bluuebunny/crossref_metadata_2025 huggingface dataset:
Incorporation of laparoscopic D2 dissection into the management of gastric adenocarcinoma (GCa) in a community-based setting.
Authors: Bischof Danielle Anna , Swallow Carol Jane , Stotland Peter Kenneth , Hagen John Anstruther , Klein Lazar Victor
Published: February 2017

117

Background: A recent meta-analysis suggests that lymph node (LN) retrieval may be inferior when gastrectomy for GCa is performed laparoscopically rather than open. The purpose of this study was to examine the pathologic evaluation, postoperative morbidity and receipt of adjuvant treatment associated with adoption of D2 lymphadenectomy in a community setting.

Methods: Routine D2 LN dissection was instituted as part of laparoscopic GCa resection at two community hospitals in Toronto in July 2008. Sequential cases up to Feb 2011 were identified and charts reviewed retrospectively. LN retrieval, margin status, morbidity, mortality and receipt of adjuvant treatment were examined.

Results: Twenty-nine patients were identified; 69% were male and the median age was 69 (28-84). All patients underwent D2 lymphadenectomy, 10 with total gastrectomy (TG) and 19 with subtotal (STG). Pathologic evaluation showed that all patients underwent an R0 resection. Median number of LNs retrieved was 32 (15-62) and 93% of patients had adequate LN assessment according to AJCC 7 staging criteria. Sixty-five percent of patients had nodal metastases. There were 8 major complications in 7 patients including 3 post-operative deaths (10% mortality): one patient died in hospital from anastomotic leak and two after discharge from PE (1) and evisceration through the specimen extraction site (1). Four patients commenced neoadjuvant chemotherapy, but only 2 completed the planned pre-operative regimen. Ten additional patients started post-operative adjuvant chemo-radiotherapy, but only 5 completed it. Fifteen patients received no adjuvant treatment. Reasons for lack of adjuvant treatment were: early stage (n=4), medically unfit (2), post-operative death (2), patient declined (5) and early post-operative distant metastatic disease (2).

Conclusions: Laparoscopic gastrectomy with D2 lymphadenectomy can be performed in a community setting with excellent margin status and LN retrieval results and complication rates comparable to those previously reported in prospective trials of open resection. Barriers to receipt/completion of adjuvant therapy in this setting should be explored.
Quality of gastrointestinal cancer care at a community hospital under the paradigm of multidisciplinary care.
Authors: McCahill Laurence E. , Konduri Sunil , Davis Alan T. , May Mary , Martinez Coralyn , Taylor Wendy K. , Wright Gerald P.
Published: February 2017

133

Background: Benefits of MDC have been established for other cancers but not GI malignancies. Benefits of GI NDC cancer care for underserved populations is yet to be quantified. Our GI-MDC was established to provide efficient, evidenced-based, high quality cancer care to patients of all ethnic and socioeconomic backgrounds.

Methods: We prospectively identified underserved patients in seven categories. A GI nurse navigator (NN) contacted patients, coordinated appointments /diagnostic studies and prepared for prospective case evaluation and weekly multidisciplinary GI clinic. Health care efficiency/quality data was abstracted by an R.N. quality analyst. Outcomes were compared between underserved and non-underserved populations. Percentages were compared using Chi square and medians by Mann-Whitney U test.

Results: From Jan 2010-July 2011, 208 patients were evaluated, with 137 confirmed new cancers, clinically estimated as Stage I=31, II=30, III=26, and IV=47. Among underserved patients, categories included age >80(n=26), public aid (n=28), uninsured (n=12), mental disability/impairment (n=15), incarcerated/institutionalized (n=4), and language barrier (n=2), more then one category could be selected. Outcomes are listed in the Table.

Conclusions: A model of GI cancer care including a GI NN, treatment planning conference, and MDC clinic is feasible in a community cancer center. Preliminary data demonstrates small differences between underserved and non underserved patient populations. This model of health care may help to reduce disparities in cancer care.

[Table: see text]
Malignant progression in intraductal papillary mucinous neoplasms of the pancreas: Results of 157 patients selected for radiographic surveillance.
Authors: LaFemina Jennifer , Gaujoux Sebastien , D'Angelica Michael Ian , Jarnagin William R. , Katabi Nora , Do Kinh Gian , Brennan Murray F. , Allen Peter J
Published: February 2017

152

Background: Natural history studies suggest that intraductal papillary mucinous neoplasm (IPMN) is a field defect of pancreatic ductal instability. The risk of malignancy is well known, but it is unclear if the radiographic abnormality is the predominant site at which this progression occurs. This study analyzes the prevalence and site of pancreatic ductal adenocarcinoma (PDAC) progression in patients initially selected for radiographic surveillance.

Methods: Patients evaluated for pancreatic cystic lesions between 1995-2010 were reviewed. Patients were included if they were followed for > 6 months for a cystic lesion with either a documented cyst fluid CEA >/= 200 ng/mL or pathologic confirmation of an IPMN.

Results: Of the 157 patients initially selected for surveillance, 97 (62%) eventually underwent resection. The median length of surveillance prior to operation was 15 mo (range: 6-193 mo). Pathologically confirmed carcinoma in situ (high grade dysplasia, n=22) or invasive carcinoma (n=18) was identified in 40 patients. Of the 18 patients who were found to have invasive carcinoma, 10 had main duct IPMN (56%), 5 had branch duct (28%), and 3 had combined (17%). Four of the 18 patients who developed invasive cancer during surveillance (22% of those resected for carcinoma and 3% of those followed) developed PDAC in a region of the gland distinct from the radiographically identified lesion for which surveillance was recommended. Invasive carcinoma was diagnosed a median of 24 mo after the original IPMN diagnosis. During follow-up (median = 8 months from the cancer diagnosis), 1 patient died of disease, 2 are cancer-free, and 1 patient is alive with recurrence.

