bluuebunny/crossref_metadata_2025 huggingface dataset:
Is primary surgery without preoperative chemotherapy the best treatment option for signet ring cell esophagogastric adenocarcinomas?
Authors: Ott Katja , Weichert Wilko , Blank Susanne , Jaeger Dirk , Heger Ulrike , Sisic Leila , Büchler Markus W. , Lordick Florian
Published: February 2017

106

Background: Recent retrospective multicentric data favor a primary resection without neoadjuvant chemotherapy for signet ring cell (SRC) gastric cancer. Aim of this retrospective exploratory study is the comparison of primary resected with neoadjuvantly treated locally advanced SRC esophagogastric adenocarcinomas (EGA) in respect of outcome. Methods: From 2002-2012 200/646 resected EGA were classified as SRC by WHO classification (more than 50% signet ring cells) and staged cT3/4 Nany M0/x. Clinical response evaluation was based on endoscopy and CT-scan and histopathological regression was based on the Becker score (<10% residual tumor cells: responder). UICC 7th was used. Analysis was retrospectively from a prospective data base. Results: 103 were treated by preoperative chemotherapy (CTx), 97 were primary resected. 73 (37%) had AEG, 127 (63%) gastric cancer. Postoperative CTx was delivered in 62/103 (60%) of the patients with preoperative CTx and in 51/97 (53%) of the primary resected patients (p=0.28). In-hospital mortality was 4.5% (9/200). 20 (20%) were classified as clinical, 15 (8%) as histopathological responders. Preoperative CTx was significantly associated with worse pretherapeutic cT- (p=0.005) and cN- (p=0.008) categories, but subsequent lower (y)pN-category (p=0,001) and improved lymphnode ratio (p=0.001). Overall survival was significantly improved after preoperative CTx compared to primary resection (median survival 30.2 versus 17.6 months, p=0.001). Median survival of responding patients is not reached, median survival of nonresponder was 24.4 months (identical for clinical and histopathological responders) compared to 17.6 months in primary resected patients (p=0.002). The positive prognostic effect of preoperative CTx was significantly higher in AEG (p=0.004) compared to gastric cancer (p=0.067). In the 119 completely resected patients the survival was significantly improved by preoperative CTx (p=0.005), but it was no independent prognostic factor. Conclusions: A pre/periopative CTx seems also to be justified in SRC EGA. Relevant limitations are the retrospective and non-randomized design.
ALK, MET, and HER2 in esophageal adenocarcinoma with signet ring cell morphology.
Authors: Moore Catherine Elizabeth , Darbro Benjamin , Berg Daniel James , Clamon Gerald H. , Askeland Ryan W. , Abu Hejleh Taher
Published: February 2017

138

Background: Signet cell morphology (SCM) is seen in various cancers. In Non-Small Cell Lung Cancer (NSCLC), SCM is associated with ALK gene rearrangements and MET amplification. Crizotinib is an ALK/MET inhibitor that showed dramatic responses in ALK rearranged NSCLC. In this study, we explored ALK rearrangements as well as MET and HER-2 amplification in esophageal carcinoma with SCM. Methods: We reviewed the medical records for 9 patients (pts) seen at the University of Iowa with a diagnosis of esophageal adenocarcinoma and SCM. Clinical characteristics were abstracted. The tumors were tested for ALK rearrangement by fluorescence in situ hybridization (FISH) using the ALK break-apart probe set (Abbott Vysis) and for MET amplification utilizing a MET/CEP7 FISH-probe combination. Both rearrangements and copy number of ALK were assessed as was amplification of MET relative to the centromere signal of chromosome 7. HER-2 was tested by immunohistochemistry (IHC) utilizing the FDA approved DAKO Hercept Test per the ToGA trial methods. Results: Average age at diagnosis was 60 years (43-82). Five pts were males. Neoadjuvant treatment was delivered in 5 of 9 pts. Esophagectomy was done in 7 of 9 pts. Median survival time was 5.8 months (range, 2.4 to 24 months). Histology was consistent with adenocarcinoma in all specimens. No ALK rearrangements were detected. One case had 4-15 extra copies of ALK in 58% of the nuclei. In that same case, there was a relative gain of MET compared to CEP7 (ratio MET/CEP7 = 1.88). Regarding HER-2, 7 of 9 pts were negative (<2+), 1 was equivocal (2+), and one was not done due to lack of tissue. The patient with high copy gain of ALK and a relative copy number increase of MET was treated with Crizotinib on compassionate use basis for 3 weeks after which the treatment was discontinued due to significant progression clinically and radiographically. Conclusions: SCM in esophageal adenocarcinoma was not associated with ALK rearrangements, or increased frequency of MET or HER-2 amplification. Overall, the results were most consistent with copy number variable status of ALK and MET as a result of chromosomal aneuploidy as opposed to locus specific rearrangement or amplification and did not result in significant response to Crizotinib.
Surgical treatment of gastric cancer: Oncologic outcome of neoadjuvant treatment in the German multicenter observational study II.
Authors: Stuebs Patrick , Garlipp Benjamin , Meyer Frank , Gastinger Ingo , Lippert Hans , Fahlke Joerg , Ridwelski Karsten
Published: February 2017

