bluuebunny/crossref_metadata_2025 huggingface dataset:
Is computed tomography necessary for clinical T1 gastric cancer?
Authors: Fujikawa Hirohito , Yoshikawa Takaki , Shirai Junya , Iwasaki Kenichi , Hasegawa Shinichi , Hayashi Tsutomu , Aoyama Toru , Ogata Takashi , Cho Haruhiko , Oshima Takashi , Rino Yasushi , Masuda Munetaka , Tsuburaya Akira
Published: February 2017

1

Background: Initial diagnosis of gastric cancer is based on upper gastrointestinal tract endoscopy (GF) and/or upper gastrointestinal series (UGI) which also determines invasion depth of T1 or Non-T1. Subsequently, TNM is evaluated by Multi Detector-row Computed Tomography (MDCT). TNM is indispensable to decide treatment of gastric cancer, however, T1 disease has low metastatic potential and is almost curable only by local treatment. It remained unclear whether MDCT is necessary for clinical T1 (cT1). 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, confirmed by endoscopic biopsy (2) patients were diagnosed with cT1 by GF/UGI, (3) patients received MDCT, (4) patients received no prior treatment before the examination, and (5) patients received endoscopic mucosal dissection (ESD) or radical surgery with D1 or more lymphadenectomy as a primary treatment. Efficacy of MDCT was evaluated by incidence of cM1 in all patients with cT1 disease and by accuracy to diagnose pathological N+ in patients who received surgery. Regional lymph nodes were considered to be involved by metastases if they were larger than 8 mm in the short-axis diameter. Results: A total of 761 patients were entered into this study. Of these, 236 patients received ESD while 525 underwent surgery. No cM1 disease was found in 761 patients. Among 525 patients who underwent surgery, 484 were pathologically diagnosed with T1 (pT1, 92.2%), 31 with pT2 (5.9%), 5 with pT3 (0.9%), and 5 with pT4 (0.9%). Clinical N+ was observed in 8 patients (1.5%), while pathological N+ in 45 (8.6%). The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value was 90.3%, 4.3%, 98.7%, 25%, and 91.3%, respectively. Conclusions: The present study suggested that MDCT was unnecessary for cT1 gastric cancer because cM1 was extremely rare and diagnosis of N+ was unreliable in cT1 disease.
Result of HER2 status in Japanese metastatic gastric cancer: Prospective cohort study (JFMC44-1101).
Authors: Nishikawa Kazuhiro , Chin Keisho , Nashimoto Atsushi , Miki Akira , Miwa Hiroto , Tsuburaya Akira , Miyanaga Tamon , Hara Takuo , Fukushima Ryoji , Gamoh Makio , Fukushima Norimasa , Sano Takeshi , Kodera Yasuhiro , Kakeji Yoshihiro , Morita Satoshi , Sakamoto Junichi , Saji Shigetoyo , Yoshida Kazuhiro
Published: February 2017

10

Background: Randomized phase III (ToGA trial) has demonstrated that the addition of trastuzumab to standard chemotherapy improved overall survival in patients (pts) with HER2-positive metastatic gastric cancer (mGC). In screening of the ToGA trial, HER2 positivity rate was 22.1 % in total, but the rates varies between countries. Therefore, to determine the HER2 incidence rate in Japanese mGC, we planned prospective cohort study JFMC44-1101. Methods: JFMC44-1101 is a multicenter epidemiological trial assessing HER2 status in Japan. Patients with histologically confirmed gastric adenocarcinoma, not suitable for curative resection were eligible. HER2 status was centrally assessed both immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) using formalin fixed paraffin embedded (FFPE) tissues from tumor. HER2 positive is defined as either IHC3+ or FISH+ in accordance with ToGA trial. Overall and subgroup estimates calculated with 95%CI. Results: Between September 2011 to June 2012, 1466 pts were registered from 157 sites. Patients characteristics were; gender (M/F):1044/422, median age (min-max): 68 (25-99), advance / recurrence: 1068 / 398. Samples are 768 from biopsy and 698 from excision. In August 2012, 1427/1466 pts were assessed. Overall, HER2 positivity was 20.5% (293 pts). Each IHC status (0/1+/2+/3+) with FISH+ was 3.0% / 11.3% / 46.9% / 97.2%, respectively. The frequency of IHC 0/1+ with FISH+ was almost as high as IHC 2+ with FISH+ (5.6%/4.2%). HER2 positivity rate of background factors were; male/female:23.6%/14.3%, biopsy/ excision: 22.7%/19.0%, advance / recurrence: 21.6%/17.6%. Conclusions: JFMC44-1101 confirmed the incidence of HER2 positivity in Japanese mGC. HER2-positivity rate and HER2 status were similar to the ToGA screening population. Clinical trial information: UMIN000006190.
Prognostic impact of postoperative radiation in patients with radical esophagectomy and pathologic lymph nodes positive esophageal cancer.
Authors: Xu Yaping , Sun Xiaojiang , Zheng Yuanda
Published: February 2017

