bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlating radiologic response criteria with pathologic tumor viability in HCC patients undergoing localized radiation followed by surgical resection.
Authors: Lee Ik Jae
Published: February 2017

217

Background: Various radiologic response criteria have been developed for solid tumors. This study attempts to identify the optimal criteria for hepatocellular carcinoma (HCC) after localized treatment including radiotherapy. Methods: We reviewed 40 consecutive HCC patients who underwent surgical resection after radiotherapy of curative intent between 2000 and 2011. Radiation was delivered concurrently with intraarterial 5-fluorouracil/cisplatin (36), concurrently with capecitabine (2), and after receiving transarterial chemoembolization (2). For radiotherapy, 45 Gy in 25 fractions (32) or 50 Gy in 20 fractions (8) was delivered. Images from pre-RT and pre-resection CT were compared to determine treatment response according to Response Evaluation Criteria in Solid Tumors (RECIST), the World Health Organization (WHO) criteria, modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) criteria. Findings from pathologic reports including extent of tumor necrosis were correlated with degree of response from each set of criteria. Results: Intermodal agreement among criteria was highest between RECIST and WHO (p<0.0001) and between mRECIST and EASL (p<0.0001). All criteria showed strong correlation with reduction in α-fetoprotein (p=0.001 for EASL and mRECIST, 0.026 for RECIST, and 0.043 for WHO). Percent of viable tumor by EASL was most strongly correlated with percent of pathologic viable tumor (p<0.0001), followed by RECIST, mRECIST, and WHO (p = 0.011, 0.013, and 0.013). Resection was carried out after 2 complete (5%), 36 partial (90%), and 2 stable (5%) responses according to EASL criteria. Three year disease-free (DFS) and overall survival (OS) were 29 and 61 months. Complete necrosis showed trends toward improved DFS (p=0.136) and OS (p=0.088). Multiplicity was independent prognostic factor for both DFS and OS (p=0.005 and 0.001). Conclusions: EASL criteria showed strongest correlation with pathologic tumor viability after localized treatment for HCC. Prospective clinical trial is warranted.
Efficacy and safety of everolimus in patients with advanced low- or intermediate-grade pancreatic neuroendocrine tumors previously treated with chemotherapy: RADIANT-3 subgroup analysis.
Authors: Lombard-Bohas Catherine , Yao James C. , Hobday Timothy J. , Van Cutsem Eric , Wolin Edward M. , Panneerselvam Ashok , Castellana Ramon , Stergiopoulos Sotirios G. , Shah Gaurav D. , Shah Manisha H. , Pommier Rodney F.
Published: February 2017

224

Background: In the phase 3 RADIANT-3 trial, everolimus (EVE) demonstrated significantly improved median progression-free survival (PFS) versus placebo (PBO) (11.0 vs 4.6 months; HR=0.35, p < 0.0001) in patients (pts) with pancreatic neuroendocrine tumors (pNET) (Yao et al, NEJM, 2011). Here we present a planned exploratory analysis by prior chemotherapy (chemo) use. Methods: Pts with progressive low- or intermediate-grade pNET were prospectively stratified by prior chemo use and randomized (1:1) to EVE 10 mg/d (n = 207) or PBO (n = 203) plus best supportive care. Results: Of the 410 pts, 206 (50%) had received prior chemo and 204 (50%) were chemo naive. Baseline characteristics (age, sex, race, tumor type, histologic grade) and baseline tumor biomarker levels were similar for pts with/without prior chemo. More chemo-naive pts were newly diagnosed (time since initial diagnosis ≤ 6 mo: 50 [25%] vs. 7 [3%] pts with prior chemo). A lower proportion of chemo-naive pts received prior somatostatin therapy (45% vs. 54% prior chemo). EVE significantly prolonged median PFS regardless of prior chemo use (with prior chemo: 11.0 vs. 3.2 months; HR = 0.35, 95% CI 0.25-0.49, p < 0.001; chemo naive: 11.4 vs. 5.4 months; HR = 0.42, 95% CI 0.29-0.60; p < 0.001). Stable disease was the best overall response in 73% of EVE-treated pts irrespective of prior chemo use. The benefit from EVE irrespective of prior chemo was further demonstrated by disease stabilization or minor tumor shrinkage and in the lower incidence of progressive disease in waterfall plots. Safety of EVE was consistent regardless of prior chemo use. The most common drug-related adverse events (chemo vs chemo naive) included rash (53% vs. 52%), stomatitis (52% vs. 56%), diarrhea (41% vs. 52%), and fatigue (37% vs. 51%). Conclusions: This planned subgroup analysis demonstrated the beneficial effects of EVE in pts with pNET regardless of prior chemo use. These findings support the possible first-line use of EVE for pts with pNET.
Effect of altering fibroblast integrin associated protein expression on the growth and protein expression of pancreas cancer cells.
Authors: Shea Jill E. , Hewitt Kelly C. , Scaife Courtney L.
Published: February 2017

