bluuebunny/crossref_metadata_2025 huggingface dataset:
Engraftment of resected pancreatic adenocarcinoma in SCID mice and patient survival following surgical resection: Roswell Park's experience.
Authors: Aranez Jose Luis , Jitawatanarat Potjana , Hylander Bonnie , Pitoniak Rose , Levea Charles , Repasky Elizabeth S , Ma Wen Wee
Published: February 2017

185

Background: Preclinical models developed by implanting resected pancreatic cancer from human donors into immunocompromised (SCID) mice have been valuable in understanding the disease’s biology and developing therapies. The ability of resected tumors to engraft successfully has previously been reported to be a poor prognostic marker. This study was conducted to investigate the relationship between successful engraftment and clinical outcome by analyzing such a model developed at Roswell Park over the last decade. Methods: A retrospective review of 48 donor patients (27 males and 21 females) whose resected pancreatic adenocarcinoma was xenografted in SCID mice between 1999-2009 was conducted. The clinical outcome and baseline information were correlated with engraftment outcome. The expression of potential biomarkers correlating with engraftment was evaluated by performing immunohistochemistry on the initial donor surgical specimens. The expression was scored, assigned an average index value and categorized into groups (High vs Low expression) based on a median cutoff of values. Results: Resected tumors from 21 of the 48 donors successfully engrafted when implanted subcutaneously in SCID mice (44%). The baseline demographics and disease characteristics were balanced between engrafters versus non-engrafters. All of the engrafters and 26 (of 27) of non-engrafters received adjuvant treatment. The 2-year overall survival (OS) of patients whose tumors successfully engrafted was 17% compared to 39% in those whose tumors failed to engraft (P=0.09; hazard ratio 1.305 [95% CI 0.717-2.375]). Analysis to identify potential biological markers associated with engraftment success is underway. Conclusions: A review of the clinical outcome of patients whose tumors were procured and used for the patient-derived primary pancreatic cancer xenograft program at Roswell Park showed that successful engraftment in SCID mice is potentially a poor prognostic marker in patients with resectable pancreatic cancer. Our analysis did not reach statistical significance which is likely due to a smaller sample size but the potential link is consistent with that reported by others.
Prognostic value of metabolic tumor volume and total lesion glycolysis on preoperative 18F-FDG PET/CT in patients with pancreatic cancer.
Authors: Lee Jeong Won , Kang Chang Moo , Lee Sang Mi , Lee Jae-Hoon , Lee Jong Doo
Published: February 2017

190

Background: In this study, we aimed to assess the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) measured on 18F-fluorodeoxyglucose (18F-FDG) PET/CT in pancreatic cancer patients who underwent resection with curative intent. Methods: Eighty-seven patients with pancreatic ductal adenocarcinoma who underwent 18F-FDG PET/CT and subsequent surgical resection with curative intent with (30 patients) or without (57 patients) neoadjuvant therapy were retrospectively enrolled in this study. The maximum standardized uptake value (SUVmax), MTV, and TLG were measured on 18F-FDG PET/CT in all patients. The prognostic significance of SUVmax, MTV, TLG, and tumor factors for predicting recurrence-free survival was evaluated by univariate and multivariate analyses. Results: Of the 87 patients enrolled, 57 (64%) experienced recurrence during the follow-up period, and the 1-year recurrence-free survival rate was 52%. Among the variables determined to be significant on univariate analysis including tumor size, pT stage, the presence of lymph node metastasis, SUVmax, MTV, and TLG, only tumor size, MTV, and TLG were significant prognostic factors on multivariate analysis (p < 0.05). Patients with low MTV (71%) or TLG (74%) had significantly higher 1-year recurrence-free survival rates than those with high MTV (42%) or TLG (38%; p < 0.05). In the 57 patients who did not undergo neoadjuvant treatment, MTV and TLG remained significant predictive factors for tumor recurrence, along with tumor size and SUVmax. Conclusions: MTV and TLG are independent prognostic factors for predicting recurrence in patients with pancreatic cancer. Thus, 18F-FDG PET/CT can provide useful prognostic information for patients undergoing resection of pancreatic cancer with curative intent irrespective of neoadjuvant treatment.
Upper gastrointestinal cancers: Are all carcinomas truly carcinomas?
Authors: Sagaert Xavier , Van Cutsem Eric , Tejpar Sabine , Prenen Hans , De Hertogh Gert , Nafteux Philippe , Haustermans Karin , Debiec-Rychter Maria
Published: February 2017

20

Background: Poorly differentiated cancer of the upper GI tract is a challenging diagnosis for the pathologist, who will rely on a positive cytokeratin immunostaining to confirm the epithelial origin of the tumor. Being confronted with a highly unusual case (a poorly differentiated esophageal “carcinoma” with immunophenotypic and genetic sarcoma-like features, arising in the background of high grade Barrett dysplasia), we retrospectively investigated whether other cancer cases displayed the same unusual features. Methods: 34 poorly differentiated GI cancers were selected based on availability of FFPE. All cases were investigated by (1) immunohistochemistry for selected carcinoma and sarcoma markers (prekeratin, NCAM, vimentin, CD99) and by (2) FISH for presence/absence of abnormalities of 2 genes, SYT and EWS, that are frequently rearranged in synovial and Ewing’s sarcoma respectively. Results: 6/34 cases displayed an aberrant immunophenotype, with expression of NCAM, vimentin, and/or CD99. FISH revealed a substantial number (9/34) of SYT and EWS related anomalies: 1 EWS rearrangements, 1 SYT rearrangements, 1 SYT and 1 EWS focal amplification, and 4 aneuploidies. While EWS and SYT are (mostly) fused to ERG or SSX1/2 in Ewing’s and synovial sarcoma respectively, these genes were found to be intact in our EWS and SYT rearranged cases. Conclusions: Our data show that SYT & EWS abnormalities are recurrently occurring in poorly differentiated GI cancers that are (mis?)diagnosed as carcinomas. While EWS rearrangement has previously been described in cancer types other than Ewing’s sarcoma, SYT rearrangement was so far thought to be exclusive to the diagnosis of synovial sarcoma. In addition, EWS/SYT abnormalities in our series seemed to target cancers that are at risk of not responding well to the conventional chemoradiotherapy regimen. Of interest, the one “carcinoma” patient that started this study went into complete remission after being administered a sarcoma targeted therapy. We also infer from our results that good histologic assessment of GI cancers is essential for clinical trials aiming at targeted therapy, as not all carcinomas may present true carcinomas.
Long-term results of salvage endoscopic treatment for patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma.
Authors: Hatogai Ken , Yano Tomonori , Kojima Takashi , Onozawa Masakatsu , Doi Toshihiko , Kaneko Kazuhiro , Ohtsu Atsushi
Published: February 2017