101

Background: Though postoperative radiation for esophageal cancer is offered in selected cases, there is conﬂicting evidence as to whether it improves overall survival (OS). We performed a retrospective investigation to analyze the prognosis impact of adjuvant radiation in a large cohort of patients. Methods: From 2002 to 2008, 545 patients underwent radical esophagectomy (R0) with or without postoperative radiation were eligible for retrospectively analysis. Patients were grouped to surgery only (n=346) and surgery plus postoperative radiation therapy (PORT) (n=199). Radiation dose was 50 Gy in 25 fractions. Kaplan-Meier and Cox regression analysis were used to compare OS. Results: The use of PORT was associated with signiﬁcantly improved OS ( p =0.006). The median OS was 31 months in the group receiving PORT and 21 months in the group undergoing surgery alone. The addition of PORT improved OS at 3 years from 38.3 to 45.8% compared with surgery alone. For American Joint Committee on Cancer (AJCC) stage III esophageal cancer (T1-2N2M0, T3N1-2M0, T4N1-3M0), there was signiﬁcant improvement on OS ( p < 0.001) in PORT group, for not only metastatic lymph-node ratio <0.25 ( p = 0.047), but also metastatic lymph-node ratio >0.25 ( p = 0.013). However, for stages IIB disease (T1-2N1M0) there was no signiﬁcant differences. Conclusions: This large population-based analysis supports the use of PORT for pathologic lymph nodes positive stage III esophageal cancer. Our results suggest that a subset of such patients may benefit from aggressive local therapy.
Significance of accurate HER2 testing as a new biomarker in advanced gastric cancer.
Authors: Kusumoto Tetsuya , Ohtsu Hajime , Kawano Hiroyuki , Ando Koji , Ida Satoshi , Kimura Yasue , Saeki Hiroshi , Oki Eiji , Morita Masaru , Maehara Yoshihiko
Published: February 2017

106

Background: The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2)-positive advanced or recurrent gastric or gastroesophageal junction cancer, which demonstrated that trastuzumab plus chemotherapy improved overall survival in the overall population (hazard ratio 0.74). HER2 testing in gastric cancer differs from testing in breast cancer due to inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity and incomplete membrane staining. The aim of the present study was to evaluate the frequency of HER2-positive cases by application of the standard criteria in Japanese patients with advanced gastric cancer (AGC) and to investigate the relationships between HER2 expression and therapeutic responses. Methods: A total of 199 tumor samples were assessed for HER2 expression both by immunohistochemistry (IHC) and HER2 amplification by fluorescence in situ hybridization (FISH). HER2-positive status was defined as IHC2+ and FISH-positive or IHC3+. Objective responses were evaluated in the patients with AGC who were treated with chemotherapy plus trastuzumab or chemotherapy alone based on the HER2 expression status. Results: HER2-positive tumors were identified in 12 patients (5.5%), less than 28.1% in the Japanese subgroup analyses of ToGA study. The positive rates varied with histological type; 14%, 5.3% and 0.95% in the well, moderately and poorly differentiated adenocarcinoma, respectively. Although high concordance between the results of IHC and FISH in all samples was found, IHC2+ samples retested here showed FISH-negative. Of all 10 patients with AGC, 3 patients with HER2-positive tumor were treated with capecitabine/cisplatin plus trastuzumab, and partial response was found in 2 cases; response rates were 67%. Conclusions: Specific consideration and scoring modification are required before embarking on HER2 testing in gastric cancer. Accurate and reliable HER2 testing and scoring will allow appropriate selection of patients eligible for treatment with trastuzumab.
PCF chemotherapy combined with surgical treatment of advanced gastric cancer.
Authors: Xiangdong Cheng
Published: February 2017

113

Background: Local advanced gastric cancer that could not receive R0 resection or gastric cancer with distant metastasis usually received palliative chemotherapy or entered into a number of clinical trials, and surgery usually roled as a symptomatic treatment. This study is to investigate the efficacy and safety of PCF chemotherapy combined with surgery in the treatment of these patients. Methods: From July 2008 to February 2011, 72 cases of local advanced gastric cancer that cannot be treated with R0 resection (T4N2~3M0) or gastric cancer with single organ metastases (M1) were prospectively analysed. Patients received 2-4 cycles of PCF chemotherapy (PTX 150mg/m2, d1, CDDP 25mg/m2, d1-3, CF 250 mg/m2, d1-3,5-FU 750 mg/m2, d1-3, repeated every 3 weeks), then the primary and metastatic tumor were treated with cytoreductive surgery: mainly treated with radical resection of gastric tumor, combined with D3 and D4 lymph node dissection, pancreaticoduodenal resection, colon resection, ovariectomy, peritoneal resection, liver resection, and tumor radio frequency, followed with another 2-4 cycles of PCF chemotherapy. The treatment completion rate, patients’ tolerance, and overall survival (OS) time were analyzed. Results: 50 patients (69.4%) accomplished chemotherapy and surgical resection as planned. 42 cases had R0 resection (58.3%). The postoperative complication rate was 6.0%. Grade 3/4 toxic effects included bone marrow suppression (30.6%) and gastrointestinal reaction (40.3%), the overall response rate (CR+PR) was 72.2%. Survival analysis: the median survival time was 23.5 months. 1-year and 2-year survival rate was 67.0% and 47.0%. The OS of patients with surgical resection was much longer than that of the non-surgery group. (30.2 vs. 8.9 months) (p <0.01). The OS of local advanced group was 30.3 months, and was significantly longer than 17.6 months of the distant metastasis group (p <0.01); however, it had no significant difference compared to 28.2 months of the distant metastasis group with R0 resection. Conclusions: PCF chemotherapy combined with surgical resection were safe and effective, and can make survival benefits for patients with local advanced gastric cancer or gastric cancer with single organ metastasis.
Prognostic significance of HER2 expression and associated clinical characteristics in esophageal adenocarcinoma.
Authors: Chan Ellie , Alkhasawneh Ahmad , Duckworth Lizette Vila , Zuluaga Toro Tania , Hou Wei , Yan Hui , Hughes Steven J. , George Thomas J.
Published: February 2017

