bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and biomarker evaluations of sunitinib in patients (pts) with advanced well-differentiated grade 3 (G3) and poorly differentiated neuroendocrine neoplasms (PD-NEN).
Authors: Dreyer Chantal , Couvelard Anne , Walter Thomas , Lombard Bohas Catherine , Niccoli Patricia , Seitz Jean-François , Hentic Olivia , Pellat Anna , Andre Thierry , Couffignat Camille , Lobbe Nathalie , Mentre France , Bedossa Pierre , Hammel Pascal , Faivre Sandrine J. , Zappa Magalie , Ruszniewski Philippe B. , Raymond Eric
Published: February 2017

274

Background: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumors (PNET) where sunitinib was showed to prolong progression-free survival leading to FDA and EMA approval. However, clinical experience in pts with well-differentiated G3 & PD-NEN remains limited. Methods: This prospective phase II trial evaluate potential biomarkers correlating with sunitinib activity in pts with advanced well differentiated G3 or PD-NEN. Sunitinib was given at the dose of 37.5 mg/d as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAEv4. Pharmacokinetics (PK) of sunitinib and SU12662 (main active metabolite) were evaluated. Tumor biomarkers (PDGFR-b, VEGFR2, Carbonic Anhydrase 9, Ki67 and p-AKT) were evaluated in tumor tissues, quantified in tumor cells and stroma (vessels, fibroblasts) using immunohistochemistry and correlated with response by RECIST. Results: Among 31 pts (M/F: 18/13, median age 61), 13 pancreatic, 5 gastric, 5 rectal, 4 colonic, and 4 other G3 & PD-NEN were entered. 27 pts had previous treatment with chemotherapy (mainly platinum/VP16). Among 26 pts evaluable for safety and activity, 7 pts (23%, 95%CI: 6.9%-39.3%), including 3 pts classified as well-differentiated G3 neoplasms) experienced partial responses and tumor stabilizations (clinical benefit). Safety and PK exposure to sunitinib and SU12662 in those pts was consistent with that experienced in PNET. Among the above evaluated tumor biomarkers, only Ki67 correlated with sunitinib activity. The median Ki67 was 20% and 77.5% in pts with CB versus non-responders (p=.002), respectively. ROC curves showed correlations between lower Ki67 in tumors and sunitinib activity (OR:0.9; IC95%:0.831-0.9, p=.039). With a threshold value of Ki67 of 47%, sensitivity and specificity were 80%, the predictive positive value was 67% and the negative predictive value was 86%. Conclusions: In pts with well-differentiated G3 & PD-NEN, sunitinib showed evidence of activity that was more pronounced in pts with Ki67<47%. Clinical trial information: NCT01215578.
DNA sequencing to identify potentially novel targets for therapy in pancreatic cancer.
Authors: Toll Jeffrey , Osipov Arsen , Khanuja Jasleen , Pan Dana , Patel Rishi , Zhou Jenny , Shinde Arvind Manohar , Annamalai Alagappan , Hendifar Andrew Eugene , Tuli Richard
Published: February 2017

275

Background: Molecular differences in solid tumors have been shown to correlate with heterogeneity of response. Unfortunately, minimal data exists in pancreatic ductal adenocarcinoma (PDA). Next generation sequencing (NGS) may provide genetic signatures that allow prognostic stratification and predict response to targeted therapy. Methods: DNA was extracted from biopsy specimens of 64 patients (pts) with PDA at Cedars-Sinai Medical Center. DNA sequencing was performed for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (Foundation Medicine, Cambridge, MA). We report all genetic alterations including those classified as variants of unknown significance (VUS) as these may potentially be important for further study. Results: 94% of our patients had KRAS mutations, SMAD(39%) P53 (69%), and CDKN2A (48%). 17% of the pts had all 4 mutations. 4.6% had none. MLL and ARID genes, both involved in chromatin remodeling, were altered in (45%) and (35%) of the patients respectively. Alterations in MLL2 (22%) have been previously described. Interestingly, we also identified mutations in MLL3 (15%) and MLL (8%) of patients. We also identified an equal frequency of mutations in ARID1A mutations (17%) and ARID 1B (17%). ATM (19%) and ATR (11%) genes involved in double stranded DNA repair were mutated in a total of 30%. BRCA1 (12.5%) and BRCA2 (14%) were mutated in 26.5%, and PALB2 in another 2%. PMS2 (mismatch repair) was also mutated in 9% of patients. In total 67% of patients had alterations in one of these DNA repair pathways. There were a number of other genes noted to harbor mutations in greater than 10% of patients including BCOR, which is known to interact with MLL and seen in acute leukemia, FANC complex, GPR124 (angiogenesis), as well IRS2, PIK3A in the akt-PIK pathway. Conclusions: NGS in a cohort of advanced pancreatic cancer patients identified novel alterations in genes associated with chromatin modeling and DNA repair. These pathways may serve as potential avenues for targeted therapy in pancreatic cancer.
Effect of intratumoral CD3+ and NKp46+ cells on tumor progression in resected colorectal liver metastases treated with neoadjuvant chemotherapy.
Authors: Donadon Matteo , Cimino Matteo , Hudspeth Kelly , Di Tommaso Luca , Preti Max , Roncalli Massimo , Mavilio Domenico , Torzilli Guido
Published: February 2017

