bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factor of carcinoma of the ampulla of vater after surgery.
Authors: Tomiyasu Shinjiro , Oda Eri , Tanaka Hiroshi , Ishikawa Shinji , Sugita Hiroki , Arita Tetsumasa , Yagi Yasushi , Takamori Hiroshi , Kanemitsu Keiichiro , Hirota Masahiko , Baba Hideo
Published: February 2017

270

Background: General rules for biliary tract cancer in Japan were revised and Stage of biliary tract cancer was compliant with the seventh UICC. Carcinoma of the Ampulla Vater (CAV) is relatively good prognosis among the biliary tract cancer, such as lymph node metastasis, pancreatic invasion and perineural invasion has been reported to be prognostic factors. We investigated the validity of TNM-Stage by examining the prognostic factors from the outcome of resection experienced. Methods: To evaluate prognostic factors after surgery based on a series of 70 patients of CAV from 1996 to 2014. Twenty-eight patients received pancreatoduodenectomy (PD), 25 patients received pylorus-preserving pancreatoduodenectomy (PPPD) and 17 patients received subtotal stomach-preserving pancreatoduodenectomy (SSPPD). We reviewed and analyzed the clinicopathologic data, surgical outcomes, recurrence and survival. Results: Actuarial disease-specific survival (DSS) was 65 % at five years. In univariate analysis, pancreatic invasion, lymph node metastasis and duodenal invasion are significantly poor prognosis. In multivariate analysis, pancreatic invasion is the only poor prognostic factor (p = 0.0023, hazard ratio (HR) 5.31 [confidence interval (CI) 1.77-18.9 95%]); lymph node metastasis and duodenal invasion are not significantly different (p = 0.0672 and 0.8769, respectively). Also, in the study of relapse risk factors, pancreatic invasion and lymph node metastasis are significantly different. In TNM-Stage II, those of T3N0, 1 are poor prognosis than T1, 2N1 (p = 0.0334). Conclusions: Pancreatic invasion is an independent poor prognostic and recurrence risk factor. The Stage of Japanese Society of Biliary Surgery has reflect prognosis than TNM-Stage in carcinoma of the Ampulla Vater.
Adenosquamous cell carcinoma derived from intraductal papillary mucinous neoplasm of the pancreas confirmed by genetic analysis.
Authors: Karasaki Hidenori , Kono Toru , Ono Yusuke , Maejima Taku , Mizukami Yusuke
Published: February 2017

275

Background: Adenosquamous cell carcinoma (ASC) is an uncommon histologic variant of pancreatic cancer, representing only 1-4 % of all pancreatic neoplasms. Here we reported the extremely rare case of ASC derived from intraductal papillary mucinous neoplasm (IPMN) of the pancreas with intensive pathological and molecular analysis. Methods: A 72-year-old diabetic male with five-year history of non-alcoholic chronic pancreatitis was admitted to our hospital with complaint of epigastric pain. The patient was diagnosed as pancreatic cancer associated with IPMN and pylorus preserving pancreaticoduodenectomy was performed in April 2012. The resected pancreas was fixed in 10% formaldehyde, and the whole specimen was sliced at a thickness of 5-mm for i) pathological analyses using hematoxylin-eosin (H-E) staining and immunostaining with specific antibodies against MUC-1, -2, -5AC, -6, p63 and CD5/6, and ii) deep sequencing of multiplex PCR amplicons of 50 cancer-associated genes utilizing Ion Torrent PGM platform. DNA was obtained from intraepithelial lesions of IPMN, invasive squamous cell carcinoma (SCC) and adenocarcinoma (AC) after enrichment for neoplastic cellularity, using manual microdissection. Results: Pathological findings showed IPMN extended from main pancreatic duct to branch ducts. The invasive tumor was predominantly consisted of poorly-differentiated SCC and small poorly-differentiated AC was also found in the edge of the SCC. All IPMN area analyzed shared combination of the mutations, KRASG12D and GNASR201C. The identical mutations in KRAS and GNAS as IPMNs were also found in SCC and AC. Conclusions: It generally difficult to fully discriminate IPMN-derived cancer (invasive IPMN) from concomitantly and independently developed de novo pancreatic ductal adenocarcinoma (PDA) originating from the “field defect”. In the current case, although SCC is a rare histotype of IPMNs, we considered that the invasive carcinoma was derived from IPMN based on their mutational profile.
Gene-pair classifier in circulating tumor and invasive cells to predict pharmacological response.
Authors: Sangar Vineet , Earls John C , Yu Kenneth H.
Published: February 2017

279

Background: Improved diagnostic tools for predicting treatment response and prognosis are needed in pancreatic adenocarcinoma (PDAC), the fourth leading cause of cancer mortality in the U.S. In this study, we explored the diagnostic potential of gene expression signatures from circulating tumorigenic and invasive cells (CTICs). Methods: We recruited 50 PDAC patients to participate in our IRB-approved study. 35 patients were evaluable for response to chemotherapy treatment. 10 mL of peripheral blood was collected from patients with unresectable PDAC prior to initiating chemotherapy and again at disease progression. Clinical data was prospectively collected. Blood was processed for isolation of circulating TP cells (Vita-Cap, Vitatex Inc.), total RNA was extracted and gene-expression analysis was performed (Affymetrix GeneChipHuman Genome U133 Plus 2.0 array). Using time to progression (TTP) as a threshold, twenty-five patients with TTP>120 days were labeled as responders and ten patients with TTP<=120 days were labeled as non-responders. Results: Network analysis of expression profiles revealed that the PTC1 and CDC25 pathways were significantly different in responders and non-responders. Both pathways contribute towards tumorigenesis, and enhance tumor resistance to therapeutic intervention in PDAC. Further investigation into these pathways revealed that the relative expression of ATM and XPO1 was the most accurate classifier (76% accuracy, Specificity = 80% and Sensitivity = 72%). Additionally, 18 out of 20 patients of the patients with ATM < XPO1expression pattern responded to treatment. Mechanistically, this observation suggests that ATM may be counteracting DNA damage inflicted by chemotherapy during G2/M transition of the cell cycle. Conclusions: Computational analysis of gene expression data from CTICs can reliably predict pharmacological response. Pathway analysis identifies gene interaction networks relevant to tumorigenesis and drug response. Data will be updated with longitudinal analysis of treatment response in both responders and non-responders to the treatment.
A high density of tumor infiltrating CD3 and CD8 cells to predict recurrence free survival in patient with hepatocellular carcinoma.
Authors: Gabrielson Andrew , Wu Yunan , Kallakury Bhaskar , Jiang Jiji , Wang Hongkun , Johnson Lynt B. , Island Eddie , Fishbein Thomas , Satoskar Rohits , Jha Reena , Kachhela Jaydeep , Feng Perry , Zhang Tiger , Tesfaye Anteneh , Bhuvaneshwar Krithika , Gusev Yuriy , Prins Petra , Marshall John , Atkins Michael B. , He Aiwu Ruth
Published: February 2017

