bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and feasibility of adjuvant chemotherapy with S-1 in Korean patients with curatively resected advanced gastric cancer.
Authors: Jeong Jae Ho , Ryu Min-Hee , Lee Sung Sook , Ryoo Baek-Yeol , Lee Sang Hong , Kim Kab Choong , Yook Jeong Hwan , Oh Sung Tae , Kim Byung Sik , Kang Yoon-Koo
Published: February 2017

121

Background: Adjuvant chemotherapy with S-1 has been proven effective for patients with curatively resected advanced gastric cancer with D2 lymph node dissection in Japan. We assessed the safety and feasibility of adjuvant S-1 chemotherapy in Korean patients with stage II, III or IV(M0) gastric cancer.

Methods: A total of 305 patients with stage II, III or IV(M0) gastric cancer received adjuvant S-1 chemotherapy following curative gastrectomy with D2 lymph node dissection in Asan Medical Center between October 2007 and December 2009. Adjuvant chemotherapy with S-1 was started 3-6 weeks after surgery and it was administered orally twice daily at the dose of 40 mg/m2 for 4 weeks followed by 2 weeks of rest, every 6 weeks 8 times for 1 year. We retrospectively reviewed the medical records of the patients and evaluated the safety and feasibility of adjuvant S-1 chemotherapy in Korean patients.

Results: Among the 305 patients, 248 (81.3%) and 198 (64.9%) patients completed 4 and 8 cycles of adjuvant chemotherapy, respectively. The most common reasons for discontinuation of treatment were adverse event (43.9%) and recurrence (26.2%). Among the 305 patients, 75 (24.6%) patients required dose reduction because of toxicities. The most common grade 3/4 toxicities were neutropenia (12.8%), diarrhea (5.3%), abdominal pain (3.8%), and anemia (3.3%). Multivariate analysis showed that total gastrectomy (H.R. 2.50; 95% C.I. 1.32-4.72, p=0.005) and female gender (H.R. 1.95; 95% C.I. 1.03-3.66, p=0.039) were independent risk factors for grade 3/4 hematologic toxicities, and old age (>65 years) (H.R. 2.92; 95% C.I. 1.50-5.69, p=0.002) was an independent risk factor for grade 3 non-hematologic toxicities.

Conclusions: Adjuvant chemotherapy with S-1 for 1 year was safe and feasible in Korean patients. Old age, female gender, and total gastrectomy were independent risk factors for severe toxicities of adjuvant S-1 chemotherapy.
Intensive up-front treatment versus a sequential approach in advanced gastric cancer patients: Does first line matter?
Authors: Bittoni Alessandro , Scartozzi Mario , Pistelli Mirco , Galizia Eva , Del Prete Michela , Giampieri Riccardo , Faloppi Luca , Bianconi Maristella , Maccaroni Elena , Cascinu Stefano
Published: February 2017

131

Background: The definition of the standard chemotherapy regimen for advanced gastric cancer is still a matter of debate. A recent meta-analysis suggested that the addition of a third drug to a doublet regimen should be considered the state-of-the-art strategy to improve overall survival. Aim of our analysis was to retrospectively assess whether an intensive, three-drugs, front line approach could be comparable to a sequential (two-drugs front line then second line) in terms of RR (response rate), PFS (progression free survival), and OS (overall survival) in advanced gastric cancer patients.

Methods: Patients with metastatic gastric cancer who have received a first-line combination chemotherapy with a two or three-drugs regimen were included in our analysis. We divided our patients into two groups, A and B, based on the first line chemotherapy administered (group A=three drugs; group B= two drugs).

Results: A total of 390 patients were eligible for our analysis. 211 patients (54%) received three chemotherapeutic agents (group A) and 179 patients (46%) received a two drugs regimen as first-line combination chemotherapy (group B). The 2 groups of patients resulted comparable for all known prognostic factors of clinical relevance. RR for group A and B was 46,5% and 28%, respectively (p=0,0007), median PFS was 7,12 months in group A and 3,96 months in group B (p<0,0001). No significantly difference resulted for the median OS of patients in the two groups (13 months for group A and 11,8 months for group B; p= 0,962).