207

Background: Local failure is a major problem after chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC), and salvage surgery presents high morbidity and mortality rates. We have introduced photodynamic therapy (PDT) and endoscopic resection (ER) for local failures to develop a less invasive salvage treatment.The aim of this retrospective study was to clarify the long-term outcome of salvage endoscopic treatments (SET). Methods: Between 1998 and 2008, 716 patients with ESCC were treated with definitive CRT in our institution. There were 314 patients with incomplete response and 103 with local recurrence after achieving complete response (CR) once. The indication criteria of SET were as follows: 1) absence of lymph node and distant metastasis and 2) local failures limited within T2. ER was performed for local failures limited to T1b (SM1), and PDT was performed for lesions invading T1b (SM2) or T2, in patients who could not tolerate or who refused surgery. We assessed overall survival (OS), relapse-free survival (RFS), and also prognostic factors. This study was approved by an institutional review board. Results: A total of 164 patients with local failure underwent SET (ER: 58, PDT: 106). The characteristics before CRT were as follows: T1/2/3/4, 44/25/75/20; N0/1, 85/79; stage I/II/III/IV, 35/59/57/13; and those of before SET were as follows: T1/2, 126/38; residue/recurrence, 76/88. ER achieved curative resection in 51 (87.9%), and PDT achieved CR in 61 (57.5%) patients. With a median follow up period of 73 months, the OS and RFS rates at 5 years from SET were 38.6% (95% CI 31.0–46.2) and 28.1% (95% CI 21.0–35.2). Multivariate analysis revealed 2 preferable prognostic factors in common for OS and RFS, N0 before CRT (OS HR: 0.47 [95% CI 0.32–0.69], RFS HR: 0.61 [95%CI 0.43–0.87]) and a period from initiation of CRT to SET longer than 6 months (OS HR: 0.57 [95%CI 0.39–0.84], RFS HR: 0.67 [0.47–0.95]). After 5 years of follow up, 58 patients (35.4%) were alive without any metastasis under esophagus preservation. Conclusions: SET demonstrated a favorable outcome in an analysis of a large number of patients with local failure after definitive CRT for ESCC.
Prediction of nodal metastasis in clinical T1 gastric cancer.
Authors: Fujikawa Hirohito , Sakamaki Kentaro , Kawabe Taiichi , Hayashi Tsutomu , Aoyama Toru , Wakasugi Takehiro , Hasegawa Shinichi , Sato Tsutomu , Cho Haruhiko , Makuuchi Yousuke , Ogata Takashi , Oshima Takashi , Rino Yasushi , Masuda Munetaka , Yoshikawa Takaki
Published: February 2017

21

Background: Clinical T1 gastric cancer sometimes metastasizes to regional lymph nodes. Standard surgery is D2 gastrectomy for clinical T1N+ gastric cancer patients, however, clinical detection of nodal metastasis by Computed Tomography is unreliable, with only 4% sensitivity in our previous study. The present study aimed to predict pathological nodal metastases in clinical T1 gastric cancer. Methods: Patients were selected from the prospective database of Kanagawa Cancer Center between Oct 2000 and Oct 2007 based on the following criteria; (1) histologically proven adenocarcinoma of the stomach, (2) patients were diagnosed with clinical T1 by gastrointestinal endoscopy, (3) patients received radical surgery with D1 or more lymphadenectomy as a primary treatment. First, univariate logistic-regression model was used to select risk factors for prediction of pathological nodal metastasis by analyzing clinical factors of tumor location, clinical depth (cT1a or cT1b), macroscopic type, maximal tumor diameter, and pathological type. Then, the optimal cut-off value and predictive accuracy was determined by ROC curve using significant factors selected in logistic regression. Results: A total of 511 patients were entered into this study. Among these, pathological N+ was observed in 46 patients (9.0%). Clinical depth (p=0.002), tumor diameter (p<0.001) and pathological type (p=0.002) were significant risk factors for pathological nodal metastasis. Using these factors in multivariate logistic regression, the AUC was calculated to be 0.75. Cut-off value was different depending on the histology and clinical depth; 7.9 cm for differentiated type and 4.8 cm for undifferentiated type in cT1a and 4.3 cm for differentiated type and 1.1 cm for undifferentiated type in cT1b. Using these criteria, sensitivity and specificity for prediction of pathological nodal metastasis were 67.4% and 71.6%, respectively. Conclusions: Pathological nodal metastasis in clinical T1 gastric cancer was predictable by clinical depth, pathological type, and tumor size, however, specificity was not so high. D2 surgery is highly recommended for clinical T1 when the tumors satisfy these criteria.
A multi-transcript blood signature for detection and assessment of gut neuroendocrine tumors.
Authors: Kidd Mark S. , Alaimo Daniele , Callahan Stephen , Texeira Nancy Smith , Drozdov Ignat , Modlin Irvin Mark
Published: February 2017