139

Background: Neoadjuvant chemotherapy is broadly established in European centers when treating locally advanced gastric cancer. However, there still remain questions as to the benefit of this extended form of treatment in regards to tumor location and stage. Methods: Data obtained in the ongoing prospective, multicenter observational study (German Gastric Cancer Study II) on quality assurance in surgical therapy of gastric cancer containing a total of 2897 patients treated from 01/01/2007 through 31/12/2009 in 145 surgical departments to evaluate. Results: Overall, 506 patients (18.4%) received neoadjuvant treatment in regards to all tumor stages. Of the 530 patients with adenocarcinoma of the gastroesophageal junction (GEJ) 34.5% (n=183) received chemotherapy. In detail, 30.1% (n=873) of the patients were found to be in stage I. In regards to the mean time of survival for advanced stages (III/IV 6th editiion) a survival benefit for patients receiving neoadjuvant treatment (n=356) of 12.0 months was demonstrated versus 10.0 months (p=0.048) for patients not being treated neoadjuvantly. Improved survival through neoadjuvant treatment could not be demonstrated in GEJ tumors, both, comparing different types of GEJ and matching cancer of the GEJ and distal gastric cancer. Overall survival in GEJ tumors is significantly lower (25 months) compared to the overall survival in distal gastric cancers (38 months). In addition, 5-year survival rate of GEJ tumor patients (33.1 %) was distinctly lower than for patients with distal gastric cancer (41.4 %). Conclusions: The results reflect the difficulties of applying currently available study results to daily clinical practice. In order to achieve improved treatment results, requirements in diagnostics, oncological and surgical settings are paramount. Future data of this observational study can provide additional insight for this process.
Clinical significance of fibrinogen and albumin score for postoperative recurrence in esophageal cancer patients.
Authors: Matsuda Satoru , Takeuchi Hiroya , Fukuda Kazumasa , Nakamura Rieko , Takahashi Tsunehiro , Wada Norihito , Kawakubo Hirofumi , Saikawa Yoshiro , Omori Tai , Kitagawa Yuko
Published: February 2017

14

Background: In order to predict the postoperative recurrence in esophageal cancer patients, we previously reported that esophageal cancer patients who had preoperative hyperfibrinogenemia (>350 mg/dl) showed high recurrence rate. Currently, combining the preoperative plasma fibrinogen level and serum albumin level, we established a new scoring system. In this study, we aim to clarify the validity of the fibrinogen and albumin score (FA score) in esophageal cancer patients. Methods: We retrospectively reviewed 215 patients who underwent curative transthoracic esophagectomy in our institution between January 2004 and August 2012. Preoperative plasma fibrinogen level and serum albumin level were confirmed in 204 patients. We investigated patient characteristics, clinicopathological factors, preoperative plasma fibrinogen level and plasma albumin level. Based on our previous reports, we defined a cutoff value of fibrinogen as 350 mg/dl. The cut off value of albumin was determined after the analysis of the albumin distribution in the present study. Prognostic score was constructed by assigning one point for hyperfibrinogenemia or hypoalbuminemia. Cumulative FA score was obtained by combining them. Results: Based on the result that preoperative serum albumin level was 4.1 ± 0.34 g/dl (mean ± SD), we defined a cutoff value of albumin as 4.0 g/dl. Approximately, 33% had hyperfibrinogenemia and 34% had hypoalbuminemia. The number of each FA score 0/1/2 was 98(48%)/75(37%)/31(15%) cases. The patients with advanced stage showed significantly high score. In survival univariate analysis, neoadjuvant treatment, depth of tumor invasion, lymph node metastasis, pretreatment stage, preoperative fibrinogen level and FA score were significantly correlated with postoperative disease free survival. In multivariate analysis, pretreatment stage and FA score were shown to predict postoperative DFS significantly. Conclusions: FA score was shown to predict postoperative recurrence in esophageal cancer patients. Both fibrinogen and albumin are popular indicators routinely measured in daily clinical practice, FA score may be highly validate and feasible.
Metastatic esophagogastric adenocarcinomas (EGA): Treatment, prognosis, and pretherapeutic selection options.
Authors: Ott Katja , Blank Susanne , Jaeger Dirk , Weichert Wilko , Sisic Leila , Grenacher Lars , Büchler Markus W. , Lordick Florian
Published: February 2017

142

Background: Nowadays an increasing number of patients (pts.) with metastatic disease (MD) are discussed in interdisciplinary tumor boards. Preliminary results of the FLOT-3 study suggest a benefit for pts. with limited MD after resection compared to pts. with chemotherapy (CTx) only. Own published data suggest that a subgroup of pts. may benefit from surgery (ESJO, 2013). Primary objective of this retrospective explorative study was the outcome of pts. with resected metastatic EGA and the evaluation of our preoperative prognosis score (PPS) in a larger patients`series. Methods: From 2001-2012 123/800 EGA were classified as cM1 either confirmed intraoperatively as pM1 or confirmed by imaging during follow-up. Response evaluation was performed clinically by endoscopy and CT-scan, histopathologically by the Becker regression score. The PPS for pts. treated with CTx contains grading, clinical response and presumed R-category. Analysis was performed retrospectively from a prospective database. Results: M1 sites (70 AEG, 53 gastric cancer): 27 liver, 43 distant lymph nodes, 16 peritoneum, 10 lung, 6 others, 21 multiple. 11 (9%) were only explored, the rest resected. 49/112 (40%) had multivisceral resections. 63/112 (56%) were completely resected (R0). 72 had preoperative CTx, 51 primary resection. 26 (21%) were classified as clinical responder, 16 (13%) as histopathological responder, 30 (42%) as subgroup with improved prognosis by the PPS. The median survival was 20.0 months (m.). Survival was significantly increased by resection, a complete resection and a preoperative CTx (primary resection: 11m., after CTx: 30 m.)(all p=0.001), but not by multivisceral resection, number or type of metastases or localization of the primary tumor. In pts. who had preoperative CTx, clinical response and the PPS (21 m. versus 66 m., p=0.005) significantly influenced survival. In R0 pts. preoperative CTx (p=0.03), clinical response and the PPS remained prognostic (both p=0.001). Conclusions: A primary resection without preoperative CTx is not appropriate for metastatic EGA. Subgroups of pts. with limited metastatic spread may be selected for surgery using the PPS. Prospective randomized studies are required.
Correlation between standardized uptake value in pre- and post-neoadjuvant chemoradiotherapy and tumor regression grade in patients with locally advanced esophageal cancer.
Authors: Baksh Kathryn , Almhanna Khaldoun
Published: February 2017