Conclusions: The addition of a third drug to a doublet chemotherapy regimen appeared more active in terms of response rate and PFS. However median OS resulted comparable. On this basis, a triplet regimen may represent an optimal choice, particularly when response and PFS are relevant treatment endpoints. Nevertheless the use of a sequential approach may also represent a reasonable strategy for patients unwilling or unable to undergo a more intensive treatment without compromising OS.
Preventive effect of rikkunshito, traditional Japanese medicine, for chemotherapy-induced nausea and vomiting.
Authors: Kajiura Shinya , Hosokawa Ayumu , Yoshita Hiroki , Nakada Naokatsu , Itaya Yuko , Ueda Akira , Ando Takayuki , Fujinami Haruka , Ogawa Kohei , Sugiyama Toshiro
Published: February 2017

135

Background: Supportive therapies are being developed for chemotherapy-induced nausea and vomiting (CINV). Rikkunshito is a Kanpo medicine, which is a part of traditionally practiced Japanese-based ancient Chinese medicine. It has been reported to be effective against cisplatin-induced anorexia in rats. In the present study, we evaluated the preventive effect of rikkunshito for CINV in patients receiving high-dose cisplatin.

Methods: We selected subjects who received chemotherapy including cisplatin (≥60mg/m2) for gastric or esophageal cancer between April 2008 and July 2011 at our institution. We targeted 26 cases treated without a reduction in the anti-cancer medication in the second course and added 7.5g/day of rikkunshito, orally administered for seven days, to their second course treatment regimen. All cases were treated with 5-HT3 receptor antagonist and steroid, and 12 cases were treated with palonosetron for the prevention of CINV in their first and second courses. We evaluated the complete response (CR, defined as no emesis and no rescue medication) rate and other toxicity, according to CTCAE v4.0, of the first and second courses.

Results: The median age of the patients was 67 years (range, 49–77 years). There were nine cases of gastric cancer and 17 cases of esophageal cancer. The chemotherapy regimens were cisplatin + irinotecan in two cases, cisplatin + 5-FU in 15 cases, cisplatin + S-1 in seven cases and cisplatin + 5-FU + docetaxel in two cases. Six cases received concomitant radiation therapy. Anorexia in the first course was grade 0/1/2 = 4/12/10, but had been mitigated in the second course to grade 0/1/2 = 11/11/4 (P = 0.020). CR rate was 69.3% in the first course (95% CI, 51.6%–87.0%) and by the second course had improved to 88.5% (95% CI, 76.2%–100%) (P = 0.089). And about the other major toxicity, there was no significant difference between first and second courses.

Conclusions: These results suggest that rikkunshito has the potential to improve CINV in patients receiving high-dose cisplatin.
A pilot study of WCA (a Chinese Jianpi Herbal Formula) integrated to systemic chemotherapy (CT) in the first-line treatment for advanced gastric cancer (AGC).
Authors: Zhao Aiguang , Li Zhaoyan , Zhao Gang , Cai Yong , Xu Yan , Zhu Xiaohong , Cao Nida , Yang Jinkun
Published: February 2017

143

Background: To improve survival of AGC, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on their clinical experiences. WCA, a Chinese “Jianpi” herbal formula, could inhibit gastric cancer cells MKN-45, SGC-7901 growth in vivo on our previous studies. All the herbs formed the formula have been used for thousands of years in Chinese clinical practices.

Methods: A nonrandomized concurrent control trial was performed to investigate the role of WCA for AGC. Patients (pts) with gastric adenocarcinoma (locally advanced, recurrent, or metastatic) were prospectively enrolled. All pts were assigned to receive WCA+CT q3w for 3 or more than 3 cycles or CT alone. WCA was formulated as following: Radix pseudoxtellariae 12g, Stir-fried Rhizoma atractylodis macrocephalae 12g, Poria cocos 30g, Sargentodoxa cuneata 30g, Concha ostreae 30g, Prunellae vulgaris 9g. It was given orally every day until disease progression. The primary end point was overall survival (OS). The baseline comparison was analyzed by using chi-squared test.