216

Background: Gut neuroendocrine tumors (NETs or “carcinoids”) are difficult to manage since they present with advanced disease and limited treatment options are available. Imaging is relatively insensitive in identifying treatment efficacy and the current biomarker, a neurosecretory peptide, Chromogranin A (CgA), has limited value. There is a lack of specific blood biomarker tests both to detect tumors and measure treatment responsiveness. We report the utility of a 51 marker peripheral blood signature (NETest) in comparison to CgA. Methods: The signature was validated using a 2-step qPCR method for detecting NETs in two sets (n=115; n=120) and for measuring treatment responses in a third set (n=133, including complete remission: n=4, clinically stable disease: n=82 and non-responders/clinically progressive disease: n=47). Comparison with CgA (DAKO-ELISA) was undertaken. The confounding effects of PPIs, age, sex and race were also determined for the PCR test. Results: The PCR NETest detected NETs with high sensitivity (85-98%) and specificity (93-97%). It identified pancreatic and gastrointestinal NETs with similar efficacy (>85%) as well as metastatic and non-metastatic lesions. NETest score was significantly reduced (p<0.004) following surgery or RFA and significantly higher in clinically progressive disease compared to stable disease (5.8±0.3 versus 0.6±0.1, p<0.002). The performance metrics for differentiating stable and progressive disease were sensitivity: 91% and specificity: 91%. The score was robust (reproducibility: Coefficient of Variation<2%).Long-term PPI use (>1yr), did not alter the NETest values, neither did age, sex or ethnicity. The PCR score was significantly (p<0.0005) more accurate than CgA for identifying NETs and was elevated in 91% of NETs when CgA was normal. Conclusions: This study demonstrates that a multi (51)-gene NET panel is both sensitive and specific for detecting NETs and is capable of differentiating clinically stable from progressive disease. The test is robust and significantly more sensitive and specific (accurate) than CgA. The NETest thus facilitates both accurate disease detection, and disease progress thereby permitting assessment of treatment efficacy.
Measurement of circulating tumor DNA as a cancer biomarker in gastrointestinal malignancies using a novel next-generation sequencing method.
Authors: James Edward Samuel , Narayan Azeet , Stein Stacey , Lacy Jill , Patel Abhijit , Hochster Howard S.
Published: February 2017

217

Background: Circulating tumor DNA (ctDNA) holds promise as a highly specific cancer biomarker. The presence of mutant tumor-derived DNA fragments in the blood provides an opportunity to non-invasively assess tumor mutation profiles and to quantify changes in tumor DNA levels over time. Methods: After obtaining informed consent, plasma samples were collected prospectively at multiple time points in a cohort of patients (pts) with various gastrointestinal (GI) malignancies in the locally advanced, metastatic and adjuvant settings. Hotspot regions of genes known to be commonly mutated in GI tumors were amplified by multiplexed PCR, and the resultant amplicons were subjected to next-generation ultra-deep sequencing. Suppression of sequencer and PCR errors allowed mutations to be identified and quantified with a sensitivity of approximately 1 variant in 5,000 molecules. Sample-specific barcoding allowed simultaneous analysis of up to 96 samples. Results: 29 out of 74 available samples from 17 pts were analyzed for the presence of ctDNA. 3 pts had KRAS mutations exclusively. 2 pts had mutations in two of the evaluated genes: KRAS plus PIK3CA and KRAS plus TP53. 2 pts with measurable mutant ctDNA had samples analyzed at multiple time points. One of these patients with locally advanced pancreatic cancer initially had a KRAS G12D mutation which disappeared after treatment with chemo-radiation therapy, but then he developed significantly rising levels of a different KRAS G12L mutation just preceding the diagnosis of liver metastases by imaging. A second pt with metastatic colon cancer had high levels of ctDNA prior to treatment that decreased dramatically after initiation of mFOLFOX and bevacizumab therapy. Conclusions: Our initial analysis indicates that our technique is able to quantify multiple mutations at very low copy numbers accurately in this cohort of pts with GI cancers. Moreover, we were able to monitor changes in mutation type and quantity using this non-invasive “liquid biopsy” approach. Analysis of remaining samples is ongoing, and additional longitudinal data will be presented.
Changing patterns in presentation and therapy of esophagogastric junction cancers in the United States.
Authors: Schwarz Roderich , Smith David D. , Nelson Rebecca A.
Published: February 2017

22

Background: Esophagogastric junction cancer (EGJC) has recently been included within the esophageal cancer (EC) AJCC TNM staging criteria. Trends in clinical presentation, therapeutic approach and outcomes are of interest. Methods: We identified EGJCs from the U.S. population SEER database and examined incidence, demographic, therapeutic and outcomes information. Siewert classification-related EGJC subtype-associated findings were also examined. Results: EGJC age-adjusted incidence rates (x10-5) have increased from 3.3 in 1973 to 7.5 in 2009. While the incidence rate for females has remained around 2, rates in males have increased from 6 to 13. Among 30,710 EGJC patients diagnosed between 1992 and 2009, potentially curative resection increased from 31% to 36% and radiation increased from 32% to 41% (p<0.0001). For resected EGJCs, significant trends over time include: increased total LN count (mean: 15.5 vs. 12.3), fewer positive LNs (3.1 vs. 4), smaller tumor size (29% vs. 36% >5 cm), lower T category (39% vs. 29% T1/2), lower N category (42% vs. 35% N0), lower stage group (29% vs. 38% stage 3/4), increased preoperative radiation (26% vs. 3%), decreased 90-day mortality (6.5 vs. 14.1%), longer overall survival (OS, median: 2.9 vs. 1.7 years) and longer disease-specific survival (median: 3.9 vs. 2.0 years) (all at p<0.0001). Multivariate predictors of OS include TNM categories, age, ethnicity, radiation, and total LN count (all at p<0.0001). There were significant differences in stage-for-stage OS between EC subtypes based on histology and primary tumor location, and in DSS between EGJC subtypes (Siewert I, II or III) as well. Conclusions: EGJC incidence rates, diagnosis and treatment have undergone significant changes within the U.S. population. The regional dissection extent remains an area of importance as it is associated with OS. Comparisons of various survival outcomes do not support using the same staging criteria for EGJC as for EC.
Mouse models of pancreatic cancer induced by chronic pancreatitis and smoking.
Authors: Edderkaoui M. , Grippo Paul J. , Ouhaddi Y. , Benhaddou H. , Xu S. , Pinkerton K. , Tsukamoto H. , Knudsen Beatrice , Gukovskaya A. S. , Pandol Stephen
Published: February 2017