150

Background: A multimodality approach with neoadjuvant chemotherapy and radiation is the standard of care in the United States in the treatment of patients with locally advanced esophageal cancer. It is well established that neoadjuvant chemoradiotherapy (CRT) in these patients can facilitate downstaging, correlating with pathologic response, and improving overall survival. Our clinical practice involves the use of positron emission tomography (PET) to assist with staging in patients prior to undergoing neoadjuvant CRT and surgery. While there has been evidence showing correlation between tumor regression grade (TRG) and increased overall survival in these patients, the relationship between standardized uptake values on PET scans and TRG has not been discerned. The purpose of this study was to determine whether pre and post-chemoradiotherapy SUV on PET scans correlate with TRG in esophageal cancer patients receiving neoadjuvant chemoradiotherapy. Methods: A retrospective review of 56 patients with stage II-III esophageal cancer treated with neo-adjuvant CRT followed by surgery was performed. Pre- and post- treatment PET scans were reviewed. Maximum SUV at the site of the primary tumor was recorded. Upon completion of surgery, tumor regression grade was determined by a specialized pathologist. Spearman correlation was used to compare pre, post, and change in max SUV, to the 4 level TRG variables. Results: The median follow-up was 24 months. No significant correlation was found between pre-treatment or post treatment SUV and TRG with p value of 0.73 and 0.94 respectively. There was no significant correlation between decreased FDG uptake following CRT and TRG with p value of 0.82. Consistent with previous data, TRG predicted the therapeutic efficacy and prognosis for patients with locally advanced esophageal carcinoma treated by neoadjuvant chemotherapy. Conclusions: Our results are preliminary and retrospective in nature. A larger sample is needed to confirm these findings. Decreased FDG uptake in sequential PET scans strongly correlates with tumor response, but is not accurate enough to predict pathological response.
Quantification of MET expression using mass spectrometry (MS): Assay precision and stability in FFPE tumor tissue.
Authors: Hembrough Todd A. , Liao Wei-Li , Thyparambil Sheeno , Henderson Les , Rambo Brittany , Cecchi Fabiola , Bottaro Donald P. , Darfler Marlene , Xu Peng , Xiao Shu-Yuan , Zhao Lei , Veenstra Timothy D. , Burrows Jon , Catenacci Daniel Virgil Thomas
Published: February 2017

16

Background: Overexpression of MET in gastroesophageal cancer (GEC) is associated with poor prognosis and potentially predictive of anti-MET therapeutic benefit. IHC has been the method chosen to quantify MET expression to date. However, IHC is semi-quantitative, suffers from cross-reactivity, and is low throughput. Moreover, MET IHC is hampered by antigenic instability in FFPE sections, limiting its utility to recently cut FFPE sections. Increasing recognition of the importance of other biomarkers in GEC suggests that ‘economic’ testing of scarce samples will be required. We sought to develop a MET quantitative assay within our ‘GEC-plex’ Liquid-Tissue-selected reaction monitoring (LT-SRM) MS test. Methods: We used trypsin digestion mapping of rMET to identify unique peptides for MS assay development. The assay was pre-clinically validated in 5 cell lines, where electrochemiluminescence (ECL) immunoassay measurement of MET was also performed. To assess the MET MS assay stability from archival FFPE sections, freshly cut FFPE tissue sections were immediately microdissected, processed and analyzed, while adjacent sections were processed and analyzed one year after cutting, to compare temporal quantification from the same FFPE samples (n=33). MET expression was assessed in GEC cases (n=121), and compared to IHC and FISH in select cases. Results: Tryptic digestion mapping of rMET showed that peptide TEFTTALQR was optimal for MET quantification. The LLOD for this peptide was 150 amol with CV<20%. Validation of the MET MS assay on 5 cell lines revealed concordance when compared to ECL (R2=0.99). The MET MS assay demonstrated temporal stability of serial sections cut from 33 samples analyzed one year apart: CVs<20%, R2=0.75. Analysis of 121 GEC FFPE tissues showed a broad range of MET expression levels (<150-4600 amol/ug), with 36/121 (29.7%) having detectable levels, similar to that observed using IHC. MS expression thresholds were determined that reliably identified MET gene amplification; sensitivity and specificity of these thresholds will be presented. Conclusions: ‘GEC-plex’ has a quantitative, sensitive, and specific MET MS assay that can be multiplexed along with other GEC biomarkers.
A pilot study of low-dose capecitabine plus trastuzumab as first-line treatment for patients older than 75 years with HER2-positive advanced gastric cancer.
Authors: Sym Sun Jin , Kim Young Saing , Park Inkeun , Ahn Hee Kyung , Hong Junshik , Park Jinny , Cho Eun Kyung , Lee Jae Hoon , Lee Woon Ki , Chung Min , Kim Hyung-Sik , Shin Dong Bok
Published: February 2017