281

Background: The long-term outcome of patients resected for colorectal liver metastases (CLM) after neoadjuvant chemotherapy (CHT) depends by several tumoral and non-tumoral factors, such as the immune response to the tumor and to the CHT. The aim of this study was to investigate the impact of the pathological and immunological response in patients undergoing liver resection for CLM after CHT in regards to the long-term outcome. Methods: The immunoreactivity to CD3+ and NKp46+ cells inside the tumor, at the border between the tumor and the normal liver, and inside the normal liver was tested by computer-assisted image analyses in 121 patients undergoing liver resection for CLM between 2005 and 2013 preoperatively treated with oxaliplatin or irinotecan with or without bevacizumab or cetuximab. The survival was assessed in relation to several prognostic factors and to that immunoreactivity. Results: At univariate analysis T1/T2- and N0-status of the primary tumor, metachronous CLM, the radiological response, and the higher density of intratumoral CD3+ ( > 1%) and of NKp46+ (mean > 1) were found to be significantly associated with prolonged survival, but only intratumoral CD3+ ( > 1%) and NKp46+ (mean > 1) were significant on multivariate analysis (P = 0.005 and P = 0.004 respectively). On logistic regression analysis the metachronous CLM (OR = 2.781; P = 0.002), the use of irinotecan and cetuximab (OR = 3.891; P = 0.001) and the radiological response (OR = 3.219; P = 0.001) were found to be associated with increasing density of intratumoral CD3+ and NKp46+ cells. No significant associations were found with CLM number or size, CEA, or number of CHT courses. Combining the intratumoral CD3+ and NKp46+ cells density we defined four stages of survival (P = 0.003): patients presenting intratumoral CD3+ ( > 1%) and NKp46+ (mean > 1) had 100% overall survival at 5 years. Conclusions: Intratumoral CD3+ and NKp46+ cells density is a crucial prognostic factor in patients undergoing hepatic resection for CLM after CHT, and the kind of CHT seems related to their density. Further external validations are required to confirm our promising findings.
Multi-Omic profiling (MoP) for patients (pts) with pancreatic cancer (PDA): Initial results of the Know Your Tumor (KYT) initiative.
Authors: Pishvaian Michael J. , Brody Jonathan Robert , Matrisian Lynn , Hendifar Andrew Eugene , Engebretson Anitra , Hoos William Arthur , Mikhail Sameh , Chung Vincent M. , Picozzi Vincent J. , Ramos Corinne , Heartwell Craig , Mason Kimberly , Varieur Katelyn , Rahib Lola , Petricoin Emanuel , Madhavan Subha
Published: February 2017

282

Background: Emerging insights into the molecular biology of tumors and recent developments in MoP have led to the identification of targets that can be used for selecting treatment (tx) regimens. Multiple testing platforms are available, though most studies to date have used only next generation DNA sequencing (NGS). Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera have initiated an IRB-approved registry trial wherein we facilitate commercial MoP on tumor tissue from PDA patients. MoP includes NGS, immunohistochemistry (IHC), and phosphoproteomics (PHO). The results are reviewed by a team of PDA specialists in the context of the pt’s tx history. Tx options are prioritized based on the actionable molecular abnormalities. Pts are being followed longitudinally to assess physician acceptance of the tx options and track survival outcomes. Results: From 06/2014 to 09/2015, Perthera reports were delivered for 117 pts. 44% of the analyses were for second-line tx and 43% for ≥ third-line. Tumor based NGS and IHC were available for 75% and 90% of pts, respectively, and research use only PHO data was available for 20 pts. Actionable findings, defined based on a high response rate in pts with an identified molecular abnormality (in any cancer type), or based on a mechanism/pathway-defined implication of response to tx were identified in 43% of pts, primarily based on NGS. Incorporation of IHC refined and expanded chemotherapy tx options in all pts. PHO revealed pathway activation (e.g. mTOR, JAK-STAT, MET, RET, or EGFR) in 16/20 samples. Interestingly, only 45% of KRAS mutant samples had PHO-defined activation of the MEK-ERK pathway. Conclusions: MoP resulted in actionable findings in 43% of PDA pts using NGS and IHC. Incorporation of PHO data could have a significant impact on MoP-based therapy options. Analysis of the MoP in the context of patient history by a PDA specialist provided a service to treating oncologists in the community that was frequently incorporated into their treatment decisions. Survival outcomes will be presented. As additional testing platforms and results become available, the breadth and confidence of actionable markers is expected to increase.
Next-generation sequencing (NGS) in an advanced hepatocellular carcinoma (HCC) cohort: Analyses of TP53 and CTNNB1.
Authors: Kelley Robin Kate , Gordan John Dozier , Evason Kimberley , Bracci Paige M. , Joseph Nancy M. , Bocobo Andrea Grace , Rosenthal Blake K. , Nimeiri Halla Sayed , Venook Alan P.
Published: February 2017

286

Background: Mutations in TP53 and CTNNB1 are common in early stage HCC resection samples. The frequency and prognostic impact of these mutations in advanced HCC is not known. We conducted this retrospective analysis using a large NGS panel to explore for association between tumor genetics, clinicopathologic features, and prognosis in an advanced HCC cohort. Methods: Eligible cases had diagnosis of unresectable HCC or mixed HCC-cholangiocarcinoma and were enrolled on NCT01008917 or NCT01687673 clinical trials of sorafenib plus temsirolimus with informed consent for specimen banking for future research including genetic testing. Paired tumor and germline (blood) DNA samples were sequenced using a capture-based NGS cancer panel to allow for determination of somatic variants. Analysis was based on the human reference sequence UCSC build hg19. Variants were called using GATK Unified Genotyper software. Somatic, non-synonymous, and exonic calls were curated using COSMIC, cBioPortal, and Pubmed. Results: Cases with HCC (n = 21) and mixed HCC-cholangiocarcinoma (n = 2) comprised the cohort (N = 23). Male/female: 83%/17%. Race: White 56%, Asian 39%. BCLC stage: B 35%, C 65%. Etiology: HBsAg+ 26%, HCV+ 39%. Immune infiltrates ( ≥ 1 on scale 0-3) were present in 7/12 (58%) evaluable tumor samples. TP53 mutations were present in 14/23 (61%, 95% CI: 38.5, 80.0). CTNNB1 mutations were present in 7/23 (30%, 95% CI: 13.2, 52.9). There was no significant difference between HBsAg+ and HCV+. Both TP53 and CTNNB1 mutation were present in 4/23 (17%). CTNNB1 mutation was present in 2/7 (29%) cases with immune infiltrate score ≥ 1, and 1/5 (20%) with score < 1 (not significant). Other mutations and variants will be reported. Conclusions: NGS in this advanced HCC cohort suggests a higher incidence of TP53 and coexisting TP53 plus CTNNB1 mutations than has been reported in early stage HCC which requires confirmation in a larger cohort. There was no clear relationship between these mutations, HCC etiology, or tumor immune infiltrates though interpretation is limited by small sample sizes. Analyses are ongoing to explore for association between TP53 and CTNNB1 mutations and prognosis in this advanced HCC cohort.
Lymphatic invasion as an independent prognostic factor in pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy with gemcitabine or S-1.
Authors: Kazama Keisuke , Aoyama Toru , Katayama Yusuke , Yamaoku Koichiro , Murakawa Masaaki , Higuchi Akio , Kanazawa Amane , Atsumi Yousuke , Shiozawa Manabu , Ueno Makoto , Morimoto Manabu , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka , Morinaga Soichiro
Published: February 2017