114

Background: The incidence of adenocarcinoma of the esophagus (EA) and gastroesophageal junction (GEJ) is on the rise. Her2Neu (HER2) is overexpressed in 20-25% of gastric cancers and is associated with poor prognosis. However, the prognostic significance of HER2 in EA/GEJ is less clear. Methods: This retrospective analysis included all sequential patients (pts) with EA or GEJ who underwent primary resection at the University of Florida from 2001 to 2011without neoadjuvant therapy or HER2 inhibition. Demographics, risk factors, tumor features, and outcome data were analyzed. Central blinded immunohistochemistry (IHC) was performed on paraffin embedded tumor specimens with HER2 expression scored as negative (-) (0 or 1+), indeterminate (2+) or positive (+) (3+). Results: 56 pts were eligible for analysis (45 M/11 F) with median age 67 years (37-83). Mean BMI was 29.6±6.6 and 43 pts (92%) had underlying Barrett’s esophagus. Most tumors (60%) were stage I (T1N0). Overall testing revealed tumors to be HER2 + (38%), indeterminate (21%) or - (41%). 50% of Stage I, 18% of stage IIA, 33% of stage IIB, and 14% of stage III tumors were HER2 + (p=0.035 for stage I compared to other stages). Underlying Barrett’s esophagus was associated with HER2 + (60 vs. 0%; p=0.045). The median follow up of the entire cohort was 2.9 years. Overall survival (OS) at 3 years was 80% for stage I, 50% for stage IA, 40% for stage IIB and 50% for stage III (p= 0.153). 3 year OS for HER2+ pts was 64% vs. 70% for HER2- (p=0.63). Univariate analysis did not show significant correlation among tobacco use, BMI, disease progression, survival and HER2 expression. Conclusions: This data suggests that HER2 overexpression is more frequent in early stage disease with underlying Barrett’s esophagus. Our data do not support HER2 as a prognostic factor in EA/GEJ. The relationship of HER2 overexpression in the development of early stage GEJ, particularly in the setting of Barrett’s, is of clinical interest. Further investigation is warranted.
Concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil (5 FU) and cisplatin for locally advanced resectable esophageal cancer: A retrospective study.
Authors: Almhanna Khaldoun , Hoffe Sarah , Shridhar Ravi , Strosberg Jonathan R. , Dinwoodie William R. , Meredith Kenneth
Published: February 2017

119

Background: Neoadjuvant CCRT has become the standard treatment for esophageal cancer. Most clinicians use a conventional cisplatin/5 FU combination which is associated with moderate to severe toxicity. For the last 15 years we have used contiuous low-dose 5-FU combined with two doses of cisplatin. Methods: Between July 1997 and June 2012, 155 patients with locally advanced esophageal cancer (T3 or N1 and higher), received CCRT consistent of cisplatin 75 mg/m2 on day 1 and day 29 and continuous infusion of 5-FU (225 mg/m2/day) on the days of radiation. Results: Median age of patients was 63 year (30-76).Seventeen percent of pts were female and 85% had adenocarcinoma. (3, 34, 86 and 31 pts had stage I, II, III and IVa disease respectively. One hundred and twenty seven pts had N1 disease. Radiation dose (RT) ranged from 45-60 Gy (median 56Gy). Median weight loss was 6.5%. All patients completed treatment. 20% of patients had >=grade 3 toxicity, with 29 patients requiring hospital admission. 53% of patients had surgical resection between 37-149 days following CCRT (median 62 days). R0 resection was achieved in 96% of patients. A pathological complete response was achieved in 38 of 83 pts (45%) who underwent surgical resection. With a median follow up of 26 months (1.2 -144 months), 36% of pts recurred and total of 50% died. Conclusions: Compared to conventional chemotherapy regimen, our CCRT regimen for locally advanced esophageal cancer is well tolerated and associated with a high pathological response rate.
Comparison of lymph node staging system in gastric cancer using time-dependent ROC analysis with Harrell’s concordance index.
Authors: Bando Etsuro , Sugisawa Norihiko , Tokunaga Masanori , Tanizawa Yutaka , Kawamura Taiichi , Kinugasa Yusuke , Kanemoto Hideyuki , Uesaka Katsuhiko , Terashima Masanori
Published: February 2017

12

Background: The aim this study was to clarify what the most informative pathologic lymph node staging system in gastric cancer is, by using time-dependent receiver operating characteristic (ROC) analysis with Harrell’s concordance (c) index. Methods: This study enrolled 2747 primary gastric cancer patients, without prior chemotherapy, who underwent R0 or R1 macroscopically curative resection. We calculated concordance indices of different 3 nodal staging systems (anatomical level based on JPN 13th edition vs. numbers of metastatic nodes based upon TNM 7th edition vs. ratio of metastatic nodes; derived from Yu’s definition {Yu et al. Br J Surg;1997,N0:0, N1;0-0.1, N2;0.1-0.25, N3;0.25-}) for survival. Results: (Anatomical level) Harrell’s c-index was 0.754 with 5-year survival rate of N0; 93%, N1; 73%, N2; 51%, N3; 19%. C-index without node-negative patients was 0.628. (Numbers of positive nodes) C-index was 0.767 with 5-year survival rate of N0; 93%, N1; 81%, N2; 68%, N3; 37%. C-index without node-negative patients was 0.669. (Ratio of nodal involvement) C-index was 0.770 with 5-year survival rate of N0; 93%, N1; 80%, N2; 63%, N3; 29%. C-index without node-negative patients was 0.691, which is significantly larger than those in anatomical level or numbers of positive nodes (p<0.001, p=0.014, respectively). (Comparison of Staging System) If combined pT category with ratio grading system without pStage IA, new staging system is the significantly most informative (c-index; 0.760) than JPN 13th (c-index; 0.735) or TNM 7th (c-index; 0.742) (p=0.009, p=0.023, respectively). Conclusions: Lymph node staging system based on the conception of ratio of metastatic nodes is the most informative staging system than those with anatomical location or numbers of metastatic nodes. These results suggested that in gastric cancer pathologic staging system in next TNM classification should include the ratio of metastatic nodes.
Various clinical outcomes in patients with esophageal or gastroesophageal junction (E-GEJ) adenocarcinoma undergoing trimodality therapy: Prognostic implications.
Authors: Suzuki Akihiro , Xiao Lianchun , Taketa Takashi , Sudo Kazuki , Blum Mariela A. , Komaki Ritsuko , Liao Zhongxing X. , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Hofstetter Wayne Lewis , Swisher Stephen , Ajani Jaffer A.
Published: February 2017

