including fatigue (2), thrombocytopenia (2), and anemia (2; each 2.7%). There was 1 treatment-related death (hepatic failure/autoimmune hepatitis). Responses were observed in 7 pts (3/20 2L, all PRs; 4/55 Mn, 1 CR, 3 PRs). PD-L1 expression was evaluable in 55 pts (12/20 2L, 43/55 Mn), including in 3 pts with a response. Median PFS in 2L group was 36.0 wks (95% CI: 6.0, 36.0) for PD-L1+ and 11.6 wks (2.1, 21.9) for PD-L1− ( ≥ 1% cutoff). In Mn group, median PFS for PD-L1+ and PD-L1− status was 17.6 wks (5.9, 18.0) and 11.6 wks (5.7, 17.7), respectively ( ≥ 1% cutoff). Conclusions: Single agent avelumab showed an acceptable safety profile and clinical activity in GC/GEJ pts. Objective responses and disease stabilization were observed in both groups. Median PFS was longer in PD-L1+ pts. Phase III trials in 1L and 3L GC/GEJ are underway.*Proposed INN Clinical trial information: NCT01772004.
Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance).
Authors: Abou-Alfa Ghassan K. , Niedzwieski Donna , Knox Jennifer J. , Kaubisch Andreas , Posey James , Tan Benjamin R. , Kavan Petr , Goel Rakesh , Murray John J. , Bekaii-Saab Tanios S. , Tam Vincent Channing , Rajdev Lakshmi , Kelley Robin Kate , Siegel Abby , Balletti Jennifer , Harding James J. , Schwartz Lawrence HOWARD , Goldberg Richard M. , Bertagnolli Monica M. , Venook Alan P. 
Published: February 2017

192 Background: An exploratory analysis of a randomized phase II study in HCC comparing doxorubicin (D) alone to doxorubicin plus sorafenib (D+S) showed a significant improvement in overall survival favoring D+S (JAMA, 2011). The results appeared promising compared to the historic outcomes seen in the pivotal sorafenib (S) trials. CALGB 80802 was designed to determine if D+S improved survival compared to S alone. Methods: Patients with histologically proven advanced HCC, no prior systemic therapy and Child-Pugh A were randomized to receive D 60 mg/m2 every 21 days plus S 400 mg PO twice daily (D+S) or S alone. For bilirubin ≥ 1.3x normal, D and S doses were halved. D was maxed out at 360 mg/m2. The study was stratified by extent of disease (locally advanced; metastatic), the primary endpoint was overall survival (OS); and secondary endpoint progression-free survival (PFS). The final analysis was to occur when 364 events were observed among 480 total patients, with 90% power to detect a 37% increase in median OS (10.7 to 14.7 months; 1-sided α = 0.05). Results: The Alliance DSMB halted the study after accrual of 346 patients (173 on each of D+S and S) when a futility boundary was crossed at a planned interim analysis. With 107 events in each arm, median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5 months (95% CI 7.4-14.3) for S with a hazard ratio (HR) 1.06 (95% CI 0.8-1.4) for D+S vs. S. Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1), respectively (HR = 0.90, 95% CI 0.72-1.2). There were 38 deaths on treatment: 18 on D+S and 20 on S. Among these 8 [sepsis (1), dysphagia (1), pneumonia (1), cardiac (2), hepatic failure (2), and not otherwise specified (1)] on D+S, and 3 [fatigue (1), hepatic failure (1), and a secondary malignancy (1)] on S, were at least possibly related to treatment. A maximum grade 3 or 4 only hematologic adverse events (AE) occurred in 37.8% of patients on D+S and 8.1% of patients on S. Non-hematologic AEs were comparable, in 63.6% and 61.5% of patients, respectively. Conclusions: The addition of D to S resulted in higher toxicity and did not improve OS or PFS. The S median OS of about 10 months is consistent with previous reports. NCI Grant U10CA180821 Clinical trial information: NCT01015833.
Auranofin to prevent progression of pancreatic ductal adenocarcinoma.
Authors: Rios Perez Mayrim V. , Roife David , Dai Bing Bing , Kang Ya'an , Li Xinqun , Pratt Michael , Fleming Jason B. 
Published: February 2017