280

Background: The ability to define risk of hepatocellular carcinoma (HCC) recurrence after resection could improve the clinical management of patients. The pathological factors currently indicative of tumor invasiveness, such as vascular invasion, elevated AFP and advanced pTNM stage, are the established risk factors for recurrence. It has been suggested that immune cells that infiltrate a tumor are a prognostic factor in predicting patient outcome. In this study, the prognostic significance of tumor immune infiltration, as defined by the Immunoscore methodology, was assessed in patients with HCC. Methods: The influence of immune infiltration on clinical outcome was evaluated in patients who had undergone resection of HCC. The density of intratumoral immune infiltrates were measured in the center of the tumor (CT) and in the invasive margin (IM) of 45 stage I to IV HCC tissue specimens from a single cohort. The density of total (CD3+) and cytotoxic (CD8+) T lymphocytes in the CT and IM were obtained by immunohistochemistry and quantified using a Nuance FX Multiplex Biomarker Imaging system in tandem with ImageJ image processing software. Immune cell density in the CT and IM was converted to a binary score (0 as Low, 1 as High), with a cutoff threshold determined by the median density of CD3+ and CD8+ cells (273 cells/mm² and 217.5 cells/mm², respectively). The Immunoscore values were correlated with tumor recurrence and recurrence-free survival. Results: High densities of both CD3+ and CD8+ T lymphocytes in the CT and IM, along with a corresponding Immunoscore of 3+ (on a scale from 0 to 4), were significantly correlated with a low rate of recurrence (p-value = 0.0004). High densities of CD3+ lymphocytes alone were correlated with a prolonged recurrence-free survival (p-value = 0.0005). High densities of CD8+ lymphocytes alone were also correlated with a prolonged recurrence-free survival (p-value = 0.0031). Conclusions: The Immunoscore is a useful prognostic marker in patients with HCC who have received primary tumor resection. To better characterize the immune landscape of HCC tumors, the correlation between the Immunoscore and additional immune biomarkers are being evaluated.
A phase II, open-label, randomized clinical trial of panitumumab plus gemcitabine and oxaliplatin (GEMOX) versus GEMOX alone as first-line treatment in advanced biliary tract cancer: The Vecti-BIL study.
Authors: Leone Francesco , Marino Donatella , Filippi Roberto , Cereda Stefano , Belli Carmen , Spadi Rosella , Nasti Guglielmo , Montano Massimo , Amatu Alessio , Aprile Giuseppe , Cagnazzo Celeste , Fasola Gianpiero , Siena Salvatore , Ciuffreda Libero , Reni Michele , Aglietta Massimo
Published: February 2017

281

Background: Biliary tract cancer (BTC) is a rare and lethal disease with very few therapeutic options. Preclinical data suggest that Epithelial Growth Factor Receptor (EGFR) pathway activation could be involved in BTC pathogenesis, envisaging a potential role of anti-EGFR monoclonal antibodies. Methods: Patients (pts) with metastatic or unresectable BTC, harboring wild-type KRAS status, with ECOG performance status 0-2, without prior systemic therapy, were randomized to GEMOX (gemcitabine, 1000 mg/m² and oxaliplatin, 100 mg/m²) therapy with (arm A) or without (arm B) panitumumab (6 mg/kg), q2w for up to 12 cycles. Maintenance therapy with panitumumab alone was allowed in arm A in case of clinical benefit after 12 cycles. The primary endpoint was the progression-free survival (PFS). The target hazard ratio was 0.60 requiring 88 pts for 74 PFS events (80% 1-β power, α = 0.10, log-rank test 1-sided). Secondary endpoints were objective response rate (RR) (RECIST vers.1.1), overall survival (OS), and safety. Results: From 06/2010 to 09/2013, 89 pts were enrolled (median age 64 years; metastatic 78%; gallbladder 32%, extra-hepatic 21%, intra-hepatic 47%). After a median follow-up of 8.6 months (mo), with six pts (two progression-free) in arm A, and eight pts (none progression-free) in arm B still in follow-up, median PFS was 7.7 mo in arm A (95% CI 4.7–10.6) and 5.5 mo (95% CI 3.2–7.8) in arm B (p=0.10). RR was 25.0% in arm A and 18.2% in arm B. No differences in survival were seen, being median OS 9.5 mo (95% CI 5.7-13.3) in arm A and 9.9 mo in arm B (95% CI 5.1-14.6), p= 0.49. The most common all grade toxicities were skin toxicity (71%), nausea (67%), and fatigue (53%) in arm A; nausea (64%), neurotoxicity (57%), and fatigue (52%) in arm B. The most common grade 3 or 4 toxicities were: hepatic toxicity (20%), diarrhea (13%), and nausea (13%) in arm A; cholestasis (14%), dyspnea (9%), and diarrhea (9%) in arm B. Conclusions: Although the results are not fully mature, the combination of GEMOX and panitumumab showed a trend towards better PFS and RR in KRAS wild-type BTC pts as compared to GEMOX alone. No impact on OS seems evident. Clinical trial information: NCT01389414.
Effect of KRAS mutation on long-term outcomes of patients undergoing hepatic resection for colorectal liver metastases.
Authors: Margonis Georgios A , Spolverato Gaya , Kim Yuhree , Karagkounis Georgios , Choti Michael A. , Pawlik Timothy M.
Published: February 2017