120

Background: Preoperative chemoradiation (trimodality therapy) has the strongest evidence in trimodality-eligible patients with E-GEJ adenocarcinoma. Pathological complete response (pathCR) and clinical complete response (clinCR) are favorable prognostic factors. We hypothesized that pathCR is associated with best prognosis. Methods: Patients with E-GEJ adenocarcinoma undergoing trimodality therapy were identified from the prospectively maintained databases at our institution. Multiple statistical methods were used. Results: For 314 esophageal cancer patients, the median follow-up time was 44.0 months (95% CI; 34.2-50.9). 107 of 314 patients died at this analysis. 80 patients (25.5%) had a pathCR. 160 patients (51.0%) had a clinCR prior to surgery but did not have pathCR. The remaining 74 (23.6%) had <pathCR and <clinCR. Median OS were: not achieved in pathCR patients, 82.8 months (95% CI; 63.9, NA) in clinCR patients and 27. 6 months (95% CI; 19.4, NA) <pathCR/<clinCR (p<0.001). The median recurrence-free survival (RFS) were: 79.6 months (95% CI; 37.4, NA) in pathCR patients, 67.4 months (95% CI; 31.8, NA) in clinCR patients and 13.5 months (95% CI; 10.4, 21.4) in <pathCR/<clinCR (p<0.001). In multivariate analysis, no lymph node metastasis (p<0.001), not poorly differentiated adenocarcinoma (p=0.002) and pathCR (p=0.02), and cCR (p<0.001) were independent prognosticators of OS and RFS. Conclusions: pathCR and clinCR are independent prognosticators (pathCR producing the best results) and may be helpful in devising new therapeutic and surveillance strategies.
An open, multicenter, phase II clinical trial to evaluate efficacy and safety of S-1 split cisplatin in patients with advanced gastric cancer (AGC): HGCSG0702—Safety analysis.
Authors: Iwanaga Ichiro , Yuki Satoshi , Fukushima Hiraku , Ishiguro Atsushi , Takahata Takenori , Miyagishima Takuto , Kudo Mineo , Uehata Yasuko , Sakata Yuh , Komatsu Yoshito
Published: February 2017

121

Background: From the results of SPIRITS trial, S-1 plus cisplatin has been regarded as standard first-line chemotherapy for patients with AGC in Japan. However, many facilities are forced hospitalization of hydration upon administration of high dose Cisplatin (60mg/m2). Therefore, in Hokkaido Gastrointestinal Cancer Study Group (HGCSG), to investigate the safety and efficacy, we conducted a multicenter phase II clinical trials of S-1 plus split cisplatin as a therapeutic strategy that can be administered in the outpatient. Methods: Eligibility criteria included pathologically confirmed AGC; no prior chemotherapy; Age 20 to 75, ECOG performance status (PS) of 0 to 1; adequate organ function; and written informed consent. S-1 (40-60 mg depending on patients body surface area) was given orally, twice daily for 3 consecutive weeks, and 30 mg/m2 cisplatin was given intravenously on day 1 and 15, followed by 2-week rest period, within a 5-week cycle. Primary endpoint was the response rate (RR), and secondary endpoints were progression-free survival, overall survival, safety profile, and duration of hospitalization. Results: Between Mar 2008 and Mar 2012, 40 pts were enrolled. Patients characteristics were as follows: median age 63 years (range 41-75), Male: female 30:10, PS 0:1 33:7. Median no. of cycles was 3. The most common non-hematological adverse events (AE) were anorexia (70%), nausea (60%), fatigue (60%) and diarrhea (48%) and hematological AE were anemia (88%), neutropenia (83%), leukocytopenia (68%) and thrombocytopenia (60%). The main grade 3-4 AE were neutropenia (40%), anemia (30%), anorexia (30%) and fatigue (15%). These AE were as expected. The median dose intensity of S-1 was 270mg/m2/week (relative dose intensity (RDI) 80%), and cisplatin was 10.1mg/m2/week (RDI 84%). These toxicities were tolerable and manageable. No treatment-related death was observed. Conclusions: We conclude that this S-1 plus split cisplatin regimen was well tolerated in the treatment of AGC, and most patients could be administered in the outpatient. We are planning the final efficacy analysis for February 2013.
Resting palliative chemotherapy in patients with gastric cancer.
Authors: Lee Hee Yeon , Hong Young Seon , Jeon Hae Myung , Park Cho Hyun , Song Kyo Young , Roh Sang Young
Published: February 2017

122

Background: In gastric cancer, platinum and fluorouracil combination chemotherapy (CTx) is commonly used. But the optimal duration of CTx in palliative setting is not known. Thus, we reviewed the pts who rested CTx despite of persistent disease control. Methods: From Mar 2007 to Feb 2012 at Seoul St. Mary’s hospital, we retrospectively reviewed pts as follows; (1) had metastatic or recurrent gastric cancer, (2) received 9 cycles of FOLFOX as 1st-line, (3) had no progressive disease (PD) and rested after completion of 9th cycle. Results: Total 25 pts were reviewed. Median age was 54 (36~77) and 15 pts (60%) were male. 13 pts (52%) had recurrent disease and 12 metastatic initially. All pts were treated with oxaliplatin 100 mg/m2, leucovorin 400 mg/m2 on day 1 and 5-FU 1200 mg/m2 on day 1-2 every 2 weeks. All pts had metastasis; carcinomatosis peritonei (CP, 56%), lymph node (36%), liver (20%) and bone (8%). Nine pts (48%) had non-measurable lesions and 3 no evidence of disease (NED) on CT after palliative surgery. Response evaluation was done every 3 cycles. Among 22 pts with evaluable disease, 5 (20%) showed complete response (CR), 8 (32%) partial response (PR), 2 (8%) stable disease (SD) and 7 (28%) non-CR/non-PD as best response. Median progression free survival (PFS) was 14.2 m (95% CI, 6.6-21.9). The PFS in CP vs. non-CP was 9.9 vs. 21.5 m (log rank P = .037). And PFS according to best response were as follows; 25.5 m in CR + NED group, 15.7 PR, 13.4 non-CR/non-PD and 4.3 SD (log rank P = .014). Other factors did not seem to affect PFS. Conclusions: This study suggested that resting CTx in selected pts would be reasonable in gastric cancer. Especially the presence of CP and the grade of response seemed to be important in patient selection.
Significance of multimodality therapy for esophageal cancer synchronously or metachronously associated with head and neck cancer.
Authors: Kimura Yasue , Morita Masaru , Kawano Hiroyuki , Ohtsu Hajime , Ando Koji , Ida Satoshi , Saeki Hiroshi , Oki Eiji , Kusumoto Tetsuya , Maehara Yoshihiko
Published: February 2017