251

Background: The lack of success of current treatments for pancreatic ductal adenocarcinoma (PDA) may be due in part to the presence of the dense surrounding stromal response and the interactions between the stroma and cancer cells. We have shown that integrin associated proteins, in particular PINCH, are expressed to a higher degree in the stroma adjacent to the tumor cells and PINCH expression is positively correlated with poorer PDA patient outcomes. We hypothesize that decreasing PINCH protein expression in the tumor associated stroma will decrease the growth and expression of growth promoting proteins in PDA cells. Methods: Red fluorescent protein (RFP) stably expressing MiaPaCa-2 cells were co-cultured with WI38 fibroblasts, or WI38 fibroblasts with shRNA knockdown of PINCH protein (PINCH KD). Cell growth of the PDA cells alone and upon exposure to WI38 and PINCH KD fibroblasts was determined using RFP at 48 hours. PINCH, Akt, and pAKt protein expression in cultured PDA cells, exposed to media, WI38, or WI38 PINCH KD cells via a transwell system, were determined by western blot with values normalized to GAPDH protein expression at 48 hours. Results: MiaPaCa-2 cells grown in co-culture with WI38 cells had a 70%±5% increase in RFP, while those grown in co-culture with WI38 PINCH KD cells had a 40%±3% increase relative to MiaPaCa2 cells grown alone. In terms of relative PINCH protein expression there was an increase in MiaPaCa-2 (20%±5%) cells grown in co-culture with WI38 cells compared to alone but not when grown with PINCH KD (6%±3%). MiaPaCa-2 cells had a greater increase in AKT (47%±6% compared with 19%±4%) and pAKT (36%±5 and 22%±4%) in the cells grown with WI38 cells compared to PDA cells grown with WI38 PINCH KD. Conclusions: Reductions in fibroblast PINCH protein expression are associated with reductions in the growth of adjacent PDA cells, as well as the expression of growth enhancing proteins (PINCH, AKT, and pAKT). Since greater PINCH expression within PDA stromal cells is associated with poorer patient outcomes, understanding the mechanisms associated with this tumor-stromal interaction may provide intervention opportunities.
Hepatic imaging response to 90y-microsphere therapy administered for tumor progression during systemic chemotherapy in patients with colorectal liver metastases.
Authors: Kennedy Andrew S. , Ball David , Cohen Steven J. , Cohn Michael , Coldwell Douglas M. , Drooz Alain , Ehrenwald Edward , Kanani Samir , Nutting Charles W. , Moeslein Fred M , Putnam Samuel G. , Rose Steven C. , Savin Michael , Schirm Sabine , Sharma Navesh K , Wang Eric
Published: February 2017

270

Background: Hepatic tumor progression after one or more lines of 5FU-based systemic chemotherapy, with or without biologic agents, is an indication for radioembolization using 90Y microspheres. Methods: An independent imaging review following resin-only 90Y microsphere treated cases of mCRC from July 2002 to December 2011 at 9 US institutions was conducted. A board certified radiologist systematically reviewed hepatic Computed Tomography (CT) images (portal-venous phase) at baseline and 3 months after 90Y treatment. Tumor response was assessed using RECIST 1.0 criteria, based on a maximum of 5 target lesions. Peri-tumoral edema and necrosis; known artifacts which can affect the interpretation of RECIST response, were documented for each lesion. Kaplan Meier analysis compared survival for responders [Partial Response (PR)] vs. non-responders [Stable Disease (SD) or Progressive Disease (PD)]. Results: A total of 184 patients were studied; male (61%) and Caucasians (61%) most common, mean age 62.5 years received a median of 2 (range 1–5) lines of chemotherapy prior to 90Y therapy. Median tumor/liver ratio at 90Y therapy was 15% (IQR 20%). Median 90Y activity administered was 1.18 GBq (IQR 0.55). RECIST response at 3 months was 9.8% PR (n=18), 72.3% SD (133) and 17.9% PD (33); Disease Control Rate = 82.1%. Peri-tumoral edema was documented in 33% (n=60); necrosis in 42% (79); both in 22% (40) of cases, respectively. No significant differences in background characteristics between responders and non-responders were evident (p>0.05). RECIST response at 3 months predicted survival: PR median 13.9 months (95% CI 9.2-30.3) vs. SD 11.0 (8.9-13.5) vs. PD 6.7 (5.5-8.1) [p=0.002]. Conclusions: Radiological lesion response to 90Y therapy at 3 months must be interpreted with caution due to the significant proportions of peri-tumoral edema and necrosis encountered. Both of these artifacts may lead to either the under estimation of PR/SD or the overestimation of PD, respectively. Given these caveats, early (3 month) hepatic radiological response to 90Y therapy appears to predict longer term prognosis.
Significance and clinical outcome of lymph node level assessment in biliary tract cancers.
Authors: Martínez-Galán Joaquina , Soberino Jesús , González Rivas Cynthia S. , Ruiz Vozmediano Julia , Portellano Lucia , Conde Veronica , Ortega Jose Antonio , Garcia Javier , González Vicente Aranzazu , Delgado Juan Ramon
Published: February 2017

274

Background: Biliary tract cancers (BTCs) are relatively rare neoplasms encompass both cholangiocarcinoma (CC).The role of routine lymphadenectomy at the time of surgical resection remains poorly defined.We sought to identify factors associated with outcome following and examine the impact of lymph node (LN) assessment on survival. Methods: 43 pts who underwent curative intent surgery between 2000-10 were identified from a database.We calculated prognostic factors and impact lymph node assessment for survival. Results: A total 43 pts were identified with no metastatic BTCs.The median age was 65 years (29–82 years); PS0:33/43 (76%); PS1:8/43 (19%) and PS2:2/43 (5%) pts.A histological diagnosis of adenocarcinoma was confirmed in 100%.Surgical resection was performed in all patients.After resection 42% (18/43) had positive nodes.Adjuvant chemotherapy had 31/43(72%),preferred with gemcitabine and a median number of cycles 6. Grade 3 or 4 toxicities rarely occurred.During median follow-up of 6.6 years tumor recurrence or metastatic disease occurred in 63% with median survival global were 2 years and 1.5 years for disease free survival.For stage T, the median survival global rates were 58 months (95% CI 44.6-71.3) for T1-T2 and 35 months (95% CI 23.3-46.8) for T3-T4 p=0.015 and for median recidive-free survival were 23 months (95% CI 11.8-34) for T1-T2 and 14 months (95% CI 6.5-21) for T3-T4 p=0.05.For N stage, the median SG were 58 months (95% CI 50.5-65.4) for negative nodes and 26 months (95% CI 3.7-48.2) for positive nodes p=0.003 and for median recidive-free survival were 55 months (95% CI 31.7-57.5) for negative nodes and 10 months (95% CI 6.8-13) for positive nodes p=0.006.The pts who had nodal affectation in hepatic hilio had better recidive-free survival that those patients who had nodal affectation in celiac trunk p<0.05. Conclusions: This represents a biliary cancer cohort with survival benchmarks obtained in the modern era of multidisciplinary care.Surgical resection and adjuvant QT offers the optimal treatment outcome in patients with ICC.From our results depth of tumor invasion (T),the presence the lymph node metastases (N) and level nodal affections are the strongest predictors of relapse and survival.
Preoperative bowel preparation for pancreaticoduodenectomy: Is it necessary?
Authors: Newhook Timothy E. , Lindberg James M. , Adams Reid B. , Bauer Todd W.
Published: February 2017