282

Background: The impact of KRAS mutation on overall (OS) and recurrence-free (RFS) survival of patients with colorectal liver metastases (CLM) remains poorly defined. We sought to investigate the prognostic value of KRAS in a large cohort of patients undergoing liver resection for CLM. Methods: Between 2003 and 2013, 334 patients underwent hepatic resection for CLM at Johns Hopkins Hospital and met the inclusion criteria. Somatic mutations at codons 12/13 were evaluated through a sequencing analysis of the tumor samples. Clinicopathological characteristics, perioperative details, and outcomes were stratified by KRAS status (mtKRAS vs. wtKRAS) and analyzed. Results: Among 334 patients undergoing liver resection for CLM, mtKRAS was identified in 115 (34.4%) patients. Median CEA was 7.3 ng/dL; 40.4% of patients had a solitary tumor and median tumor size was 2.5 cm. At a median follow-up of 28.2 months, recurrence was observed in 59 (51.3%) patients with mtKRAS and 117 (53.4%) patients with wtKRAS (P=0.71); there was no difference in the pattern of recurrence (liver: mtKRAS, 39.0% vs. wtKRAS, 52.1%; lung: mtKRAS, 55.6% vs. wtKRAS, 64.3%; both P>0.05). While 5-year log-rank OS was comparable among mtKRAS (41.6%) vs. wtKRAS (48.5%), on multivariable Cox survival analysis mtKRAS was associated with worse OS(HR, 1.65; 95%CI, 1.07-2.54). Moreover, among patients who experienced a recurrence, 5-year OS was worse among those patients who had mtKRAS (mtKRAS, 28.1% vs. wtKRAS, 44.5%; P=0.004). After controlling for tumor factors, as well as receipt of chemotherapy, mtKRAS status remained independently associated with a worse outcome among patients who recurred(HR 2.07, 95% CI 1.31-3.27; P=0.002). Conclusions: mtKRAS was noted in one-third of patients with CLM. While KRAS status did not impact pattern of recurrence, mtKRAS was an independent predictor of worse OS among patients who experienced a recurrence following resection of CLM.
Overall survival and clinical characteristics in BRCA mutation carriers with stage I/II pancreatic cancer (PC).
Authors: Golan Talia , Sella Tal , Javle Milind M. , Borgida Ayelet , O'Reilly Eileen Mary , Kelsen David Paul , Epelbaum Ron , Kindler Hedy Lee , Katz Matthew H. G. , Gallinger Steven
Published: February 2017

287

Background: BRCA1/2 mutation carriers with PC may have distinct biologic outcomes. We recently described favorable overall survival (OS) in patients with early-stage resected PC. However the prognostic impact of germline (GL) BRCA1/2 mutations in surgically-resected PC cases has not been yet compared with institution-matched controls. Methods: A multi-center, case-control retrospective analysis was performed of patients with surgically-resected, BRCA1/2 mutated PC from years 2001-2012. Non-hereditary PC controls were defined as BRCA negative or absence of a personal and first degree familial history of breast, ovarian or PC. Cases were matched by: age at diagnosis (+/- 5 years), treatment (neoadjuvant vs. adjuvant) and institution. Demographics, clinical history, overall survival (OS) and disease-free survival (DFS) were abstracted from patient records. Statistical comparisons were assessed using χ2and Fisher's exact test and median DFS/OS using Kaplan-Meier method and log-rank testing. Results: 20 patients with GL BRCA1/2 mutation PC were identified and matched (1:2) with 40 non-hereditary controls. Cases were comparable to controls in all tumor and treatment (neoadjuvant vs. adjuvant) related variables except lymphovascular involvement (30.6% vs 64.7%, p= 0.014). However, BRCA cases frequently received neoadjuvant (8/10 vs 6/14)/adjuvant (7/15 vs 3/34) platinum-based treatment. Clinical characteristics of GL BRCA1/2PC cases: BRCA1=3, BRCA2=17. Mean age was 56.7 years (41-78, SD 10.0), 65% (n=13) were female, 55% (n=11) were Jewish, 55% (n=11) had a family history and 95% (n=19) were stage II at resection. We demonstrated no difference in median OS (23.8 vs 25.9 months, p=0.397) and in DFS (13.6 vs 12.6 months, p=0.404) in BRCA1/2 mutation carriers vs controls. BRCA1/2mutation carriers did not experience improved DFS or OS with platinum-based chemotherapy. Conclusions: In this retrospective analysis, the prognosis of surgically-resectable BRCA associated PC is no different than that of sporadic PC from the same institution. The role of DNA damaging agents in this setting is still inconclusive.
A phase I/II study of TRC105 in combination with sorafenib in hepatocellular carcinoma (HCC).
Authors: Duffy Austin G. , Ma Chi , Ulahannan Susanna Varkey , Makarova-Rusher Oxana V. , Fioravanti Suzanne , Walker Melissa , Venkatesan Aradhana , Turkbey Ismail B. , Choyke Peter L. , Trepel Jane B. , Cao Liang , Compton Kathryn , Figg William Douglas , Greten Tim F.
Published: February 2017