290

Background: The objective of this retrospective study was to clarify prognostic factors in pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy with gemcitabine or S-1. Methods: Both overall survival (OS) and recurrence-free survival (RFS) were examined in 122 pancreatic cancer patients who underwent curative surgery and received adjuvant gemcitabine or S-1 after surgery between 2005 and 2014. Results: When the length of OS was evaluated according to the log-rank test, significant differences were observed in lymphatic invasion and the T status. Univariate and multivariate Cox’s proportional hazard analyses demonstrated that lymphatic invasion was the only significant independent prognostic factor for both OS and RFS. The 5-year OS was 30.1% in the lymphatic invasion-negative group and 12.1% in the lymphatic invasion-positive group (p < 0.001). Moreover, the 5-year RFS was 20.5% in the lymphatic invasionnegative group and 10.4% in the lymphatic invasionpositive group (p = 0.006). Conclusions: Lymphatic invasion is the most important prognostic factor for OS and RFS in patients with pancreatic cancer who undergo curative resection followed by adjuvant chemotherapy. The present results suggest that adjuvant chemotherapy is not sufficient, especially in patients with risk factors. Such patients should be evaluated as a target group for clinical trials of novel treatments.
Myeloid deprived suppressive cell to mediate the prognostic value of neutrophil to hemoglobin ratio for hepatocellular carcinoma patients receiving transcatheter arterial chemoembolization.
Authors: Li Xing , Yang Quan , Lin Zhi-Huan , Hong Yingfen , Liu Yu-Feng , Wu Dong-hao , Wang Tian-tian , Chen Zhan-hong , Lin Qu , Huang Mingsheng , Xing Yan-Fang , Wu Xiang-yuan , Zhou Jie
Published: February 2017

292

Background: The prognosis of hepatocellular carcinoma (HCC) patients receiving transcatheter arterial chemoembolization (TACE) is far from being identified. The present study aimed to assess role of blood cell counts, routine liver function tests and neutrophil to hemoglobin ratio (NHR) in predicting the progression-free survival (PFS) of these patients. Methods: A total of 243 HCC patients receiving TACE were analyzed retrospectively. Results: Cancer of the Liver Italian Program (CLIP) score system was identified to be the best score system among current 12 staging systems for this patient subgroup according akaike information criterion (AIC) index and linear trend χ2. Then, the novel prognostic value of parameters was determined by integration into CLIP score system. As a result, NHR were confirmed to an independent predictor for PFS of HCC patients receiving TACE (p = 0.001) with the other parameters, including neutrophil and neutrophil-lymphocyte ratio (NLR), failed to reach statistical significance. Moreover, NHR improved the performance of CLIP by adjusted into it, thus improved the discriminatory ability. Furthermore, NHR were defined value ≤ 0.02 as low level and > 0.02 as high level, according to which patients were dichotomized into two groups. HCC patients receiving TACE with low NHR presented higher 1 year disease control rate (DCR) (50.0% vs 39.35%) and 2 year DCR (45.4% vs 27.0%) compared with patients with high NHR level. Besides, NHR level was associated with prognostic factors such as portal vein thrombosis and distant metastasis. Furthermore, in order to determine the mechanism of predictive value of AHR, we tested the proportion of myeloid deprived suppressive cell (MDSC) in peripheral blood mononuclear cells (PBMC) of 43 HCC patients. It was revealed that MDSC was positively correlated with neutrophil (P< 0.05). Since MDSC was cancer promoter, it might be the mechanism of the prognostic value of NHR. Conclusions: The present study firstly identified NHR as an independent prognostic factor in HCC patients receiving TACE. The positive correlation of MDSC and neutrophil might be the latent mechanism.
Second-line chemotherapy by FOLFIRINOX with unresectable pancreatic cancer (phase I, II study).
Authors: Kobayashi Noritoshi , Tokuhisa Motohiko , Goto Ayumu , Endo Itaru , Ichikawa Yasushi
Published: February 2017