Conclusions: In this study, 11% of patients with IPMN initially selected for surveillance developed invasive disease; 22% of those tumors arose in an area of the gland distinct from the initially identified lesion. Diagnostic and operative strategies for IPMN should consider the cancer risk in the entire gland.

[Table: see text]
The association between metabolic syndrome and primary liver cancer: A meta-analysis.
Authors: Jinjuvadia Raxitkumar , Njei Basile M. , Ditah Ivo C.
Published: February 2017

175

Background: The Metabolic syndrome (MetS) and/or its individual components have been liked to the development of cancer. Recent studies have suggested a similar link to Primary Liver Cancer (PLC). The mechanism for the development of cancer in this group of patients remains unclear. The aim of this study was to evaluate the direction and magnitude of the association between the MetS and PLC.

Methods: Two reviewers independently conducted a systemic search of the PubMed, OvidSP and Cochrane Library databases from January 1980 to July 2011. Search terms included ‘Metabolic syndrome’, ‘insulin resistance syndrome’ combined with ‘hepatocellular carcinoma’, ‘liver cancer’ and ‘GI malignancy’. No language restriction was applied to the search. Only studies reporting an effect measure for the association between MetS and PLC were eligible for inclusion. Metabolic syndrome was defined according to NCEP/ATP III, IDF, AHA and WHO guidelines. Identified articles were reviewed for additional references. Combined analysis including all studies was done using a random effects model. Publication bias was assessed using the Begg and Egger’s tests, with a visual inspection of funnel plot. All analyses were performed using Comprehensive Meta-Analysis version 2 software.

Results: Five studies (4 cohort and 1 case-control) including 863,714 participants were included in the analysis. The age range of participants was between 20 and 88 years. The combined analysis showed an overall 74% increase risk of PLC in cases with MetS (RR: 1.74, 95% CI: 1.36-2.24). After excluding the single case-control study from analysis, the overall risk ratio remained statistically significant (RR: 1.62, 95% CI: 1.22-2.15). Funnel plot inspection, Begg and Egger’s tests showed no evidence of publication bias, whether in the combined or subgroup analysis.

Conclusions: Though studies are scarce, currently available epidemiologic data is suggestive of positive association with significantly higher risk of liver cancer among patients with metabolic syndrome. More studies are required before reaching conclusive statement regarding this association. Further better-designed studies with good quality data with definitely aid in strengthening this association.
Use of DARPP-32 to increase interactions between EGFR and ERBB3 and to promote gastric cancer resistance to gefitinib.
Authors: Zhu Shoumin , Belkhiri Abbes , Zaika Alexander , El-Rifai Wael
Published: February 2017

18

Background: Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP−32), is overexpressed during gastric carcinogenesis. Gefitinib is a specific and effective EGFR inhibitor that has shown antitumor activity in clinical trials against gastrointestinal cancers. Gastric tumors can become resistant to gefitinib. However, molecular mechanisms that mediate resistance to gefitinib remain poorly understood.

Methods: The expression of DARPP−32 in the multi-step carcinogenesis cascade was examined using IHC analysis. Cell survival was determined by clonogenic survival and ATP−Glo assays. Apoptosis was assessed by Annexin-V and immunoblot analyses. The association between DARPP−32 and EGFR was evaluated by immunofluorescence and co-IP assays.

Results: The composite expression score progressively increased significantly from normal or gastritis to adenocarcinoma (p<0.001). Overexpression of DARPP−32 in MKN-28 cells blocked gefitinib-induced apoptosis and increased the drug’s IC50 10−fold, compared to that of control cells (P<0.01). And DARPP-32 expressing MKN−28 cells had activated the PI3K-AKT pathway as compared to control cells. The three−way co-IP experiments demonstrated the existence of DARPP-32, EGFR, and ERBB3 in the same protein complex. DARPP-32 enhanced EGFR-ERBB3 heterodimerization promoting phosphorylation of ERBB3, and then activated the PI3K-AKT pathway. Following treatment with gefitinib (25 μM) overnight, MKN−28 cells expressing DARPP-32 displayed stable protein levels of EGFR. The knockdown of endogenous DARPP-32 by DARPP-32 shRNA in SNU-16 cell lines reversed these signaling effects and increased sensitivity to gefitinib (p<0.01).

Conclusions: Our results suggest that DARPP-32 overexpression may participate in the progression to neoplasia. DARPP-32 also plays a role in increasing the stability of EGFR protein; DARPP-32 promotes resistance of gastric cancer cells to gefitinib by promoting interaction between EGFR and ERBB3 and activating PI3K–AKT signaling. DARPP-32 may have potential as a predictive biomarker in gastric cancer prognosis and clinical response to treatment.
Variable expression of somatostatin receptor type 2 in metastatic midgut carcinoid.
Authors: Liu Eric H. , Revetta Frank , Merchant Nipun B. , Washington Mary Kay , Shi Chanjuan
Published: February 2017

189

Background: Somatostatin receptor type 2 (SSTR2) is frequently highly expressed in carcinoid tumors of the midgut. The presence of the receptor is the basis of imaging and therapeutics. Because of the high dependence of clinical care on SSTR2, we evaluated the immunohistochemical staining of specimens and correlated with clinical parameters.

Methods: A tissue microarray (TMA) of 1 mm cores from paraffin embedded specimens of surgically resected midgut carcinoid were created with primary, lymph node, and liver metastatic lesions. These sections were stained by immunohistochemistry with anti-SSTR2 antibody, and scored on staining intensity. Sections were evaluated by membrane (0-none, 1 – weak, 2 – partial, 3- complete) and cytoplasmic (strong vs. weak) staining.