291

Background: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and causes ADCC and apoptosis of proliferating endothelium. Sorafenib is the only FDA-approved drug in HCC. Methods: Preclinical: Murine BNL HCC cells were grown subcutaneously in wildtype Balb/c mice and treated with antibody to murine CD105, (clone MJ7/18; 10-200ug) + sorafenib (10 mg/kg daily p.o.) or sorafenib alone with assessment for CD105 expression, tumor size. Clinical: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks plus sorafenib 400mg bid. Correlative biomarkers included DCE-MRI, color Doppler ultrasonography, circulating endothelial and endothelial progenitor cells, plasma levels of angiogenic factors, soluble CD105 and tumor IHC for CD105. Samples were also collected for immunogenicity and pharmacokinetics. Results: Preclinical studies: CD105 expression was increased in BNL HCC tumors by sorafenib. Anti-CD105 antibody + sorafenib reduced tumor volume compared to sorafenib alone. Clinical trial: 19 pts were enrolled; Hep B/C/NA: 2/10/7; M:F 13:6; Mean age of 60 (range 18-76); 1 DLT (increased AST) occurred at 10mg/kg. Three of 14 (21%) evaluable pts achieved PR by RECIST. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median time on study was 4 months (range 2 to 22 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity was observed and the study is proceeding to the phase 2 stage. Full correlative and clinical data will be presented. Clinical trial information: NCT01306058.
The association of HGF/Cmet overexpression with clinicopathologic factors in hepatocellular carcinoma.
Authors: Goff Laura Williams , Shaikh Fyza Y , Du Liping , Washington Mary Kay , Salaria Safia N
Published: February 2017

297

Background: The Cmet receptor tyrosine kinase is overexpressed in 20-50% of hepatocellular cancers (HCC) and has been associated with aggressive features. Little is known about the clinical characteristics of patients whose tumors overexpress Cmet. We examined Cmet expression levels on a series of 80 HCC samples to evaluate for an association between overexpression and clinicopathologic features. Methods: Samples from 80 patients with HCC were assessed with immunohistochemistry (IHC) analysis for hepatocyte growth factor (HGF) and Cmet. Positive staining was correlated with age, sex, race, HCC risk factors, tumor grade, stage, metastatic sites and survival. Results: Hepatitis B virus (HBV) patients were more likely to have Cmet positive tumors than those with other risk factors for HCC such as hepatitis C or alcohol. Higher tumor grade was associated with Cmet positivity. No evidence of association between Cmet positivity and survival was seen although HGF positivity tended to associate with a trend toward decreased survival. Conclusions: Cmet pathway overexpression in HCC is associated with distinct clinical and pathologic features. [Table: see text]
ING3 as a novel regulator of pancreatic cancer growth and aggressiveness.
Authors: Koutsioumpa Marina , Hatziapostolou Maria , Polytarchou Christos , Joshi Swapna , Iliopoulos Dimitrios
Published: February 2017

304

Background: Recent studies demonstrate that chromatin regulation by posttranslational means, such as histone methylation or acetylation, is an essential control mechanism in tumorigenesis and tumor progression. Accumulative findings support the notion that pancreatic cancer tumorigenesis is not only governed by genetic alterations but also aberrant epigenetic regulation. The aim of the present study was to identify and assess the role of chromatin regulators in pancreatic cancer. Methods: The gene expression profile of chromatin regulators was assessed using gene expression microarray analysis in pancreatic cancer and uninvolved human tissues. Validation of microarray findings was performed by qRT-PCR in two extended cohorts of patients and by immunohistochemistry in pancreas tumor tissue microarrays. PANC-1, MIA Paca-2, Capan-2, HPAF-II and AsPC-1 cell lines were used for in vitro assays. Efficiency of knockdown experiments, performed by RNAi interference assays and shRNA-expressing lentiviral vectors, was evidenced by qRT-PCR and Western Blot Analysis. Cell proliferation, invasion and colony formation assays were conducted in genetically modified cells. The significance of variability between the results from each group and corresponding control was determined by unpaired t-test. Results: Differential expression analysis of chromatin regulators in pancreatic cancer versus uninvolved tissues demonstrates that 27 epigenetic molecules are significantly de-regulated (>1.5 fold, P<0.05). By hierarchical clustering, the samples are classified into two major groups that reflect the normal and cancer state. The decreased expression of inhibitor of growth family member 3 (ING3), a component of the NuA4 histone acetyl-transferase complex, was further validated by qRT-PCR and immunohistochemistry analysis in tumor tissues. Transient or stable silencing of ING3 caused significant increase of viability, proliferation, colony formation and invasion in several pancreatic cell lines. Conclusions: Our data show that human pancreatic cancer is characterized by loss of ING3 expression and we defined a potential role of the latter in pancreatic cancer cell growth and invasion.
Association of SLC15A2 genomic variation with the response to sorafenib treatment: Whole-genome analysis in patients with hepatocellular carcinoma.
Authors: Kim Bo Hyun , Lee Yeon-Su , Kim Byung Chul , Shin Aesun , Kim Jin Sook , Hong Seung-Hyun , Hwang Jung-Ah , Lee Jung Ahn , Nam Seungyoon , Lee Sung Hoon , Bhak Jong , Park Joong-Won
Published: February 2017