279

Background: Preoperative bowel preparation (PBP) before pancreaticoduodenectomy (PD) is commonly performed; however, the effect of PBP on intraoperative fluid requirements and acute renal failure (ARF) after PD has not been reported. The goal of this study was to determine the effect of PBP on postoperative complications, intraoperative fluid requirements, and ARF after PD. Methods: In this retrospective sequential analysis, all patients undergoing PD consecutively from September 2005 to July 2012 by a single surgeon were identified. Clinical data from patients who received PBP from September 2005 to November 2008 was compared to those without PBP from December 2008 to July 2012. Results: In all, 140 consecutive patients were identified with 49 (35%) having received PBP. There was no significant difference in the frequency of chronic renal failure between groups. The PBP group received a larger total intraoperative fluid volume (9.33 vs 6.54 L, p<0.001) and had a higher incidence of postoperative ARF (22.4% vs. 5.4%, p = 0.003) compared to those without PBP. There was no significant difference in the rates of superficial, deep, or organ space surgical site infections between the two groups. Additionally, there was no significant difference in the rates of pancreatic leak, other GI tract leak, or postoperative ileus between the groups. Conclusions: Surgical site infections are not significantly reduced with PBP prior to PD. In contrast, PBP is associated with a 2.8 L increase in intraoperative fluid administration and a 17% increase in the incidence of postoperative ARF. Thus, PBP should not be offered routinely prior to pancreaticoduodenectomy. [Table: see text]
Prognostic factors for achieving resection following neoadjuvant radiation therapy for borderline resectable pancreatic adenocarcinoma.
Authors: Dholakia Avani Satish , Hacker-Prietz Amy , Wild Aaron Tyler , Raman Siva P. , Wood Laura D. , Laheru Daniel A. , Zheng Lei , De Jesus-Acosta Ana , Le Dung Thi , Rasheed Zeshaan , Ellsworth Susannah G. , Kumar Rachit , Fan Katherine Y. , Pawlik Timothy M. , Makary Martin , Hruban Ralph H. , Cameron John L. , Fishman Elliott K. , Wolfgang Christopher Lee , Herman Joseph M.
Published: February 2017

285

Background: Margin-negative (R0) surgical resection is the only potentially curative therapy for pancreatic cancer. For patients deemed borderline resectable (BL), neoadjuvant chemoradiotherapy (NCRT) increases the likelihood of subsequent R0 resection and improves overall survival. Prognostic factors for achieving resection following NCRT have yet to be clearly identified. Methods: 50 consecutive patients diagnosed with BL pancreatic cancer by a multidisciplinary tumor board from 2008-12 were retrospectively identified. Pre- and post-NCRT CT scans and surgical specimens were centrally reviewed by a blinded radiologist and pathologist, respectively. Results: 29 patients underwent resection following NCRT, while 21 remained unresectable. Between the two groups, age, gender, mean RT dose, and proportion of pancreatic head tumors were not significantly different. Lack of the following factors was favorably associated with resection: SMV/PV encasement (p=0.01), SMA involvement (p=0.02), ascites (p=0.01), and questionable/overt metastases (p=0.01). Notably, celiac artery involvement/encasement, common hepatic artery encasement, and percentage change in tumor volume were not significant predictors of resectability (all p>0.05). Additionally, tumor volume and degree of individual vessel involvement did not significantly change from scans before and after NCRT (all p>0.05). Median OS was 22.9 vs.13.0 months in resected and unresected patients, respectively (p<0.001). Of resected patients, 93% had negative margins, 28% had positive nodes, 27% demonstrated <10% viable tumor, and 12% had pathologic complete response at surgery. Conclusions: Certain radiographic features appear more strongly associated with resectability after NCRT than others. Despite the fact that tumor-vessel interactions do not change significantly due to NCRT, subsequent R0 resection rates are high, nodal involvement is low, nearly 1/3 of patients have minimal residual tumor, and outcomes are improved. Further studies are needed to elucidate novel biomarkers or functional imaging predictors for successful resection following neoadjuvant therapy.
Long-term survival after multidisciplinary treatment of small-bowel neuroendocrine tumors with synchronous liver metastases. A single-institute experience.
Authors: Bertani Emilio , Fazio Nicola , Chiappa Antonio , Botteri Edoardo , Spada Francesca , Grana Chiara , Ravizza Davide , Cossu Laura , Bonomo Guido , Andreoni Bruno
Published: February 2017