165

Background: Elderly patients often present with concomitant co-morbidities and age-associated physiologic problems, such as impaired organ function and functional changes that make the selection of optimal treatment difficult. We report the treatment outcome in 13 elderly patients with HER2-positve advanced gastric cancer who treated with low-dose capecitabine plus trastuzumab. Methods: Patients older than 75 years with gastric cancer were eligible for inclusion if their tumors showed overexpression of HER2 protein by immunohistochemistry (IHC) (3+) or gene amplification by FISH and IHC 2+. Capecitabine 1000 mg/m2was given orally twice a day for 14 days followed by a 1-week rest. Trastuzumab was given by intravenous infusion as a dose of 8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks. Chemotherapy was given every 3 weeks for eight cycles. Results: Between December 2011 and July 2013, 13 consecutive patients (IHC 3+;7, IHC 2+ and FISH+;6) with a median age of 79 years (range, 75-92 years) were enrolled in this study. ECOG PS was 0/1/2:1/7/5, respectively. A total of 54 cycles of capecitabine plus trastuzumab were administered (median, three cycles; range, 2-8 cycles). Of the 12 patients with measurable lesions, the overall response rate was 41.6% (95% CI, 13.7 to 69.5%). Disease control was achieved in 75.0% of patients. Median progression-free survival was 8.2 months (95% CI, 2.5-13.7 months) and median overall survival was 10.9 months (95% CI, 1.4-20.4 months). Grade 3-4 toxicities were stomatitis (7.6%) and anemia (7.6%). No treatment-related deaths and symptomatic congestive heart failure were observed. Conclusions: Our findings suggest that low-dose capecitabine plus trastuzumab is effective and well tolerated in elderly patients with advanced HER2-positive gastric cancer who are considered ineligible for combination chemotherapy. Prospective trials investigating this regimen in elderly patients with advanced gastric cancer are warranted. Clinical trial information: Gachon University IRB.
A novel biomarker panel examining response to adjuvant pancreatic cancer therapy in RTOG 9704.
Authors: Heestand Gregory M. , Murphy James Don , Moughan Jennifer , Regine William , Luo Jia , Graber Madeline Sydney , Kunz Pamela L. , Fisher George A. , Guha Chandan , Lin Bryan , Mowat Rex B. , Gaur Rakesh , Buyyounouski Mark K. , Chen Yuhchyau , Chang Daniel Tandel , Koong Albert
Published: February 2017

176

Background: RTOG 9704 was an adjuvant pancreatic adenocarcinoma trial. Patients with resected stage I-III disease were randomized to receive 5-FU vs. gemcitabine (GEM) chemotherapy pre and post 5-FU chemoradiation. Prior to adjuvant therapy, patients had baseline serum samples drawn and archived for future study. Methods: To better understand the biology of pancreatic cancer, investigators involved with this project have evaluated numerous proteins of interest via literature review and gene expression data. By using the multiplex capabilities and high sensitivity detection of the proximity ligation assay (PLA), a probe panel was built from commercially available antibodies capable of quantifying 42 key proteins from 24 uL of patient serum. To determine if any of these proteins corresponded with survival or predicted response, the baseline serum specimens were obtained for assay with our PLA panel. Clinical endpoints were overall (OS) and disease-free survival (DFS). Univariate and multivariate statistical techniques were used. Using a Bonferroni correction, a p-value of <0.0012 was considered statistically significant. Results: Of the 451 eligible patients, 213 had samples available for study – 112 (53%) in the 5-FU arm and 101 (47%) in the GEM arm. As expected, decreased levels of CEA and CA 19-9 were prognostic for improved OS in all patients. Low levels of matrix metalloproteinase-7 (MMP-7) predicted an OS benefit from adjuvant GEM, but not 5-FU. Conclusions: PLA is a powerful tool for identifying potential biomarkers from archived, small volume serum samples. These data suggest that pancreatic cancer patients with low MMP-7 serum levels were most likely to benefit from adjuvant GEM. Supported by RTOG grants U10 CA21661, CCOP grant U10 CA37422, and RTOG Biospecimen Resource grant U24 CA114734 from the National Cancer Institute. [Table: see text]
Discriminant, identifiable plasma metabolites in pancreatic cancer–associated diabetes.
Authors: Urayama Shiro , Tolstikov Vladimir
Published: February 2017

180

Background: Pancreatic cancer has been associated with development of glucose intolerance and dysregulation. Based on our previous report of strong potential for existence of metabolite biomarkers for PDAC detection, in this study, we have pursued initial characterization of plasma metabolites for discriminating PDAC cases among diabetic patients. Methods: IRB-approved prospectively collected database and corresponding plasma from UC Davis Pancreas Registry was searched for appropriate cases: PDAC patients with recent-onset diabetes (≤3yrs prior to the index PDAC diagnosis) (Grp 1) and non-PDAC patients with long history of diabetes mellitus (>3 yrs) (Grp 2). The plasma was processed and non-targeted GC/MS and targeted LC/MS were performed to assay for identifiable plasma metabolites. The data was processed and the peak intensity levels were normalized, scaled and identifiable metabolites were processed via metabolomics specific multivariate analysis and bootstrap methods as well as ROC evaluation (Metaboanalyst and ROCCET) for visualization and biomarker development. Results: We have identified 36 patients in Grp 1 and 22 patients for Grp 2. The metabolite specific multivariate and ROC analyses revealed specific features such as elaidic acid, uric acid, 2,3-propanediol, arachidonic acid, docosahexanoic acid, 5-oxo-EET, lysine, LysoPC(18:2), 9(10)-EpOME, LysoPC(16:0), sphingosine-1-phosphate and others as strong discriminators for recent-onset diabetic patients with pancreatic cancer. Such set yielded AUC of 0.964 with 15 features [CI=0.876-1]. Conclusions: We have demonstrated that an identifiable set of plasma metabolite biomarkers exists for discriminating diabetic patients with developing pancreatic cancer. These features could be utilized in a larger set of new-onset diabetic population for further validation in near-future study.
A joint United Kingdom (UK) and Hong Kong (HK) study to determine prognostic factors for hepatocellular carcinoma (HCC) undergoing curative and palliative treatment.
Authors: Chan Stephen Lam , Johnson Philip James , Mo Frankie , Berhane Sarah , Ma Brigette , Teng Mabel , Poon Darren M. C. , Morse Janet , Chan Anthony T. C. , Yeo Winnie
Published: February 2017