308

Background: Reliable biomarkers are required to predict patient response to sorafenib. We attempted to investigate genomic variations associated with responsiveness to sorafenib treatment in patients with unresectable hepatocellular carcinoma (HCC) and their functional relevance. Methods: We obtained blood samples from 4 strong and 3 poor responders to sorafenib treatment and subjected these samples to whole-genome analysis. Next, we performed validation tests for candidate single-nucleotide polymorphisms (SNPs) in the samples of 174 HCC patients who were treated with sorafenib, followed by in vitro functional analysis and in silico analyses of candidate SNPs. Results: On average, 90 gigabases/sample was generated at ~34X sequencing depth. In total, 1813 genomic variations were perfectly matched to sorafenib responses in the clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes—36 within the coding regions and 6 identified as non-synonymous single-nucleotide variants from 4 ADME-related genes (ABCB1, FMO3, MUSK, and SLC15A2), which potentially cause functional alterations. Validation tests of 174 patients confirmed sequencing results and revealed that patients with the C/C genotype for rs2257212 in SCL15A2 displayed higher risk for cancer progression than did patients with C/T or T/T genotypes (HR: 2.18; 95% CI, 1.15–4.15; P = 0.018). In vitro functional analysis revealed that cells harboring C/C genotype for this SNP displayed lower response to sorafenib treatment than did cells harboring the T/T genotype. Structural prediction analysis revealed change in protein phosphorylation levels, potentially affecting sorafenib-associated enzymatic activity. Conclusions: SLC15A2 could be a robust biomarker of response to sorafenib treatment in HCC patients.
Challenges with genomic testing in pancreaticobiliary cancers: Results of a prospective cohort study.
Authors: Sohal Davendra , Rini Brian I. , Estfan Bassam N. , Shepard Dale Randall , McNamara Michael J. , Dreicer Robert , Bolwell Brian James , Khorana Alok A.
Published: February 2017

314

Background: Therapeutic options for advanced pancreaticobiliary (PB) malignancies may be improved by genomics-driven therapies. We conducted a prospective cohort study of outpatient genomic testing to identify prevalence of actionable alterations and therapeutic impact of such testing in PB cancers. Methods: Eligibility requirements included confirmed pathologic diagnosis of select solid tumor malignancies without a known curative option, age ≥ 18 years, and an ECOG performance status of 0-2. Data for the PB cancer subgroup are presented here. Tumor samples were sequenced for up to 315 candidate genes in collaboration with Foundation Medicine, Inc. (Cambridge, MA). Results were discussed at the Cleveland Clinic Genomics Tumor Board that made therapeutic recommendations to treating physicians. Results: From Aug 2013 to Aug 2014, samples from 228 patients were analyzed; 24 (11%) had PB cancers. For the latter subgroup, median age was 60 years; 14 (58%) were male; 20 (83%) were white. Twelve (50%) tumors were pancreatic, 11 (46%) from biliary tract/gallbladder, and 1 (4%) periampullary. Median time from consent to result was 24 (range, 3-84) days. Eight (33%) samples had inadequate tissue compared with 6/174 (3%) non-PB samples (p<0.001). Among patients with adequate tissue (n=16), a median of 3 (1-7) mutations were detected per sample; TP53 (50%), CDKN2A/p16 (44%) and KRAS (38%) were most common. A targeted therapy was recommended in 7 (44%) patients. Of these, 78% of recommendations were for specific clinical trials. To date, no patient with PB cancer has received a targeted therapy, compared with 6/45 (13%) patients with colorectal cancer (p=0.18). The most common reason for non-receipt of recommended targeted therapy was non-availability of clinical trials. Conclusions: Compared with other common solid tumors, genomic profiling in pancreaticobiliary cancers is challenged by paucity of diagnostic tissue collected during routine clinical care. Targeted therapy options (on-study or off-label) are few at this time. Precision oncology in pancreaticobiliary cancers will remain under-utilized until access to clinical trials is enhanced.
Tumor c-Met expression and prognosis of advanced hepatocellular carcinoma patients treated with sorafenib.
Authors: Shao Yu Yun , Hsiao Chi-Huang , Lee Ray , Puig Oscar , Chan Soa-Yu , Li Yong-Shi , Hsu Chih-Hung
Published: February 2017

317

Background: Overexpression of c-Met signaling has been associated with development and progression of hepatocellular carcinoma (HCC). We explored the prognostic role of tumor c-Met expression in patients with advanced HCC. Methods: Patients who had received sorafenib alone as first-line therapy for advanced HCC and had available archival tumor tissues were enrolled. Expression of total c-Met was determined by immunohistochemical staining using CONFIRM anti-total c-MET (SP44) rabbit monoclonal primary antibody (Ventana) on the BenchMark ULTRA staining platform. We evaluated c-Met expression by H scores and by a clinical score as defined in the table. Results: The study enrolled 62 patients, all with Child-Pugh class A status. The HCC etiology was hepatitis B in 48 patients, and hepatitis C in 12 patents; 57 had BCLC disease; 40 had extrahepatic metastasis, and 37 had macrovascular invasion. Clinical scores of c-Met were 0 in 30 (48%) patients, 1 in 31 (50%) patients, 2 in 1 (2%) patients, and 3 in 0 patients. Patients with different clinical scores of c-Met had similar PFS (p = 0.821) or OS (p = 0.533). The median membranous H score and cytoplasmic score were 32.5 and 5, respectively. Patients with higher (≥ median) and lower c-Met membranous H scores or cytoplasmic H scores also had similar PFS and OS. Conclusions: High c-Met expression was rare in this advanced HCC cohort. Tumor expression of c-Met had no obvious associations with the prognosis of advanced HCC. (This study was supported by National Science Council, Taiwan (NSC-102-2314-B-002-120, NSC-103-2314-B-002-181-MY2, NSC-103-2314-B-002-092)). [Table: see text]
Oncologic impact of monocarboxylate transporter 4 (MCT4) in pancreatic cancer.
Authors: Lee Sung Hwan , Kang Chang Moo , Hwang Ho Kyoung , Lee Woo Jung
Published: February 2017

