bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic strategy involving endoscopic resection for cN0 superficial carcinoma of the esophagus.
Authors: Iizuka T. , Kikuchi D. , Hoteya S.
Published: February 2017

1

Background: With the progress in endoscopic submucosal dissection (ESD) which enables en bloc resection irrespective of the size of lesion, a therapeutic strategy has become feasible whereby ESD is undertaken first, followed by considering additional treatment based on the results of histologic exploration. In this study, we attempted to clarify the clinical results in patients who had undergone additional treatment after endoscopic resection (ER) for cN0 superficial carcinoma.

Methods: Of 140 patients diagnosed as having T1a-MM-SM2 lesions of squamous cell carcinoma of the esophagus who had undergone ER between January 1998 and March 2010, 83 patients who received additional treatment after ER (surgery, 27 pts; chemoradiotherapy [CRT], 56 pts.) were the subjects of this study. The mean duration of observation was 45.1 months.

Results: The en bloc resection rate was 86%. There were 5 patients (6%) who had complications associated with ER, including perforation in 2 patients, secondary hemorrhage in a patient and pneumonia in 2 patients. Complications associated with additional treatment were noted in 13 patients (15.6%), including secondary hemorrhage, recurrent laryngeal nerve paralysis and pulmonary infarction in one patient each, pneumonia in 3, grade ≥ 3 myelosuppression in 5, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and radiation pneumonitis in one patient each. Long-term follow-up revealed no local recurrence and no patients who experienced late toxicity due to CRT. The tumor recurred in 4 patients, the site of recurrent lesion being the mediastinum in 3 patients and the cervical lymph node in one patient, of whom 2 patients died of the primary disease. The 5-year survival rate was 88.4%.

Conclusions: Endoscopic resection plus additional treatment for superficial carcinoma of the esophagus did not entail the development of any serious complications; thus, such combined treatment was safe and feasible. The long-term follow-up results were fairly gratifying, and ER with subsequent additional treatment is considered to be valid for patients with cN0 superficial carcinoma of the esophagus.

No significant financial relationships to disclose.
Phase II trial report of preoperative chemotherapy (CX) with S-1 plus cisplatin for stage IV gastric cancer (StIV GC).
Authors: Satoh S. , Okabe H. , Teramukai S. , Hasegawa S. , Ozaki N. , Ueda S. , Tsuji A. , Sakabayashi S. , Sakai Y. ,   Kyoto University Surgical Oncology Group
Published: February 2017

107

Background: Prognosis of StIV GC is poor. S-1 plus cisplatin now becomes one of the Japanese standards for unresectable or recurrent GC. We conducted a multicenter phase II study of preoperative S-1 plus cisplatin for StIV GC (KYUH-UHA-GC03-01, NCT00088816 ). In ASCO 2010, we reported early outcomes, indicating that this regimen is feasible and safe. We will report here the results concerning prognosis and recurrence.

Methods: Eligibility criteria included histologically proven StIV GC according to Japanese classification. Helical CT and staging laparoscopy were mandatory. Patients (pts) received oral S-1 (80-120 mg/body/day, day 1-21) and intravenous cisplatin (60 mg/m2 on day 8) every 5 weeks for 2 courses. After CX, operation was performed. S-1 (80-120 mg/body/day, day 1-14) was administered every 3 weeks for one year postoperatively. The primary endpoint was 2-year overall survival (OS), and the secondary endpoints were progression free survival (PFS), response, pathologic response, R0 resection, surgical complication, the first recurrence sites and toxicities. Sample size was set at 50.

Results: 51 pts were enrolled and all pts were observed more than 2 years after registration. The median age was 63 (range 35-79). PreOp CX was accomplished in 44 cases. Response was 50% (95% CI: 27.2-72.8). 44 (86.3%) pts underwent surgery and R0 resection was done in 26 pts (51%). Adjuvant chemotherarpy was accomplished in 11 cases. Recurrences were observed 14 cases (53.8%). Most frequent recurrence site was peritoneum. 2-Y OS and PFS were 43.1% [96% CI: 29.4-56.1] and 33.3% [20.9-46.2], respectively. R0 in GC with single StIV factor (n = 24) was 79.2% and that in GC with multiple StIV factors (n = 27) was 25.9%, respectively. All pts with only Cy+ (n = 12) showed complete eradication of cancer cell by S-1/CDDP. Pts with only Cy+ showed significantly better prognosis than other pts.

Conclusions: As compared to Japanese national StIV control (OS: 20.8%), this induction CX showed promising survival. Especially, pts with only Cy+ was popular and showed significantly better prognosis by S1/CDDP induction CX.

No significant financial relationships to disclose.
Gastric adenocarcinoma treated with radiation with or without epirubicin-based chemotherapy: Evaluation of radiation-induced liver disease.
Authors: Schoenfeld J. D. , Mamon H. J. , Blaszkowsky L. S. , Enzinger P. C. , Wo J. Y. , Allen J. N. , Wadlow R. C. , Ryan D. P. , Hong T. S.
Published: February 2017

110

Background: Anthracycline chemotherapy has been associated with radiation-induced liver disease (RILD). We sought to compare the incidence of liver toxicity among patients with gastric adenocarcinoma treated with radiotherapy (RT) with or without epirubicin-based chemotherapy.

Methods: We performed a retrospective analysis of 94 patients with gastric adenocarcinoma treated at Massachusetts General Hospital since November 2005 and the Dana-Farber Cancer Institute since August 1998. All patients underwent definitive surgery and RT (median dose 45 Gray) with a minimum follow up of 6 months. Primary endpoints were development of ascites, radiographic liver change and elevations in liver function tests (LFTs), including alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT).