Results: Thirty-five patient samples were included in the TMA. There were a total of 62 cores embedded: 21 primary lesions, 26 lymph node metastases, and 15 liver metastases. The total disease burden was captured in 17 patients, and specimens from all three sites were captured in 6 patients. Of the thirty-five patients, 6 had consistently weak SSTR2 staining (17% either 0 or 1). One of these cases had an intermediate grade tumor with Ki67 >20%. Of the patients where more than one location was captured, 19/21 (90%) had consistent SSTR2 staining at all sites. Most cases had strong staining in the membrane (69%) while a minority had strong cytoplasmic staining (31%). Of the patients with weak SSTR2 membrane staining, 2 still had positive octreoscans. Clinically, most patients had good outcomes and 94% are still alive. Eight cases had carcinoid carcinomatosis (23%). Of the six with weak membrane staining, three had carcinomatosis (50%), while only 5/30 (17%) with strong membrane staining had carcinomatosis.

Conclusions: While the majority of small bowel carcinoids and their metastatic lesions have strong SSTR2 staining, not all do. However, even in cases with low amounts of SSTR2 on the membrane, the tumors can still be detected on octreoscan, demonstrating the effect of receptor turnover. The loss of SSTR2 may be associated with more advanced disease, but is not completely predictive.
A phase Ib trial of IPI-926, a hedgehog pathway inhibitor, plus gemcitabine in patients with metastatic pancreatic cancer.
Authors: Richards Donald Anthony , Stephenson Joe , Wolpin Brian M. , Becerra Carlos , Hamm John Turner , Messersmith Wells A. , Devens Shannon , Cushing Jill , Schmalbach Tess , Fuchs Charles S.
Published: February 2017

213

Background: IPI-926 is a novel, natural product-derived small molecule that targets the Hedgehog (Hh) pathway by inhibiting smoothened. In preclinical models of pancreatic cancer, repressing activation of the Hh pathway diminishes tumor-associated desmoplasia and improves chemotherapy delivery.

Methods: This is the final report of the Phase 1b portion of a Phase 1b/2 trial evaluating the safety and efficacy of IPI-926 plus gemcitabine. Eligible patients (pts) with untreated metastatic pancreatic cancer and ECOG status 0-1 were administered oral IPI-926 daily (QD) for 28-day cycles, in 3 to 6 pt dose cohorts. Gemcitabine (1,000 mg/m2) was administered IV weekly for 3 weeks with 1 week off. DLTs were evaluated during Cycle 1.

Results: 16 pts (median age 69 years; range 58-86) were enrolled at IPI-926 doses of 110, 130 or 160 mg QD (single agent MTD). Pts received a median of 5 cycles (1-13). Two pts remain on trial. No IPI-926-related serious AEs have been observed. One DLT of Grade 3 AST increase was observed (130 mg dose cohort) and was asymptomatic; it resolved with dose interruption, and did not recur with dose reduction. The most common AEs occurring were fatigue (75% total, 6% ≥ Grade 3), thrombocytopenia (63%, 25%), anemia (56%, 13%), nausea (50%, 0%), diarrhea (44%, 0%), vomiting (44%, 0%), peripheral edema (44%, 0%), pyrexia (44%, 0%), and AST increase (44%, 13%). Dose reductions of IPI-926 occurred in 3 (19%) pts. Dose reductions of gemcitabine occurred in 11 (69%) pts, primarily for thrombocytopenia (9 pts). One pt (6%) discontinued due to an AE (microangiopathic hemolytic anemia). Five (31%) radiographic partial responses were observed (1/3 at 110 mg, 2/6 at 130 mg, 2/7 at 160 mg). Median progression-free survival is > 7 months. 74% of pts were alive 6 months after study entry.

Conclusions: IPI-926 plus gemcitabine is well tolerated in pts with untreated metastatic pancreatic cancer, with evidence of activity and no unexpected toxicity. Complete Phase 1b data, including final overall survival, will be presented. Clinical evaluation of this combination continues in the randomized, double-blind, placebo-controlled Phase 2 portion of the trial.
Paradoxical cross-talk between the Stat3 and MAPK pathways in CCL25-CCR9 mediated pancreatic cancer growth and proliferation.
Authors: Le Maithao N. , Shen Xiaoming , Lee Wendy , Duldulao Marjun Philip , Garcia-Aguilar Julio , Kim Joseph
Published: February 2017

231

Background: Chemokine receptors have been shown to regulate the progression of several malignancies. Signal transducer and activator of transcription 3 (Stat3) may contribute to the invasive phenotype of several human cancers, but its upstream signals have not been well characterized. Our objective was to investigate the relationship between the CCL25-CCR9 axis and Stat3 signaling in pancreatic cancer cells.

Methods: We exposed two established human pancreatic cancer cell lines PANC-1 and MIAPaCa-2 to the cytokine CCL25 (800 ug/uL for 20 min) and measured the activation of Stat3 (phosho-Stat3) by Western blot assay. Stattic, a small molecule Stat3 inhibitor, was used (20uM) to antagonize Stat3 signaling. We also measured activation level of extracellular signal-regulated kinase (phospho-ERK) following CCL25 exposure and used UO126 (10uM), a small molecule MEK inhibitor, to antagonize the MAPK pathway. Changes in cell proliferation were measured by CellTiter Glo Fluorescence assay.

Results: Constitutive phosphorylation of Stat3 was observed in both pancreatic cancer cell lines. Exposure of MIAPaCa-2 to CCL25 further increased phospho-Stat3 levels on Western blot assay. We also observed a concomitant increase in phospho-ERK levels with exposure to CCL25 in both cell lines. Exposure of pancreatic cancer cells to CCL25 significantly increased cell proliferation. To determine the mechanism of CCR9-mediated cell proliferation, we used stattic and UO126 to specifically inhibit Stat3 and MEK activation, respectively. Interestingly, pre-treatment with stattic prior to CCL25 exposure resulted in a paradoxical enhancement of phospho-ERK levels. Conversely, inhibition of the MAPK pathway with UO126 led to a paradoxical enhancement of phospho-Stat3 levels.