Results: 270 eligible pts had been histologically confirmed adenocarcinoma. At the time of last follow-up, 197 pts (73.0%) had died of disease, and 67 pts (26.7%) had censored, 1 patient (0.3%) had died of unrelated cause. The median follow-up of pts was 39.9 months. Baseline characteristics (gender; age of onset; primary tumor site; histological type; initial CT scheme; cycle of CT) were well balanced across arms. Median OS was significantly improved in WCA+CT arm (n=127) compared to that in CT (n=143) alone: 19.3 vs. 13.1 months, respectively (HR 0.550; 95% CI 0.412, 0.734; p=0.000). The treatment was generally well tolerated. There were no WCA-related adverse events observed. No patient died related to WCA treatment.

Conclusions: This prospectively concurrent control trial investigating Chinese herbal therapy in advanced GC showed that WCA+CT be a promising candidate treatment for GC superior to CT alone. A randomized controlled trial is needed to further evaluate the value of WCA in improving the OS of AGC.
Neutropenic fever and neoadjuvant intraperitoneal and systemic chemotherapy (DCF-like) in gastric cancer with peritoneal dissemination.
Authors: Muñoz Martin Andrés Jesús , Garcia Alfonso Pilar , Gonzalez Bayon Luis , Vasquez Jimenez Wenceslao , Ruperez Blanco Ana Belen , Lopez Marti Maria Pilar , Tapia Rico Gonzalo , Blanco-Codesido Montserrat , Alvarez Suarez Sonsoles , Martin Miguel
Published: February 2017

144

Background: Neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) is a new treatment modality in gastric cancer with peritoneal seeding. Several phase I-II clinical trials with NIPS and cytoreductive surgery have shown an increase in overall survival in Japanese patients (pts) with acceptable toxicity. We report the toxicity related to neutropenia and granulocyte colony stimulating factor (G-CSF) use of the first experience in Spain with NIPS (DCF-like) in gastric cancer with peritoneal carcinomatosis.

Methods: Ten consecutive pts have been enrolled in this protocol in a compassionate use program in our center from 2009 to 2011. Chemotherapy (DCF-like) was delivered through an implantable peritoneal catheter. Primary prophylaxis with GCS-F was not used as described in the phase II studies, except in one pt. Clinical characteristics (Table).

Results: The incidence of grade 3–4 neutropenia was 70% and any grade neutropenia 80%. Febrile neutropenia was described in 50% of the pts. All pts received secondary prophylaxis according to ASCO guidelines. No treatment-related deaths were observed. One pt discontinued chemotherapy due to febrile neutropenia and diarrhoea. There were no complications due to the infection of peritoneal catheter. Late or unexpected toxicities have not been observed.

Conclusions: The first results suggest febrile neutropenia rate of this treatment modality exceeds the 20% ASCO threshold. Primary prophylaxis with G-CSF should be considered in this setting.

[Table: see text]
S-1 plus oxaliplatin compared with fluorouracil/leucovorin/oxaliplatin as neoadjuvant chemotherapy for locally advanced gastric carcinoma.
Authors: Yu Jiren , Wu Yijun , Gao Yuan , Shen Qianyun , Zhang Qing , Liu Xiaosun , Zhu Kankai
Published: February 2017

147

Background: Perioperative chemotherapy could improve the prognosis compared with surgery alone. This study is to compare the efficacy and safety of S-1 and oxaliplatin (SOX) with fluorouracil, leucovorin and oxaliplatin (FOLFOX) as neoadjuvant chemotherapy for locally advanced gastric carcinoma.