Results: In total, 34 patients received epirubicin-based chemotherapy including 9 perioperatively (6 with oxaliplatin and capecitabine [EOX]; 2 with cisplatin and 5-flourouracil [ECF]; 1 with oxaliplatin and 5-flourouracil [EOF]) and 25 postoperatively (2 EOX; 22 ECF; 1 combination). Seven patients were treated with neoadjuvant RT; 87 received adjuvant RT a median of 88 days after surgery (interquartile range 73-108 days). Twenty-one patients developed ascites within 6 months of completing RT, all but one of whom developed peritoneal carcinomatosis or metastatic disease. Among 57 patients that did not develop metastases, maximum elevations in LFTs were similar in patients that received epirubicin-based chemotherapy compared to those who did not (ALP/AST/ALT 150/44/50 vs. 142/41/44, p=0.25/0.36/0.14, respectively), as were rates of radiographic liver change (22% vs. 13%, p=0.44).

Conclusions: Epirubicin-based chemotherapy does not significantly increase the risk of RILD in a recent cohort of patients treated with modern RT techniques and dose-constraints. In this setting, treatment of gastric adenocarcinoma with RT and either pre- or postoperative chemotherapy is well tolerated with low rates of liver toxicities. Development of liver toxicity, particularly ascites, within six months of RT may be a harbinger of metastatic disease.

No significant financial relationships to disclose.
Association of baseline health-related quality of life and survival in esophagogastric cancers.
Authors: Onate-Ocana L. F. , Mireles-de-Villafranca P. , Carrillo J. F. , Vilar-Compte D. , García-Hubard G. , Aiello-Crocifoglio V.
Published: February 2017

118

Background: Baseline health-related quality of life (HRQL) is a prognostic factor for survival in patients with cancer; however contradictory results have been reported. We studied whether HRQL scores are associated with survival in patients with esophagogastric cancers.

Methods: Patients with biopsy proven esophagogastric cancer were recruited prospectively. All were invited to respond the EORTC QLQ-C30 questionnaire. The prognostic role of usual clinical variables and HRQL data was analyzed dividing patients in two groups: 1) palliative intention or 2) curative intention treatments. The Kaplan-Meier and Cox's methods were used for bivariate or multivariate analysis, respectively.

Results: A total of 259 cases were included, 99 were woman and 160 male (mean age 54.3). One-hundred thirty-three patients of group one, presented significant association with survival in nine of 15 HRQL scales (p < 0.05). A multivariate model was constructed including basal serum albumin (hazard ratio [HR] 0.48; 95% confidence intervals [CI]: 0.34–0.68), Role functioning scale (HR 0.989; 95% CI: 0.98–0.99), Social functioning scale (HR 1.01; 95% CI: 1.005–1.019) and Nausea/Vomiting scale (HR 1.01; 95% CI: 1.01; 95% CI 1.006–1.02) (model p < 0.0001). One-hundred twenty-six patients of group two, presented significant association with survival in eight of 15 HRQL scales (p < 0.05). A multivariate model was constructed including definitive TNM stages (HR 8.7, 14.2, 10.1 for stages II, III and IV, respectively; reference category stage I), age (HR 1.04; 95% CI: 1.009–1.065), Social functioning scale (HR 0.98; 95% CI: 0.98–0.99), Pain scale (HR 1.024; 95% CI: 1.01–1.04) (model p < 0.0001).

Conclusions: These results suggest that HRQL provide significant prognostic information in addition to traditional clinical measures in patients with esophagogastric cancer. Prospective confirmatory studies are warranted.

No significant financial relationships to disclose.
Impact of adjuvant chemoradiotherapy on overall survival of gastric cancer patients with D2 lymphadenectomy.
Authors: Jácome A. A. , Wohnrath D. R. , Scapulatempo Neto C. , Fregnani J. T. , Viana L. S. , Santos L. V. , Maia D. C. , Santos J.
Published: February 2017

120

Background: Adjuvant chemoradiotherapy is the standard treatment in Western countries in gastric cancer patients submitted to curative resection. However, INT 0116 pivotal trial was hampered by suboptimal surgery. There is no efficacy data of this adjuvant therapy in patients who have undergone D2 lymphadenectomy predominantly.

Methods: Retrospective study with gastric adenocarcinoma patients stage II to IV M0 who underwent curative resection at Hospital de Câncer de Barretos between January 2002 and December 2007. Standard treatment at institution is D2 lymphadenectomy. Chemoradiotherapy according to INT 0116 was considered as an option for adjuvant therapy. A group of patients did not receive adjuvant therapy based on discretion of physician. We compared 3-year overall survival of the two treatments (chemoradiotherapy versus surgery alone). Survival curves were calculated according to Kaplan-Meier method and compared with log-rank test. Multivariate analysis of prognostic factors related to survival was performed by Cox proportional hazards model adjusted for age, stage and adjuvant chemoradiotherapy.

Results: 185 patients were included (61% male). Median age was 61 years old. 34% were stage II, 39% stage IIIA, 16% stage IIIB e 11% stage IV M0. D2 lymphadenectomy was performed in all patients. Eighty-one patients (44%) did not receive adjuvant therapy and one hundred and four received chemoradiotherapy. 3-year overall survival by Kaplan-Meier method was 64.4% for patients who received adjuvant therapy and 61.7% for those who underwent surgery alone (p = 0.415). However, according to Cox proportional hazards model, adjuvant chemoradiotherapy was a prognostic factor for overall survival (HR: 0.52, IC 95% 0.31 – 0.87, p: 0.014), as well as stage (p < 0.001). Age did not present influence on overall survival (p = 0.328).

Conclusions: Adjuvant chemoradiotherapy decreased risk of death in three years in patients who underwent curative resection with D2 lymphadenectomy, with a meaningful hazard ratio in our study, and should remain as standard treatment. Ongoing trials will elucidate the role of radiotherapy in this subgroup of patients.