229

Background: Chronic pancreatitis (CP) and smoking are two major risk factors for pancreatic cancer (PaCa). Here we developed mouse models of PaCa by exposing mice to CP and/or smoking. Methods: Wild type (WT) and Pdx1-Cre;LSL-Kras transgenic mice were subjected to 7-hourly cerulein injections (50µg/kg) twice a week for 3 weeks to induce CP. Another group of mice was exposed to tobacco smoke (80mg/m3) in chambers for 5days/week during 6 weeks. A third group was exposed to both treatments. Mice were then sacrificed and pancreatic tissue analyzed. Pancreatic lesions, proliferation, fibrosis, inflammation, EMT and stem cell markers were analyzed by immunohistochemistry and Western. Results: CP significantly increased the number and stage of pancreatic neoplastic (PanIN) lesions with fibrosis, stellate cell activation and inflammation in transgenic mice. These changes were significantly less in WT mice. EMT markers (decrease in E-Cadherin and increase in vimentin protein levels) were stimulated by CP in both WT and transgenic mice. Similarly, smoking stimulated PanIN lesion formation, fibrosis and inflammation in transgenic mice, but to a lesser extent than CP model. Expression of EMT and stem cell markers was greater in the smoking model compared to CP. Combination of CP and smoking induced greater stimulation of PanIN lesion formation, fibrosis and inflammation compared to either treatment alone in transgenic mice. Conclusions: The results indicate that both CP and tobacco smoke promote PaCa progression in transgenic mice. The combination of CP and smoking has greater effects than either treatment alone. EMT and stem cell markers developed in WT as well as in transgenic mice with smoking suggesting that smoking has effects independent of Kras on cell transformation.
Searching for CDH1 gene mutations in early-onset diffuse gastric cancer in Chinese patients.
Authors: Yanjun Xu , Wenming Cao , Qi Xu , Jianmin Guo , Xinbao Wang , Xiangdong Cheng , Jieer Ying
Published: February 2017

23

Background: CDH1 germline mutations are found to be associated with the development of hereditary diffuse gastric cancer (HDGC) and the early-onset diffuse gastric cancer (EODGC). But the impact of CDH1 gene mutations and large deletions on HDGC and EODGC has not been fully determined in Asians. Although the incidence of gastric cancer is relatively high in China, the detection rate of CDH1 germline mutations in Chinese patients with EODGC is rare compared to that in European patients. Methods: We investigated the mutation status of the CDH1 gene in 57 Chinese EODGC patients younger than 40 years old who met the clinical criteria for HDGC. Polymerase chain reaction-direct sequencing was performed, and multiplex ligation-dependent probe amplification (MLPA) was used to evaluate the patients with negative sequencing results. Associations between mutation, clinicopathologic, and overall survival data were analyzed by SPSS 19. Results: The germline mutations of CDH1gene were identified in 51 (89.5%) of the 57 EODGC patients. The nonsense mutation in exon 13 (c.2200T>C, p.Ala692*) occurred in fourty-six EODGC patients. The missense mutations were detected in twenty patients (Eighteen in exon 5: c.778G>C, p.Glu218Asp; Two in exon 12: c.2012C>G, p.Leu630Val). No deletion or duplication in any patient. Most of the patients carrying the CDH1 mutation in exon 13 had lymph node metastasis when compared with patients lacking CDH1 mutation (87.2% vs 60.0%) ( P < 0.05 ). EODGC patients, lacking germline CDH1 alterations, showed a longer median overall survival (mOS) than patients carrying CDH1 mutation in exon 13 ( P < 0.05 ). Moreover, the presence of CDH1 mutation in exon 13 was associated with the incidence of neural invasion ( P < 0.05 ). Conclusions: This study reveals novel CDH1 mutations in Chinese EODGC patients which had been poorly investigated. The presence of CDH1 mutation in EODGC patients may result in lymph node metastasis and poor prognosis. More research is needed to determine additional genetic targets that trigger EODGC.
MicroRNA-21 ISH analysis to predict DFS in pancreatic cancer patients undergoing adjuvant gemcitabine after curative surgery.
Authors: Morinaga Soichiro , Nakamura Yoshiyasu , Katayama Yusuke , Sawazaki Sho , Numata Koji , Higuchi Kosei , Godai Teni , Shiozawa Manabu , Miyagi Yohei , Ohkawa Shinichi , Yoichi Kameda , Akaike Makoto
Published: February 2017

234

Background: Overexpression of microRNA-21(miR-21) in pancreatic cancer has been reported to be associated with tumor cell proliferation, invasion, and also resistance to gemcitabine (GEM) chemotherapy. The aim of this study was to evaluate whether miR-21 expression, determined by microRNA ISH, was associated with clinical outcomes of pancreatic cancer patients who underwent adjuvant gemcitabine chemotherapy after curative surgery. Methods: Expression levels of miR-21 were semi quantitatively analyzed for staining intensity and distribution of positive tumor cells, by microRNA ISH in formalin-fixed paraffin embedded tissue arrays from 41 pancreatic cancer patients who underwent adjuvant GEM chemotherapy after curative resection at Kanagawa Cancer Center. The staining intensity for the miR-21 was assigned a score from 1 to 3 based on staining with1+: weakly, 2+: moderately, and 3+: strongly positive. The percentage of positive tumor cells was scored as follows, 1+: < 50% positive cells, 2+: 50-80% positive cells, and 3+: ³a 81% positive cells. A composite score was obtained by calculating the sum of these two scores. Results: 27 patients were assigned to low miR-21 expression group (score <4) and 14 patients to high miR-21 group (score 4,5,6). High miR-21 expression group had a significantly shorter DFS (P = 0.039, by log-rank test). The median DFS was 9.8 months (95% CI, 6.9-12.6) in the low miR-21 group, and 7.9 months (95% CI, 6.1-9.8) in the high miR-21 group. The median OS was 19.6 months (95% CI, 6.3-32.8) in the low miR-21 group, and 15.1 months (95% CI, 11.7-18.5) in the high miR-21 group, but was not significant. Multivariate analysis including miR-21 expression, microscopic lymphatic invasion and microscopic perineural invasion, indicated that miR-21 expression (p = 0.024) and microscopic lymphatic invasion (p = 0.035) were the independent predictor for DFS. Conclusions: A high level of miR-21 expression in pancreatic cancer was significantly associated with shorter DFS in patients who received adjuvant GEM after curative resection. miR-21 ISH analysis may serve as a significant predictor for GEM resistance in adjuvant setting.
Phase II clinical trial of pasireotide LAR in patients with metastatic neuroendocrine tumors.
Authors: Strosberg Jonathan R. , Jump Helen , Valone Tiffany , Weber Jill , Khandelwal Vilay H. , Kunz Pamela L.
Published: February 2017