Methods: Patients with histologically confirmed locally advanced gastric carcinoma were enrolled and divided into two groups. Preoperative staging and response evaluation was achieved mainly by gastroscopy and abdominal computer tomography. Neoajuvant chemotherapy consisted of 2-6 cycles of S-1 80mg/m2 (2-week administration and 1-week rest) plus oxaliplatin 130mg/m2 on Day1 in SOX group, or 2 h infusion of 130mg/m2 oxaliplatin plus 2h infusion of 400 mg/m2 leucovorin, followed by infusion of 400 mg/m2 5-fluorouracil on Day 1 and 46 h 2.4 g/m2 bolus in FOLFOX group. The clinical response was evaluated after 2 cycles of chemotherapy, and surgery was attempted.

Results: From 2009.9 to 2011.5, 88 patients were enrolled in this study(56 in SOX and 32 in FOLFOX). The clinical response rate was significant higher in the SOX compared with FOLFOX (54.7% vs. 31.2%, p=0.03). 68 patients received surgery(45 in SOX and 23 in FOLFOX), R0 resection rate was similar in both group (SOX: 93.3% vs. FOLFOX: 82.6%, p=0.22). Pathological complete response was observed in 3 patients in SOX group. All enrolled patients were evaluated for the adverse events (AE). The most common non-hematological AE was nausea (57.1% in SOX and 50% in FOLFOX) and vomiting (41.1% in SOX and 40.6% in FOLFOX). The major hematological AE included thrombocytopenia (37.5% in SOX and 21.9% in FOLFOX), neutropenia (33.9% in SOX and 53.1% in FOLFOX) and leukocytopenia (32.1% in SOX and 40.6% in FOLFOX).

Conclusions: SOX had higher response rate and acceptable toxicity compared with FOLFOX as neoadjuvant chemotherapy.
Patient-reported toxicities and comorbidities after treatment for cancers of the upper gastrointestinal tract.
Authors: Metz James M. , Hampshire Margaret K. , Vachani Carolyn , Di Lullo Gloria A. , Hill-Kayser Christine E.
Published: February 2017

148

Background: Patients may be at risk for significant late effects after multimodality therapy for gastric and esophageal (GE) cancers, the impact of which may be difficult to evaluate using conventional methods. This Internet-based study evaluates patient perceptions of toxicity after treatment for GE cancer.

Methods: Patient-reported data was gathered via a convenience sample frame from GE cancer survivors voluntarily utilizing a publically available, free, Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com and through the OncoLink website, the tool allows survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, GE cancer survivors are queried regarding late effects associated with specific treatments. All data have been maintained with IRB approval.

Results: Sixty-six GE cancer survivors answered queries regarding late effects; 62% were female and 93% Caucasian. Median diagnosis age was 55 yrs (19–74 yrs), median current age 59 yrs (19–77 yrs), and average time since diagnosis 3.8 yrs. Most reported having had multimodality therapy—88% surgery, 80% chemotherapy, and 48% radiation. When queried regarding persistent health problems after cancer treatment, 35% reported cardiovascular disease (21% hypertension, 13% hyperlipidemia, 3% angina), 28% sexual dysfunction, 36% tinnitus, 24% peripheral neuropathy, 42% cognitive changes, 100% difficulty swallowing, 60% dry mouth or taste changes, 40% dental changes, and 14% chronic lung disease.

Conclusions: Survivors using this tool anonymously and voluntarily report significant health problems after treatment for GE cancers. The data reported here may be of significant impact in future study of quality of life, as well as patient counseling and survivor care.
What are the limiting factors related to discontinuance of chemotherapy after failure of first-line S-1 plus CDDP in Japanese patients with advanced gastric cancer?
Authors: Ohhara Yoshihito , Chin Keisho , Ogura Mariko , Suenaga Mitsukuni , Shinozaki Eiji , Matsusaka Satoshi , Mizunuma Nobuyuki , Yamaguchi Toshiharu , Hatake Kiyohiko
Published: February 2017

149

Background: Recently, it is suggested that second-line chemotherapy improved survival in advanced gastric cancer (AGC) and it is commonly performed in Japanese daily practice in these several years. We investigated the limiting factor not to be able to receive second-line chemotherapy in Japanese patients with AGC.