236 Background: Auranofin, an FDA anti-rheumatic agent shown to have anticancer properties for lung and ovarian cancer has never been studied for pancreatic cancer. We hypothesize that Auranofin may prevent pancreatic ductal adenocarcinoma (PDAC) progression by induction of apoptosis. Methods: We performed in vitro and in vivo studies using human PDAC cell lines and patient-derived xenografts (PDX) to assess Auranofin anticancer activity. Sensitivity to the compound was determined based on IC50s. Western blot assay was used to interrogate mechanisms of apoptosis, autophagy, and resistance. Two PDAC orthotopic mouse models were designed to determine optimal dose (survival), and antitumor effect (non-survival). Results: We found more than half of PDAC cell lines (10/18) to be sensitive to Auranofin based on IC50s below 5µM. Ex vivo tissue growth inhibition greater than 44% was observed for 13 PDX tissue cases treated with 10 µM Auranofin. Treatment with low-dose Auranofin (0.5-1µM) was found to induce PARP cleavage and LC3B expression among sensitive cell lines when compared to control (0.1% DMSO). High Txnrd1 and low Nrf2 expression was observed for resistant cell lines. Survival study using MiaPaCa-2 Luc+ showed 15mg/kg IP as the optimal dose due to absence of gross solid organ metastasis up to 13 weeks post-treatment (median survival 8 and 12, respectively; p = 0.0953). Non-survival study using MDA-Patc53 Luc+ showed a decreased tumor bioluminescence (p = 0.1097) and a 9-fold decrease in mean tumor progression from baseline (p = 0.1640) 3 weeks post-treatment. Conclusions: We have demonstrated that Auranofin prevents PDAC progression using two animal models. In vitro studies suggest apoptosis and autophagy as possible mechanisms of action, and Txnrd1 as a biomarker of resistance. This study altogether demonstrates both primary and metastatic antitumor effect of Auranofin for PDAC, which could represent an advantageous therapeutic approach for a broad selection of patients in both neoadjuvant and adjuvant settings.
BIOSHARE multicenter neoadjuvant phase 2 study: Results of pre-operative sorafenib in patients with resectable hepatocellular carcinoma (HCC)—From GERCOR IRC.
Authors: Bouattour Mohamed , Fartoux Laetitia , Rosmorduc Olivier , Scatton Olivier , Vibert Eric , Costentin Charlotte , Soubrane Olivier , Ronot Maxime , Granier Muriel Magali , De Gramont Armand , Belghiti Jacques , Paradis Valerie , Wendum Dominique , Tijeras-Raballand Annemilai , Hadengue Alexandra , Brusquant David , Chibaudel Benoist , Raymond Eric , Faivre Sandrine J. 
Published: February 2017

252 Background: This open-label, multicenter, phase II study aimed at investigating the activity of sorafenib including radiological, pathological and biological changes in tumor from patients with resectable HCC. Methods: Preoperative administration of sorafenib 400 mg bid for 4 weeks was followed by surgery. Primary endpoints were antitumor activity and histological changes on paired tumor samples and plasma biomarkers between baseline and post sorafenib. Secondary endpoints were safety, R0 surgery and post-surgical complications. Results: Among 30 patients enrolled, 28 were evaluable for safety. Neoadjuvant sorafenib was not feasible in 3 patients (early limiting toxicities). Twenty-five patients (21 men; median age: 61.5 years) were evaluable for the primary endpoints. Baseline median tumor size was 37 mm and 21 patients (84%) had a single lesion. Median duration and dosing of sorafenib were 28 days and 793 mg/day respectively. Overall, the safety profile of preoperative sorafenib was good. According to RECIST criteria, all patients showed stable disease. Among 19 patients evaluated according to mRECIST and Choi criteria, objective responses were observed for 6 (32%) and 10 (53%) patients respectively. All evaluable patients went on liver resection and no unexpected complication occurred. R0 tumor resection was achieved in 22 patients (88%). Surgical specimen showed macrovascular and microvascular invasion in 12% and 48%, respectively. Intratumor necrosis was observed in 17 (68%) surgical specimen with necrosis ≥ 50% in 24 % of cases. Blood biomarkers analysis showed a trend toward increased angiogenesis biomarkers (VEGF-A, VEGF-C and PlGF) after sorafenib treatment. Biomarkers from pre- and post-treatment tissue will be presented during the meeting. Conclusions: Neoadjuvant sorafenib displays a favorable toxicity profile and yields significant activity in patients with resectable HCC. BIOSHARE trial also allows exploration of drug effects on tumor biology. Clinical trial information: NCT01182272.
Evaluation of triptolide pro-drug (Minnelide) as an anti-stromal and anti-tumoral therapeutic option for pancreatic cancer.
Authors: Banerjee Sulagna , Modi Shrey , Zhao Xianda , Dudeja Vikas , Saluja Ashok 
Published: February 2017