No significant financial relationships to disclose.
Outcomes associated with T4 esophageal cancer.
Authors: Meredith K. , Weber J. , Shridhar R. , Hoffe S. E. , Almhanna K. , Melis M. , Biagioli M. , Mcloughlin J. , Barthel J. S. , Karl R. C.
Published: February 2017

130

Background: Esophageal cancer often presents as locally advanced disease with 15% of patients having T4 tumors upon diagnosis. Esophagectomy was often reserved for palliation given the dismal survival rates and high rates of R1/R2 resections. However, neoadjuvant therapy (NT) has the potential to significantly downstage esophageal cancers and thus increase complete resection rates. We report our experience with surgically resected T4 cancers of the esophagus.

Methods: Using a comprehensive esophageal cancer database, we identified patients who underwent an esophagectomy for T4 tumors between 1994 and 2008. Neoadjuvant therapy and pathologic response were recorded and denoted as complete (pCR), partial (pPR), and non-response (NR). Clinical and pathologic data were compared using Fisher's exact and chi-square when appropriate while Kaplan Meier estimates were used for survival analysis.

Results: We identified 39 patients with T4 tumors who underwent esophagectomy of which 38 (97%) underwent NT. The median age was 61 (31-79) years with a median follow-up of 32 (5-97) months. There were 3 (7.9%) pCR, 17 (44.7%) pPR, and 18 (47.4%) NR. R0 resections were accomplished in 37 (94.9%). Two patients had incomplete resections. One patient had a R2 resection after NT and was deemed as NR. An additional patient had a R1 resection after NT and was a pPR with a residual 0.2 cm tumor on permanent pathology. There were 14 (35.9%) recurrences with a median time to recurrence of 19.5 (4-71) months. Complete pathologic response represented 1 (7.1%), whereas pPR and NR represented 6 (42.9%), and 7 (50%) respectively of all recurrences. The overall and disease free survival for all patients with T4 tumors was 28% and 34% respectively. Patients achieving a pCR had a 5-year overall and disease free survival of (43% and 47%), compared to pPR (30% and 21%) while there were no 5-year survivors in the NR cohort.

Conclusions: T4 esophageal cancer often portends a dismal prognosis even after surgical resection. Historical incomplete resections and dismal survival rates often make surgery palliative rather then curative. However, we have demonstrated that neoadjuvant therapy and down staging of T4 tumors leads to increased R0 resections and improvements in overall and disease free survival.

No significant financial relationships to disclose.
The efficacy and tolerability of modified docetaxel, cisplatin, and 5FU in patients with advanced or recurrent gastric cancer: A retrospective analysis.
Authors: Kim J. , Park K. , Yi S. , Lee H.
Published: February 2017

146

Background: Docetaxel, cisplatin, and 5FU (DCF) significantly improved TTP, OS, and response rate in gastric cancer patients, but resulted in some increase in toxicity compared with cisplatin and 5FU (CF) in multinational study such as V325 report. The main goal of this study is to report the experience of a single center about efficacy and tolerability of modified DCF in advanced or recurrent gastric cancer patients.

Methods: A total of 23 patients with advanced or recurrent gastric cancer who had been treated with modified docetaxel, cisplatin and 5FU (mDCF) at Seoul Paik Hospital between Feb 2009 and June 2010 were included. Treatment protocol was 60 mg/m2 of docetaxel, 50 mg/m2 of cisplatin on D1, and 950 mg/m2/day of 5FU continuous infusion on D1-3 until disease progression or intolerance to chemotherapy. Clinical data were collected retrospectively.

Results: Twenty-one patients were assessable for response. The ORR was 34.8% (8/23), and DCR 69.6% (16/23). Median PFS and OS were 6.8 months (95% CI, 3.8-9.8) and 11.9 months (95% CI, 6.6-17.2). The main toxicities were anorexia, diarrhea, and neuropathy. Grade 3 or 4 hematologic toxicities were neutropenia in 4 patients (17.4%), leukopenia in 5 patients (21.7%), anemia in 2 patients (8.7%) and thrombocytopenia 1 patient (4.3%). The treatment related death occurred in 1 patient (4.3%) due to febrile neutropenia. The median cycle was 5. Ten patients (43.5%) received chemotherapy more than 8 cycles with tolerable toxicities.

Conclusions: Compared with previous studies, the presented mDCF showed a lower ORR, but more acceptable toxicities profiles, and similar PFS and OS in patients with advanced gastric cancer.

No significant financial relationships to disclose.
MicroRNA expression profiles associated with pancreatic cancer.
Authors: Schultz N. A. , Werner J. , Willenbrock H. , Roslind A. , Horn T. , Wøjdemann M. , Johansen J. S.
Published: February 2017

153

Background: The aim was: 1) to define the global microRNA (miRNA) expression pattern in pancreatic cancer (PC) and compare it with normal pancreas (NP) and chronic pancreatitis (CP); 2) to validate reported diagnostic miR profiles in PC; 3) to discover new diagnostic miRs in pancreas samples without micro-dissection of cancer cells.

Methods: MiR expression patterns in FFPE tissue blocks from patients operated for pancreatic ductal adenocarcinoma (PDAC, n=170) and ampullary adenocarcinomas (A-AC, n=107) were determined using TaqMan Human miR microarrray (Applied Biosystem; 754 miRs were determined) and compared to profiles of CP (n=23) and NP (n=28). Raw Ct-values were normalized using quantile-normalisation.

Results: 83miRs were differentially expressed in PDAC and NP (42 higher expression; 41 reduced expression in PDAC). 32 miRs were differentially expressed in PDAC and CP. The most differentially expressed miRs were miR-614, miR-492, miR-622, miR-135b* and miR-196. The miR signatures of PDAC and A-AC were highly correlated (0.99; only 5 miRs were significantly differentially expressed). An earlier reported diagnostic miR profile for PDAC was validated (mirR196b - miR217), and 3 other significant profiles were identified (Table). A more complex Lasso classifier using 19 miRs could separate PDAC from NP and CP (accuracy = 98%).