241

Background: Pasireotide LAR is a novel somatostatin analog (SSA) with avid binding to somatostatin receptor subtypes (SSTR) 1, 2, 3 and 5. It has been studied in patients who are refractory to SSAs, but has not yet been investigated in treatment naïve patients. Methods: We performed a phase II trial of first-line pasireotide LAR 60mg q4 weeks in patients with metastatic low and intermediate grade NETs. Prior systemic therapy, including octreotide and lanreotide, was not permitted. The primary endpoint was PFS. Immunohistochemical SSTR subtype analysis was performed on archival tissue. Results: 29 patients were enrolled of whom 28 patients were assessable for response. Primary sites included small intestine (14 pts), pancreas (6), rectal (2), unknown (4) and other sites (3). 13 patients had low-grade and 16 patients had intermediate-grade tumors. Best radiographic response was stable disease in 17 patients (60%), progressive disease in 10 patients (36%) and partial response in 1 patient (4%). Median PFS was 12.2 months (95% CI 7.7-17.5). The 1 year OS rate was 92% (CI 72%-98%). Although generally well tolerated, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia. 4 patients (14%) developed grade 3 hyperglycemia. 6 patients were started on insulin during the trial period, and at least 2 have remained on long-term insulin therapy despite discontinuation of pasireotide. Conclusions: Although the median PFS of 12.2 months in a heterogeneous population of NET patients is encouraging, the high rate of hyperglycemia requiring intervention represents a significant concern. Future studies of pasireotide should explore specific populations such as octreotide refractory patients. Clinical trial information: NCT01253161.
Clinical impact of reflection to expression of EMT marker in intraductal papillary mucinous neoplasm.
Authors: Ikemoto Tetsuya , Shimada Mitsuo , Utsunomiya Toru , Imura Satoru , Morine Yuji , Arakawa Yusuke , Mori Hiroki , Kanamoto Mami , Iwahashi Shuichi , Saito Yu
Published: February 2017

244

Background: We have already reported that regulatory Tcells (Treg) reflects the aggressiveness of intraductal papillary mucinous neoplasms (IPMN) (Pancreas 2013), Notch signaling is related to agressiveness of IPMN (DDW 2012). Notch signaling, important pathway of expansion of Tregs, is considered to be one of the important factors which cause cancer progression especially through epithelial-mesenchymal transition (EMT). It still remains unclear whether EMT leads to pathological agressiveness in IPMN. Therefore, we evaluated that peripheral Treg reflected the expression of EMT-promoting transcriptional factors, Twist1 and Bmi1 in IPMN. Methods: The patients who received resections at out institute were enrolled in this study (from 2000 to 2012, n=35). Twist1, Bmi1 and E-cadherin protein expressions were investigated by immunohistochemistry. These protein expressions were compared to clinicopathological factors and peripheral Treg population. Results: Positive expression of Twist1 and Bmi1 was observed in 40.0% and 34.3%, respectively. Twist1 and Bmi1 expression were significantly higher in IPMNs with high-grade dysplasia and invasive carcinoma than IPMNs with low to moderate-grade dysplasia (p<0.05). High Twist1 expression was correlated with Jagged1 expression and inversely correlated with expression of E-cadherin (p<0.05). IPMN aggressiveness correlated to Jagged1 expression and Treg (p<0.05) Higher expression of Twist1 and Bmi1 simultaneously were correlated with an poor disease-free-survival (p<0.05). Conclusions: Twist1 and Bmi1 may cause the progression of IPMN through EMT promotion which is induced by Notch signaling. High expression of both Twist1 and Bmi1 is associated with a worse clinical outcome and Treg population may be a marker to reflect these EMT status.
Prognostic impact of pancreatic intraepithelial neoplasia (PanIN)-III accompanying chronic pancreatitis in patients who underwent R0 resection for pancreatic adenocarcinoma.
Authors: Hwang In kyeom , Kang Bong Kyun , Lee Yoon Suk , Kim Jaihwan , Hwang Jin-Hyeok
Published: February 2017