Conclusions: Our results demonstrate that CCL25 activates Stat3 and MAPK pathways to contribute to pancreatic cancer proliferation. We also show potential cross-talk between Stat3 and MAPK pathways, wherein antagonism of one pathway resulted in paradoxical activation of the other pathway. Our findings suggest that therapeutic targeting of downstream pathways may require a multi-drug approach.
Use of PG545, a heparanase inhibitor, to inhibit pancreatic cancer tumor cell proliferation and migration in vitro and in vivo.
Authors: Ostapoff Katherine , Awasthi Niranjan , Schwarz Roderich , Brekken Rolf A.
Published: February 2017

234

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to conventional chemotherapy, as result there is an ongoing search to find novel effective strategies. Resistance is due in part to the high proportion of stromal tissue within the primary tumor. This intricate ECM (extracellular matrix) includes heparan-sulfate glycosaminoglycans which participate in tumor progression, angiogenesis and metastasis. PG545 is a heparanase inhibitor developed to target these pathways.

Methods: In vitro cell viability assays were performed using WST-1 reagent and migration was evaluated using T- scratch assay. Animal survival experiments were performed by intraperitoneal injection of AsPC-1 (0.75 x 10^6) cells. In vivo tumor growth experiments were performed by orthotopic injection of PanO2-HY (5x10^5) cells.

Results: PG545 significantly inhibited proliferation of tumor cells (AsPC-1 and PanO2) and fibroblasts (WI-38). PG545 caused only a modest inhibition in endothelial cell (HUVECs) proliferation. Migration was significantly inhibited by 1 µM PG545 in AsPC-1 and PanO2 after 12 hours. In a metastatic model of pancreatic cancer, treatment with PG545 (10 mg/kg 1st week, 5 mg/kg 2nd week) improved survival (35 days) compared to saline (22 days) and gemcitabine (28 days). In an immunocompetent orthotopic model, mice treated with PG545 (5 mg/kg twice weekly) had significantly decreased tumor weights after 3 weeks of therapy (p=0.002). Total metastatic events were also reduced in PG545 compared to gemcitabine and control treatment in the PanO2 model.

Conclusions: PG545 inhibits tumor cell proliferation and migration in vitro and prolongs survival and inhibits tumor growth in vivo. Additionally it inhibits metastasis in vivo. Further studies are underway to elucidate the mechanism of inhibition and changes to pancreatic tumor microenvironment.
Usefulness of circulating tumor cell detection for the diagnosis of malignant pancreatic head tumors: A pilot study.
Authors: Coget Julien , Blanchard France , Lamy Aude , Toure Emmanuel , Chiavelli Helene , Basile Paul , Di Fiore Frédéric , iwanicki-Caron Isabelle , Michel Pierre , Lemoine Francoise , Sabourin Jean-Christophe
Published: February 2017

235

Background: Pancreatic adenocarcinomas account for 90% of pancreatic malignancies. It is often diagnosed at an unresectable stage (at a metastatic and / or at a locoregional invasion stage). Histological diagnosis is mandatory to establish palliative chemotherapy. Endoscopic ultrasound-guided fine needle aspiration (EUGA) of pancreatic tumors is a difficult gesture, not without risk. Furthermore, it frequently provides pauci-cellular, hemorrhagic or necrotic material unsuitable for precise histologic diagnosis. Techniques for detecting circulating tumor cells (CTC) have been recently developed to highlight the presence of malignant cells circulating in peripheral blood. Screencells technology is based on the separation of CTCs from other circulating cells by blood filtration through a polycarbonate membrane with 7m pores. The aims of this pilot study were 1) to compare the results of detections CTC to EUGA, 2) to assess the feasibility and the contribution of this innovative technique in the care of a limited series of patients.

Methods: A sample of peripheral venous blood was performed in 15 patients with a suspicious CT scan of a pancreatic head tumoral lesion, before the completion of an EUGA. 4 ml of blood were filtered using ScreencellsCyto columns. After Giemsa staining, a pathologist analyzed each filter. Cells visualized on the filter under light microscopy were considered as tumoral if they met the following morphological criteria: anisocytosis, anisokaryosis, nuclear diameter>7m, nuclear membrane irregularitie, large nucleolus.

Results: The malignant feature of the pancreatic lesion could be histologically assessed after liver biopsy for two patients. EUGA showed malignancy in 10 cases. CTC presence was identified in 7 patients with tumoral histological diagnosis.

Conclusions: This study demonstrates the feasibility of CTC detection in patients with pancreatic head tumor. The identification of CTCs could facilitate patient care, thus avoiding difficult and potentially dangerous EUGA. A prospective trial is needed to confirm the positive predictive value of this biomarker and to evaluate its contribution in the diagnosis procedure of such tumors.
Overall survival with everolimus, sunitinib, and placebo for advanced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials.
Authors: Signorovitch James , Swallow Elyse , Kantor Evan , Wang Xufang , Metrakos Peter
Published: February 2017

237

Background: Everolimus and sunitinib are approved in the US and EU for treating advanced pancreatic neuroendocrine tumors (pNET). No randomized trial has directly compared these treatments for pNET. This study indirectly compared overall survival (OS) with everolimus vs. 1) placebo and 2) sunitinib.