262 Background: In pancreatic cancer, the stromal microenvironment is considered to be the major reason behind the failure of conventional and targeted therapy. The desmoplastic stroma is responsible for compression of vasculature in the tumor resulting in impaired drug delivery. Pancreatic stellate cells contribute extensively to this desmoplastic reaction. Our group has recently evaluated a water-soluble pro-drug of triptolide (Minnelide) in pre-clinical studies for pancreatic cancer with very promising results. The current study evaluates the ability of Minnelide to deplete the stromal architecture and the stellate cell population in pancreatic cancer resulting in increased drug delivery. Methods: Patient tumor xenografts in SCID mice (PDX) and KRASG12DTP53-PDX-Cre spontaneous pancreatic tumor mice (KPC) were treated with 0.42mg/kg Minnelide. Vascular patency was studied by terminal perfusion of mice with 4% PFA following injection with tomato lectin. Drug delivery was determined by quantitating accumulated doxorubicin in the tumor tissue. Cell viability was studied by MTT assay and the invasion of cells in vitro was studied using Boyden Chamber assay. Results: Minnelide treatment decreased Hyaluronic acid (HA) in PDX (48% of control) as well as in KPC model (52% of control). Expression of HA synthase (HAS) genes were decreased in both tumor models in response to Minnelide (22% of control in PDX and 35% of control in KPC tumors). HAS Enzyme activity also consistently decreased in both the models after treatment with Minnelide (28% of control in PDX and 31% of control in KPC). In vitro, triptolide decreased the invasion of the tumor cells towards the stellate cells indicating an inhibition of crosstalk. Treatment with Minnelide resulted in “open” and functional vessels in the treated animals resulting in increased drug delivery. Median survival of animals increased by 38 days after treatment with Minnelide. Conclusions: Our study showed that Minnelide depleted the stromal architecture leading to increased functional vasculature and enhanced drug delivery in the tumor. This is an extremely promising observation for Minnelide that is currently under clinical trial.
The role of myeloid derived suppressor cells in cholangiocarcinoma: A potential target for therapy.
Authors: Dunne Richard Francis , Figueroa Nathania , Belt Brian , Findeis-Hosey Jennifer , Lunt Michael , Ye Jian , McMahon Loralee , Baran Andrea , Shubin Andrew , Noel Marcus Smith , Tejani Mohamedtaki Abdulaziz , Hezel Aram F. , Linehan David 
Published: February 2017

273 Background: Cholangiocarcinoma (CC) is a highly lethal malignancy with a poor 5 year overall survival in the advanced setting. Benefits of treating CC with chemotherapy are limited and no FDA approved targeted therapies currently exist. CC is associated with a desmoplastic reaction comprised of extracellular matrix, fibroblasts and inflammatory leukocytes. Myeloid-derived suppressor cells (MDSC) are the predominant tumor infiltrating leukocytes in several cancers, but little is known about their role in CC. MDSCs are derived from a monocytic (M-MDSC) or granulocytic (G-MDSC) origin and infiltrate the tumor microenvironment (TME) where they suppress anti-tumor immunity and play a crucial role in tumor growth, chemoresistance and metastasis. Here, we characterize the prevalence and prognostic significance of MDSC in CC. Methods: A de-identified human CC clinical database (n = 220) with linked tumor tissue was collected under an IRB approved protocol. Total white blood cell count and percent monocytes (a surrogate marker for M-MDSC prevalence in peripheral circulation) before starting therapy were collected and correlated with overall survival in patients with unresectable CC. Immunohistochemistry for myeloid cell markers (CD33, CD11b, CD14, CCR2, and CD15) was performed on formalin-fixed paraffin embedded human CC and normal liver sections. Staining was scored by a pathologist or quantified with digital imaging software. Results: Analysis of chemotherapy naive blood specimens revealed that an increase in monocyte percentage inversely correlated with survival in patients with unresectable CC (p = 0.0117). Statistical significance was more pronounced in patients with intrahepatic CC (p = 0.0091) compared to other disease sites. There was an increased level of M-MDSC and G-MDSC in CC compared to normal liver tissue and all 22 tested CC samples stained positively for MDSC markers within the tumor stroma. Conclusions: The prevalence of circulating monocytes correlates negatively with prognosis and MDSCs infiltrate the TME in unresectable CC. Therefore, targeting MDSC is an attractive therapeutic strategy and future studies aim to fully characterize the TME and block MDSC recruitment in a mouse model of CC.