132

Background: Esophageal cancer is highly aggressive and until recently is associated with a poor prognosis. Another clinical problem of esophageal cancer is the frequent association of head and neck cancer. The therapy for esophageal cancer and head and neck cancer is difficult. Definitive chemoradiotherapy is frequently indicated, while invasive surgical resections have been aggressively performed for patients with esophageal cancer associated with head and neck cancer. Methods: The Japanese 202 patients underwent esophagectomy were divided into two groups according to the association of head and neck cancer. The clinicopathological factors and the method of operations were evaluated and statistically analyzed. Results: The double cancer group included 26 (12.9%) patients that had the cancer of esophagus and the head and neck either synchronously or metachronously, while the control group included 176 (87.1%) patients with esophageal cancer. Seventeen patients were operated synchronously in double cancer group. No statistically significant differences were recognized in other clinical backgrounds such as the gender, location of the tumor, etc. Several types of operations were performed for two groups, such as subtotal esophagectomy, total laryngo-pharyngo-esophagectomy, cervical esophagectomy and laryngo-pharyngectomy and free jejunal transfer.salvage esophagectomy, and two-staged operation after definitive chemoradiotherapy. Salvage esophagectomy was performed in five patients with either remnant or recurrent esophageal cancer after definitive chemoradiotherapy. The mortality as well as morbidity rate of the double cancer group was not significantly different from the control group. Furthermore, patients’ prognosis was similar in the two groups. Conclusions: Esophagectomy can be an effective treatment option by adopting techniques that appropriate for each cases, such as staged operations after definitive chemoradiotherapy, muscular flaps and microvascular anastomosis, even in patients with double cancers of the esophagus and the head and neck cancer.
Prognostic factors after R2 surgery in patients with advanced gastric cancer.
Authors: Tokunaga Masanori , Goto Hironobu , Makuuchi Rie , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Terashima Masanori
Published: February 2017

140

Background: In patients with advanced gastric cancer, chemotherapy is a standard treatment if they have non-curable factors. However, gastrectomy is sometimes performed even in patients having non-curable factors, particularly when they have tumor associated symptoms. The aim of this study is to investigate clinicopathological characteristics of patients who underwent R2 surgery, and to identify prognostic factors. Methods: This study included 157 patients who underwent gastrectomy with macroscopic residual disease (R2 surgery) between September 2002 and June 2011 at the Shizuoka Cancer Center. Clinicopathological characteristics and surgical outcomes were investigated. In addition, we conducted Cox-proportional Hazards model which included age, sex, number of non-curable factors, chemotherapy, macroscopic type, histology, and postoperative intraabdominal infectious complications as covariates, to identify independent prognostic factors after R2 surgery. Results: There were 103 male and 54 female patients with median age of 69 years. The reasons why R2 surgery was performed were low oral intake due to stenosis in 120 patients and bleeding in 54 patients. Total gastrectmy was the most frequently performed procedure (93 patients) followed by distal gastrectomy (61 patients) Median operation time and intraoperative blood loss were 193 minutes and 337 mg, respectively, and intraabdominal infectious complications (Clavien-Dindo classification grade II or more severe) were observed in 24 patients (15.3%). Chemotherapy was given after surgery in 112 patients (71.3%) with median survival time of all patients being 8.7 months. Multivariate analysis identified postoperative chemotherapy (Hazard ratio, 0.34; 95% confidential interval, 0.24 – 0.65) and postoperative intraabdominal infectious complications (Hazard ratio, 1.74; 95% confidential interval, 1.06 – 2.88) as independent prognostic factors. Conclusions: The incidence of postoperative infectious complications after R2 surgery was thought to be higher than that after curative gastrectomy reported before. Safe procedure and administration of postoperative chemotherapy would be necessary to offer improved overall survival after R2 surgery.
Identification of germline genetic mutations in patients with pancreatic adenocarcinoma.
Authors: Salo-Mullen Erin E , O'Reilly Eileen Mary , Kelsen David Paul , Lowery Maeve Aine , Yu Kenneth H. , Rau-Murthy Rohini , Siegel Beth , Saltz Leonard , Kurtz Robert C , Offit Kenneth , Robson Mark E. , Stadler Zsofia Kinga
Published: February 2017