Methods: Individual patient data were used from the RADIANT-3 trial of everolimus 10 mg/day vs. placebo (cutoff: April 4, 2010); published summary data were used from the A6181111 trial of sunitinib 37.5 mg/day vs. placebo (cutoff: June 1, 2010). To adjust for cross-trial differences, RADIANT-3 patients were subjected to exclusion criteria used in A6181111 and then re-weighted to match A6181111 in terms of baseline demographics, performance status, time since diagnosis, disease sites, distant metastases and prior therapy. After matching, OS was compared between balanced trial populations for everolimus in RADIANT-3 vs. 1) the placebo arm in A6181111, which had access to sunitinib after early stopping, and 2) the sunitinib arm in A6181111. Progression-free survival (PFS) was also assessed, but was confounded by early stopping of A6181111.

Results: Analyses included 394 patients from RADIANT-3 (after excluding 15 with worse performance status than allowed in A6181111 and 1 with missing baseline data) and all 171 patients in A6181111. Before matching, patients in RADIANT-3 had better performance status, more prior use of somatostatin analogues and less prior use of systemic chemotherapy. After matching, these and all other baseline characteristics were well-balanced between trials. Everolimus was associated with prolonged OS vs. placebo in A6181111 (hazard ratio [HR] for death = 0.61, 95% CI = 0.38-0.98, p=0.04). No statistically significant difference was observed with everolimus vs. sunitinib in OS (HR for death = 0.81, 95%CI=0.49-1.31) or in PFS (HR for progression = 0.84, 95% CI=0.46-1.53).

Conclusions: After adjusting for cross-trial differences, treatment of advanced pNET with everolimus was associated with prolonged OS compared to treatment with placebo.
Efficacy of gemcitabine as second-line therapy after S-1 therapy failure in advanced pancreatic carcinoma.
Authors: Fukahori Masaru
Published: February 2017

248

Background: Gemcitabine (GEM) and GEM-containing combination chemotherapy have been established as standard first-line therapies for advanced pancreatic carcinoma (APC). In the GEST study, a phase III clinical trial that compared the results for GEM, S-1, and GEM+S-1 therapies, there was no significant difference between overall survival (OS) for GEM and GEM+S-1; S-1 and GEM had similar efficacies as first-line treatment for APC. Therefore, S-1 is expected to be used as first-line therapy. In our study, we have evaluated the efficacy and outcomes of second-line GEM therapy after S-1 therapy failure in APC.

Methods: We retrospectively examined the data for 27 patients (pts) with APC refractory to first-line S-1 therapy. All the pts had undergone second-line GEM therapy during October 2000–February 2009 at National Cancer Center Hospital after first-line S-1 therapy. Tumor responses were analyzed using Response Evaluation Criteria in Solid Tumors. The Kaplan-Meier method was used to evaluate tumor progression and survival.

Results: The Eastern Cooperative Oncology Group Performance Status was 0 or 1. The male:female ratio was 16:11 and median age was 62 years (range, 42–75 years). Four pts (14%) exhibited a partial response to second-line GEM therapy, 11 (40%) showed stable disease, and 12 (44%) showed progressive disease. Grade 3 adverse events for second-line GEM therapy were neutropenia in 2 pts and upper gastrointestinal hemorrhage in 1 pt. Grade 4 adverse events were not observed. The median progression-free survival was 77 days (95% confidence interval, 33–121 days) and the median OS after second-line GEM therapy was 240 days (95% confidence interval, 156–324 days).

Conclusions: Although this study had a small sample population and retrospective design, the results indicate that GEM has good antitumor activity with tolerable toxicity. Second-line GEM therapy was found to be effective after first-line S-1 therapy failure in APC.
Neoadjuvant interferon-based chemoradiation for locally advanced pancreas cancer: A phase II pilot study.
Authors: Jensen Eric Hans , Armstrong Leonard , Tuttle Todd M. , Vickers Selwyn M. , Sielaff Timothy D. , Greeno Edward
Published: February 2017

266

Background: Neoadjuvant chemoradiotherapy (CRT) is a viable treatment strategy for patients with locally advanced pancreas cancer. We evaluated the Virginia Mason Protocol (5-fluorouracil, cisplatin, interferon-α and radiation) given in the neoadjuvant setting for the treatment of locally advanced pancreatic cancer.

Methods: We performed a phase II pilot study treating patients with locally advanced pancreas cancer, including borderline resectable and initially non-resectable cases. Patients with evidence of metastases, previous chemotherapy, ECOG performance status >1, or inadequate hematologic, renal or hepatic function were excluded.

Results: We enrolled 23 patients between 1/2005 and 10/2010. Mean age at enrollment was 58.6 years. Males made up 73.4% of the cohort. Of 23 patients, 7 (30.4%) completed all treatments. The remaining 16 (69.6%) patients did not receive all scheduled treatments due to severe side effects (n=7, 30.4%), progressive disease (n=3, 13%), alternative treatment (n=3, 13%), patient withdrawal (n=1, 4.3%), other disease (n=1, 4.3%), and death on study (n=1, 4.3%). Hospitalization was required due to toxicity for 47.8% (n=11) of patients. The most commonly reported grade 3 or 4 toxicities were leucopenia/cytopenia (n=19, 82.6%) and gastrointestinal (n=19, 82.6%). Other toxicities were much less common (fatigue, weight loss, pain, skin rash, all n<3). Tumor regression was not seen in any patient. Surgical resection was ultimately successful in 7 (30.4%) cases. Surgical margins were negative in 6 of 7 cases (85.7%). The mean lymph node count was 11. Positive lymph nodes were identified in 3 of 7 cases (42.8%). Overall survival for all patients was 11.5 months. Surgical resection provided significantly improved survival (22.6 months) compared to CRT alone (8.8 months). Disease free survival in resected patients was 17.2 months.