319

Background: Transporters for monocarboxylate play an integral role in cancer metabolism in terms of the regulation of intracellular pH. The aim of our study is to check the oncologic impact of Monocarboxylate Transporter 4 (MCT4) expression in pancreatic cancer. Methods: To identify oncologic impact of MCT4 in pancreatic cancer, we performed immunohistochemical (IHC) stains for MCT4 in paraffin embedded block of resected pancreatic cancer tissue. MCT4 expression was correlated with short-term and long-term oncologic outcomes. Results: Fifty patients were enrolled to this study and formalin-fixed, paraffin-embedded (FFPE) tissue block of surgically resected pancreatic cancer and survival data were used for identify the oncologic impact of MCT4. Overall expression of MCT4 in pancreatic cancer was observed (84.5% above intensity grade 1) compared to normal pancreatic tissue in immunohistochemical stain. High expression of MCT4 was observed in twenty-two patients (44%). There were no statistical difference regarding tumor size, T-stage, N-stage, perineural invasion, lymphovascular invasion, tumor grade, R0 resection, and postoperative adjuvant treatment between high and low MCT4 expression group (p>0.05). However, high MCT4 expression group showed significantly poorer cancer-specific survivals than low expression group (median survival; 15 vs. 32 months, p=0.001). Conclusions: The expression of monocarboxylate transporter 4 (MCT4) was identified as poor prognostic factor in pancreatic cancer. Further study to identify the possibility of MCT4 as a potential therapeutic target for treating pancreatic cancer is mandatory.
Effect of neoadjuvant treatment with gemcitabine with nab-paclitaxel on SPARC and Ki-67 in patients with resectable pancreatic adenocarcinoma.
Authors: Sliesoraitis Sarunas , Collinsworth Amy L. , Trevino Jose Gilberto , Zlotecki Robert , Lu Xiaomin , Lightsey Judith L. , Allegra Carmen Joseph , Alkhasawneh Ahmad , Dang Long H. , Daily Karen Colleen , Behrns Kevin , Liu Chen , Hughes Steven J. , Ivey Alison Marguerite , Chauhan Shailendra , Desai Neelam Vijay , George Thomas J.
Published: February 2017

322

Background: Nab-paclitaxel (nab-P) and gemcitabine (Gem) improve survival in metastatic pancreatic cancer (PCa). We sought to determine the impact of nab-P and Gem on the primary tumor and associated microenvironment in neoadjuvant treatment (NAT). Methods: All patients in the GAIN-1 study (NCT01470417) received NAT with nab-P and Gem with or without radiation depending on risk status. A comparator group without NAT was matched for age, sex, race, resection status, smoking, primary tumor site, and tumor size. Surgical specimens of tumor, associated stroma and lymph nodes were analyzed. Routine immunohistochemistry (IHC) for Ki-67 and TUNEL was performed. Immunolabeling was assessed using anti-SPARC antibody (Invitrogen) with scoring consistent with prior reports: Negative = intensity absent to weak (+) with extent <10%; Positive = intensity moderate (++) to strong (+++) with extent ≥ 10%. For Ki-67 and TUNEL, the percentage of positive tumor cells was averaged over four HPF/specimen. Study was conducted with IRB approval. Results: A total of 30 unique patients were included in this analysis, 8 NAT cases and 22 matched controls. Clinical outcomes have been previously reported. Minimal to no SPARC expression was noted in either group of tumor cells. However, stromal SPARC expression was markedly reduced in NAT group (mean 2.88 ± 0.69%) compared to controls (28.43 ± 5.80%; p = 0.0002). Ki-67 was reduced in NAT group compared to controls (10.5 ± 2.83% vs. 36.76 ± 4.32%; p = 0.0004). TUNEL stain revealed a trend toward lower levels in NAT group (mean 1.13 ± 0.30% vs. 1.62 ± 0.31%; p = 0.574). SPARC, Ki-67 and TUNEL did not correlate with survival. Conclusions: SPARC expression in pCa primary tumors is low. Neoadjuvant nab-P and Gem significantly decreased stromal SPARC and tumor Ki-67. There was no change in TUNEL expression, indicating a population of residual viable cells. Additional stromal microenvironment change analysis in response to treatment is ongoing.
RAS mutations and their correlation with survival of patients with advanced pancreatic adenocarcinoma.
Authors: Almeida Thiago Lins , Gomes Jessica Ribeiro , Machado Marcel Cerqueira Cesar , Buzaid Antonio C. , Maluf Fernando C.
Published: February 2017

325

Background: The prognosis of pancreatic adenocarcinoma (PA) remains poor despite FOLFIRINOX and nab-paclitaxel-gemcitabine based chemotherapy. The epidermal growth factor receptor (EGFR) has a major role in pancreatic cancer carcinogenesis.The RAS status showed to be a predictive factor for response to anti-EGFR therapy in colon cancer. We aim to analyze the K-RAS and N-RAS status in PA and its prognostic impact. Methods: Retrospective analysis included 24 patients with metastatic (67%) or locally advanced (29%) PA at diagnosis (AEMOC, Brazil). K-RAS and N-RAS profile were performed by polymerase chain reaction and bidirectional sequencing (codons 12, 13, 61, 117, 146). The results were then analyzed in regards to overall survival (OS) and progression-free survival (PFS) in PA. Results: The sample showed: median age of 63 years (28-86), 62.5% male, 45.8% smoker, head site (67%), ductal (68%), and mild differentiation features (45%). The first-line therapy was FOLFIRINOX (62.5%) and gemcitabine (33.3%). The median PFS and OS were 6.5 and 13 months (mo), respectively. Nineteen patients (79.1%) presented mutation in K-RAS: four c.35G>A (G12D), four c.34G>C (G12R), four c.35G>T (G12V), three c.35G>C (G12A), one c.437C>T (A146V), and one c.34G>T (G12C). Mutation in N-RAS (c.38G>A (G13D) was detected in only one patient (4%). The only independent factor for survival was K-RAS status: the c.35G>A (G12D) polymorphism yielded worse PFS and OS when compared to non-c.35G>A (G12D) mutation: 3 vs 7 mo [HR 0.25, 95% CI, (0.04–1.63)] for PFS (p<0,0043) and 3.5 vs13 mo [HR 0.17, 95% CI, 0.01-1.58)] for OS (p<0,0001), respectively. Conclusions: K-RAS was the only prognostic factor for PFS and OS, with the polymorphism c.35G>A (G12D) being related to a worse prognostic. Further studies are necessary to better evaluate whether K-RAS and N-RAS status is prognostic and/or predictive factor.
Impact of preoperative neutrophil to lymphocyte ratio on long-term survival in patients with esophageal squamous cell carcinoma.
Authors: Kamachi Kenichi , Ozawa Soji , Kazuno Akihito , Makuuchi Hiroyasu , Oguma Junya , Yamasaki Yasusi , Ninomiya Yamato
Published: February 2017