299

Background: Neuroendocrine tumors (NETs) that originate in the distal jejunum and ileum are commonly diagnosed in stage IV, with liver metastases in 50-75% of cases. The aim of this study was to ascertain the impact of surgery in a consecutive series of patients with small bowel NET and synchronous liver metastases treated at a single institute. Methods: Ninety-one patients managed between 1995 and 2011 were extracted from the institutional tumor registry. All patients had diagnosis by histology of small bowel NET and synchronous liver metastases. Results: Among the 91 patients 28 (30.8%) underwent primary tumor removal and liver metastases resection or intraoperative termal ablation (Group 1), 54 (59.3%) underwent resection of only the primary tumor (Group 2), and the remaining 9 (9.9%) did not receive any surgery (Group 3). After a median follow-up of 64 months an overall survival (OS) of 93.1%, 81.8% and 76.2% at 3, 5 and 8 years was registered for the whole group. Cancer-specific survival (CSS) was 93.1%, 83.3% and 77.6% at 3, 5 and 8 years, respectively. Five-years OS differed significantly according to the surgical approach (96.0% for Group 1 vs 79.8% for Group 2 vs 48.6% for Group 3, p=0.02). During the course of the illness octreotide was administered in 78 patients (85.7%), peptide receptor radiotherapy in 61 (67.0%), systemic chemotherapy in 21 (23.1%), hepatic artery embolization in 17 (18.7%), interferon in 11 (12.1%), molecular targeted agents in 2 (2.2%). For patients who underwent any surgery (Group 1 and Group 2) the multidisciplinary approach was associated with a better OS (85.7% vs 77.2% 5-years OS, p=0.04). In the multivariate analysis only age was associated with OS, HR: 1.05 (C. I.: 1.01-1.10). The results of CSS were comparable to those of OS. Conclusions: In this metastatic setting of small bowel NETs the 5 year OS was as high as 82% with a maximum benefit achievable for patients who had primary tumor resection and liver disease amenable to surgical or thermal ablation. However, the potential impact of age in prognosis should be carefully considered when choosing the treatment to be delivered in such patients.
Continuous-dose regorafenib (REG) in hepatocellular carcinoma (HCC): Phase I safety and pharmacokinetic (PK) study.
Authors: Finn Richard S. , Blumenschein George R. , Tolcher Anthony W. , Leong Stephen , Boix Oliver , Diefenbach Konstanze
Published: February 2017

300

Background: REG is a novel oral inhibitor of multiple kinases involved in angiogenesis, oncogenesis, and tumor microenvironment. A multicenter, open-label, single-arm phase I dose-escalation study evaluated REG given with a continuous schedule and established 100 mg once daily as the maximum tolerated dose. This study explored the safety and PK of this dose in an expanded cohort of advanced HCC pts. Methods: Adults with advanced treatment-refractory HCC (Child Pugh [CP] A or B) received REG 100 mg daily until tumor progression, unacceptable toxicity, or pt/investigator decision to stop. Safety and PK were primary endpoints. Tumor response was a secondary endpoint. Results: The HCC expansion cohort included 20 pts: male/female ratio: 14/6; 10 Asian, 4 white, 4 Hispanic, 1 black, 1 other; mean age: 56.8 ± 13.5 years; 16 CP A, 4 CP B; 2 stage II, 3 stage IIIA, 1 stage IIIC, 13 stage IV; 14 pts had disease progression at entry; 11 pts had 2+ metastatic sites; 19 pts had received prior sorafenib. Median duration of treatment was 42 days (range 23–329); 2 pts were still on treatment at data cutoff. Two pts died during the study (both due to disease progression). Drug-related AEs were reported in 18 pts (90%). The most common grade 3+ drug-related AEs were hypertension (n=4, 20%), fatigue (n=2, 10%), hand-foot skin reaction (n=2, 10%), pain (n=1, 5%), and hemoglobin, ALT, AST, lipase, and other metabolic/laboratory abnormalities (n=1, 5% each). Nine pts required REG dose modifications, and 2 pts stopped treatment permanently because of drug-related AEs. No drug-related serious AEs were reported. Single-dose PK data (cycle 1, day 1) were available from 18 pts, but only 1 pt was evaluable for steady-state PK samples. Single-dose analysis did not indicate any effect of CP status on REG PK. One pt had a partial response and 6 pts had stable disease; median time to progression was 36 days (range 28-237). Conclusions: Continuous-dose REG 100 mg once daily was well tolerated in pts with advanced HCC that progressed on prior sorafenib. PK data obtained after a single 100 mg dose did not indicate any effect of CP status on the PK of REG or its primary metabolites. Disease control was achieved in 7 pts. Clinical trial information: NCT01117623.
Pretreatment metabolic tumor volume (MTV) as a predictor of survival in borderline resectable pancreatic cancers treated with neoadjuvant therapy.
Authors: Cruz Alex , Chen Dung-Tsa , Fulp William J. , Chuong Michael , Hoffe Sarah , Shridhar Ravi , Rao Nikhil G , Hodul Pamela Joy , Malafa Mokenge Peter , Figura Nicholas , Eikman Edward , Springett Gregory M.
Published: February 2017