181

Background: There have been few international studies that systematically evaluate the impact of geographical region on the prognosis of HCC. Methods: Prospective cohorts of patients (pt) were accrued in UK (n=567; 2006-2011) and HK (n=517; 2007-2012). Clinical data were documented at baseline; treatments were decided by multidisciplinary teams at both centers. Results: The median follow-up time of the UK and HK cohort was 27.9 and 29.8 months, respectively. The median overall survival (OS) of the whole UK and HK cohort was 22.9 months and 8.6 months. In the HK cohort, 425 underwent palliative treatment (TACE, systemic agents or supportive care) and 92 had curative treatment (surgery and locoablation); in the UK cohort, 338 had palliative treatment and 228 underwent curative treatment. In the curative group, the median OS was 54.8 months in the UK cohort but has not yet been achieved in the HK cohort. For the palliative group, the median OS was 12.7 and 5.5 months in the UK and HK cohort respectively. In the palliative group, geographical difference was an independent prognostic factor (HK vs. UK, HR=2.0; p<0.0001). Other prognostic factors were mainly tumorous features and Child’s liver function (Table). In the curative group, neither geographical difference nor Child’s score were prognostic factors. Conclusions: Separate prognostic factors exist for curative and palliative treatment. Geographical differences need to be considered during design of clinical trials on novel agents where palliative treatments are investigated but not for surgery or locoablation. [Table: see text]
Disconnect between earlier presentation patterns and application of curative treatments in HCC.
Authors: Ulahannan Susanna Varkey , Duffy Austin G. , Kish Jonathan K , McGlynn Katherine , Rahma Osama E. , Greten Tim F. , Altekruse Sean
Published: February 2017

187

Background: In the U.S., a greater proportion of small hepatocellular carcinomas are being diagnosed. The extent to which patients with small HCCs are receiving potentially curative therapies is unclear. Methods: Receipt of liver transplantation, resection, radiofrequency ablation, and other or unspecified surgery/ablation as first therapy was examined among HCC cases in the NCI SEER18 cancer registries during the years 2000 to 2010. Survival of HCC by treatment modality was also examined. Results: The diagnosis of small tumors (≤5 cm) significantly increased between 2000 and 2010, surpassing diagnosis of larger tumors beginning in 2005. Among patients diagnosed during 2007-2010 with complete data available, 57% had small tumors and more than three quarters had a single tumor, however fewer than one third received surgical or ablative treatment. Incidence rates of resection, ablation and transplantation (therapies with curative intent) increased 17.6% per year between 2000 and 2005, then decreased by -2.9% per year through 2010. Resection was the leading treatment followed by radiofrequency ablation and transplantation. The number of patients treated with curative intent decreased as tumor size or tumor number increased; 42% of patients with single tumors ≤5 cm in size were treated with curative intent compared to 20% with single tumors >5 cm. While radiofrequency ablation was used to treat small tumors, resection was used to treat both small and large tumors. Patients who received transplants had the best five-year survival rate (71%), followed by patients who received resection (42%) and radiofrequency ablation (30%). Five-year survival of patients who did not receive surgery or ablation was 6%. Conclusions: Despite more patients being diagnosed with small tumors, the US-SEER database analysis demonstrates a recent decrease in the use of curative treatments. Treatment guidelines suggest that early diagnosis HCC cases are eligible for treatment with curative intent. Investigations of reasons for the limited treatment are recommended with the goal of improving outcomes.
Hepatitis B viral load to predict survival of HCC patients treated with sorafenib.
Authors: Lim Seungtaek , Han Kwang-Hyub , Choi Hye Jin
Published: February 2017

188

Background: Sorafenib demonstrated survival prolongation in patients with advanced hepatocellular carcinoma (HCC). Until now, the effect of HBV DNA titer on prognosis of HCC patients treated with sorafenib has not been determined. Methods: From 2008 to 2012, 78 HBV-related HCC patients who received sorafenib at Severance hospital were included in our analysis. The prognostic effect of pretreatment HBV DNA level was examined by univariate and multivariate analysis. Results: The median overall survival was 5.2 months (95% confidence interval [CI]: 4.0-6.4) and median progression free survival was 3.5 months (95% CI: 2.3–4.7). Multivariate analysis revealed that a high baseline HBV DNA level (>2,000 IU/L) was an independent risk factor for worse overall survival (p=0.005; hazard ratio [HR], 2.85), and rapid disease progression in a subgroup who did not receive antiviral prophylaxis with sorafenib (p=0.008; HR, 87.4). Moreover, viral reactivation occurred more frequently in patients who did not receive prophylactic antiviral therapy with sorafenib compared to those who did (4/38 vs. 0/40; p=0.025). Conclusions: A higher HBV DNA level before sorafenib was associated with poorer prognosis and increased viral reactivation. This result suggests the role of prophylactic antiviral therapy in patients who received sorafenib. [Table: see text]
CYFRA 21-1 as a novel diagnostic serum biomarker in pancreatic cancer.
Authors: Kim Jung Hoon , Song Joon Cheol , Kwon Jung Hyun , Kim Dae Kyun , Jekarl Dong Wook , Jang Jeong Won , Yoon Young Chul
Published: February 2017