Conclusions: Aggressive neoadjuvant CRT with immunotherapy may allow for resection of initially non-resectable, locally advanced pancreas cancer, but with significant toxicity. Overall survival was similar to other, less toxic regimens. In the absence of surgical resection, survival remains dismal.
Patterns of recurrence after resection of intrahepatic cholangiocarcinoma: Results from a multi-institutional cohort of 449 patients.
Authors: Hatzaras Ioannis , Choti Michael A. , Schulick Richard D. , Alexandrescu Sorin , Pulitano Carlo , Clary Bryan M. , Zhu Andrew X. , Popescu Irinel , Marques Hugo , Barroso Eduardo , Ferrone Cristina , Bauer Todd W. , Walters Dustin M , Gamblin T. Clark , Nguyen Kevin Tri , Hubert Catherine , Gigot Jean Francois , Mentha Gilles , Pawlik Timothy M
Published: February 2017

267

Background: Outcomes following surgical management of intrahepatic cholangiocarcionma (ICC) have largely focused on overall survival. Data on recurrence following surgery for ICC are limited. We sought to investigate rates and patterns of recurrence in patients following curative intent surgery for ICC.

Methods: 449 patients who underwent surgery for ICC between 1973 and 2010 were identified from an international multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed.

Results: Most patients had a solitary tumor (70%) with a median tumor size of 6.5 cm. The majority of lesions did not have vascular invasion (69%). Surgical treatment was < hemi-hepatectomy (47%), hemi-hepatectomy (26%), or extended hepatectomy (27%). On pathology, 23% patients had lymph node metastasis and 18% had a microscopically positive (R1) margin. A subset of patients received adjuvant chemotherapy (32%) or chemoradiation (39%). While 5-year overall survival was 31%, 351 (78%) patients recurred with a median RFS time of 13.2 months. First recurrence site was intra-hepatic only (54%), extra-hepatic only (24%), intra- and extra-hepatic (22%). There was no difference in RFS based on site of recurrence (intra-hepatic: 11.2 months; extra-hepatic 11.6 months; intra- and extra-hepatic: 9.6 months; P=0.16). An R1 surgical margin (HR: 1.56, p=0.02) and neural invasion (HR: 1.55, p=0.02) were associated with overall recurrence, while male gender (HR: 1.70, p=0.011), >50% liver parenchyma resection HR: 1.97, p=0.03), primary tumor size (1.05, p=.02), and poor differentiation (HR: 1.92, p=0.01, were associated with intrahepatic recurrence. Receipt of adjuvant therapy was not associated with risk of recurrence (P>0.05).

Conclusions: Over 75% of patients developed recurrence following curative intent surgery for ICC. The pattern of failure was distributed relatively equally with half of patients recurring with liver only disease while half had an extrahepatic metastatic site of recurrence. Future efforts need to be directed toward identifying more effective adjuvant regimens given the high rate of recurrence.
Effect of treatment-related lymphopenia on survival in newly diagnosed patients with resected adenocarcinoma of the pancreas.
Authors: Balmanoukian Ani Sarkis , Ye Xiaobu , Herman Joseph M. , Laheru Dan , Grossman Stuart A.
Published: February 2017

270

Background: Severe treatment-related lymphopenia is associated with shorter survival in patients with high grade gliomas. This study was performed to determine if patients with resected pancreatic adenocarcinoma treated with post-operative radiation and chemotherapy develop significant lymphopenia and if this affects overall survival.

Methods: Patients selected for this retrospective analysis underwent pancreatic cancer resection between 1997 and 2008, and received post-operative radiation with gemcitabine or 5-FU based chemotherapy at Johns Hopkins Hospital. Serial lymphocyte counts were recorded and survival was analyzed as a function of lymphopenia and known prognostic factors.

Results: Fifty-three adults met the eligibility criteria. Their median age was 64, median tumor size was 3 centimeters, 83% underwent a pancreaticoduodenectomy, 47% had positive margins, and 92% had positive nodes. Total lymphocyte counts were normal in 91% of patients prior to receiving radiation and concomitant chemotherapy with 5FU(59%) or gemcitabine (41%). Total lymphocyte counts fell to <500 cells/mm3 in 45% of patients two months after initiating therapy with a median reduction of 63% from the baseline (p<0.0001). The median survival of patients with lymphocyte counts <500 cells/mm3 at 2 months was 14 months versus 20 months in patients with more lymphocytes (p=0.0485). Univariate analysis revealed no significant association between pre-treatment patient characteristics and survival. Multivariate analysis revealed a significant association between survival and lymphocyte count (<500 vs ≥ 500 cells/mm3) at 2 months (HR 2.2, p = 0.014).

Conclusions: Adjuvant radiation and chemotherapy induced lymphopenia is frequent, severe, and an independent predictor for survival in patients with resected pancreatic adenocarcinoma.
Endoscopic or percutaneous biliary drainage for Klatskin tumors? A large retrospective study.
Authors: Walter Thomas , Ho Chia , Horgan Anne M. , Warkentin Andrew , Gallinger Steven , Beecroft Rob , Hedley David W , Tan Kongten , Kortan Paul , Knox Jennifer J.
Published: February 2017

277

Background: Controversy exists over the preferred technique of biliary drainage in patients with Klatskin tumors as few comparative studies exist. This study compared outcomes of endoscopic biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD).

Methods: 129 patients with Klatskin tumors with an initial EBD or PTBD were identified from 01/01/1991 to 31/05/2011 and their clinical histories were retrospectively reviewed. The primary end point was the time to therapeutic success (TTS: time between the first drainage and a total bilirubin<40µmol/L), estimated by Kaplan-Meier analysis.