246

Background: The clinical significance of pancreatic intraepithelial neoplasia (PanIN)-III, known as carcinoma in situ of pancreatic ductal adenocarcinoma (PDAC), remains unclear yet. Recent research showed inflammation enhanced early cellular invasion of PanIN-III by facilitating epithelial to mesenchymal transition (EMT), even before frank malignancy in experimental model. Therefore we decided to investigate whether PanIN-III accompanying chronic pancreatitis (CP) might have an important prognostic impact in patient who underwent curative resection for PDAC. Methods: Medical records of 199 PDAC patients with R0 resection were reviewed. Presence and grade of PanIN and CP in resected specimen were determined based on College of American Pathologists protocol. Overall survival (OS) and disease free survival (DFS) were analyzed according to PanIN-III and CP. Results: CP was observed in 19.6% (39/199) of resected specimen and PanIN-III in 21.1% (42/199). In the group with CP, PanIN-III was associated with poor prognosis in univariate analysis (16.6 months vs. 32.0 months, P=0.001 for OS and 7.5 months vs. 15.1 months, p=0.012 for DFS), whereas PanIN-III was not a prognostic factor in the group without CP. When we divided into two groups [PanIN-III accompanying CP (n=12) vs. the others (n=187)], it showed that median DFS and OS were significantly shorter in PanIN-III and CP group than those of the others (7.5 months and 16.6 months vs. 12.4 months and 26.0 months, p=0.017 and p=0.003, respectively). In multivariate analysis, PanIN-III accompanying CP remained a statistically significant poor prognostic factor (HR: 2.06; 95% CI: 1.008 to 4.221; p=0.048 for OS, HR: 2.6; 95% CI: 1.267 to 5.462; P=0.009 for DFS using Cox proportional hazard ratio). Conclusions: PanIN-III accompanying CP might influence on poor long-term outcomes in patients who underwent R0 resection for PDAC. Therefore, it would support that chronic inflammation could enhance the dissemination of carcinoma in situ.
GATA6 expression in Barrett’s metaplasia development and malignant progression.
Authors: Pavlov Kirill , Honing Judith , Meijer Coby , Boersma-van Ek Wytske , Peters Frans , van den Berg Anke , Karrenbeld Arend , Plukker John Theodorus , Kruyt Frank , Kleibeuker Jan
Published: February 2017

26

Background: Barrett’s metaplasia is characterized by the presence of a columnar metaplastic epithelium in the esophagus. Barrett’s metaplasia can show malignant progression towards esophageal adenocarcinoma by a metaplasia-dysplasia-carcinoma sequence. The underlying mechanisms of Barrett’s metaplasia development and malignant progression are poorly understood. The transcription factor GATA-6 is known to be involved in columnar differentiation and carcinogenesis. GATA6 gene amplification was recently linked with aggressiveness in esophageal adenocarcinoma. Here, we studied GATA6 protein expression in normal squamous, metaplastic, dysplastic and esophageal adenocarcinoma tissues in order to identify a possible role of GATA-6 in the development and malignant progression of Barrett’s metaplasia. Methods: Samples of squamous epithelium (N=37), Barrett’s non-intestinal metaplasia (N=16), Barrett’s intestinal metaplasia (N=29), high-grade dysplasia (N= 39), in situ esophageal adenocarcinoma (N=29) and an esophageal adenocarcinoma tissue microarray (N=95) were stained with a polyclonal antibody against GATA6. Staining intensity was categorized as absent, weak, normal or strong. Scoring was performed by two independent observers and validated by a pathologist. Results: GATA6 expression was absent in squamous epithelium but expressed in all samples of Barrett’s metaplasia, preferentially in the lower half of the crypt. Expansion of GATA6-positive cells throughout the crypt was observed in high-grade dysplasia. While all cases of in situ esophageal adenocarcinoma showed GATA6 expression we observed complete loss of GATA6 expression in 17% of esophageal adenocarcinoma samples. Conclusions: GATA6 is absent in squamous epithelium but its expression increases along the metaplasia-dysplasia carcinoma sequence. GATA6 expression remains predominantly present in esophageal adenocarcinoma, however, its expression is lost in a subset of samples. Analysis of the relation between GATA6 expression and clinicopathological characteristics in esophageal adenocarcinoma is pending.
Phase I/II study of gemcitabine plus S-1 with concurrent radiotherapy in patients of unresectable locally advanced pancreatic cancer.
Authors: Ioka Tatsuya , Katayama Kazuhiro , Ishida Nobuko , Sueyoshi Hironari , Takada Ryoji , Yamai Takuo , Fukutake Nobuyasu , Ashida Reiko , Akita Hirofumi , Takahashi Hidenori , Kawaguchi Yoshifumi , Konishi Koji , Teshima Teruki
Published: February 2017

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Background: We conducted chemoradiotherapy of gemcitabine plus S-1, key drugs for pancreatic cancer. Methods: Patients were eligible for the study if they had received a histopathological diagnosis of locally advanced pancreatic cancer and were diagnosed as unresectable by multiple clinicians including surgeons due to main arterial invasions and more. Radiation (RT) was perfomed for twenty-eight days continuously except Saturday, Sunday and National holiday in 1.8Gy once daily (total 50.4Gy). PTV was defined as GTV plus 10-15mm. Prophylactic irradiation to regional lymph nodes was not performed. Administration level of the anti-cancer drugs was referred to the following table. Results: A total of fifteen cases were enrolled to the phase I study from February, 2006 through May, 2007. RT was achieved in 13 of 15 cases (87%). Two cases of DLT occurred in level 2 (two cases of emesis) while three did in level 3 (one case of emesis and two of neutropenia of grade 4). We decided level 3 as MTD and level 2 as recommended dose. The overall response rate (more than PR) was 33.3% (5 in 15 cases) and tumor-control (more than SD) was achieved in 13 of 15 cases (87%). The one-year and two-year survival rate was 86.7% and 44.4%, respectively. Conclusions: We conducted the phase 1 study of chemoradiotherapy with two key drugs of pancreatic cancer and achieved the recommended dose in this phase I study. Ongoing study We have already finished the enrollment of 110 cases for a phase II randomized allocated study, comparing the chemoradiotherapy of administration dose decided in this phase 1 study with the combination therapy of gemcitabine plus S-1. Now we are carefully following the patients to compare two-year survival rate as a primary endpoint in phase II study. Clinical trial information: NCT01430052.
Survival outcome of a phase I trial: Hypofractionated stereotactic body radiation therapy concurrent with nelfinavir following gemcitabine and 5FU in patients with locally advanced pancreatic adenocarcinoma.
Authors: Lin Chi , Sasson Aaron R. , Ly Quan P. , Schwarz James K. , Are Chandrakanth , Kos Beth M , Lazenby Audrey J , Ketcham Marsha A , Sehi Eugene D , Grem Jean L.
Published: February 2017