310

Background: A higher initial metabolic tumor burden is associated with lower median survival in locally advanced pancreatic cancer (LAPC), yet the prognostic utility of PET/CT is not defined in the setting of borderline resectable pancreatic cancer (BRPC). Methods: We performed a retrospectivereview of our institutional experience treating BRPC. Initial staging included endoscopic ultrasound as well as pancreatic protocol CT and PET/CT scans. All patients underwent neoadjuvant gemcitabine-based chemotherapy and radiation therapy (RT). RT was delivered using standard fractionation intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT). Restaging CT and PET/CT scans were obtained approximately 4 weeks following RT completion. We measured the significance of the pre-treatment and post-treatment SUV maximum and metabolic tumor volume (MTV) 2.5 to 5.0, which was defined as the MTV above a threshold SUV of 2.5, 3.0, 4.0 and 5.0. Cox regression models were used to evaluate the significance between these parameters and disease free survival (DFS) and overall survival (OS). Results: We evaluated a total of 72 BRPC patients. Median follow up was 12.7 months. 56 patients (77%) received induction chemotherapy with gemcitabine, docetaxel and capecitabine (GTX). 43 (59.7 %) underwent surgical resection. Significant predictors for OS in the whole cohort included pre-treatment SUV maximum (p=0.0042), post-treatment SUV maximum (p=0.0183), pre-treatment MTV 2.5 (p=0.0016) and pre-treatment MTV 4.0 (p=0.0111). In addition, the difference between the MTV 4.0 pre-treatment and post-treatment was significant (p=0.0285). In patients who underwent surgical resection, there was a significant correlation between OS with pre-treatment SUV max (p=0.0229) and post-treatment SUV maximum (p=0.0325) but not pre-treatment MTV 2.5 (p=0.0654) nor MTV 4.0 (p=0.0928) nor the differences between each variable pre (0.1482) or post-treatment (0.0959). Conclusions: This is the first study to suggest that pre and post treatment PET activity is prognostic for BRPC.
A phase II study of PD-0332991 in patients with advanced hepatocellular cancer.
Authors: Littman Susan Joy , Knudsen Erik S. , Witkiewicz Agnieszka , Hyslop Terry , Lewis Nancy , Pillai Madhavan V. , Brus Christina , Mitchell Edith P.
Published: February 2017

321

Background: Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide and the 3rd most frequent cause of cancer-related mortality. Surgical resection & liver transplantation are the main curative options. Most patients present with advanced stage and poor liver function and are ineligible. Cytotoxic drugs give poor response rates and little benefit. The MKI sorafenib has been shown to significantly increase PFS and OS in advanced HCC in 2 rPhase 3 trials. PD-0332991 is an orally available, pyridopyrimidine-derived, selective inhibitor of CDK4/6, that results in the inhibition of RB protein phosphorylation & cell cycle arrest. In preclinical studies, PD-0332991 has cytostatic activity, dependent on RB protein Methods: This is an open-label non-randomized single-institution study for subjects with inoperable, recurrent/refractory advanced HCC. Subjects must have failed or be intolerant of standard first-line therapy, sorafinib. Subjects receive 125 mg PD-0332991 po/d 1-21 of 28-day cycle until disease or clinical progression, unacceptable toxicity, withdrawal of consent or death. Tumor response by CT or MRI using mRECIST v1.1 is q8 w. Subjects are assessed for toxicity per NCI CTCAE, v4.0. Results: 10 pts (8m,2f) have been enrolled. Median age is 61.7 (r32-74) yr. PD-0332991 is well tolerated. The most common toxicities were neutropenia and thrombocytopenia with 3 G3 neutropenia requiring therapy delay. Non-serious AEs were ascites, pain, nausea, vomiting, diarrhea, lightheadedness, anorexia, neuropathy. LFT abnormalities were consistent with underlying ESLD. 3 pts expired due to liver failure before disease progression was observed by RECIST, at 70, 85 and 136 d. 3 subjects developed PD at 3, 5 and 8 m. 2 have received additional therapy. 4 subjects are on therapy, with best PFS being 8 m. Conclusions: PD-0332991 is well tolerated in subjects with HCC and cirrhosis. Primary toxicity is neutropenia and thrombocytopenia consistent with known safety profile of PD-0332991. No unexpected toxicities have been observed. Preliminary responses are encouraging. TTP compares favorably to other drug regimens. Clinical trial information: NCT01356628.
Evaluating malignant intraductal papillary mucinous neoplasm: A population-based study.
Authors: Luu Carrie , Nelson Rebecca A. , Lee Byrne , Singh Gagandeep , Kim Joseph
Published: February 2017

324

Background: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been increasingly recognized. Due to a paucity of evidence, the management and treatment of IPMN is still under debate. We hypothesize that with increased awareness, the incidence and resection rates for IPMN would increase. Using a population-based cancer registry, we examined incidence, prognostic factors, and survival for IPMN. Methods: Patients diagnosed with invasive IPMN from 1988 to 2009 were identified by the Surveillance, Epidemiology, and End Results (SEER) database. Patient demographics, clinical and pathologic factors, and therapies received (surgery and/or radiation) were analyzed. Survival was assessed by Kaplan-Meier method; Cox proportional hazard modeling was used for multivariate analysis. Results: 2,987 patients were identified. Over the study period, there was a decrease in age-adjusted incidence. The overall resection rate was 20.6% with an increase in annual rates of resection. On univariate analysis, age greater than 65 years, tumor location, poorly differentiated tumor grade, higher T stage, and positive lymph nodes predicted worse survival; more recent diagnosis, higher number of lymph nodes examined, and surgery were indicators of improved survival. On multivariate analysis, curative surgery remained predictive of survival. Patients who underwent surgery had median survival rates of 87, 18, and 14 months compared to 6, 7, and 5 months in the no surgery group for stages I, II, and III, respectively. Conclusions: Although recent reports show increasing incidence of IPMN, our study involving a population-based cohort demonstrates decreasing incidence of malignant IPMN. This may be accounted for by increased detection of non-malignant disease. It is imperative that we identify patients with invasive IPMN early so that they may benefit from the survival advantage conferred by curative resection.
Analysis of second primary cancers in gastroinstestinal stromal tumor patients using SEER database.
Authors: Ghimire Krishna Bilas , Nepal Barsha , Shah Binay Kumar
Published: February 2017