Results: The first biliary decompression procedure was EBD in 87 patients and PTBD in 42 patients. The technical (98% vs 78%, p=0.004) and therapeutic (79% vs 49%, p=0.002) successes were significantly higher in the PTBD group than EBD group, respectively; Forty four patients (51%) in the EBD group subsequently underwent a PTBD before achieving therapeutic success or starting their antitumoral treatment. The median TTS was 55 days in EBD group vs 44 days in the PTBD group (multivariate analysis: HR=0.63, 95% CI=0.41-0.99, p=0.045). In patients treated by surgery or chemotherapy +/− radiotherapy, the median time to treatment was 68 and 76 days in the PTBD group and the EBD group, respectively, p=0.76. 25% and 21% of cholangitis occurred in EBD and PTBD group, respectively (p=0.34).

Conclusions: In the era where chemotherapy prolongs life even in advanced disease, shortening time to success matters. Our results suggest relying on PTB for biliary decompression would be an improved treatment strategy when treating patients with Klatskin tumor.
Second interim analysis of GIDEON (Global Investigation of Therapeutic Decisions in Unresectable HCC and of Its Treatment with Sorafenib): Sorafenib treatment and safety in U.S. patients with Child-Pugh B status.
Authors: Piperdi Bilal , McGuire Brendan , Mantry Parvez , Martin Robert C. G. , Gholam Pierre Michel , Marrero Jorge A. , Geschwind Jeff H. , Venook Alan Paul , Sanyal Arun
Published: February 2017

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Background: Sorafenib (SOR) is the first systemic therapy to demonstrate a survival benefit in patients (pts) with late-stage hepatocellular carcinoma (HCC). GIDEON is an ongoing, global, prospective, noninterventional study of HCC pts receiving SOR in real-life practice. We present results from the second interim analysis, describing dosing and safety of SOR in HCC pts with Child-Pugh (CP)-B status in the US.

Methods: From Jan 2009 – Nov 2010, 326 pts were enrolled (n = 313, safety population) and followed ≥4 months at 92 US centers. Eligible pts had unresectable HCC and were treated with SOR. Demographics, initial dose, treatment duration (TD), dose modifications (mods), and adverse events (AE) were analyzed in pts with available CP status.

Results: 119 (38%) pts were CP-A and 100 (32%) were CP-B. 94 (30%) pts were excluded (Table). Median (med) SOR dose was 580 mg/d in CP-A pts and 577 mg/d in CP-B pts. Med TD was 14.4 weeks (wks) in CP-A pts and 10.1 wks in CP-B pts. TD was <4 wks, 4-12 wks, and >12 wks in 14%, 29%, and 56% of CP-A pts, and 22%, 36%, and 39% of CP-B pts, respectively. Treatment-emergent (TE) drug-related AE (all grades) were similar between groups, but more CP-B pts discontinued SOR due to AE (Table). In CP-A and -B pts, all-grade AE were as follows: hand-foot skin reaction (HFSR) (28% vs 19%), diarrhea (28% vs 27%), and fatigue (15% vs 16%). All-grade elevations in ALT, AST, and bilirubin were 2.5%, 2.5%, and 3.4% in CP-A pts and 3%, 1%, and 4% in CP-B pts.

Conclusions: These interim US data suggest that SOR safety may be similar in HCC pts with CP-A and CP-B status. Med SOR dose was similar, but med TD was shorter in CP-B pts. AEs were as expected, although HFSR may be underreported in CP-B pts. Limitations of an observational registry must be considered.

[Table: see text]
A phase I study of temsirolimus in combination with gemcitabine in previously untreated metastatic pancreatic cancer.
Authors: Faris Jason Edward , Blaszkowsky Lawrence Scott , Abrams Thomas Adam , Enzinger Peter C. , Hezel Aram F. , Wolpin Brian M. , Ryan David P. , Kwak Eunice Lee
Published: February 2017

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Background: The PI3K/mTOR/Akt pathway has been demonstrated to be active in pancreatic cancer, and preclinical data in mouse xenograft models has suggested possible synergy between gemcitabine and temsirolimus, an inhibitor of the mTOR pathway. The objective of this Phase I study was to assess toxicity and tolerability of gemcitabine and temsirolimus combination therapy in patients with newly diagnosed metastatic pancreatic cancer.

Methods: The study was conducted with a modified, 3+3 phase I design for dose escalation. Patients in cohort 1 received temsirolimus at a fixed dose of 10mg IV on days 1,8,15, and 22, while gemcitabine was administered at 800mg/m2 IV on days 1 and 15 of each 28 day cycle.

Results: Between November 2007 and September 2008, 9 patients were enrolled in the trial, with a median age of 56. 6/9 patients were male, and all enrolled patients had a performance status of 1. One patient discontinued prior to starting treatment. 5 of the 8 patients receiving at least one infusion of gemcitabine and temsirolimus were removed from the study for toxicities associated with treatment. There were two episodes of Grade 4 neutropenia, and multiple Grade 3 toxicities, including cytopenias (neutropenia, leukopenia, and lymphopenia), elevated liver function tests, hyperglycemia, hypophosphatemia, diarrhea, and allergic reaction. There were no partial or complete responses observed. One patient demonstrated stable disease, receiving 6 cycles; this patient developed grade 3 neutropenia, requiring a dose delay and subsequent 20% dose reductions for temsirolimus and gemcitabine. No patients were enrolled after the first cohort, and no patients remain on study. In the 8 patients who began the study, the median time on study was 22 days, and overall survival was 126 days from study administration (range 88-416 days).

Conclusions: This is the first published report of a human study involving gemcitabine and temsirolimus, which was associated with substantial toxicity in patients with advanced, previously untreated pancreatic cancer precluding further exploration of this combination.
A single-institution survey of de novo secondary malignancies in patients occurring after orthotropic liver transplantation.
Authors: Gillebert Quentin , Bouattour Mohamed , Durand Francois , Francoz Claire , Paradis Valerie , Dreyer Chantal , Belghiti Jacques , Raymond Eric , Faivre Sandrine J.
Published: February 2017

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Background: We aim to evaluate in our institution the incidence of de novo malignancies following orthotopic liver transplantation (OLT) and their impact the prognosis of patients (pts).