297

Background: The purpose of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and efficacy of the second-line chemotherapy (after gemcitabine based chemotherapy) by FOLFIRINOX with unresectable pancreatic cancer. Methods: The subjects were histopathologically proven unresectable pancreatic cancer patients. The schedule was oxaliplatin 85mg/m2 on day1, irinotecan on day1, leucovorin 400mg/m2 on day 1 followed by FU 400mg/m2 as a bolus on day 1 and 2400mg/m2 as 46-hour continuous infusion biweekly. We were planned the dose of oxaliplatin, leucovorin and FU were fixed and the dose of irinotecan was defined as follows: level 0: 100mg/m2, level 1: 125mg/m2, level 2: 150mg/m2, and level 3: 180mg/m2. We started level 1 and at least three patients were enrolled at same dose two cycles. If DLT was observed two patients in six or three patients, we suspected the level was MTD. We also evaluated this study as phase II. Primary end point was response rate (RR). We also evaluated progression free survival (PFS), overall survival (OS) and adverse event (AE). Results: Eighteen patients were enrolled in this study (man: n = 11, woman: n = 7). We evaluated initial eight patients as phase I study. One patient had neutropenia and another one patient had hyperglycemia and severe infection. We decided level 1 was MTD and recommended dose was level 0. According to phase II study, RR was 22.2% (CR: n = 0, PR: n = 4, SD: n = 7, PD: n = 7) and disease control rate (DCR) was 61.1%. PFS was 2.8 (0.7-11.7) months and OS was 9.8 (2.4-14.4) months. The most common severe AE was neutropenia (66.7%). Fibril neutropenia was occurred one (5.6%) case. Conclusions: Recommended dose was oxaliplatin 85mg/m2 on day1, irinotecan 100mg/m2 on day1, leucovorin 400mg/m2 on day 1 followed by FU 400mg/m2 as a bolus on day 1 and 2400mg/m2 as 46-hour continuous infusion. RR was 22.2% and major AE was neutropenia but FN was rare. Second-line FOLFIRINOX is marginally effective treatment for gemcitabine-base chemotherapy failure cases.
NEOSCOPE: A randomised Phase II study of induction chemotherapy followed by either oxaliplatin/capecitabine (OXCAP) or carboplatin/paclitaxel (CarPac) based chemoradiation (CRT) as pre-operative regimen for resectable oesophageal adenocarcinoma.
Authors: Mukherjee Somnath , Hurt Chris , Gwynne Sarah , Bateman Andrew , Gollins Simon , Radhakrishna Ganesh , Canham Jo , Ray Ruby , Grabsch Heike I , Sharma Ricky A. , Maggs Rhydian , Hawkins Maria A , Sebag-Montefiore David , Maughan Tim , Griffiths Gareth , Crosby Tom David Lewis
Published: February 2017

3

Background: NEOSCOPE compared toxicity and efficacy of 2 pre-op CRT regimens. Methods: Eligibility: Resectable ACA of the oesophagus/GOJ ≥ T3 and/or ≥ N1. Randomisation: 1:1 to OXCAP-CRT (oxaliplatin 85 mg/m2 Day 1,15,29; capecitabine 625 mg/m2 bd on days of RT) or CarPac-CRT (Carboplatin AUC2; paclitaxel 50 mg/m2 Day 1,8,15,22,29); concurrent RT: 45Gy/25 fractions/5 weeks. Both arms received induction chemo: 2 cycles of OXCAP (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m2D1-21, q 3wk). Surgery: 6-8 weeks after naCRT. Detailed RT and pathology quality assurance was built into the protocol. Primary end-point: pathological complete response (pCR). Secondary: toxicity, surgical morbidity/mortality, R1 rate, OS. Statistics: A pCR of 15% would not warrant further investigation but a pCR of 35% would. 76 patients (38/arm) gave 90% power and one-sided type I error of 10% meaning that either arm having ≥10 pCR out of first 38 patients would be considered for Phase III. 85 patients to be recruited (allows 10% loss to follow up). Results: 85 patients were randomised between Oct 2013 and Feb 2015 from 17 UK centres. Patient characteristics: median age 65 yrs, Male (81%), WHO PS 0 (85%). Tumour characteristics: T3 (86%), N1 (48%), lower third/GOJ (90%), median tumour length 5.8cm. CTCAE grade 3/4 toxicity rate during CRT was OXCAP-CRT 42.1%, CarPac-CRT 52.4% (p=0.358). Protocol dose RT OXCAP-CRT 90.5%, CarPac-CRT 93%. Conclusion:Both regimens were well tolerated. CarPac-CRT passed the criteria for taking forward to a phase III study but OXCAP-RT did not. Funding: Cancer Research UK (C44694/A14614), ClinicalTrials.gov: NCT01843829, coordinated by Wales Cancer Trials Unit. Clinical trial information: NCT01843829. [Table: see text]
Treatment of pancreatic ductal adenocarcinoma (PDAC) by argyrin F (AF) + gemcitabine (G).
Authors: Plentz Ruben R , Chen Xi , Barat Samarpita , Bozko Przemyslaw , Bui Cuong , Sipos Bence , Kalesse Markus , Malek Nisar P
Published: February 2017

310

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of < 5%. Early diagnosis is rare and treatment options are often limited. Recent studies have reported that the proteasome inhibitor Argyrin A, a cyclic peptide derived from the myxobacterium Archangium gephyra, shows antitumoral activities. The aim of the present study is to explore the anti-tumor activity of this analogue Argyrin F (AF) + Gemcitabine (G) in PDAC carcinogenesis. Methods: We analyzed the effect of AF on proliferation and epithelial plasticity of different human pancreatic cancer cell lines by using MTT-, wound healing-, invasion-, colony formation-, apoptosis- and senescence assay, as well as cell cycle analysis and Western Blot. In vivo, we assessed the effects of AF and combinational (AF + G) therapy in a genetically engineered mouse model (Pdx1- Cre; LSL-KrasG12D; p53 lox/+) of PDAC. Results: AF inhibited pancreatic cancer cell proliferation, migration, invasion and colony formation compared to their respective untreated controls (DMSO). We also found that AF impairs epithelial-mesenchymal-transition (EMT) and induces considerable apoptosis and senescence in a dose-and time-dependent manner. AF application resulted in cell cycle G1/S phase transition. Most importantly, double treatment by AF + G showed prolonged survival and caused significant tumor reduction. Expression of Ki67 (anti-proliferative marker) and CD34 (tumor angiogenesis marker) was reduced both after AF and AF + G treatment of PDAC tumors in mice. Conclusions: Our work demonstrates that treatment with AF can successfully inhibit the growth of PDAC cells and combinational treatment with AF + G might be also a new and promising combinational therapy for human PDAC treatment.
Valproate as a novel radiosensitizer in selective internal radiation therapy (SIRT) for unresectable hepatocellular carcinoma.
Authors: Chin Kenneth , Udumala Sunil Kumar , Kannadorai Ravi Kumar , Yu Sidney Wing Kwong , Chow Pierce K. H.
Published: February 2017