Methods: Between 2007 and 2009, 155 patients received S-1 plus cisplatin (SP) treatment as first-line chemotherapy in Cancer Institute Hospital of JFCR, Japan. Among them, 148 patients could not continue SP treatment because of disease progression or unacceptable toxicity. 109 patients could receive second-line chemotherapy (Group A), while 39 patients could not (Group B). We evaluated the clinicopathologic factors that affected not to receive second-line chemotherapy, retrospectively. Univariate and multivariate analyses were performed on the baseline factors before starting first-line chemotherapy.

Results: Characteristics of patients were below (Group A vs B): median age, 60 vs 66 (years); gender (male), 71.6 % vs 66.7 %. Median progression-free survival were not different in both Group statistically (6.5 vs 7.2 months; log-rank, p=0.861). Median overall survival were 16.5 vs 10.3 months (log-rank, p<0.001), respectively. Univariate analyses found 4 limiting factors not to initiate second-line chemotherapy: age over 65 years old (p=0.025), performance status>1 (p=0.017), alkaline phosphatase (ALP) >400 IU/l (p<0.001), C-reactive protein (CRP) >1.0 mg/dl (p=0.004). Multivariate analyses showed ALP elevation was a limiting factor (HR 4.122, p=0.003).

Conclusions: Alkaline phosphatase can be an uncomplicated and potent limiting factor of discontinuance of chemotherapy after failure of the first line S-1 plus CDDP in Japanese patients with AGC.
The effect of vascular reconstruction on early postoperative outcomes after pancreaticoduodenectomy: An analysis of the American College of Surgeons National Surgical Quality Improvement Program database.
Authors: Castleberry Anthony W. , White Rebekah Ruth , De La Fuente Sebastian G. , Tyler Douglas S. , Pappas Theodore N. , Scarborough John E.
Published: February 2017

153

Background: Several single-center reports have been published suggesting that vascular reconstruction (VR) during pancreaticoduodenectomy (PD) allows an acceptable oncologic outcome in patients with pancreatic adenocarcinoma without affecting early postoperative mortality or morbidity. The objective of our study was to review the outcomes associated with VR during PD using a large multicenter data source.

Methods: A retrospective cohort analysis was performed using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Participant User Files for 2005-2009. All patients undergoing PD for a postoperative diagnosis of malignant neoplasm of the pancreas were included. Forward stepwise multivariate regression analysis was used to determine the association between VR during PD and 30-day postoperative mortality and morbidity after adjusting for patient demographics and comorbidities.

Results: 3582 patients were included for analysis, 281 (7.8%) of whom underwent VR during PD. VR during PD was associated with significantly greater risk-adjusted 30-day postoperative mortality (5.7% with VR vs. 2.9% without VR, Adjusted Odds Ratio (AOR) 2.1, 95% CI 1.22-3.73, p = 0.008) and overall morbidity (39.9% with VR vs. 33.3% without VR, AOR 1.36, 95% CI 1.05-1.75, p = 0.02). Patients undergoing VR required significantly longer operative times, and were more likely to require intraoperative transfusion or early reoperation, than patients not undergoing VR during PD. There was no significant difference in risk-adjusted postoperative mortality or morbidity between those patients undergoing VR by the primary surgical team versus those patients undergoing VR by a vascular surgical team.

Conclusions: Contrary to the findings of several previously published single-center analyses, data from ACS-NSQIP suggests that VR significantly increases the risk of 30-day postoperative death or complications after PD. Patients who may require VR during PD will likely benefit from referral to centers with sufficient experience with this procedure.
Neoadjuvant chemoradiation versus surgery first for resectable pancreatic head adenocarcinoma: An economic and outcome analysis.
Authors: Abbott Daniel Erik , Tzeng Ching-Wei David , Merkow Ryan P. , Cantor Scott B. , Katz Matthew H.G. , Bentrem David J. , Bilimoria Karl Y. , Crane Christopher H. , Varadhachary Gauri R. , Fleming Jason B.
Published: February 2017

156

Background: The optimal sequence of treating pancreatic cancer (PC) with chemotherapy, radiation and surgical intervention remains elusive. Thus, cost should be considered. This study was conducted to compare the cost and outcome of a surgery first approach versus neoadjuvant chemoradiation (CRT) followed by surgery.