Methods: Pts treated with OLT from August 1991 To March 2009 were considered in this analysis. All pts data had been prospectively recorded in the database of French “Bio-medecine Agence”. Pts were considered for this analysis only if they survived at least 3-months after. Occurrence of de novo malignancies we analyzed and additional data (including immunosuppressive profile, type of cancer, potential independent risk factors of cancers, prognosis and the influence of immunosuppression protocols or risk factors on occurrence of cancers) were collected in patients who developed secondary cancers.

Results: A total of 833 patients who underwent OLT were considered for this analysis. With a median follow-up of 7.9 years, 72 pts developed 92 de novo malignancies. The overall incidence of cancers in our population was 10.4% occurring with a median time of 6.1 years following OLT. Sixteen pts developed 2 different types of cancer and 2 pts had more than 3 tumor types. Before 12/1998, immunosuppression was primarily based on cyclosporine, steroids and/or azathiopirine, and since 01/1999 was switched to tacrolimus. Incidence of cancers regarding these two periods is summarized in the table. Before 1998, only 3 pts (17.6%) with secondary cancer had prior history of alcoholism and/or smoking compared to 27 pts (50%) after 1999. Thirty one deaths were observed and the median overall survival (OS) after the time of diagnosis of secondary malignancy was 5.62 years.

Conclusions: The risk of de novo cancer after OLT is similar to reported series. History of smoking and alcohol use, increase the incidence of de novo malignancies especially head and neck and lung cancers however, immunosuppression type may not interfere with this risk.

[Table: see text]
Yttrium-90 microspheres (SIR) verses transarterial chemoembolization (TACE) in the treatment of inoperable metastatic neuroendocrine tumors (NETS).
Authors: Wu Yuhsin V. , Tomaszewski Garin , Groman Adrienne E. , Iyer Renuka V. , Kuvshinoff Boris W.
Published: February 2017

300

Background: There are limited modalities in the treatment of inoperable liver NET metastases. This study compares the efficacy and safety of liver-directed yttrium-90 microspheres, SIR-spheres, to TACE.

Methods: Medical records and axial imaging studies were retrospectively reviewed for all patients with NET liver metastases who underwent SIR or doxorubicin based TACE at our institution from Jan 2001 to Dec 2010. The demographics, immediate effects, and time to radiologic progression were assessed and compared between the two treatment modalities.

Results: A total of 99 liver directed treatments were performed on 46 pts (n=19 Y-90, n=27 TACE). Median post-treatment follow-up was 20 months (range 4-103). Pt characteristics including age, performance status, type of primary NET, and systemic therapy were similar in both groups. Pts in the SIR group waited longer from the time of metastatic diagnosis to liver-directed therapy (SIR 35 mo vs. TACE 15 mo (p=0.0015)). SIR patients had less liver burden (65% with <25% liver burden) than TACE patients (23% with <25% liver burden). Immediate treatment response (1-3 mo) was measured radiologically using WHO criteria multiplied by EASL criteria. SIR pts achieved 26% complete response (CR), 51% partial response (PR), 15% stable disease (SD), and 8% progressive disease (PR). TACE pts achieved 13% CR, 59% PR, 8% SD, and 21% PD. SIR (44 mo) had a longer radiologic effect than TACE (12 mo) (p=0.015). SIR patients underwent less treatments (95% with < 2 treatments) than TACE patients (70% with < 2 treatments) (p=0.045). Both treatments were well tolerated with minimal side effects. With only 11/46 (25%) deaths, there was no statistically significant difference in overall survival between the two groups at a median follow up of 104 months (range 12-267).

Conclusions: Liver metastasis from NETs can be successfully treated with yttrium-90 radioembolization. Earlier intervention using SIR allows fewer treatments with more durable responses. Prospective studies controlling for rate of disease progression and disease burden are needed to validate these findings.
Worldwide trends in locoregional therapy for hepatocellular carcinoma (HCC): Second interim analysis of the Global Investigation of Therapeutic Decisions in HCC and of Its Treatment with Sorafenib (GIDEON) study.
Authors: Geschwind Jeff H. , Lencioni Riccardo , Marrero Jorge A. , Venook Alan Paul , Ye Sheng-Long , Nakajima Keiko , Cihon Frank , Kudo Masatoshi
Published: February 2017

317

Background: Locoregional treatments (LRTs) are widely used for HCC, with recognized regional variations but no universal standard. GIDEON is a global, prospective, non-interventional study evaluating sorafenib use in HCC patients (pts). The study allows evaluation of global trends in LRTs.

Methods: >3000 pts were enrolled in 39 countries (January 2009 to April 2011). Per protocol, the 2nd interim analysis was planned when ~1500 treated pts were followed for ≥4 months.

Results: In the safety population analyzed (N=1571), 55% and 46% of pts received prior LRT and transarterial chemoembolization (TACE), respectively. Prior LRTs, including TACE, were more frequent in Asia-Pacific (AP) and Japan than in other regions. In pts who received TACE prior to the initiation of sorafenib therapy, the number of TACE treatments ≥3 was higher in AP and Japan than in other regions. Overall, 76% of pts received conventional TACE, and the most common TACE agent was doxorubicin. Median time from last TACE to initiation of sorafenib therapy was 3.1 months (Table). Worldwide, 8% of pts received TACE, concomitantly with sorafenib. The incidence of sorafenib-related adverse events/serious adverse events was generally similar in pts who did (70%/4%) or did not (64%/9%) receive concomitant TACE.

Conclusions: The GIDEON study provides unique insight into the utilization of LRTs worldwide and contributes to better understanding and management of HCC pts.

[Table: see text]