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Background: We analyzed overall survival (OS) of patients enrolled in a phase I trial of hypo-fractionated stereotactic body radiation therapy (HFSBRT) concurrent with nelfinavir as part of neoadjuvant chemoradiation regimen in patients with borderline resectable and unresectable pancreatic adenocarcinoma. Methods: Forty-six patients (pts) with borderline resectable or unresectable pancreatic adenocarcinoma without metastasis were enrolled between October 2008 and May 2013 and treated with 3 cycles of Gemcitabine/5-Fluorouracil followed by 5-fraction-HFSBRT/Nelfinavir. [Dose escalation: 1)25Gy/625mgBIDx3week(wk); 2)25Gy/1250mgBIDx3wk; 3)30Gy/1250mgBIDx3wk; 4)35Gy/1250mgBIDx3wk; 5)35Gy/1250mgBIDx5wk; 6)40Gy/1250mgBIDx5wk] Surgery was performed within 4-8 wk for those down staged to resectable disease. Survival was evaluated using the K-M method. Results: The median follow-up is 12 months (M) [5-38]. The median OS (MOS) for the group is 15M [12-17]. The MOS for 13 patients with resected tumor is significantly higher than those with unresectable tumor (21M [12-29] vs. 14M [10-17]), Log-Rank p=0.02). Among patients with unresectable tumor, the MOS for those (22 pts) who received ≥ 35 Gy is significant higher than those (11 pts) who received < 35 Gy (16M [12.5-22] vs. 10M [4-15], Log-Rank p=0.006). During and 1.5M post HFSBRT, ≥ grade 3 GI, hematologic and other toxicities were 2.6%, 2.6% and 13% respectively. Postoperative ≥ grade 3 GI, hematologic and other toxicities were 8%, 8% and 24%, respectively. [Number]=95%CI. Conclusions: Overall survival in patients with resectable disease after HFSBRT/Nelfinafir is higher than those with unresectable disease. Among those who continue to have unresectable disease after HFSBRT/Nelfinavir, overall survival is higher in those who received 35-40 Gy than those who received < 35 Gy. Clinical trial information: NCT01068327.
A phase 1 trial of GSL (gemcitabine, S-1, LV) combination therapy in advanced pancreatic cancer.
Authors: Nakai Yousuke , Isayama Hiroyuki , Sasaki Takashi , Saito Kei , Takahara Naminatsu , Mizuno Suguru , Hamada Tsuyoshi , Miyabayashi Koji , Yamamoto Keisuke , Kogure Hirofumi , Yamamoto Natsuyo , Hirano Kenji , Ijichi Hideaki , Tateishi Keisuke , Tada Minoru , Koike Kazuhiko
Published: February 2017

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Background: Our previous randomized controlled trial, GEMSAP study (Br J Cancer. 2012 5;106:1934-9), showed a combination therapy of gemcitabine (Gem) & S-1 (GS) for advanced pancreatic cancer was superior to Gem monotherapy in terms of progression-free survival (PFS) but not overall survival (OS). Leucovorin (LV) is known to enhance efficacy of S-1 and we conducted this phase 1 trial of combination therapy of Gem, S-1 and LV (GSL). Methods: A primary endpoint of this classical “3+3” design phase 1 trial is to determine recommended dose of GSL. Inclusion criteria were 1. histologically-confirmed advanced pancreatic cancer without prior treatment, 2.PS 0-2, 3. age over 20. Treatment schedule was S-1 80 mg/m2 2x p.o. days 1-7, LV50mg 2x p.o. days 1-7, Gem 600(Level1), 800(Level2), 1000 mg/m2(Level3) div 30-min day 1 in a 2-week schedule. Dose-limiting toxicities were Grade 4 hematological and Grade ≥3 non-hematological toxicities, or delay of recovery from treatment-related toxicity for more than 2 weeks. Results: Between May 2012 and Feb 2013, 15 patients (Level 1/2/3: 6/6/3 patients) were enrolled; 7 males, a median age of 66, PS 0/1: 5/10, locally advanced/metastatic: 5/10. DLT was observed in 2/6 in Level 1 (Grade 3 anorexia in 1 and Grade 3 anorexia/stomatitis/diarrhea in 1) and 1/6 in Level 2 (Grade 3 pulmonary embolism). No DLT was observed in Level 3 and RD was determined as 1,000 mg/m2of Gem. Tumor response by RECIST was PR 5, SD 9, NE 1 with response rate of 33% and disease control rate of 93%. Overall toxicities greater than 3 were neutropenia 20%, anemia 7%, anorexia 13%, diarrhea 7%, stomatitis 7% and pneumonitis 7%. Conclusions: RD of GSL was determined as GEM 1000 mg/m2 div 30 min day 1, S-1 80 mg/m2 2x, LV50mg 2x p.o. days 1-7. GSL was tolerable and showed promising tumor response in advanced pancreatic cancer. Clinical trial information: UMIN000007556.
Efficacy and safety of cisplatin and gemcitabine (CG) chemotherapy for advanced biliary tract cancer (ABC) in jaundiced patients (pts).
Authors: Lamarca Angela , Benafif Sarah , Bridgewater John A. , Ross Paul J. , Valle Juan W.
Published: February 2017