314

Background: A large majority of Hepatocellular Carcinomas (HCC) present in locally advanced or metastatic stages; patients are usually poor candidates for surgical resection. Yttrium-90 Selective Internal Radiation Therapy (SIRT) is employed in both palliative and bridging therapy for unresectable HCCs. Histone Deacetylase Inhibitors (HDACi) are an emerging class of chemotherapeutics which exert their cytotoxicity through epigenetic modification. By maintaining DNA in an open conformation, it increases the surface area exposed for radiation damage- a postulated mechanism of its radiosensitizing effect. It is envisioned that HDACi will greatly augment therapeutic efficacy in brachytherapy. Here, the radiosensitizing effects of valproate, a known HDACi is investigated as potential adjunct with SIRT. Methods: 3 HCC cell lines were studied: HepG2, Hep3B and JNN4. They were first treated at various concentrations of valproate and cell viability was assessed. Next, a Caspase-3/7 assay was carried out to assess cell apoptosis. Westernblot analysis was performed on treated cells to elucidate histone acetylation status with Anti-Acetyl H3/H4 Antibodies. Finally, a clonogenic survival assay compared the effect of Yttrium-90, Lutetium-177, valproate and combination treatment on clonogenic proliferation. Results: Cell viability studies showed that valproate is cytotoxic to all HCC cell lines at concentrations from 10mM. Westernblot analysis demonstrated that valproate treatment maintained histone acetylation across all HCC cell lines validating it’s mechanism of action. Clonogenic Survival demonstrated a significant reduction of cell survival for all HCC cell lines treated with valproate and Isotope as compared to monotherapy. Conclusions: The use of HDACi such as valproate is not only novel in SIRT but showed great promise as an adjunct therapy. Experiments not only demonstrated its cytotoxicity, but also, reduction in clonogenic and proliferative ability of cancer cells. It can be postulated that the co-administration of valproate with SIRT will enhance therapeutic efficacy, allowing more aggressive and efficacious treatment of HCC.
Pancreas resection for unresectable locally advanced pancreatic cancer (LAPC): Resection rate in the era of FOLFIRINOX and GEM+nabPTX.
Authors: Takahashi Shinichiro , Ikeda Masafumi , Gotohda Naoto , Kato Yuichiro , Konishi Masaru
Published: February 2017

317

Background: Resection for unresectable LAPC after down-staging by chemo(radio)therapy sometimes leads to long-term survival in highly selected pts. However, neither the pts who have best possibility for resection nor resection rate according to the specific treatment were elucidated in LAPC. Methods: A retrospective single-institutional study. From a prospective database, 130 pts received any treatment for LAPC from Jan. 2010 to Mar. 2015 were identified. Main criteria for unresectability were tumor contact with superior mesenteric artery, celiac axis or common hepatic artery > 180°, aortic involvement, and unreconstructible portal vein /superior mesenteric vein due to marked invasion. All MDCT findings before and during treatment of 130 pts were reviewed to check the resectability by a surgeon. Conversion rate to resection according to treatment and situation of tumor-vessel contact before treatment were analyzed. Conversion was considered when tumor was down-staged to borderline resectability. Results: Of 130 pts, gemcitabine (GEM) was administered as initial treatment to 75; GEM and erlotinib to 18; modified FOLFIRINOX to 15; S-1 and concurrent radiotherapy (S1/RT) to 12; GEM and nab-paclitaxel (GEM+nabPTX) to 4; and other regimens to 6. Six patients underwent resection after down-staging. Of the 6 pts (4.6%), 4 received S1/RT, and 1 each received GemErlo and FOLFIRINOX. Furthermore, 7 pts (5.4%) seemed to deserve further examination to check resectability because marginal resectability was shown in follow up MDCT during treatment. Resection rates among treatments were not different significantly. On the other hand, unresectability because of single-vessel invasion and the tumor-vessel contact less than 360° at the same time before treatment showed best opportunity for conversion to resection. The 6 resected pts (MST 30m) showed marginal superiority over unresected 124 pts (MST 16m) in survival (p = 0.17). Conclusions: Resection rate of LAPC did not increase significantly even after FOLFIRINOX or GEM+nabPTX treatment. Pts with LAPC due to single tumor-vessel contact less than 360° have best chance of convert to resection after effective treatment.
Pattern of CA19-9 response to neoadjuvant chemotherapy in locally advanced, borderline resectable pancreatic cancer to predict progression.
Authors: Rose J Bart , Edwards Alicia M , Alseidi Adnan , Biehl Thomas R , Lin Bruce S. , Picozzi Vincent J. , Rocha Flavio G. , Helton Scott
Published: February 2017