159

Background: The emergence of PARP-inhibitors for potential treatment of BRCA-associated cancers highlights the importance of identifying germline mutations in individuals with pancreatic adenocarcinoma (PAC) (NCT 01585805 for PARP-i in PAC). Optimal selection of PAC patients for genetic testing remains to be determined. Our objective was to investigate prevalence of germline mutations in our PAC patients. Methods: MSKCC Clinical Genetics database was reviewed for PAC patients offered germline testing from 1/1/2011 to present. Clinical data was extracted from records. Pedigrees were reviewed to verify NCCN (PAC at any age with ≥2 close relatives with breast/ovarian/PAC at any age) and/or other testing criteria. Results: 70 PAC patients (33 males, 40 Ashkenazi Jewish (AJ)) were seen; 36 met NCCN criteria and 16 were AJ with 1 close relative with breast/ovarian/PAC. Of 18 not meeting these criteria, 7 were AJ, 3 were early-onset, and 7 were non-AJ with at least 1 additional BRCA-associated cancer in either themselves or a close relative. 63 patients accepted BRCA testing: 6 (9.5%) had a BRCA1 (n=2) or BRCA2 (n=4) mutation. Only 2 of these met NCCN criteria; 3 were AJ with 1 close relative with a BRCA-associated cancer; and 1 was non-AJ descent with 1 close relative with early-onset breast cancer. 36 AJ patients pursued BRCA testing: 4 (11.1%) had a BRCA1 (n=1) or BRCA2 (n=3) mutation; all were founder mutations. Additional genetic testing, based on family history, identified 1 MSH2 mutation, 1 MSH6 mutation, and 1 p16 mutation. Overall mutation detection rates were 13.6% (9/66) in total cohort who pursued any genetic testing and 15.8% (6/38) in tested AJ group. 6 patients with PAC before age 50 were tested: 1 non-AJ patient had a BRCA1 mutation and 1 (with history of melanoma) had a p16 mutation. Conclusions: With mutation detection rates of nearly 14% in total tested population & 16% in AJ cohort, germline genetic testing is important for PAC patients with potential implications for treatment and for relatives. By limiting BRCA testing to patients who meet current NCCN testing criteria, 66.7% (4/6) of our patients with BRCA mutations would not have been identified. Reassessment of testing criteria is needed for optimal care of PAC patients.
Clinicopathologic correlations of gallbladder cancer by ethnicity in New Mexico, 1980-2009.
Authors: Madden Kathleen , Wiggins Charles , Nir Itzhak , Rajput Ashwani , Morris Katherine T.
Published: February 2017

160

Background: Gallbladder cancer (GBCA) is a rare malignancy; however, within the U.S. incidence varies geographically. GBCA has a higher occurrence in the American Indian (AI) population versus non-Hispanic whites (NHW) and Hispanics (H). The goal of the study is to determine if clinicopathologic features correlate with ethnicity. Methods: Incident GBCA diagnosed in New Mexico from 1980-2009 were identified from the population-based New Mexico Tumor Registry. Average age-adjusted incidence rates were calculated by direct method using the United States 2000 standard population. Chi-squared statistic was used to assess ethnicity differences in case distribution at diagnosis by sex, age, stage and grade. Cause-specific survival was calculated by the Kaplan-Meier method and assessed with log-rank statistic. Results: GBCA incidence rates in New Mexico are highest for AI (7.6 per 100,000–95% confidence interval (CI)=6.5-8.9), followed by H (2.8 per 100,000 – 95% CI=2.5-3.2) and NHW (1.0 per 100,000 – 95% CI=0.9-1.1). Females are predominantly affected (Table). Median ages varied among NHW (74 years), H (71 years) and AI (69 years). There are no appreciable differences with respect to stage and tumor grade. Cause-specific survival at 60 months is also similar among NHW (20.25%), H (17.94%), and AI (22.43%) (log-rank p-value=0.7388). Conclusions: GBCA has a higher prevalence in AI. Regardless it shares similar characteristics in all evaluated ethnicities as it is predominantly a disease of older females, with similar tumor grade and stage and with equally poor survival. [Table: see text]
The role of microRNA-9 in hepatocellular oncogenesis.
Authors: Drakaki Alexandra , Hatziapostolou Maria , Polytarchou Christos , Iliopoulos Dimitrios
Published: February 2017

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Background: Hepatocellular carcinoma (HCC) is the main type of liver cancer. MicroRNAs are non-coding RNAs that have been involved in the pathogenesis of different cancer types. Our aim was to identify microRNAs that have functional and clinical significance in liver oncogenesis and understand how manipulation of their levels could have a therapeutic potential. Methods: MicroRNA expression analysis was performed in 38 HCC tissues and 25 normal liver tissues. A microRNA library (318 microRNAs) was transfected in SNU-449 liver cancer cells and invasiveness was measured 24 h later by a matrigel invasion assay. Cell growth and matrigel invasion assays were performed in SNU-449 cells that were transfected with miR-9 or antisense-miR-9 (20nM). TargetScan algorithm was used to identify miR-9 direct downstream target genes. The mRNA levels of PPARalpha, and E-cadherin were assessed by real-time PCR 48h after miR-9 overexpression and down-regulation in SNU-449 cells. Results: MicroRNA expression analysis in 38 HCCs and 25 normal liver tissues identified a 25-microRNA signature of HCC. Integration of the library screen and patient data revealed that miR-9 has clinical and functional relevance for liver cancer. Specifically, we found that miR-9 increases 2.7-fold the invasiveness and the growth of SNU-449 cells, 48h post transfection. Bioinformatic analysis revealed that miR-9 has a binding site in the 3’UTR of PPARalpha gene. MiR-9 overexpression inhibited 35% PPARalpha 3’UTR luciferase activity and 60% mRNA levels, while miR-9 down-regulation led to 75% increased PPARalpha mRNA levels. These data suggest that miR-9 targets directly the 3'UTR of PPARalpha and regulates its expression levels in liver cancer cells. In addition, miR-9 overexpression led to 95% suppression of E-cadherin mRNA levels in SNU-449 cells, thus increasing their metastatic potential. Conclusions: We found that miR-9 is highly overexpressed in liver cancer patients and its up-regulation increases the growth and metastatic potential of liver cancer cells. Overall these data suggest that miR-9 is a novel oncogene involved in liver oncogenesis and its suppression could have therapeutic potential in liver cancer patients.
Pretreatment serum ferritin and overall survival in metastatic pancreatic cancer.
Authors: Zubritsky Lindsey , Alkhateeb Ahmed , Leitzel Kim , Ali Suhail M. , Campbell-Baird Cynthia , Connor James , Lipton Allan
Published: February 2017