327

Background: Development of second primary cancers among gastrointestinal stromal tumor (GIST) patients is not very well studied. This study was conducted to evaluate second primary malignancies in GIST patients using U.S. Surveillance, Epidemiology, and End Results (SEER) cancer registry database. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER Stat) database: Incidence - SEER 13 Regs Research Data, Nov 2011 Sub, Vintage 2009 Pops (1992-2009) using MP-SIR session. We analysed secondary cancer rate among adult GIST patients during the period 1992-2009. We also compared the risk of secondary malignancies in pre- (1992-2001) to post-imatinib (2002-2009) eras. We used SEER MP-SIR session and Graph pad scientific software to calculate p value. Results: There were 2,436 (693 in pre-imatinib era and 1,743 in post-imatinib era) GIST patients reported during 1992-2009 period in SEER database. Among them, 163 GIST patients developed second primary malignancy, which is significantly higher than expected in general population, with observed/expected (O/E) ratio: 1.31, p value = <0.05, (95% CI: 1.11-1.52) and excess risk of 39.76 per 10,000 population. The total number of second primary cancers in GIST in pre- and post-imatinib eras were 69 and 94, p value = <0.0001 with observed/expected (O/E) ratio of 29.18 and 48.22 respectively. The total number of second primary solid tumors in pre- and post-imatinib era was: 59 and 84, p value=0.0008 and O/E ratio: 20.18 vs 43.32 respectively. Conclusions: This study showed overall increased risk of second primary malignancies among GIST patients as compared to general population. There was significantly increased risk of second primary malignancies, especially solid tumors in post-imatinib era. [Table: see text]
Definitive chemoradiation with full-dose gemcitabine for unresectable pancreatic cancer: A single-institution experience.
Authors: Zhou Jessica , Shen Jincheng , Schipper Matthew J , Lawrence Theodore Steven , Feng Mary Uan-Sian
Published: February 2017

331

Background: Definitive chemoradiotherapy (chemoRT) for unresectable pancreatic cancer has traditionally involved 5-FU-based chemotherapy. We have a long-history of combining gemcitabine and radiotherapy and performed a retrospective review of patients (pts) treated in this manner over the past 13 years. Methods: After IRB approval, the records of pts who underwent definitive treatment with radiotherapy (RT) and concurrent gemcitabine-based chemotherapy at the University of Michigan from February 1999 – May 2012 were reviewed. 193 pts were identified. Mean radiation dose was 40.5 Gy (median 36 Gy, range 24-60 Gy) in 2.2 Gy fractions (range 1.6 to 2.8), and targeted only radiographically apparent disease. 32% of pts received ≥50 Gy, and IMRT was used for 33%. The majority (97.9%) of pts were treated with concurrent full-dose weekly gemcitabine at 1000mg/m2. 48% of pts received at least 1 cycle of chemotherapy prior to chemoRT, and 13% received 2+ cycles. 85% of pts received additional chemotherapy after RT. Cox proportional hazard models were used for survival analysis. Results: Treatment was well-tolerated, with 91% of pts completing RT without a toxicity-related treatment break. With a median follow-up of 10 months, median overall survival (OS) was 13.5 months. 1, 2, and 5 year OS was 57%, 25%, and 5%, respectively. On univariate analysis, pre-treatment CA 19-9 and KPS predicted for OS (p=0.02 and 0.04). Tumor diameter was marginally associated (p=0.06). Age, gender, comorbidities, RT dose, and change in CA 19-9 before or after RT did not predict for OS. With regards to local response to treatment, 1 pt achieved a radiographic complete response (CR) and 30% of pts had a partial response (PR). Distant disease relapse occurred in 52% of all pts, including metastatic disease in the liver in 30%, peritoneum 15%, and lung 14%. 11 pts (6%) had late gastric or duodenal bleeds. Conclusions: Definitive chemoRT utilizing full dose gemcitabine is well-tolerated and achieves survival outcomes which compare favorably with reported series on 5-FU based therapy.
Classification of a VUS in MLH1 using a combination of family segregation studies and protein biochemistry.
Authors: Zbuk Kevin M. , Bell Kathleen , Zhou Anna , Guarne Alba , Aronson Melyssa , Lerner-Ellis Jordan , Pollett Aaron , Palma Laura , Chong George
Published: February 2017

342

Background: The identification of variants of unknown clinical significance (VUS) presents a challenge for diagnostic laboratories and clinicians working with families with Lynch syndrome (LS). Although a variety of strategies exist to attempt clarification, data from multiple sources is often required before a VUS is re-classified to pathogenic or benign. Methods: We report on the investigation of 2 families with a variant in the MMR gene MLH1, c.2038T>C (p.Cys680Arg). In addition to segregation analysis, and review of published literature, the c-terminal domain of MLH1was cloned, the p.Cys680Arg variant was generated using site-directed mutagenesis and protein expression was induced. In addition, this point mutation was modelled onto the crystal structure of the dimerization domain of MLH1. Results: Both families fit Amsterdam criteria for a diagnosis of LS. All available tumours exhibited MLH1 deficiency and microsatellite instability and all living affected individuals available were positive for MLH1 p.Cys680Arg variant. Protein studies confirmed that p.Cys680 resides in a tight hydrophobic cavity and the p.Cys680Arg mutation disrupts the folding of the C-terminal domain of MLH1. In two families this variant segregated with disease in a total of 12 individuals (>10 meiosis and >1000:1 odds in favor of linkage) and 3 had an MLH1 deficient tumour, supporting a pathogenic role for this variant. Inspection of the crystal structure of MLH1 suggested that the Cys680Arg mutation should severely alter the folding of the dimerization domain. As opposed to the dimerization domain of MLH1 that can be readily produced recombinantly and is stable in solution, the same domain of MLH1 encoding the Cys680Arg mutation was expressed as inclusion bodies, confirming that this mutation causes misfolding of the dimerization domain of MLH1. Conclusions: Our data confirms that the p.Cys680Arg mutation destabilizes the dimerization domain of MLH1, and presumably the DNA mismatch repair proficiency of individuals carrying this mutation. Based on this evidence and family history data, the MLH1 C680R missense variant is classified as pathogenic. This approach may prove useful in the classification of other variants.
A new noninvasive blood-test for the early detection of colorectal cancer.
Authors: Sobhani Iradj , Incitti Roberto , Roperch Jean-Pierre
Published: February 2017