321

Background: As neoadjuvant therapy of locally advanced, borderline resectable pancreatic cancer (BRPC) is becoming more widely utilized; better indicators of progression are needed to help guide therapeutic decisions. The aim of this study is to determine if CA19-9 response during treatment predicts disease progression. Methods: A retrospective review was performed on all patients with BRPC (by AHPBA/SSO consensus criteria) between 2008-2015 who received 24 weeks of neoadjuvant gemcitabine and docetaxel. Patients with medical comorbidities limiting treatment completion were excluded. Serum CA19-9 levels were checked at baseline and every 3 weeks while on therapy. A normal CA19-9 level was defined as < 37.5 units/mL and levels with concomitant biliary obstruction were censored. CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. Results: Eighty patients were included with a mean of 11 CA19-9 levels checked per patient during treatment. Thirty-two (40%) progressed on treatment (18 local and 14 distant) and 48 (60%) were resected (79% R0). CA19-9 responses were categorized into 5 groups: 1) Always normal [n = 13]; 2) Increasing [n = 3]; 3) Slow decline [n = 7]; 4) Rapid decline with plateau [n = 41]: and 5)Rapid decline with late rise [n = 16]. Univariate logistic regression analysis found that a final CA19-9 decline > 50% of baseline (OR 0.06, p = <.0001), a normal final CA19-9 (OR 0.08, p = <.0001), pattern group 1 (OR 0.16, p =.0001), and group 4 (OR 0.10, p =.0001) were predictive of non-progression. Baseline or maximum CA19-9 levels were not predictive of progression. All patients in group 2 progressed; none were resected. Patients in pattern group 5 that underwent resection had an increased risk of recurrence (HR 12.5, p =.0005). Median overall survival for groups 1-5 were 20.4, 9.3, 20.8, 31.4, and 16.4 months respectively. Conclusions: Patients with measurable CA19-9 levels who do not have rapid decline with sustained low or normal levels should be considered high risk for progression or recurrence and alternative treatment strategies should be entertained prior to curative resection.
Effect of preoperative bilirubin on outcomes of completely resected hilar cholangiocarcinoma: A multi-institutional analysis.
Authors: Mogal Harveshp , Dodson Rebecca , Fino Nora , Ethun Cecilia Grace , Pawlik Timothy M. , Poultsides George A. , Tran Thuy , Idrees Kamran , Fields Ryan C. , Jin Linda , Weber Sharon M. , Salem Ahmed I. , Martin Robert C. G. , Scoggins Charles Raben , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Shenoy Rivfka , Maithel Shishir Kumar , Shen Perry
Published: February 2017

326

Background: Perioperative and long-term outcomes of patients with Hilar cholangiocarcinoma (HC) and preoperative hyperbilirubinemia have not been clearly defined. Methods: Patients with HC undergoing hepatectomy with a complete (R0/R1) resection between 2000 and 2014 were identified within a 10-institution prospectively maintained database. Using receiver operating characteristic curves from logistic regression models, a peak bilirubin cutoff point that minimized the difference between the sensitivity and specificity, was determined. Factors affecting perioperative complications were estimated using logistic regression. Results: 191 of 328 (58.2%) patients who underwent complete resection with a hepatectomy, with available preoperative bilirubin data were analyzed. 37.2% (n = 71) had bilirubin > 7.9. Patients with higher preoperative bilirubin were more likely to have a higher CA 19-9 (1776±3721.5 vs 302.1±518.6, p = 0.0006), more comorbidities (1.6±0.8 vs 1.4±0.9; p = 0.002), preoperative biliary drainage (PBD) (91.4% vs 75.6%, p = 0.007), positive lymph nodes (48.5% vs 31.5%, p = 0.025) and perioperative death (14.5% vs 5.2%, p = 0.0292). Multivariate analysis identified PBD (OR 3.2, CI 1.4-7.5; p = 0.008) and smoking (OR 2.3, CI 1.2-4.4; p = 0.016) to be independent predictors of any and major complications. Peak bilirubin > 7.9 (OR 3.1, CI 1.1-8.9; p = 0.04) and preoperative systemic sepsis (PSS) (OR 5.0, CI 1.2-21.5; p = 0.03) were associated with increased risk of postoperative mortality. However, on multivariate analysis only PSS was significant (OR 14.4, CI 2.2-93.9; p = 0.005); 5/13 (23.1%) of patients with PSS died within 30 days after surgery. Conclusions: PSS portends increased operative mortality in HC patients undergoing hepatectomy, independent of preoperative peak bilirubin levels. Prevention and aggressive treatment of PSS should be the priority in the preoperative optimization of these patients.
Regional differences in efficacy/safety/biomarkers in a randomised study of axitinib in 2nd line patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: Kudo Masatoshi , Park Joong-Won , Obi Shuntaro , Qin Shukui , Assenat Eric , Umeyama Yoshiko , Chakrabarti Debasis , Valota Olga , Fujii Yosuke , Martini Jean-Francois , Williams James Andrew , Kang Yoon-Koo
Published: February 2017

329

Background: A randomised, double-blind phase II study of axitinib plus BSC [AXI] vs placebo plus BSC [PBO] was conducted in HCC pts after failure of one antiangiogenic therapy. Primary outcome was presented at ESMO 2014. No significant differences in overall survival (OS) between two arms were noted overall and in pre-specified subgroup analysis (non-Asian [nA] and Asian [A]). Interestingly, improvements favouring AXI (P < 0.01) were observed in secondary efficacy endpoints and retained among A. Methods: Exploratory efficacy/safety/biomarker analyses were performed by geographic region (nA; A; A subgroups: Japan/Korea [JK] and China/Hong Kong/Taiwan [CHT]) including: OS excluding pts intolerant to prior therapy; relationship between a subset of 26 baseline micro RNAs (miR) and AXI effect. Results: 78 nA pts (76% male, 60% with vascular invasion/extrahepatic spread) and 124 A pts (73JK/51CHT) (86% [84% JK, 90% CHT] male; 86% [82% JK, 92% CHT] with vascular invasion/extrahepatic spread) were randomized. In regional subgroups, OS HR excluding pts intolerant to prior therapy was: nA HR = 0.700 (95% CI 0.373–1.316; p = 0.1318) for AXI (45) vs PBO (16); A HR = 0.653 (95% CI 0.415–1.027; p = 0.0312) for AXI (76) vs PBO (35); JK HR = 0.479 (95% CI 0.250–0.918; p = 0.0118) for AXI (46) vs PBO (17); CHT HR = 0.918 (95% CI 0.480–1.756; p = 0.3954) for AXI (30) vs PBO (18). AXI safety profile was generally similar in regional subgroups. Differences were seen in dose modification pattern: dose reduction or discontinuation due to adverse events in 24% nA / 41% A / 51% JK / 26% CHT or in 39% nA / 22% A / 16% JK / 32% CHT, respectively. miR analysis for OS showed a trend of predictive and/or prognostic effect in overall population (e.g., let-7e-5p); a strong predictive effect of multiple miR (e.g., miR-3648) was seen in A but not in nA. Conclusions: AXI showed favorable OS vs PBO in nA and A, particularly in JK, when pts intolerant to prior therapy were excluded, suggesting that pts who progress on prior therapy are more suitable population for new agent studies in HCC. Appropriate dose modifications may also play a role in treatment duration. Baseline miR signature may have predictive value for AXI OS in A. Clinical trial information: NCT01210495.
Staging laparoscopy with cytology analysis in gastric cancer.
Authors: Ikoma Naruhiko , Elimova Elena , Blum Mariela A. , Ajani Jaffer A. , Chiang Y. Sabrina , Fournier Keith F. , Mansfield Paul F. , Badgwell Brian D.
Published: February 2017