33

Background: Elevated neutrophil to lymphocyte ratio (NLR) reflects patients’ inflammation status and closely relates to tumor progression. The aim of this study was to evaluate the clinical significance of the preoperative NLR in patients who undergo an esophagectomy for esophageal squamous cell carcinoma. Methods: A total of 340 patients who underwent an esophagectomy for esophageal squamous cell carcinoma between 2003 and 2008 were retrospectively reviewed. The NLR ≥ 3 was considered to be elevated and the patients were divided into two groups. The overall and disease-free survival curves of the two NLR groups were determined using the Kaplan-Meier method and were compared using a log-rank test. A cox proportional hazards regression analysis was used for the univariate and multivariate analyses. Results: The study included 306 males and 34 females. Seventy-two patients (21%) had an elevated NLR. The 5-year overall survival for patients with high NLR was significantly worse than that for patients with normal NLR (41% vs 69%, p < 0.001). The 5-year disease-free survival for patients with high NLR was significantly worse than that for patients with normal NLR (41% vs 59%, p < 0.001). In multivariate analysis, a high NLR (HR 1.76, 95% CI 1.19-2.60, p = 0.005), an upper tumor location (HR 1.97, 95% CI 1.18-3.30, p = 0.010), an advanced T stage (HR 2.71, 95% CI 1.70-4.31, p < 0.001), and a larger number of metastatic lymph nodes (HR 4.38, 95% CI 1.18-3.30, p < 0.001) were independent predictors of poor overall survival. Conclusions: Our results suggested that the elevated preoperative NLR predicts poor overall and disease-free survival after an esophagectomy for esophageal squamous cell carcinoma.
Metachronous pancreatic cancer originating from disseminated founder pancreatic intraductal neoplasias.
Authors: Ono Yusuke , Karasaki Hidenori , Imai Koji , Sasajima Junpei , Chiba Shin-ichi , Funakoshi Hiroshi , Muraki Miho , Hanaoka Hideki , Furukawa Takahisa , Furukawa Hiroyuki , Kono Toru , Nagashima Kazuo , Mizukami Yusuke
Published: February 2017

330

Background: Clonal populations originated from benign-looking “founder cells” may spread widely within pancreas instead of being localized in situ before frank pancreatic ductal adenocarcinoma (PDA) can be detected. Metachronous PDA is not common event, and we here sought to define potent origin of multiple PDAs developed in a woman by using advanced genetics technologies. Methods: In addition to precise pathological assessment, genetic approaches such as deep sequencing of multiplex PCR amplicons of cancer-associated genes (Ion Torrent PGM platform) and digital PCR were employed. Results: Curative resection of pancreatic head tumor was performed; however, “recurrent” lesions in the remnant pancreas were found 3.5-years later and total pancreatectomy was subsequently performed. The metachronous lesions were morphologically similar to the primary PDA. All 3 PDAs were shown to possess rare somatic mutations in KRAS (p.T58I and p.Q61H). Curiously, identical KRAS mutations were found in low-grade “intraepithelial” lesions, which localized in normal area of the pancreas and one of them possessed p53mutation, which was also found in the PDAs. Conclusions: Rare KRAS haplotype was identified in the metachronous PDAs in the current case. Surprisingly, the identical somatic mutations were also found in independent low-grade “intraepithelial” lesions with and without additional mutation in p53. The footprint of the tumor evolution marked by mutational profiling supports a human correlate to the mouse models of “dissemination” occurring at the earliest stages of pancreatic neoplasia.
Efficacy and safety of nintedanib versus sorafenib in Asian patients with advanced hepatocellular carcinoma (HCC): A randomized phase II trial.
Authors: Cheng Ann-Lii , Yen Chia-Jui , Kim Tae-You , Feng Yin-Hsun , Chao Yee , Lin Deng-Yn , Loembe Arsene-Bienvenu , Hocke Julia , Choi Caren , Ryoo Baek-Yeol
Published: February 2017