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Background: Ferritin, an iron storage protein, is elevated in the serum of certain types of cancers, including breast and pancreatic. Ferritin has been shown to play a role in tumorigenesis and cancer cell growth and survival through angiogenesis, immune regulation, and iron delivery. Ferritin may serve as a potential biomarker in evaluating survival of pancreatic cancer patients. Methods: This study determined pretreatment ferritin levels in a phase III clinical trial of 162 patients with advanced pancreatic cancer. A quantitative sandwich ELISA (Human Ferritin ELISA (Assaypro, St. Charles, Missouri) was used to measure pretreatment serum ferritin levels in 162 patients with advanced pancreatic cancer. Serum ferritin level was correlated with overall patient survival using log-rank regression and Kaplan-Meier analysis on a continuous and categorical dichotomous basis (median cutpoint). Results: The median pretreatment serum ferritin in 162 patients was 832.6 ng/ml, a 25th and 75th percentile of 446 and 1735 ng/ml, respectively, and ranged from 51 ng/ml to 35914 ng/ml. When analyzed on a continuous basis, patients with higher serum ferritin had reduced overall survival (p= 0.001). When analyzed on a categorical basis (median 832.6 ng/ml), patients with higher ferritin had shorter overall survival (median 121 days vs. 180 days) (p=0.003). In multivariate analysis with pretreatment serum ferritin, TIMP-1, uPA, and VEGF, TIMP-1 remained the only significant predictive factor (p<0.0001), with ferritin trending toward significance (p= 0.076). Conclusions: Pretreatment serum ferritin in 162 patients with advanced pancreatic cancer was quantified using ELISA. Pretreatment serum ferritin predicted for significantly shorter overall survival in a phase III trial of metastatic pancreatic cancer. Pretreatment serum ferritin level has prognostic biomarker utility in pancreatic cancer, and should be evaluated as a predictive factor for response to novel treatment regimens.
An exploratory phase I trial of immunochemoradiotherapy in locally advanced and borderline resectable (LA/BR) pancreatic adenocarcinoma (PC).
Authors: Crocenzi Todd S. , Crittenden Marka , Wolf Ronald , Hammill Chet , Newell Pippa , Savoy Alan , Somogyi Lehel , Phillips Michael , Regan James , Owens Michael , Solhjem Matthew C. , Seung Steven , Kurup Anupama , Rogosin Shane Orion , Urba Walter John , Bifulco Carlo Bruno , Cai Xiaohong , Bageac Alexandru , Gough Michael
Published: February 2017

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Background: The primary aim of this exploratory trial was to determine the feasibility and safety of chemoradiotherapy (CRT) with combinatorial immunotherapy in LA or BR PC. Methods: 10 patients (pts) with untreated, LA (n=6) or BR (n=4) biopsy-proven PC received gemcitabine (GEM) in combination with telomerase peptide vaccine (GV1001) and sargramostim (GM-CSF) both by intradermal injection. Tadalafil was taken once daily throughout the course of therapy for myeloid derived suppressor cell inhibition. The 2nd month of treatment included external beam radiation therapy (50.4 Gy, 28 fractions) and concurrent twice-weekly GEM 50 mg/m2. Disease response was assessed at 12 weeks. Following recovery from either concurrent CRT or resection, 8 weeks of GV1001 + GM-CSF, tadalafil and GEM completed treatment. Peripheral blood was analyzed by quantitative multiparameter whole blood flow cytometry of immune cell subtypes. Samples were also cryo-preserved for future analysis of peripheral blood mononuclear cell (PBMC) populations and ELISPOT analysis of antigen-specific T cell numbers. Tumor resection specimens were sectioned for immunohistological analysis of macrophage and T cell infiltration. Results: 9 of 10 pts completed therapy to assess response. Grade (Gr) 3-4 hematologic adverse events (AE) were observed during CRT. Immune-related AE were infrequent and mild. 3 of 4 pts with BR disease and 1 with initial LA (unresectable) disease achieved R0 resection. No unanticipated surgical complications were observed. Changes in monocytes and granulocytes occurred throughout treatment and may correlate with clinical benefit. At least 50% reduction in serum CA19-9 was observed in 8 pts. Partial response (n=2) or stable disease (n=7) was achieved in 9 pts. Conclusions: Combinatorial immunotherapy concurrent with GEM-based CRT is feasible and appears safe in LA or BR PC. Initial biochemical responses as well as disease control were observed in the majority of pts. Preliminary immune correlative data suggest a relationship between hematopoietic populations and clinical response.
Circulating tumor cells as a possible marker for micrometastatic disease in patients with localized pancreatic cancer.
Authors: Aufforth Rachel D. , Baker Justin J. , Witek Malgorzata A. , Kamande Joyce W. , Kim Hong Jin , Kuan Pei-Fen , Soper Steven A. , Yeh Jen Jen
Published: February 2017