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Background: The ABC-02 study established cisplatin/gemcitabine (CG) as a 1st-line regimen for pts with advanced/metastatic biliary tract cancer (ABC). Biliary tract obstruction (BTO) is common in ABC and pts with bilirubin (bili) ≥1.5xULN were excluded from ABC-02. We assessed retrospectively the safety/efficacy of CG in ABC pts with high bili despite optimal stenting. Methods: Eligible pts had biopsy-proven ABC; received 1st-line CG; baseline bili levels ≥1.5xULN and had follow-up, response and toxicity data available. Survival analysis (Kaplan-Meier), long-rank test, Cox regression and multiple linear regression analyses were performed. Results: Thirty-three pts (of 545 pts screened) met inclusion criteria: median age 58.8 years (range 23-79); male 58%; cholangiocarcinoma 76%; gallbladder 18% or ampullary cancer 6%; locally advanced 42%; metastatic 58% (79% in liver); 68% had a biliary stent; and 97% of pts had good baseline performance status (PS) 0/1/2: 33%/64%/3%. Median baseline bili was 55umol/l (range 32-286); due to BTO in 76% or liver metastases (LM) in 24%. A median of 6 (range 1-8) cycles were given, 70% of pts started full dose CG; 40% completed 8 planned cycles; 40% needed a dose reduction. Early discontinuation (61% of all pts) was due to toxicity (25%), clinical (60%) or radiological progression (15%). Bili normalised in 64% of pts after CG; no unexpected side effects occurred. Most pts achieved stable disease (61%); with one partial response (3%); the median PFS was 6.9 mo (95%-CI: 4.4-9.0) and median OS 9.5 mo (95%-CI: 5.7-12.8). BTO pts had a trend for longer PFS than LM (7.0 vs. 2.6 mo; p=0.1633). Normalisation of bili and completion of CG were associated with longer OS (11.4 vs. 2.9 mo, HR 0.49; p=0.08 and 15.2 vs. 5.4 mo, HR 0.12 p<0.001, respectively). Completion of CG was an independent prognostic factor for OS (multivariate analysis, p=0.001); no difference in OS was shown between the percentiles of baseline bili (p=0.57). Conclusions: For fit ABC patients with high bili, CG can be employed safely with encouraging results. Cause of jaundice (BTO, rather than bilirubin level), completion of chemotherapy and normalisation of bili are associated with improved OS.
A phase II study of ganetespib (G) as second- or third-line therapy for metastatic pancreatic cancer (MPC).
Authors: Thota Ramya , Goff Laura Williams , Chan Emily , Berlin Jordan , Jones C. Michael , McClanahan Pamela , Ayers Gregory Dan , Cardin Dana Backlund
Published: February 2017

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Background: Heat shock protein 90 (HSP90) regulates folding, stability and function of signaling proteins such as EGFR, IGF-1R, c-Met, ERBB4, PDGFRα and c-Ret, several of which are key pathways for MPC pathogenesis. G prevents Hsp90 binding to client proteins leading to inactivation and degradation, disrupting signaling that promotes cancer progression. This phase II study is designed to evaluate the efficacy of G in patients (pts) with refractory MPC. Methods: Pts with MPC in the 2nd or 3rd line setting, with PS 0-1, received G 175 mg/m2intravenously once weekly for 3 weeks out of a 4 week cycle. Primary endpoint was disease control rate (DCR) at 8 weeks, with a goal of 70% DCR. Secondary endpoints were response rate (RR), overall survival (OS), and safety. 43 pts were planned for initial accrual. Simon’s optimal two-stage design was used to assess 8 week DCR. G was considered inactive if 8 or fewer pts among the first 15 treated had disease control after 8 weeks of treatment (tx). Results: Seventeen pts were enrolled, and 14 received G. Median age was 65 (range 33-77), 4 female and 10 male. Eight received 1 prior line of therapy, and 6 received 2 prior lines of therapy. Grade 3 related toxicities include abdominal pain (4), fatigue (4), diarrhea (4), hyponatremia (9), nausea (1) and vomiting (1). There were no Grade 4-5 related events. DCR at 8 weeks was 21%, and OS was 2.5 months. Three pts didn’t complete tx; 1 due to disease progression after first cycle, 1 due to tx related toxicity, and 1 withdrew after 2 tx’s. Early stopping rules for lack of clinical efficacy led to study closure. Conclusions: Single agent G was tolerable with modest disease control when used as a single agent in refractory MPC. This disease is resistant to chemotherapy, and given the emerging data in both lung and breast cancer suggesting improved activity of G in combination with cytotoxic agents, studies combining this agent with chemotherapy in MPC are under development. Supported by Vanderbilt-Ingram Cancer Center CCSG (P30CA68485) and Synta. Clinical trial information: NCT01227018.
Effect of dose intensification (DI) of octreotide-LAR (O-LAR) among symptomatic patients with neuroendocrine tumors (NETs).
Authors: Al Efraij Khalid S. , Aljama Mohammed A , Kennecke Hagen F.
Published: February 2017

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Background: O-LAR 20 to 30 mg IM monthly (qM) is approved for the management of symptomatic NETs. While higher doses are sometimes used for improved symptom control, the benefit of this is not well described. The objectives of the study were to evaluate pre-DI and post-DI symptom, biomarker and tumor size among patients who received O-LAR 40-60 mg qM. Methods: With approval of the BC Cancer Agency research ethics committee the charts of all referred patients with NETs who received O-LAR 40-60 mg qM between 2005 and 2001 were reviewed. Symptom severity was graded on a 4 point scale and any post-increase improvement from grade 2,3 or 4 to 1 or no symptoms was classified an improvement. Pre-DI Chromogranin A (CGA) and 24-hour urine 5-HIAA were compared with the median of 3 post-DI levels and a 10% decrease was classified as a decrease. Results: A total of 37 patients received DI therapy with 40 mg (36), 50 mg (3), and 60 mg (16), for a total of 55 DI events. Median age was 60 and 49, 19, 32% had a tumor of small bowel, pancreas, other, respectively. Post-DI CGA and 5 HIAA levels decreased in 31% (15/49) and 23 % of patients (8/35) respectively. Symptom improvement post DI was observed in 62% (13/21) with diarrhea, 76% (13/17) with flushing, 53% (8/15) with abdominal pain. Post DI, no decreases in tumor size were observed, 29% (14/49) had radiological stable disease and the remainder had progressive tumors. Conclusions: O-LAR 40-60 mg qM was associated with improved symptom control among NET patients with refractory secretory symptoms. CGA and 5-HIAA levels varied in response to DI and were not accurate indicators of symptom control. There was no evidence of tumor regression with O-LAR DI. [Table: see text]