Conclusions: We identified systematic differences in patterns of miR expressions between tumor tissue including both cancer cells and surrounding desmoplasia obtained from patients with PDAC and A-AC compared to tissue from patients with CP and NP. We validated the diagnostic miR expression profile (miR-196b, miR-217) described by Szafranska et al. (Clin Chem 2008;54:1716-24). Furthermore, we identified 5 miRs which were better to discriminate PDAC and A-AC from CP and NP. Prospective studies are needed to evaluate if this panel of miRs is useful for early diagnosis of patients with PDAC.

[Table: see text]

No significant financial relationships to disclose.
A molecular prognostic nomogram for resectable pancreatic cancer.
Authors: Chang D. K. , Colvin E. K. , Scarlett C. J. , Pajic M. , Pinese M. , Gill A. J. , Musgrove E. A. , Sutherland R. , Kench J. , Biankin A. V. ,   New South Wales Pancreatic Cancer Network
Published: February 2017

154

Background: Defining clinically and biologically relevant phenotypes in other cancers has led to substantial improvements in the overall outcomes, but as yet none have been defined for pancreatic cancer (PC). About 80% of patients with pancreatic cancer succumb to the disease despite curative resection, many of whom within 6 months of surgery. There is a clear need to better define the biology and clinical behaviour of PC. This study aimed to evaluate the potential clinical utility of biologically relevant molecules as prognostic factors in resected PC.

Methods: We assessed the relationship of aberrant S100A4 calcium-binding protein expression with survival in a cohort of 372 patients who underwent surgical resection for PC and derived a nomogram using clinicopathologic variables and aberrant expression of S100A4 and S100A2.

Results: High S100A4 expression was an independent poor prognostic factor in both the training (n = 76; HR = 5.00, 95% CI = 2.29 – 10.9; p < 0.0001) and validation sets (n = 296; HR = 1.78, 95% CI = 1.29 – 2.46; p = 0.0004). Incorporating previously published data on S100A2, demonstrated that high expression of S100A4 was still an independent prognostic factor. Aberrant expression of these proteins stratified the cohort into three distinct prognostic groups. A preoperative nomogram using only variables that could be measured preoperatively (tumor size and molecular biomarkers), predicted survival better than nomograms derived from using clinicopathologic variables, which are only determined after examination of the resected specimen.

Conclusions: Aberrant expression of S100A4 and S100A2 stratifies PC into distinct prognostic groups and improves the accuracy of prognostic nomograms using variables that can be determined preoperatively. The development and application of such nomograms in routine clinical practice has the potential to improve patient selection and as a consequence overall outcomes for PC.

No significant financial relationships to disclose.
Everolimus plus octreotide LAR (E+O) versus placebo plus octreotide LAR (P+O) in patients with advanced neuroendocrine tumors (NET): Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-2).
Authors: Yao J. C. , Hainsworth J. D. , Baudin E. , Peeters M. , Hoersch D. , Anthony L. B. , Klimovsky J. , Grouss K. , Jehl V. , Pavel M.
Published: February 2017

159

Background: Octreotide LAR has been the foundation of NET therapy; however, additional treatment options are needed. Everolimus, an oral inhibitor of mTOR, demonstrated promising antitumor activity in patients with NET as a single agent and in combination with octreotide LAR in two phase II studies.

Methods: Patients (n = 429) with well or moderately differentiated advanced NET and history of carcinoid symptoms received oral everolimus 10 mg/d + octreotide LAR 30 mg IM q 28 days (n = 216) or placebo + octreotide LAR (n = 213). Common primary sites included the small intestine, lung, and colon. The primary endpoint was progression-free survival (PFS) per central review by RECIST. Crossover from P+O to open-label E+O was allowed at disease progression.

Results: Median PFS (95% CI) with E+O was 16.4 months (13.67-21.19) vs. 11.3 months (8.44-14.59) for P+O. E+O was associated with a 23% reduction in risk of progression: HR = 0.77; 95% CI: 0.59-1.00; one-sided p-value = .026 (pre-specified significance boundary is p ≤ .0246). A high rate of informative censoring resulted in loss of power in central review results. Correcting for the informative censoring bias, the pre-specified marginal Cox model using inverse probability of censoring weights (IPCW) analysis showed a significant 5.5-month improvement in median PFS with E+O; HR = 0.60; 95% CI: 0.44-0.84, with one-sided p-value = .0014. The benefit of E+O was seen across all patient subgroups. Updated analyses of the impact of pre-study and post-progression octreotide LAR therapy will be reported. Most frequent drug-related adverse events (AEs) with E+O were stomatitis, rash, fatigue, and diarrhea; mostly grade 1-2. Grade 3-4 AEs reported in >5% were stomatitis, fatigue, diarrhea, infections, and hyperglycemia.

Conclusions: In this large phase III trial, E+O provided a 5.1-month clinically meaningful increase in median PFS compared with P+O in the central adjudicated review. Correcting for the informative censoring bias, a significant PFS improvement of 5.5 months was seen, with a p value = .0014. The safety profile of E+O was acceptable.

[Table: see text]
Surgical density and its effect on esophageal cancer (EC) and gastric (GC) mortality.
Authors: Ho M. Y. , Albarrak J. S. , Cheung W. Y.
Published: February 2017

16

Background: Surgical resection plays an integral role in the multimodality treatment of patients with EC or GC. The distribution of thoracic and general surgeons at the county level varies widely across the US. The impact of the allocation of these surgeons on cancer outcomes is unclear. Our aims were to 1) examine the effect of surgeon density on EC or GC mortality, 2) compare the relative roles of thoracic and general surgeons on EC and GC outcomes and 3) determine other county characteristics associated with cancer mortality.