191

Background: CYFRA 21-1 is a fragment of cytokeratin 19, a structure protein and part of intermediate filament proteins contributing to stability of epithelial cells. Serum concentration of CYFRA 21-1 is known to be elevated in many types of epithelial malignancies, and especially it has a prognostic and predictive value in patients with non-small cell lung cancer. We assessed serum CYFRA 21-1 and studied its clinical significance in patients with pancreatic cancer. Methods: The sera from 52 patients diagnosed with pancreatic cancer was collected between May 2012 and August 2013 at Incheon St. Mary’s hospital, Catholic University of Korea, School of Medicine and was measured for CYFRA 21-1 and CA 19-9. 48 patients had an advanced disease at presentation, 2 patients had a locally advanced disease, and 2 patients presented with a local disease. Control blood samples were obtained from 31 healthy individuals and 48 patients with nonmalignant hepatic or pancreatobiliary disease. We measured CYFRA 21-1 using two-step sandwich, chemiluminescent microparticle immunoassay, Architect i2000SR (Abbott Laboratories, Ltd., Il, USA). Results: Serum concentration of CYFRA 21-1 was significantly elevated in patients with pancreatic cancer compared with control group. (p=.000) CYFRA 21-1 ( >1.96 ng/ml as determined by the ROC curve) had a sensitivity, specificity, positive predictive value, and negative predictive value of 86.5%, 79.7%, 73.8%, 90% for the diagnosis of pancreatic cancer. Additionally, CA 19-9 ( >35 U/ml determined by our institute’s criteria) had a sensitivity, specificity, positive predictive value, and negative predictive value of 67.3%, 89.9%, 69.1%, 81.6%. The area under curve for CYFRA 21-1 and CA 19-9 was 86.3% and 81.5%, respectively. Conclusions: CYFRA 21-1 has a potential to become a novel serum biomarker for the diagnosis of pancreatic cancer. Serum concentration of CYFRA 21-1 in combination with CA 19-9 can be useful in clinical practice to diagnose pancreatic cancer.
Diagnostics of pancreatic duct hypertension by the serotonin-stimulating magnetic resonance cholangiopancreatography (MRCP): A preliminary study.
Authors: Kashintsev Alexey
Published: February 2017

196

Background: Serotonin is a neurotransmitter which stimulates the pancreatic secretion. Pancreatic and periampullary tumors can cause the dilatation of the main pancreatic duct. Its partial stenosis can remain undiagnosed on conventional MRCP. Increasing secretion of pancreatic juice after stimulation by the serotonin can help to detect the location and length of a lesion. Methods: Eighteen patients with pancreatic cancer (n=14) and tumor of papilla Vateri (n=4) were included into the study. Median age was 64.9 years with range 45-84 years. Serotonin (0,01mg/kg) was administered perorally (n=2), intramuscularly (n=2), or intravenously with dilution (n=5) and without it (n=9). MRCP was performed before the drug application and 7 minutes later. Results: In cases where serotonin was administered perorally, intramuscularly or intravenously with dilution we did not receive any significant results. The positive results were obtained in 5 (55.6%) of 9 cases when MRCP was performed 7 minutes after intravenous administration of concentrated solution. The mean increase in width of the main pancreatic duct was 1.1 mm (range 0.9-1.9 mm). Conclusions: The method of serotonin stimulating MRCP can improve the diagnosis of pancreatic ductal hypertension. In these 5 cases, a presented technique allowed us to detect the size and localization of a lesion more precisely: tumor of a papilla (n=2), cancer of a pancreatic head (n=3) including one case with involvement of the pancreatic body. In cases of primary ductal dilatation more than 5 mm (n=3), we did not receive any positive results, so these patients were excluded from the study.
Conditional survival for intrahepatic cholangiocarcinoma: SEER database analysis.
Authors: Muzaffar Mahvish , Kaur Sandeep , Afroz Fir , Lone Maqbool , Khan Nazir Ahmad , Teli MA
Published: February 2017

201

Background: Conditional survival can be useful for estimating survival probability for patients who have survived one or more years after the initial diagnosis. It reflects the possible change in risk profile over time especially for malignancies with poor outcome. Methods: The Surveillance, Epidemiology and End Results database was reviewed for intrahepatic cholangiocarcinoma. We reviewed data for all intrahepatic cholangiocarcinoma from year 2000-2010. Data of 8278 patients was extracted from SEER database. We sub stratified using factors like age <50 versus ≥50, gender, grade, stage, primary site surgery. SEER*Stat: Version *8.1.2 software was used to calculate conditional survival. Conditional survival is defined as the calculated probability of survival after having already survived a specified number of years from diagnosis. Results: The analysis showed that Conditional survival (CS) probability for intrahepatic cholangiocarcinoma increased from 33.25 to 85% at 5 years for all age groups conditional to surviving one year after diagnoses. For age group <50 years CS increased from 50.4% to 86.9%, while for age group >50yrs from 31.4% to 84.5%.The conditional survival for well differentiated histology increased from 60.7% to 81.0%, moderately differentiated from 53.8% to 87.7%, poorly differentiated from 37.1% to 83.6% .The conditional survival for localized stage increased from 50.7% to 88.8%, regional 40.6% to 77.7% and distant 19.0% to 65.6%.Majority of cases had missing data with regard to primary site surgery. 1707 cases had documented primary site surgery. Conditional survival for this group increased from 30.7% to 82.8% subject to surviving one year after diagnosis. Conclusions: There are several limitations associated with these results due to missing data in SEER. Nonetheless these results emphasize the trend of patient’s surviving more than 1 year after diagnosis have higher conditional survival probability. CS may provide more relevant prognostic information as compared to traditional survival estimates.
Molecular features of BRCA1/2 and PALB2 mutation associated pancreatic cancer (PAC).
Authors: Lowery Maeve Aine , Timms Kirsten , Abkevich Victor , Neff C , Gutin Alexander , Lanchbury Jerry S. , Tang Laura H. , O'Reilly Eileen Mary
Published: February 2017