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Background: Circulating tumor cells (CTCs) are cells shed into circulation from tumors. They are increasingly recognized to be important biomarkers of disease burden in patients with solid tumors. Studies in pancreatic ductal adenocarcinoma (PDAC) have been limited due in part to low sensitivity of existing assays with extremely low numbers detected (0-15 per 7.5-15ml of blood). The development of newer microfluidic platforms has resulted in the ability to detect substantially greater numbers of CTCs. Methods: 15 patients with PDAC were enrolled in an IRB-approved study. Blood was collected in EDTA tubes and processed within 3 hours. CTCs were selected from 2-3ml of whole blood using monoclonal antibodies against epithelial cell adhesion molecule (EpCAM) and enumerated using a novel microfluidic platform. CTCs were confirmed by DAPI, CK8/18/19 and CD45 staining. Results: Patients with metastatic disease (n=12) had a mean of 29.7, median of 22 (3.5-107) CTCs per 1ml of blood. Patients with localized disease (n=3) had a mean of 3.8, median of 2.9 (2.3-6.2) CTCs per 1ml of blood. 0.5-1 CTCs per 1ml were detected in normal controls (n=2). The number of CTCs was significantly different between localized, metastatic and normal patients (p=0.01). 1 patient, initially thought to have localized disease by standard imaging but found to be metastatic at time of operation, had a mean of 45.9 CTCs per 1ml of blood compared to a mean of 3.8 CTCs per 1ml in patients who underwent a curative resection (p=0.009). Conclusions: Studies of CTCs in PDAC have been very limited. Our ability to detect large numbers of CTCs with good dynamic range suggests that further investigation into CTCs as a prognostic marker in PDAC is warranted. This is the first study that we are aware of to find CTCs in patients with localized disease. The presence of CTCs in patients with localized PDAC is surprising and may be associated with findings of unexpected metastatic disease at surgery. Further follow-up will be needed to determine if the presence of CTCs in these patients is a harbinger of shorter progression-free survival and overall survival after curative operations.
Analysis of toxicity and outcomes in patients undergoing hyperthermic isolated hepatic perfusion with melphalan for metastatic melanoma to the liver.
Authors: Golas Benjamin , Magge Deepa , Zureikat Amer H. , Zeh Herbert , Alexander H. Richard , Libutti Steven K. , Royal Richard E. , Hughes Marybeth S. , Holtzman Matthew Peter , Turaga Kiran , Pappas Sam G. , Gamblin T. Clark , Bartlett David L. , Pingpank James F.
Published: February 2017

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Background: Ocular melanoma (OM) has an annual incidence of 3500 to 4000 patients per year, with liver metastases (LM) accounting for the sole or dominant site of metastases in more than 80% of patients. For patients with LM, median survival is reported to be 2 to 7 months, with an estimated 1-year survival of 10%. We present results utilizing liver directed therapy with high-dose melphalan administered via hypertermic isolated hepatic perfusion (IHP) for patients with unresectable LM from OM. Methods: Between 10/1994 and 6/2012, 105 pts with unresectable LM underwent a 60 min hyperthermic (IHP) with melphalan (1-2 mg/kg IBW). IHP included hepatic isolation at laparotomy with inflow via a cannula in the gastroduodenal artery and outflow via a cannula in the isolated retrohepatic vena cava (IVC). Patients were followed for toxicity, radiographic response (WHO criteria), and hepatic progression-free (HPFS) and overall survival (OS). HPFS and OS probabilities were calculated by Kaplan-Meier. Results: There were 51 males and 54 females (mean age: 50 yr [range: 21-76]) with unresectable OM LM (median # metastases: 26 [range: 3-50]; median percent liver replaced by tumor: 22%). There were 3 operative/treatment mortalities (2.9%). There were 62 responses (CR: n=6, PR: 56) in 102 evaluable patients (61%). For all treated patients, median OS was 12 months (range: 1 to 115 months) with 2 and 3-yr survival of 31% and 21%, respectively. Conclusions: IHP with melphalan results in marked tumor regression and prolonged OS in patients with high hepatic tumor burden from metastatic OM. Although this is a non-randomized trial, response to IHP is associated survival superior to that reported with alternative therapies.
Clinical implications of luminal membrane expression of mesothelin in intraductal papillary mucinous neoplasms.
Authors: Einama Takahiro , Kamachi Hirofumi , Nishihara Hiroshi , Homma Shigenori , Kawamata Futoshi , Tahara Munenori , Taniguchi Masahiko , Furukawa Hiroyuki , Kamiyama Toshiya , Taketomi Akinobu , Matsuno Yoshihiro , Todo Satoru
Published: February 2017

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Background: We recently explored that the expression of mesothelin was related to an unfavourable patient outcome in pancreatic cancer. Furthermore, in gastric cancer, we investigated that the luminal membrane expression of mesothelin was a reliable prognostic factor. Intraductal papillary mucinous neoplasms (IPMNs) often exhibit a spectrum of dysplasia ranging from adenoma to carcinoma in the same lesions. Therefore, we investigated the immunohistochemical analysis of mesothelin expression in IPMNs, especially focusing on the localization of mesothelin. Methods: Tissue samples from37 IPMNs were immunohistochemically examined. The types of IPMNs were classified into 2 groups: low, intermediate and high-grade dysplasia (L-H grade dysplasia) and IPMN with an associated invasive carcinoma (Invasive carcinoma). The proportion and intensity of constituent tumor cells with mesothelin expression were analyzed and classified as positive expression or negative expression. Furthermore, among the ‘mesothelin-positive’ cases, the staining localisation of mesothelin was evaluated as ‘luminal membrane positive’ and/or ‘cytoplasmic positive’. Results: In 37 cases of IPMNs, mesothelin expression was observed in 21 cases (56.8%), 46.2% (12 of 26) of L-H grade dysplasia and 81.8% (9 of 11) of Invasive carcinoma; p=0.071. Luminal membrane positive was observed in 10 cases (27%), 18.2% (4 of 22) of L-H grade dysplasia and 21% (6 of 11) of Invasive carcinoma; p=0.00016. Cytoplasmic positive was observed in 17 cases (27.0%), 38.5% (10 of 26) of L-H grade dysplasia and 63.6% (7 of 11) of Invasive carcinoma; p=0.28. Among 37 IPMNs, 6 cases showed recurrence after surgery. Five cases exhibited mesothelin expression, and all 5 cases exhibited luminal membrane positive. Conclusions: we demonstrated the clinicopathological significance of the luminal membrane expression of mesothelin in IPMNs. The immunohistochemical examination of mesothelin expression should be clinically useful for prognostication and for decision making about further treatment procedures after surgical therapy in patients with IPMNs.