Methods: Using county-level data from the Area Resources File, U.S. Census and National Cancer Institute, we constructed regression models to explore the effect of thoracic and general surgeon density on EC and GC mortality, respectively. Multivariate analyses controlled for incidence rate, county demographics (population aged 65+, proportion eligible for Medicare, education attainment, metropolitan vs. rural), socioeconomic factors (median household income) and healthcare resources (number of general practitioners, number of hospital beds).

Results: In total, 332 and 402 counties were identified for EC and GC, respectively: mean EC/GC incidence = 5.29/6.83; mean EC/GC mortality=4.70/3.92; 91% were metropolitan and 9% were rural; mean thoracic and general surgeon densities were 10 and 63 per 100,000 people, respectively. When compared to counties with no thoracic surgeons, those with at least 1 thoracic surgeon had reduced EC mortality (beta coefficient -0.031). For GC, counties with 1 or more general surgeons also had decreased number of deaths (beta coefficient -0.095) when compared with those without any surgeons. While increasing the density of surgeons beyond 10 only yielded minimal improvements in EC mortality, it resulted in significant further reductions in GC mortality. Other county characteristics, such as increased number of hospital beds and higher median household income, were correlated with improved outcomes.

Conclusions: Mortality from GC appears to be more susceptible to the benefits of increased surgeon density. For EC, a strategic policy of allocating health resources and distributing the workforce across counties will be best able to optimize outcomes at the population-level.

No significant financial relationships to disclose.
Intrahepatic cholangiocarcinoma: An international, multi-institutional analysis of prognostic factors and lymph node assessment.
Authors: Pawlik T. M. , Pulitano C. , Alexandrescu S. , Gamblin T. C. , Ferrone C. , Sotiropoulos G. , Marques H. , Bauer T. W. , Gigot J. , Mentha G. ,   International Intrahepatic Cholangiocarcinoma Collaborative Group
Published: February 2017

162

Background: Intrahepatic cholangiocarcinoma (ICC) is a rare and poorly understood primary liver cancer. The role of routine lymphadenectomy at the time of surgical resection remains poorly defined. We sought to identify factors associated with outcome following surgical management of ICC and examine the impact of lymph node (LN) assessment on survival.

Methods: 411 patients who underwent curative intent surgery for ICC between 1973-2010 were identified from an international multi-institutional database. Clinical and pathologic data were evaluated using uni- and multivariate analyses.

Results: Median tumor size was 6.5 cm. Most patients had a solitary tumor (55%) and no evidence of vascular invasion (64%). Resection involved ≥hemi-hepatectomy (74%) and margin status was R0 (82%). Overall median survival was 28 months and 5-year survival was 32%. Factors associated with adverse prognosis included positive margin status (HR=3.11; p<0.001), multiple lesions (HR=2.16; p=0.007) and vascular invasion (HR=2.13; p=0.01). Tumor size was not a prognostic factor (HR=1.05; p=0.08). Lymphadenectomy was performed in 233 (57%) patients; 87 (37%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0 39 months vs. N1 21 months; p=0.02). Preoperative factors such as tumor size, number, and morphologic subtype did not predict presence of LN metastasis (all p>0.05); however, vascular invasion did (OR=2.24; p=0.003).

Conclusions: While tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. Presence of LN metastasis cannot be predicted using preoperative tumor features. Lymphadenectomy should be routinely performed for ICC as up to one-quarter of patients will have LN metastasis.

No significant financial relationships to disclose.
A comparison of competing lymph node staging schemes in resectable biliary cancer.
Authors: Smith D. D. , Nelson R. A. , Schwarz R.
Published: February 2017

166

Background: New schemes for lymph node (LN) staging have been proposed to improve upon the AJCC TNM cancer staging convention. We compared AJCC N0/N1 staging with the LN ratio and logarithmic odds systems in predicting overall survival (OS) in resectable biliary cancer patients, including cancer of the gallbladder, extrahepatic bile duct (EHBD), and ampulla of Vater (AOV).

Methods: In a large, multiinstitutional U.S.-based biliary cancer data set, we identified 4,288 nonmetastatic resectable biliary cancer patients diagnosed between 1988 and 2006. We compared each subject's AJCC N stage with the two novel staging schemes. We split patients into two groups above or below the median for the two novel staging schemes and analyzed OS. Our comparison metric was the log-rank chi-squared statistic. As a baseline comparator, we included the median number of LNs resected.

Results: Median (range) of follow- up was 2.5 years (1 month–19 years), with an overall median survival of 2.0 years (95% CI: 2.0–2.1 years). For all biliary patients combined, we found that the AJCC N0/N1 system and LN ratio schemes performed similarly. For gallbladder cancers (N= 1,340), LN ratio showed higher OS prediction utility, whereas in EHBD (N= 1,083) and AOV cancers (N= 1,865), AJCC staging was superior among competing methods.

Conclusions: The LN ratio method is comparable with AJCC N staging for OS prediction, although the AJCC scheme is superior in two of three biliary cancers. We conclude that AJCC staging remains adequate for staging biliary cancers given the newer staging proposals.

[Table: see text]

No significant financial relationships to disclose.
The actual accuracy of endoscopic ultrasound for detailed tumor depth determination in nonserosal exposed gastric cancer: What should we do to increase the accuracy of endoscopic ultrasound?
Authors: Lee H. , Lee J. H.
Published: February 2017

20

Background: The accuracy of endoscopic ultrasound (EUS) for preoperative staging of gastric cancer varies. The aim of this study was to investigate the accuracy of EUS T and N staging in all and non-serosal exposed cases and identify the histopathological factors influencing accuracy.

Methods: A total of 309 gastric cancer patients with confirmed pathological staging underwent EUS examination for preoperative staging at Seoul St. Mary's Hospital, Korea, between January and December 2009. Of these, 262 patients were diagnosed with non-serosal exposed gastric cancer.