35

Background: The purpose of this study was to identify clinicopathologic factors associated with the identification of peritoneal disease in patients with gastric cancer and to compare the yield of laparoscopy over time. Methods: The medical records of 7,404 patients with gastric or gastroesophageal adenocarcinoma presenting to our institution (1/1995 to 12/2012) were reviewed to identify patients who underwent diagnostic laparoscopy as a staging procedure before treatment. Associations between clinicopathologic factors and peritoneal disease were examined with chi square and logistic regression analysis. The yield on laparoscopy was stratified according to time. Results: We identified 880 patients who underwent staging laparoscopy for gastric adenocarcinoma. Excluded patients included those with recurrent gastric cancer, those who underwent prior chemotherapy and/or radiation therapy, those with known distant metastatic disease (except for equivocal radiological findings), and those who underwent procedures not for staging purposes, leaving 711 patients in this study: 43.5% with gastroesophageal junctional tumors, 72.9% with poorly differentiated adenocarcinoma, and 53.0% with signet ring cell morphology. Endoscopic ultrasound (EUS) most commonly identified T3 (83.9%) and N-positive (66.4%) tumors. As results of laparoscopy, 148 patients (20.8%) were found to have macroscopic peritoneal carcinomatosis. Among 514 macroscopically negative patients who had peritoneal lavage cytology analysis, 68 (13.2%) were found to have positive. Of the 711 study patients, 42 (5.9%) had other unexpected clinically important findings (e.g., distant metastasis, cirrhosis). Multivariate analysis showed a high positive rate of laparoscopy in patients with poorly differentiated pathology, linitis plastica, or equivocal CT scan, after adjusting race, signet ring cell, and tumor location. The yield of laparoscopy did not change over time when divided into three 6-year periods (p = 0.58). Conclusions: Laparoscopy remains an important staging procedure to evaluate for peritoneal spread when considering treatment or surgery, even in the current era of high-quality imaging evaluation.
Splenic radiation during pancreatic cancer radiotherapy: Are we throwing the baby out with the bath water?
Authors: Chadha Awalpreet Singh , Liu Guan , Arora Harpreet Kaur , Thames Howard D , Krishnan Sunil
Published: February 2017

354

Background: Lymphopenia is commonly seen following chemoradiation and is associated with a poor prognosis. We conducted this study to determine if the severity of lymphopenia is dependent on the radiation dose and the fractional volume of spleen irradiated unintentionally during definitive chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Methods: 177 patients with LAPC were treated with induction chemotherapy (FOLFIRINOX or gemcitabine- based regimens) followed by chemoradiation (CRT; median 50.4 Gy with concurrent capecitabine) from 1/2006 to 12/2012. Absolute lymphocyte count (ALC) was recorded at baseline, prior to CRT and 2-10 weeks after the end of CRT. Splenic dose-volume histogram (DVH) parameters were reported as mean splenic dose (MSD) and the percentage of splenic volume receiving at least 5 Gy (V5), 10 Gy (V10), 15 Gy (V15) and 20 Gy (V20) dose. Overall survival (OS) was analyzed using Cox model and multivariate logistic regression was used to assess the development of post CRT severe lymphopenia (ALC < 0.5 K/UL) using baseline and treatment factors. Results: Median post-CRT ALC (0.68 K/UL, range 0.13 to 2.72) was significantly lower than both baseline (1.42 K/UL, range 0.34- 3.97; p < 0.0001) and pre-CRT ALC (1.32 K/UL, range 0.36- 4.82; p < 0.0001). Post-CRT ALC < 0.5 K/UL was associated with inferior OS on univariate (16.8 vs. 21.2 months, p = 0.004) and multivariate analysis (HR = 1.9, p = 0.002).The MSD was 8.8 Gy and log MSD showed a significant negative correlation (r = -0.18, p = 0.02) with post-CRT ALC. Median V5, V10, V15 and V20 were 34%, 21%, 13% and 8% respectively. Median V10 (32.6 vs. 16%, p = 0.04), V15 (23.2 vs. 9.5%, p = 0.03) and V20 (15.4 vs. 4.6%, p = 0.02) were significantly higher in patients with severe lymphopenia. On multivariate logistic regression analysis, baseline lymphopenia (ALC < 1 K/UL; p = 0.003, OR = 4.6) and MSD (p = 0.03, OR = 7.3) were independent predictors for the development of severe post-CRT lymphopenia. Conclusions: LAPC patients receiving high MSD during CRT are at increased risk of developing severe lymphopenia, which is an independent predictor of poor OS. Routine assessment of splenic DVHs prior to acceptance of treatment plans may minimize this risk.
Role of adjuvant therapy after R0 resection for patients with distal cholangiocarcinoma.
Authors: Kim Young Saing , Hwang In Gyu , Park Song-ee , Kim Eun Young , Kang Jung Hun , Go Se-Il , Park Inkeun , Oh Sung Yong , Ji Jun Ho , Song Haa-na , Park Se Hoon , Kim Seung Tae
Published: February 2017