348

Background: Colorectal cancer (CRC) remains a major medical problem in the world. Its early detection impacts the prognosis and the cost of treatment. Fecal occult blood test is a current noninvasive screening method for CRC detection in asymptomatic average risk individuals. It detects less than 50% of cancers and yields a high number of “normal” colonoscopies. The dysregulation of DNA methylation has been recognized as playing a crucial role during CRC development. The aim of the study was to develop a CRC-specific methylated DNA test in serum. Methods: First, the GoldenGate Methylation microarray containing 1,505 CpG loci within 807 cancer-related genes was used to study methylation patterns in CRC patients. We performed such assays on 9 tissues (4 CRC, 4 normal autologous tissues, 1 polyp), 17 blood and urine pooled samples (7 CRC, 6 polyps, 4 normal) and 20 stool samples (7 CRC, 3 polyps, 10 normal). The clinical status of each sample was assessed by colonoscopy and/or pathology findings. Among methylated genes detected in tumour tissue, stools, and blood, NPY, PENK and WIF1 genes were selected taking into account their high degree of methylation. We then carried out a clinical validation by quantitative multiplex methylation-specific PCR (QM-MSP) in two phases: firstly on 30 tissues (15 CRC, 15 homologous normal tissues) and secondly on 193 serum samples (32 CRC, 161 normal). Results: For to obtain the best accuracy of QM-MSP test, we defined for both biological sources a cumulative methylation index (CMI) by adding of the methylation percentage of each gene. At the CMI of 20.0% on tissues, our QM-MSP test allows to diagnose the CRC with the highest accuracy (100% of specificity and 100% of sensitivity). From sera, the CMI has been standardized at 2.0% giving a sensitivity and specificity for detecting CRC of 94.4% and 59.4% respectively (NPV of 92.1% and PPV of 67.8%). Conclusions: We developed a QM-MSP-based analysis of NPY, PENK, and WIF1 methylated genes in serum. This test classified correctly and with a high accuracy the healthy individuals and colon cancer patients. We propose here new sensitive serum-based epigenetic biomarkers as an effective and simple new noninvasive test for CRC screening in the average and high risk populations.
Prognostic and predictive value of CA19-9 in metastatic colorectal cancer.
Authors: Narita Yukiya , Taniguchi Hiroya , Komori Azusa , Nitta Sohhei , Yamaguchi Kazuhisa , Kondoh Chihiro , Kadowaki Shigenori , Takahari Daisuke , Ura Takashi , Andoh Masashi , Muro Kei
Published: February 2017

354

Background: CA19-9 has been approved by FDA as a tumor marker in pancreatic cancer. The prognostic and predictive value of CA19-9 in metastatic colorectal cancer (mCRC) is still unclear. Moreover, CA19-9, a sialyl Lewis A antigen, acts as an adhesion factor of cells lining the blood vessels, but the association between the CA19-9 value and the effect of bevacizumab (BV) has not been reported. Methods: We conducted a retrospective review of 239 patients undergoing first-line chemotherapy by oxaliplatin-based regimens at a single institution from April 2005 to December 2009. The relationship between the CA19-9 value at baseline and the various clinicopathological factors and survival data was analyzed. Results: Median age was 62 years (range 23–83 years). 133 patients had a baseline CA19-9 value above the normal upper limit (>50 U/ml, high group), 86 had ULN (<50 U/ml, normal group), and 20 had below measurement sensitivity (example of Lewis antigen negativity, low group). The rate of KRAS MT and BRAF MT was high in the CA19-9 high group (KRAS MT 41.0%/BRAF MT 10.7%) as compared with the CA19-9 normal group (KRAS MT 22.7%/BRAF MT 0%). The high CA19-9 value in all the cases was a poor prognostic factor compared with the normal value (HR: 1.61, 95% CI: 1.28–2.04, p < 0.001). In multivariate analysis, the high CA19-9 value was an independent prognostic factor (HR:1.45, 95% CI: 1.10–1.91, p = 0.0082). Moreover, in the CEA normal group (<5 ng/ml), the high CA19-9 value was a poor prognostic factor as compared with the normal CA19-9 value (HR: 1.90, 95% CI: 1.00–3.62, p = 0.049). In the CA19-9 normal group, the median survival time (MST) with BV was longer than that without BV (53.2 vs 28.4 months, HR: 0.47, 95% CI: 0.30–0.93, p = 0.030). Furthermore, in the CA19-9 high group, MST with BV was longer than that without BV (20.6 vs 16.6 months, HR: 0.65, 95% CI: 0.44–0.97, p = 0.033). Conclusions: The CA19-9 value before chemotherapy in mCRC is an independent prognostic factor and intercorrelated with KRAS/BRAF MT. Bevacizumab exhibits clinical activity in mCRC patients, regardless of CA19-9 value.
Serum C-reactive protein levels and colorectal cancer mortality.
Authors: Goyal Abhishek , Siegel Abby B.
Published: February 2017