Results: Overall accuracies of EUS for T stage, the detailed T stages of all cases, and the detailed T stage in the non-serosal exposed group were 70.2%, 43.0%, and 41.2%, respectively. In the non-serosal exposed group, tumors greater than 5 cm in diameter were significantly associated with T overstaging (odds ratio [OR], 2.583). The overall accuracies of EUS for N staging in all cases and in the non-serosal exposed group were 71.2% and 76.7%, respectively. Tumor size (2 cm ≤ size < 5 cm; OR, 4.467; and 5 cm ≤ size; OR, 8.668) and tumor depth (submucosa; OR, 3.267; muscular propria; OR, 6.675 and subserosa; OR, 4.831) were significant factors affecting incorrect nodal detection in non-serosal exposed gastric cancer cases.

Conclusions: Careful attention is required during EUS examination of large-sized gastric cancers to increase accuracy, especially for T staging.

No significant financial relationships to disclose.
Comparison of ampullary adenocarcinomas and duodenal adenocarcinomas with regard to clinical outcomes and responsiveness to fluoropyrimidine-based chemotherapy.
Authors: Overman M. J. , Jiang Z. , Lal A. , Fleming J. B. , Varadhachary G. R. , Abbruzzese J. L. , Wolff R. A.
Published: February 2017

204

Background: Though adenocarcinomas of the ampulla of Vater are classified as biliary cancers, the epithelium of origin and treatment approach for these rare tumors remains controversial. Gene expression profiling of periampullary carcinomas (GI ASCO 2011) suggest that ampullary carcinomas are more akin to duodenal than pancreaticobiliary carcinomas.

Methods: Review of a M. D. Anderson Cancer Center (MDACC) periampullary surgical database from 1/1990 to 3/2010 identified 670 pancreatic, 41 extrahepatic biliary, 63 duodenal, and 131 ampullary adenocarcinomas resected at MDACC. Review of the MDACC tumor registry from 5/1990 to 1/2009 identified 240 stage I-III surgically resected ampullary adenocarcinomas seen at MDACC. 46 patients met the following inclusion criteria: MDACC confirmed pathology, distant metastatic relapse, and ≥1 cycle of either gemcitabine or fluoropyrimidine (5-FU) based first-line chemotherapy with follow-up imaging evaluation.

Results: 5-year OS of patients with ampullary cancer did not differ from duodenal cancer (62% vs. 66%, p=0.19) but was significantly different from biliary (24%, p<0.001), and pancreatic cancer (17%, p<0.001). When ampullary (n=131) and duodenal (n=63) cases were stratified by T stage (T1/T2, T3/T4) or N stage (N0, N1) no statistically significant differences in OS were seen. First-line chemotherapy for metastatic ampullary carcinoma was 5-FU based in 27 patients (single agent 8, platinum 18, other 1) and gemcitabine based in 19 patients (single agent 7, platinum 8, other 4). Similar rates of prior adjuvant/neoadjvuant chemotherapy use (55% vs. 64%) and time to distant metastases (18 vs. 17m) were seen in the 5-FU and gemcitabine groups, respectively. 5-FU based chemotherapy was associated with an improved median TTP (9.1m v 4.8m, p=0.05) and trended to improve RR (44% v 21%, p=0.13) and median OS (16m vs. 12.7m, p=0.14).

Conclusions: OS of resected ampullary carcinomas is similar to duodenal carcinomas but not biliary or pancreatic carcinomas. Preliminary data suggest that metastatic ampullary carcinomas may benefit more from a fluoropyrimidine-based as opposed to gemcitabine-based chemotherapy.

[Table: see text]
The significance of serum interleukin-10 on the outcome of unresectable hepatocellular carcinoma (HCC).
Authors: Chan S. L. , Mo F. , Wong S. C. , Hui E. P. , Loong H. H. , Mok T. , Chan A. T. , Yeo W.
Published: February 2017

205

Background: Serum interleukin-10 (IL-10) is associated with active hepatitis in patients (pts) with hepatitis B viral (HBV) infection. In HBV-related HCC, elevation of serum IL-10 is frequently observed but its significance on the outcome of HCC is unclear.

Methods: A prospective cohort of newly diagnosed and inoperable HCC was recruited from a multidisciplinary clinic from Prince of Wales Hospital from 2006 to 2008. The baseline demographics, tumor characteristics/stage, laboratory parameters, virologic factors (HBV DNA, antiviral therapy) and first-line treatment modality were documented at the time of diagnosis. Serum IL-10 was measured by enzyme-linked immunosorbent essay. Univariate and multivariate analyses were conducted. Overall survival (OS) was the primary endpoint.

Results: Total 180 new cases of inoperable HCC were evaluated. The median follow-up time was 15.5 months. Median age was 60.5 years. Most (159 pts; 88.3%) were males. 81.1% of them were positive for HBsAg. Total 120 (66.7%) had radiologic evidence of cirrhosis. 20 (11.1%), 85 (47.2%) and 75 (41.7%) received locoablative, trans- arterial/systemic therapy and supportive care respectively. The mean level of serum IL-10 was 18.1pg/ml (range: 2.8-11.7). 114 (63.3%) had log IL-10 higher than 1.0 pg/ml. Pts with log IL-10 >1.0 pg/ml had significantly worse OS than those with log IL-10≤ 1.0 pg/ml (14.8 vs. 4.5 months; HR 2.39; p<.0001). Multivariate analysis found log IL-10 (HR=2.57; p=0.005), CLIP score, TNM stage, treatment modality and the use of anti-viral therapy for HBV infection be the independent prognostic factors. Exploratory analyses showed that pts with Log IL-10>1.0pg/ml had higher ALT and HBV DNA, lower albumin, higher chance of ascites, worse Child-Pugh stage and worse tumor stage (Table).

Conclusions: Serum IL-10 is an independent prognostic factor for inoperable HCC. Pts with high IL-10 level have poorer liver reserves and worse tumor staging.