Methods: A decision model was constructed to contrast the 2 treatment strategies. The NCDB (2003-5), ACS NSQIP (2005-9) and literature populated probabilities and outcomes in the surgery first arm, including operative outcome, complication rate, pathologic stage, adjuvant therapy and stage-specific survival based. Data from a prospectively maintained PC database (2002-8) populated the neoadjuvant arm. Costs were based on Medicare reimbursement (2011$). Survival, discounted when appropriate, was reported in quality-adjusted life months (QALM).

Results: 164 pts completed neoadjuvant CRT. Of these, 36 (22%) did not proceed to surgery. Failure was due to metastases, 18(50%), prohibitive performance status (PS), 17(47%) and pt choice, 1(3%). 12 pts (7%) proceeded to laparotomy but were deemed unresectable. 116 (71%) pts underwent definitive resection. The surgery first approach cost $95,781 to yield survival of 8.7 QALM, while the neoadjuvant strategy cost $71,416 to achieve 18.8 QALM. In the neoadjuvant population, pts not undergoing surgery, those unresectable at laparotomy and those completing surgery demonstrated a cost of $12,401 to yield 7.7 QALM, $39,112 to yield 7.1 QALM and $92,887 to achieve 23.4 QALM, respectively.

Conclusions: Treating pts with neoadjuvant CRT identifies those who develop early metastases or prohibitive PS and can be spared an ineffectual or prohibitively morbid operation. Our data suggest this approach is associated with improved OS at significantly lower cost. Neoadjuvant therapy for resectable PC should be employed more frequently to provide cost-effective care for this lethal disease.

[Table: see text]
A RAND/UCLA appropriateness study of the management of familial gastric cancer.
Authors: Dixon Matthew , Seevaratnam Rajini , Wirtzfeld Debrah , McLeod Robin S. , Helyer Lucy K. , Law Calvin , Swallow Carol Jane , Paszat Lawrence Frank , Tinmouth Jill , Cardoso Roberta , Mahar Alyson L. , Coburn Natalie G.
Published: February 2017

16

Background: Hereditary diffuse gastric cancer (HDGC) makes up 0.1-0.3% of all gastric cancers. Management of patients with HDGC is inconsistent and there is disagreement regarding management.

Methods: A multi-disciplinary expert panel of 16 physicians from 6 countries scored 47 scenarios using the RAND/UCLA Appropriateness Methodology. Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) from 1-3 were considered inappropriate, 4−6 uncertain, and 7−9, appropriate. Agreement was reached when 11 of 16 panelists scored the statement similarly. If a statement was agreed to be appropriate, it was given a necessity score (NS) in the same manner. AS and NS are reported if agreement was met.

Results: Gastric cancer (GC) patients with a family history of diffuse gastric cancer (DGC), lobular breast cancer or multiple family members with GC should be referred for genetics assessment and multidisciplinary decision-making (AS 8.0). It is appropriate for patients with DGC to have CDH1 mutation testing in a family with: (1) two or more cases of GC, with at least one case of DGC diagnosed before the age of 50 (AS 8.0); (2) three or more cases of GC diagnosed at any age, one or more of which is DGC (AS 8.0); (3) a patient diagnosed with DGC and lobular breast cancer (AS 8.0); or (4) a patient diagnosed with DGC under the age of 35 (AS 7.0, NS 5.0). A prophylactic total gastrectomy should be offered to CDH1 mutation carriers 20 years or older (AS 7.0).