360

Background: Chronic inflammation has been causally linked to colorectal cancer (CRC), and use of NSAIDs has been associated with reduced risk. Prediagnostic C-reactive protien (CRP) levels, a highly sensitive marker of inflammation, have been weakly associated with increased CRC incidence. However, their relationship with CRC mortality has not been studied well. We hypothesized that elevated baseline CRP levels in general population will predict increased CRC mortality. Methods: This cohort study used CRP data from the Third National Health and Nutrition Examination survey, 1988-94 (NHANES III), with follow-up through 2006. Of the 15,832 eligible adults, NHANES III classified 65% as having CRP levels below detection (≤0.21mg/dL). Using this as the reference, we categorized the remaining participants in three approximately equal groups, and calculated hazard ratios for CRC, all-cancer mortality excluding CRC, and overall mortality due to non-cancer causes. Results: Median follow-up period was 14.2 years. In age adjusted (not shown) and multivariable adjusted models (Table), we observed strong, dose-response associations between CRP levels and CRC mortality. Associations between CRP levels and mortality due to other causes were much weaker. Conclusions: In this large, representative study of U.S. adults, we obtained significantly higher HRs for CRC mortality, as compared to mortality from other cancer and non-cancer causes, making these results unlikely to be explained by residual confounding or other biases. Further, since mortality is a function of both incidence and survival, it provides a more valid estimate of the prognostic value of CRP compared to incidence alone. Further evaluation of CRP may help stratify high risk groups for screening and prognosis, and potentially identify those who might benefit from anti-inflammatory therapy. [Table: see text]
Prostate cancer incidence in males with Lynch syndrome.
Authors: Haraldsdottir Sigurdis , Hampel Heather , Wei Lai , Wu Christina Sing-Ying , Bekaii-Saab Tanios S. , De La Chapelle Albert , Goldberg Richard M.
Published: February 2017

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Background: Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and increases the risk of colon and several other cancers. Prostate cancer is not currently considered part of the LS-tumor spectrum. The objective of this retrospective study was to assess whether the incidence of prostate cancer is increased above that of the general population in MMR mutation carriers. Methods: Patients who were identified as MMR mutation carriers and included in previous LS studies or evaluated at the genetics clinic at The Ohio State University were contacted and their cancer history documented. Follow-up time was defined as the time between their first index cancer or their entry onto the LS studies until the last date of follow-up or date of death, whichever came first. The prostate cancer incidence was adjusted for age and race and compared to that of the SEER registry of 1999-2009. A standardized rate ratio (SRR) was obtained by comparing the observed rate to the expected rate. Results: 186 males (median age 49 years, range 17-83) were identified as MMR mutation carriers either by testing (95%) or as obligate carriers (5%) in 94 families. Their mean follow-up time was 5.1 years (SD+/-6.0 years) with a total of 938 person-years (p-ys). Caucasians comprised 95.1% of the cohort, African-Americans 3.8% and Asians 1.1%. Of the patients who were tested for mutations, MSH2 was most commonly mutated (49.2%), followed by MLH1 (23.7%), PMS2 (14.7%) and MSH6 (12.4%). Ten patients (5.4%), all Caucasian, were diagnosed with prostate cancer at a median age of 59 years (range 52-82). 7 patients were identified as MSH2 carriers, 2 as MSH6 carriers and 1 as a PMS2 carrier. The observed incidence rate was 102.8 cases per 100,000 p-ys versus the expected number of 158.2 cases per 100,000 p-ys, the standardized rate ratio was 0.65 (95% CI 0.53-0.79). Conclusions: Prostate cancer incidence was not increased in this relatively large cohort of LS patients.
Long-term efficacy and pharmacodynamic parameter analysis in pretreated KRAS-mutant metastatic colorectal carcinoma (mCRC) patients treated with RG7160 (GA201), an antibody-dependent cellular cytotoxicity (ADCC)-enhanced monoclonal anti-EGFR antibody.
Authors: Delord Jean-Pierre , Tabernero Josep , Garcia-Carbonero Rocio , Cervantes-Ruiperez Andres , Gomez-Roca Carlos Alberto , Berge Yann , Capdevila Jaume , Corral Jaime Jesus , Roda Perez Desamparados , Golding Sophie , Oppenheim David , Soehrman Brossard Sophia , Mancao Christoph , Farzaneh Farzin , Passioukov Alexandre , Manenti Luigi , Ott Marion Gabriele , Soria Jean-Charles
Published: February 2017

379

Background: EGFR-positive, KRAS-mutant mCRC patients (pts) do not benefit from anti-EGFR treatment. In this pt population we investigated the efficacy of single-agent GA201, a novel dual acting, anti-EGFR antibody which was glycoengineered to enhance ADCC on top of signaling blockage. This stimulation of immune effector cells may improve long term clinical outcomes. Methods: In an open-label, multicenter, non-randomized study, KRAS-mutant mCRC pts (1-2 prior chemotherapy lines) were treated with GA201 (1400 mg on day 1 and 8 then by 1400 mg q2W). The primary endpoint was to investigate tumor response. Here we report response rates, overall survival (OS) and pharmacodynamics analyses from archival, pre- and on-treatment biopsies and blood samples. Results: 25 pts received a median of 5 GA201 infusions (range 2–24), for up to 414 days. Median overall survival was 9.3 months (range 1.2 – 21.2). Best overall response was stable disease (40% of patients at 8 weeks), which was maintained in 24% of pts at 16 weeks, in 2 patients (8%) at 24 weeks and 1 pt (4%) at 42 weeks. Treatment-related adverse events were all manageable with rash (20% grade3), hypomagnesaemia (20% g3/4) and infusion-related reactions (4% g3) being the most common adverse events; none led to discontinuation or dose reduction. Comparison of pre- and post-treatment tumor biopsies evaluable for 11 pts revealed that tumor-infiltrating cell counts increased notably after one cycle of therapy (median composite immune reactive score of 1491 vs 898 cells/mm3 at baseline). In addition, it was noted that EGFR H-score in baseline tumor biopsies was notably higher than in archival tumors (median [range] 52 [13–161] vs 3 [1–81], respectively). High tumor immune cell infiltration at baseline might be associated with better treatment outcome and long-term survival. Conclusions: Encouraging OS is achieved with GA201 monotherapy in patients with KRAS-mutant tumors. The pharmacodynamics analyses support the hypothesis of triggering an enhanced long term immune response in this pretreated patient population. Clinical trial information: NCT00721266.