[Table: see text]

No significant financial relationships to disclose.
Effect of a novel FAK inhibitor targeted to the binding site of VEGFR3 on pancreatic cancer proliferation in vitro and in vivo.
Authors: Kurenova E. V. , Liao J. , He D. , Hunt D. L. , Chekhau A. , Hochwald S. N. , Ostrov D. A. , Cance W. G.
Published: February 2017

214

Background: Even with successful surgical resection and treatment pancreatic adenocarcinoma has a high incidence of recurrence because of metastatic spread. Vascular endothelial growth factor receptor 3 (VEGFR3) is related to lymphatic metastasis. VEGFR3 binds to the survival protein, focal adhesion kinase (FAK), to promote pancreatic cancer (PC) lymphangiogenesis. In this study we have pinpointed the site of interaction of VEGFR3 and FAK to create drug capable of disrupting their signaling with antitumor effect.

Methods: 200,000 small molecules were screened in silico for their abilities to interact with the VEGFR3 /FAK binding site. Effects of the selected compounds on PC cell lines MiaPaCa2 and Panc1 were examined by MTT assay (viability), BrdU incorporation (proliferation), Boyden chamber (motility), TUNEL and flow cytometry (cell cycle, apoptosis), and Western blot (phosphorylation, apoptosis).

Results: We selected compound C4 because it disrupted the FAK-VEGFR3 complexes in PC cells, as was shown by immunoprecipitation. It caused a dose-dependent dephosphorylation and inactivation of the VEGFR3. Inhibition of VEGFR3 with 10μM of C4 resulted in 80% reduction in cell viability, decrease in proliferation and a 50% reduction in motility. Treatment led to apoptosis in PC cells, confirmed by PARP cleavage. C4 increased the sensitivity of PC cells to chemotherapy in vitro. MiaPaca2 have shown 40% apoptosis after only 24 h of treatment with combination of C4 and gemcitabine at nanomolar concentrations ineffective alone. C4 reduced tumor growth in vivo in murine models of PC. C4 (60 mg/kg, daily IP) decreased tumor growth after 21 days of treatment to 60% (P=0.017). Lower dose of the C4 (10 mg/kg) still had an effect and inhibited tumor growth by 30%, but concomitant administration with low dose of gemcitabine (4 mg/kg, Q4dx6), had significant synergistic effect and led to 80% of tumor reduction. We also have shown that combination of C4 with gemcitabine had prolonged cytostatic effect on tumor growth after treatment withdrawal.

Conclusions: Targeting the scaffolding function of FAK with the small-molecule inhibitors can be effectively used to develop potential oral-based PC therapeutics.

[Table: see text]
Association of tumor PDGFR-α and PDGFR-β expression and survival after resection of hepatocellular carcinoma.
Authors: Patel S. H. , Kneuertz P. J. , Delgado M. , Cohen C. , Sarmiento J. , Staley C. A. , Kooby D. A. , Farris A. B. , Maithel S. K.
Published: February 2017

220

Background: Hepatocellular carcinoma (HCC) proliferates through angiogenic pathways mediated, in part, by vascular endothelial growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptors (PDGFR) α and β. We hypothesized that overexpression of these proteins is associated with decreased survival after resection.

Methods: 57 patients with available tissue for analysis who underwent liver resection for HCC between 8/00 and 3/08 at one institution were identified from a prospectively maintained database. Tumors were assessed by immunohistochemistry for VEGFR2, PDGFR-α, and PDGFR-β expression and were graded by a single pathologist. Primary outcome was overall survival (OS).

Results: Median age was 64 yrs; 65% were male. Median F/U was 25 mo, and OS was 26 mo. Median tumor size and number were 7 cm and 1, respectively. Macro- and microvascular invasion were present in 9% and 42% of patients, respectively. 25% had tumors that met Milan criteria. 9% had positive resection margins. 35% of patients had cirrhosis and the median nonadjusted MELD score was 7.5. Tumors exhibited differential expression of VEGFR2 (low: 79%, high: 21%), PDGFR-α (low: 93%, high: 7%), and PDGFR-β (low: 96%, high: 4%). After excluding all 30-day deaths (n=7), high PDGFR-α and β expression were independently associated with decreased OS (8.7 vs 29.1 mo, p=0.01; 2.8 vs 28.8 mo, p<0.001; respectively). When adjusted for tumor burden, margin status, and MELD score on independent multivariate analyses, both PDGFR-α and β expression were predictive of decreased survival (Table).

Conclusions: High PDGFR-α and PDGFR-β expression are independently associated with decreased overall survival after resection of HCC. This finding may help to select patients who would benefit from targeted inhibitor therapy in the adjuvant setting.

[Table: see text]

No significant financial relationships to disclose.
Effect of diferuloyl methane (curcumin) on radiation-induced inhibition of proliferation and cytotoxicity of pancreatic cancer cells.
Authors: Tuli R. , Surmak A. , Herman J. M.
Published: February 2017

222

Background: Pancreatic ductal adenocarcinoma carries a dismal prognosis. Unfortunately, the majority of patients present with locally advanced or metastatic disease unamenable to resection, and the benefit of radiation therapy (RT) in this population is not well substantiated. Diferuloyl methane (curcumin) is a naturally occurring polyphenol derived from the spice turmeric. Although it has been shown to have anticancer properties, it has not been well studied with radiation, particularly for pancreatic cancer. Herein, we attempt to determine whether curcumin can sensitize pancreatic cancer cells to radiation.

Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were utilized for studies. Cells were treated with curcumin (10 nM to 1 mM), RT (1 to 9 Gy), or combinations thereof and compared to untreated controls. Cells were irradiated using a 137-Cs GammaCell in a single fraction. If applicable, cells were pretreated with curcumin one hour prior to RT. Cell viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3 and -7 activities using a luminescent assay.