206

Background: Several clinical reports have indicated increased sensitivity to DNA damaging agents and PARP inhibitors in patients with PAC arising on a background of known BRCA1/2 or PALB2 germline mutation. While the mechanism of tumorigenesis in these cancer remains unclear, it appears likely that BRCA1/2germline mutations can predispose to PAC via 2 mechanisms, only one of which requires loss of the second allele. Determination as to whether biallelic inactivation of these genes is present in the tumor may have important therapeutic implications in predicting sensitivity to PARP inhibitors and other strategies targeting DNA repair. Methods: Following approval by the IRB and human bio specimen utilization committee at MSKCC, full exon sequencing of coding regions of 28 genes including BRCA1, 2 and PALB2 using exon capture by hybridization and next generation sequencing was performed on DNA extracted from 135 PAC samples. In addition, samples were analyzed for the presence of BRCA1 promotor methylation, KRAS hotspot mutations, and genome wide loss of heterozygosity (LOH) as an exploratory assessment of number and length of LOH as a marker of homologous repair deficiency / genomic instability. All patients underwent surgery for PAC at MSKCC after year 2000. Patients were selected on the basis of survival and included if they suffered a cancer-specific death within 1 year of resection or survived at least 30 months. Results: 7 tumors had mutations in BRCA2, 1 in BRCA1 and 1 in PALB2. Of 4 BRCA2 mutated samples evaluated for LOH at the BRCA2 locus, 2 demonstrated LOH while 2 did not. There was no LOH at PALB2 in the sample where a mutation was identified. Activating KRAS mutations were identified in BRCA2 mutated tumors with and without LOH. Methylation of the BRCA1promotor regions was not identified. Conclusions: The frequency of BRCA1/2 mutation carriers was as anticipated in this population. Biallelic loss of BRCA2 or PALB2 are not required for pancreatic tumorigenesis. The benefit of PARP inhibitors in BRCA1 / 2 mutated PAC may be limited to tumors with LOH of these genes. Inactivation of BRCA1 through promoter methylation is not identified in sporadic PAC.
Next-generation sequencing yields promising targets in advanced cholangiocarcinoma (CCA).
Authors: Shroff Rachna T. , Churi Chaitanya , Rashid Asif , Mishra Lopa , Zuo Mingxin , Kaseb Ahmed Omar , Janku Filip , Aloia Thomas A. , Vauthey Jean-Nicolas , Curley Steven A. , Javle Milind M.
Published: February 2017

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Background: The incidence of CCA is rising and the clinical efficacy of systemic therapy is suboptimal. Next generation sequencing (NGS) technology offers potential for targeted therapeutics against genetically heterogenous solid tumors including cholangiocarcinoma (CCA). Methods: DNA was extracted from biopsy specimens of 61 patients (pts) with CCA seen at MD Anderson Cancer Center Houston, TX. 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 (performed by Foundation Medicine, Cambridge, MA). Results: 174genomic alterations (GA) were identified from 61 pt samples with an average of 2.85 GAs/pt (range 0-10). GAs identified were mutations (75%), amplifications (16%), loss/deletions (7%) and others (2%). 6 (10%) tumors showed no GAs. Most frequent GAs were TP53 (34%), KRAS (30%), ARID1A (15%), PBRM1 (11%), BAP1 (8%), ERBB2 (8%), FBXW7 (8%), SMAD4 (8%) and IDH1 (8%). ERBB2 GAs included 4 mutations and 1 amplification. KRAS mutation was associated with a statistically significant reduction in overall survival (OS). Mean OS in pts with KRAS mutation was 32 weeks vs. 63 weeks in KRAS wt (t = -2.126, p = 0.039). Ingenuity Pathway Analysis indicated disruption in cell cycle, proliferation, development, death and DNA repair pathways. Targetable signaling pathways from this study are described in the Table. Targetable GAs were noted in 62% of pts. These are potentially targetable by inhibitors to ERBB2, FGF, mTOR, MEK, BRAF and PARP-1. Conclusions: These data are the single largest compilation of NGS analysis on CCA pts and demonstrate the range of GAs that are eligible for investigational targeted therapies. These results can be used as a basis to develop personalized treatments for CCA pts based on individual genetic profiles. [Table: see text]
Human equilibrative nucleoside transporter 1 (hENT1) in gemcitabine and FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin)-treated patients with metastatic pancreatic cancer: The randomized phase II PAN1 study.
Authors: Chua Yu Jo , Karapetis Christos Stelios , Gebski Val , O'Connell Rachel , Begbie Stephen , Nott Louise M. , Cronk Michelle F. , Underhill Craig , Abdi Ehtesham A. , Van Hagen Thomas , Wong Nicole , Hall Merryn , Ferraro Danielle Angela , Sjoquist Katrin Marie , Santos Cheryl , Mackey John Robert , Goldstein David
Published: February 2017