339

Background: Nintedanib (N) is an oral, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This randomized, multicenter, open-label, Phase II study (NCT00987935; 1199.39) evaluated the efficacy and safety of N versus sorafenib (S) in Asian patients with advanced HCC. Preliminary analysis showed similar time to progression (TTP) by independent central review (ICR). Methods: Asian patients with unresectable advanced HCC, Child–Pugh score 5–6, ECOG-PS ≤2, and alanine/aspartate aminotransferase (ALT/AST) ≤2× upper limit of normal were enrolled. Patients were randomized 2:1 to N 200 mg bid or S 400 mg bid continuously in 28-day cycles, until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. Primary endpoint was TTP by ICR (RECIST 1.0) and secondary endpoints were overall survival (OS) and investigator-assessed (IA) TTP. Results: Patients (N=95) were randomized to receive N (n=63) or S (n=32); arms were balanced except for macroscopic vascular invasion (48% vs 31%). At the final cutoff date (16 Jul 14), 88% of patients had a TTP event, and 86% had an OS event; 1 patient was on treatment beyond PD. N and S had comparable IA TTP (median 2.8 vs 3.0 months; HR 1.39 [95% CI: 0.87–2.23]) and OS (median 10.2 vs 10.7 months; HR 0.94 [95% CI: 0.59–1.49]). ICR TTP data are pending. All but 1 patient reported an AE (CTCAE 3.0). More S-treated patients had Grade ≥3 AEs (56% vs 84%), serious AEs (46% vs 56%), and AEs leading to dose reduction (19% vs 59%) and drug discontinuation (24% vs 34%). Class-specific AEs of tyrosine kinase inhibitors in >15% of S-treated patients were hypertension, hand-foot skin reaction, and thrombocytopenia; only anemia was higher with N. AEs previously observed and higher with N were vomiting and nausea; ALT/AST increases and diarrhea were higher with S. Rash was reported in >15% of patients only with S. Conclusions: N shows similar efficacy to S for TTP and OS. N was better tolerated than S and AEs were generally manageable. Further studies of N in Asian patients with advanced HCC are warranted. Clinical trial information: NCT00987935.
A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.
Authors: Scott Aaron James , O'Neil Bert H. , Gomes Christina , Baranda Joaquina Celebre , Cohen Steven J. , Tejani Mohamedtaki Abdulaziz , Maguire Robert T. , Wilhelm Francois , Maniar Manoj , Cohen Deirdre Jill , Ma Wen Wee , Aisner Dara , Cho Jonathan K. , Olowokure Olugbenga Olanrele , Coveler Andrew L. , Menter Alex R. , Rubin Peter , Cusnir Mike , Messersmith Wells A.
Published: February 2017

342

Background: Rigosertib (ON 01910.Na), a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase (PI3K) pathways, was assessed in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Methods: Patients with metastatic adenocarcinoma of the pancreas were randomized in a 2:1 fashion to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800mg/m2 via 2-hr CIV infusions given twice weekly for 3 weeks of a 4-week cycle versus gemcitabine 1000mg/m2 weekly for 3 weeks in a 4-week cycle. Results: A total of 160 patients were enrolled globally and randomly assigned to rigosertib plus gemcitabine (106 patients) or gemcitabine (54). The most common grade 3 or higher adverse events were neutropenia (8% in the rigosertib plus gemcitabine group vs. 6% in the gemcitabine group), hyponatremia (17% vs. 4%), and anemia (8% vs. 4%). The primary outcome of the study, median OS, was 6.1 months in the gemcitabine plus rigosertib arm versus 6.4 months with gemcitabine alone (hazard ratio (HR), 1.24; 95% confidence interval [CI], 0.85-1.81). The median PFS was 3.4 months for both groups (HR, 0.96; 95% CI, 0.68-1.36). The overall best response between arms were partial response rates of 19% versus 13% and stable disease in 50% versus 56% in the gemcitabine plus rigosertib versus gemcitabine alone, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40/47, 85%), which included c.35G>T, p.G12V (12 cases), c.35G>A, p.G12D (21 cases), c.34G>C, p.G12R (4 cases), c.34G>T, p.G12C (1 case) and c.183C>A, p.Q61H (2 cases). Other mutations detected included TP53 (13 cases) and PIK3CA(1 case). No correlation between mutational status and efficacy was detected. Conclusions: The combination of rigosertib plus gemcitabine failed to demonstrate an improvement in survival or response compared to gemcitabine alone in metastatic pancreatic adenocarcinoma. Clinical trial information: NCT01360853.
A phase II study of bavituximab and sorafenib in advanced hepatocellular carcinoma (HCC).
Authors: Yopp Adam Charles , Singal Amit G , Arriaga Yull Edwin , Verma Udit N. , Shan Joseph , Kallinteris Nikoletta , Beg Muhammad Shaalan , Mansour John C. , Zhu Hao
Published: February 2017

345

Background: Bavituximab a first-in-class immunomodulator targeting phosphatidylserine (PS), a lipid externalized on tumor and endothelial cells. Preclinical and phase I studies demonstrated that sorafenib upregulates PS externalization and can be given safely with bavituximab. We evaluated the safety and clinical activity of bavituximab plus sorafenib in HCC. Methods: Patients with advanced HCC deemed ineligible for curative therapy with no previous systemic treament, ECOG score ≤ 2, Child Pugh score A or B7 received bavituximab, 3 mg/kg IV weekly, and sorafenib, 400 mg PO BID until disease progression or intolerable toxicity. 38 patients were accrued providing a power of 80% and two-sided significance level of 10% to show an 8.2 month time to progression compared to historical control, 5.5 months. Secondary endpoints included safety and tolerability, 4-month progression free survival, overall survival, and response rates. Correlative studies using pre- and post-treatment tumor biopsies included IHC analysis of regulatory, cytotoxic, and helper T cells in addition to macrophage infiltrates. Results: 38 patients were accrued, 7 still on treatment. Patient characteristics: median age: 60.5 years, male 74%, HCV: 79%, Black: 47%/Hispanic: 29%/White: 21%, previous treatment 37%, and metastases: 24%. Median follow-up is currently 6.1 months with current median TTP of 6.8 months (95% CI 3,10). Four month PFS is 76% and there are no partial or complete responses. Treatment related adverse events were observed in 53% of patients, one grade 3 (GI bleed), four grade 2 (DVT, anorexia, diarrhea, and infusion reaction). Most common grade 1 events were diarrhea (18%), fatigue (16%), and anorexia (16%). Six patients had tissue analyzed pre- and post-treatment, 2 of 6 demonstrated increase tumor infiltration of CD4+, CD8+, and macrophages with a corresponding decrease in Tregs. Conclusions: Bavituximab and sorafenib were well tolerated in patients with advanced HCC. When compared with historical controls, combination therapy demonstrated an improvement in TTP and PFS at four months. Combination therapy increases immune tumor infiltrates. Clinical trial information: NCT01264705.