355

Background: There is still debated regarding the optimal treatment strategy in cholangiocarcinoma after curative resection. The aim of this study was to analyze the role of adjuvant therapy in R0-resected distal cholangiocarcinoma. Methods: We retrospectively reviewed the medical records of patients who underwent R0 resection for distal cholangiocarcinoma between January 2001 and December 2013 at six cancer centers in Korea. Adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). Multivariable Cox proportional hazards model was used to identify prognostic factors for overall survival (OS). Results: A total of 158 patients were included in the analysis; 47 patients (29.7%) had lymph node involvement. Fifty-six patients (35.4%) received adjuvant therapy (CT/CRT/RT: 27/20/9, respectively). Patients with advanced TNM stage (p = 0.001), T3/T4 disease (p = 0.009), positive lymph nodes (p = 0.052) and elevated CA 19-9 (p = 0.071) were more likely to receive adjuvant therapy. The effect of adjuvant therapy varied according to the treatment modality. Multivariable analysis showed a significant improvement in OS with CRT (Hazard ratio (HR) 0.25, 95% CI 0.08-0.83, p = 0.024) and CT (HR 0.21, 95% CI 0.08-0.53, p = 0.001). However, RT alone was associated with shorter OS (HR 2.38, p = 0.040), along with T3/T4 disease (HR 2.12, p = 0.012) and positive lymph nodes (HR 2.30, p = 0.008). In the subset analysis according to lymph node status, adjuvant therapy not including RT alone was associated with a significant OS advantage both in node-negative patients (median, 103.3 vs. 54.9 months, p = 0.037) and node-positive patients (not reached vs. 22.6 months, p = 0.013). Conclusions: Our results showed that patients receiving adjuvant CT or CRT had significant improvement in OS. In addition, the benefit of adjuvant therapy (except RT alone) was observed even in patients with negative lymph nodes.
The impact of maximum tumor shrinkage of primary site (MTSP) by FOLFIRINOX in the first-line treatment of pancreatic cancer.
Authors: Saito Kei , Ozaka Masato , Kanata Ryo , Yamada Ikuhiro , Sasaki Takashi , Matsuyama Masato , Takano Kouichi , Sasahira Naoki
Published: February 2017

356

Background: FOLFIRINOX is the first-line chemotherapy for patients with unresectable pancreatic cancer and yielded a longer overall survival, a superior progression-free survival, a higher objective response rate compared with gemcitabine alone. Maximum tumor shrinkage of primary site (MTSP) was associated with the survival outcome in colon cancer. However the data of tumor shrinkage in pancreatic cancer has not been well-documented. Therefore, we re-evaluated FOLFIRINOX focusing on the tumor shrinkage of primary site. We also assessed impact of tumor shrinkage on survival of unresectable pancreatic cancer. Methods: Medical records were retrospectively reviewed for consecutive patients receiving FOLFIRINOX as the first-line chemotherapy between January and December 2014. Response was evaluated by CT scan every 2 or 3 months until the end of treatment. We analyzed patients’ characteristics and rate of MTSP related to overall survival (OS) and progression free survival (PFS). Results: Thirty one patients were analyzed: median age of 62, male gender in 64.5%, performance status of 0 in 90.3%, metastatic cancer in 58.1%, the head of cancer in 41.9%, the UGT1A1 wild type in 48.4%, overall response rate in 25.8%. PFS was 7.7 months (95%CI: 6.57-9.6). Rate of MTSP were 18.8% (locally 18.8%, metastatic 18.1%) and rate of GRs/non-GRs/non-R (GRs (Good responders) were defined as patients whose MTSP were more than 20% and non-GRs (non-Good responders) were less than 20%) were 45.2%/35.5%/19.3%. PFS was 9.0(95%CI, 6.7- ) months in GRs, compared with 6.9(95%CI, 3.6-10.2) months in non-GRs (p = 0.15). Conclusions: MTSP by FOLFIRINOX could not affect PFS of pancreatic cancer.
Impact of radiation and surgery for intraductal papillary neoplasm of the bile duct: A population-based analysis.
Authors: Szeja Sean , Dandapani Savita V. , Swanson Todd A.
Published: February 2017

363

Background: Intraductal Papillary Neoplasm of the Bile Duct (IPNB), either in-situ or invasive, is a histological variant with better prognosis then the more common adenocarcinoma. This study’s purpose is to use the Surveillance Epidemiology and End Results (SEER) database to evaluate prognostic factors: histology, stage, location, extent of surgery and the use of radiation therapy (RT). Methods: Cases from 1973-2011 were acquired. Inclusion criteria included intrahepatic (IHD), extrahepatic bile duct (EHD) or ampulla of vater (AoV) locations, first primary, extent of surgery and RT history. Kaplan-Meier and Log-Rank methods measured overall survival (OS) and disease specific survival (DSS) in months (m) and their medians (MOS, MDSS). Cox multivariate regression computed hazard ratios (HR) controlling for stage, treatment, surgical extent and histology. Results: . For non-invasive cases, 14% were IPNB (n = 31). Survival was similar for EHD & AoV cases. Surgery was associated with prolonged MOS of 120m compared to 8m without surgery or RT. A trend suggested better survival with lesser extent of surgery for EHD & AoV cases (p < 0.16, n = 8 at both sites). For invasive cases, 5% were IPNB (n = 1309). For cases not receiving surgery, RT was associated with prolonged OS & DSS from 3 to 7m (p = 0.026) and 4 to 8m (p = 0.074). In T1N0M0 EHD cases, surgery with and without RT had similar OS & DSS. Cox analysis observed similar OS & DSS for surgery with and without RT for EHD and AoV cases. Mucin-producing IPNB was less likely local stage disease (10% vs 39%, p < 0.01), with shorter OS 5m vs 23 m (p < 0.01) and DSS 6m vs 28m (p < 0.01), and for EHD cases, with HR = 2.0 (p < 0.01) compared to papillary type IPNB. Conclusions: For non-invasive IPNB, surgery with less extensive resections was associated with better prognosis. For invasive IPNB cases not amenable to surgery, RT improved short term survival. If high-risk factors such as suboptimal surgical margins, which are not recorded in SEER, correlated with the use of RT, then the outcomes in EHD & AoV locations could be explained by an imparted benefit. As well, mucin-associated IPNB, was associated with worse survival than papillary type. Further work is necessary to validate these findings.