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Background: GEM-based treatment is a standard treatment for metastatic pancreas cancer. Monotherapy efficacy is only modest, and outcomes are improved by combination treatment or the non-GEM FOLFIRINOX triplet. There is a need for biomarkers to select between these divergent options. hENT1 is a potential predictive marker of benefit from GEM, but conflicting results have been observed in studies that have evaluated resected and metastatic pancreatic cancer. This principal objective of this study was to evaluate hENT1 prospectively as a predictive marker in GEM and non-GEM treated patients. Methods: Patients with previously untreated metastatic pancreatic adenocarcinoma and tumour tissue available for hENT1 testing were randomized between GEM (1,000 mg/m2 D1, 8, 15 Q4w) or FOLFOX (oxaliplatin 85 mg/m2, 5-fluorouracil (5FU) 400 mg/m2, leucovorin 400 mg/m2 D1 and 5FU 2,400 mg/m2over 46 hours D1-3) until disease progression or unacceptable toxicity. Tumor samples were tested prospectively for hENT1 by immunohistochemistry. The primary endpoint was progression-free survival (PFS). Results: The study was open from July 2011 to February 2013, but closed after 16 of the planned 80 patients were enrolled. 1 patient who died before treatment was excluded from the outcome analysis. 7/16 patients were hENT1 high (43.8%, 95%CI 23.1-66.8%). In the GEM arm (n=7), the 4 who were hENT1 high had longer PFS and overall survivals (OS) than those who were hENT1 low (median PFS 5.7 vs. 1.8 months; median OS 13.9 vs. 3.5 months), whereas outcomes were similar with FOLFOX for both hENT1 groups. There were no unexpected adverse events. Conclusions: This prospective study showed a longer survival in those patients with high hENT1 treated with GEM. There was no difference in survival according to hENT1 expression in patients treated with FOLFOX. Given the small sample size this may be due to chance, but supports the need for further research into the predictive value of hENT1. Clinical trial information: ACTRN12610001047088.[Table: see text]
mTOR/P70S6K signaling pathway as a potential target for advanced gallbladder cancer therapy.
Authors: Roa Juan Carlos , Leal Pamela , Weber Helga , Garcia Patricia , Sandoval Alejandra , Buchegger Kurt , Tapia Oscar , Nervi Bruno , Grez Manuel
Published: February 2017

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Background: Gallbladder cancer (GBC) is a highly malignant tumor usually diagnosed at advanced stages and characterized by a poor prognosis. Effective therapeutic strategies are urgently needed to improve the prognosis of GBC patients. Our objective was to analyze the expression of mTOR/p70S6K pathway in primary tumors and GBC cell lines, and to evaluate the effect of mTOR inhibitors in in vitro and in vivo models of GBC. Methods: The expression of mTOR/p70S6K signaling pathway components was examined by immunohistochemistry in primary tumors and chronic cholecystitis (CC), and by Western blot in eight GBC cell lines. The in vitro effect of mTOR inhibitors (LY294002, Rapamycin, Everolimus and AZD8055) on cell viability and migration was assessed by MTS and Transwell chamber assays. The therapeutic effect of Rapamycin was evaluated in subcutaneous tumor models (NOD/SCID mice). Treatment started when tumor volumes had reached 100mm3. Animals (G-415 and TGBC-2TKB xenografts) were randomly divided (n=5 per group) and treated with Polietilenglicol solution as vehicle and 10mg/kg of Rapamycin, daily IP injection (5 days/week for 3 weeks). Mice were sacrificed 30 days after treatment and tumors were dissected and measured. Tumor volume was calculated as π/6 × (large diameter) × (small diameter)2. Results: Our findings indicate that mTOR/p70S6K pathway is frequently activated in GBC (>60% of tumors showed high expression of phospho-mTOR and phospho-p70S6K, compared to CC). GBC patients whose tumors overexpressed phospho-mTOR had a poorer prognosis (p=0.02). G-415 and TGBC-2TKB cells showed a constitutive activation of this pathway and the treatment with different mTOR inhibitors significantly reduced their viability and migration capacity (p<0.001). In subcutaneous tumor models, treatment with Rapamycin significantly reduced the weight and tumor volume compared with the control group (p<0.001). Conclusions: mTOR/p70S6K signaling pathway is frequently activated in gallbladder cancer tissues and cells lines, which suggest that this pathway is a potential therapeutic target for the treatment of advanced GBC, using Rapamycin or other specific inhibitors. Supported by FONDECYT 1090171 and DIUFRO DI11-0039.
Loss of SMAD4 and effect on overall survival in resected gastrointestinal neuroendocrine tumors.
Authors: Roland Christina Lynn , Kang Ya'an , Chatterjee Deyali , Estrella Jeannelyn , Rashid Asif , Lee Jeffrey Edwin , Yao James C. , Fleming Jason B.
Published: February 2017

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Background: Studies by comparative genomic hybridization have demonstrated that the 18q chromosomal region is frequently lost in gastrointestinal neuroendocrine tumors (GI-NET). However, the impact of DPC/SMAD4 loss, which is located 18q21, in the pathogenesis of GI-NET remains controversial. In this study, we sought to determine the protein expression of SMAD4 in GI-NET and the impact on oncologic outcomes. Methods: To investigate the role of SMAD4 in GI-NET, a tissue microarray consisting of 33 GI-NET was constructed and analyzed by immunohistochemistry for SMAD4 expression. SMAD4 expression was classified as negative, SMAD4-low (≤10% cells +) or SMAD4-high (>10% cells+). Staining results were correlated clinicopathologic features and overall survival. Results: Of the 33 tumors examined, 93% were low- or intermediate-grade and 7% high-grade. 35% of GI-NET were negative for SMAD4, 45% were SMAD4-low and 15% SMAD4-high. Expression of Chromogranin was observed in 91% of all tumors, synaptophysin in 94%, CDX2 in 64%, and CK19 in 55%. We were unable to identify any association between loss of SMAD4 and stage or tumor grade. There was an inverse correlation between loss of SMAD4 and CK19 expression, whereby 75% of SMAD4-neg tumors expressed CK19 and only 32% of SMAD4+ expressed CK19 (p=0.01). At a median follow-up of 123 months, median overall survival was 203 months. Survival differences related to SMAD4 status resulted in clinically meaningful, although statistically non-significant, differences in overall survival (SMAD4-low: 132 months vs. SMAD4-high: 203 months, p=0.058). Conclusions: Differences in SMAD4 expression result in clinically important differences in overall survival, although this cohort may be underpowered to detect a statistically-significant difference. Future studies with larger patient populations may be critical to evaluate the importance of SMAD4 in the pathogenesis of GI-NET.