Results: Treatment with curcumin alone led to minimal inhibition of proliferation until concentrations exceeded 10 uM. The half maximal inhibitory concentration (IC50) was 40 uM and the IC20 was 10 uM. Cells experienced a dose- dependent inhibition of proliferation with increasing RT doses (IC20 of 5 Gy). Combined treatment with IC20 of curcumin and RT led to a synergistic increase in inhibition of proliferation (70%). The RT dose enhancement factor was 2.5 with 100 uM curcumin and 5 Gy. Caspase 3/7 activity was not significantly enhanced by treatment with curcumin alone (10 uM), but increased significantly when RT was added (5 Gy; p<.01).

Conclusions: Curcumin is a potent radiosensitizer of pancreatic cancer cells that synergistically enhances the effects of RT. It has minimal effects on proliferation and apoptosis when used as a single agent at lower doses. Curcumin also potentiates RT-induced cytotoxicity through induction of apoptosis. These data are currently being validated in an orthotopic pancreatic cancer model.

No significant financial relationships to disclose.
Sorafenib plus cisplatin and gemcitabine in the treatment of advanced hepatocellular carcinoma (HCC): A phase II study by the Gruppo Oncologico dell'Italia Meridionale (prot. GOIM 2705).
Authors: Giuliani F. , Febbraro A. , Addeo R. , Rizzi D. , Maiello E. , Del Prete S. , Pisconti S. , Colucci G.
Published: February 2017

225

Background: Sorafenib is the standard treatment in advanced HCC. The combination of cisplatin and gemcitabine demonstrated to be active and well tolerated in tumors with a similar poor outcome such as pancreatic and biliary-tract cancers. Considering these data, the GOIM started a phase II trial aiming to evaluate the activity and safety of the combination of sorafenib, gemcitabine and cisplatin in advanced HCC.

Methods: Patients affected by advanced HCC, not suitable for surgery or locoregional procedures, with measurable disease (Recist criteria), age ≥ 18 years, clip-score ≤3, ECOG performance status ≥ 60 (K.fsky), adequate bone marrow reserve and renal and hepatic function and who signed written informed consent, were enrolled and received cisplatin 40 mg/mq iv plus gemcitabine 800 mg/mq iv bi-weekly, while sorafenib was orally administrated at the dosage of 400 mg bid continuously. A maximum of 6 cycles of chemotherapy was planned; a maintenance with sorafenib was permitted for not progressing patients. The evaluation of activity was performed every three cycles. A Simon's two stage, two steps study design was applied: at the first step, at least 3 OR had to be observed among the first 28 patients to continue the enrollment. Up to now, 23 patients have been enrolled. Their main characteristics were: sex (male/female) 19/4, median age: 70 yrs, median PS 80,main sites of disease liver 22, lymph nodes 4, lung 2, others 3.

Results: Up to now 18 patients are evaluable for activity while 5 are too early. One CR, 3 PR, 6 SD and 8 PRO for an ORR of 4/18 (22%) and a tumor control of 10/18 (55%). Twenty-one patients are evaluable for safety. The main observed side effects (%G1-2/G3-4) (NCI criteria) were: hand-foot skin reaction (HFSR) 9/14, mucositis 9/4, diarrhea 23/4, nausea/vomiting 23/0, leucopenia 23/0, anemia 9/0, thrombocytopenia 19/4, asthenia 14/14, cardiovascular 0/4, others 9/4.

Conclusions: Our preliminary data seems to demonstrate that the combination of cisplatin, gemcitabine, and sorafenib is active and well tolerated in advanced HCC patients. The accrual is ongoing.

No significant financial relationships to disclose.
Retrospective analysis of first-line chemotherapy in 132 patients with advanced small-bowel adenocarcinoma.
Authors: Tsushima T. , Boku N. , Honma Y. , Takahashi H. , Ueda S. , Nishina T. , Kawai H. , Kato S. , Suenaga M. , Tamura F.
Published: February 2017

260

Background: No standard care has been established for advanced small-bowel adenocarcinoma (SBA). The aim of this study is to explore a most promising chemotherapy regimen for advanced SBA.

Methods: All data were collected from medical records of patients with advanced or recurrent SBA who received chemotherapy between April 1999 and March 2009 at 41 hospitals in Japan. Selection criteria were as follows: 1) histologically proven SBA, excluding ampullary carcinoma, 2) no previous chemotherapy or radiotherapy, 3) ECOG PS 0-2, 4) adequate bone marrow, hepatic and renal functions, 5) no concomitant malignancy. Patients were divided into the five groups by regimens: group A, fluoropyrimidine alone; group B, fluoropyrimidine + cisplatin; group C, fluoropyrimidine + oxaliplatin; group D, fluoropyrimidine + irinotecan; group E, others. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method.

Results: Demographics of selected 132 patients were: median age (range), 59 (23-78) years; male/female, 87/45; location of primary tumor, duodenum/jejunum/ileum/unknown, 80/32/17/3; advanced/recurrent disease, 91/41. The numbers of the patients in group A, B, C, D and E were 60, 17, 22, 11 and 22, and objective response rates (ORR) in the patients with target lesions were 20% (9/46), 38% (5/13), 42% (8/19), 25% (2/8), 21% (4/19), respectively. Median PFS and OS were 6.0 and 14.0 months for the whole population, and those in each group are shown in the Table.In comparison with fluoropyrimidine alone (A), oxaliplatin-combined regimens (C) associated with better PFS (HR=0.53 [0.31-0.93], p=0.03) and OS (HR=0.64 [0.33-1.25], p=0.19), while cisplatin-combined regimens (B) did not (HR=1.54 [0.88-2.68], p=0.13 for PFS and HR=1.67 [0.94-2.97], p=0.08 for OS) by univariate analysis.

Conclusions: It is suggested that oxaliplatin-combined regimens might be the most promising regimen for advanced SBA.

[Table: see text]

No significant financial relationships to disclose.