Conclusions: The Gastric Cancer Processes of Care panelists have outlined high risk patients in whom CDH1 mutation status should be determined, and cases in which a prophylactic gastrectomy is appropriate.
Combination of the PAM4 and CA19-9 biomarkers to improve the detection of pancreatic adenocarcinoma.
Authors: Gold David V. , Gaedcke Jochen , Ghadimi B. Michael , Goggins Michael , Hruban Ralph H. , Liu Mengling , Newsome Guy , Goldenberg David M.
Published: February 2017

164

Background: Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal, due mainly to the inability to detect early-stage disease. Thus, identification of biomarkers that can identify patients with early-stage PDAC may improve overall survival.

Methods: In a blinded study, PAM4 and CA19-9 immunoassays were performed on sera from 480 patients, including those with confirmed PDAC (N=234), other cancers (N=84), benign diseases of the pancreas (N=89), and healthy adults (N=50).

Results: Overall sensitivity for PDAC was similar, 74% and 77% for PAM4 and CA19-9, respectively. Sensitivity for detection of early, stage-1 disease (N=26), although somewhat higher for the PAM4-antigen, was also statistically similar, 65% and 58% for PAM4 and CA19-9, respectively (P = 0.5775). However, specificity was significantly lower for CA19-9, particularly with respect to chronic pancreatitis (CP): 68% vs.86% for the PAM4 assay (P = 0.014). Furthermore, CA19-9 results showed considerably higher detection rates for non-PDAC neoplasia, including patients with other cancers that metastasized to the pancreas. Thus, positive likelihood ratios (+LR) were lower for CA19-9 (+LR = 2.41) than for the PAM4 assay (+LR = 5.29). PAM4 and CA19-9 antigen levels in PDAC were independent of each other (r2 = 0.003, P=0.410); however, the positive and negative interpretations were concordant in 68% of the cases. Thus, we used a combined biomarker analysis that ultimately improved the overall PDAC detection rate (84%), without a significant decrease in specificity (83%). Comparison of the ROC curves for PDAC vs. CP and PDAC vs. benign disease demonstrated a statistically significant improvement for the combined immunoassay, as compared to either assay alone (P < 0.0001 in both comparisons), to detect and discriminate PDAC from benign disease.

Conclusions: While the PAM4-immunoassay provides high sensitivity and specificity for detection and diagnosis of PDAC, inclusion of the CA19-9 biomarker significantly enhanced positive identification of PDAC patients, from 74% to 84%. Further studies are needed to confirm these results. (Supported in part by NIH grants CA096924, CA120432 and CA62924, and the Turpin Foundation.)
S100A4 as a biomarker of resistance to gemcitabine: A secondary analysis of RTOG 9704.
Authors: Tempero Margaret A. , Moughan Jennifer , Kim Grace E. , Kakar Sanjay , Hyun Teresa S. , Regine William , Mowat Rex B. , Charpentier Kevin , Small William , Guha Chandan , Chang David K. , Biankin Andrew Victor
Published: February 2017

165

Background: Preclinical studies suggest that nuclear expression of the Ca++ binding protein S100A4 induces gemcitabine resistance in pancreatic cancer cell lines (Mahon et al, Cancer Research, 2007). As a consequence, we assessed the potential role of S100A4 protein expression as a clinical biomarker of gemcitabine resistance in the RTOG 9704 adjuvant trial, which compared gemcitabine to continuous infusion 5FU.

Methods: Analyzable archival tissue samples were available for 184 patients on which the secondary analysis was based. Immunohistochemistry was used to detect S100A4 expression on a tissue microarray with triplicate samples from each specimen. Tissue was semiquantitatively scored for % labeled cells and intensity and dichotomized to negative or positive expression. DSS was estimated univariately with the Kaplan-Meier method and multivariate Cox proportional hazards models were used to determine if S100A4 expression correlated with DSS.

Results: The analysis was based on 184 specimens; 97 from the 5FU arm and 87 from the gemcitabine arm (see table below). For S100A4 related DSS, the HR for negative vs. positive expression in the 5FU and gemcitabine treatment arms was 0.93 (95% C.I. = [0.53, 1.63], p=0.80) and 1.85 (95% C.I. = [0.96, 3.56], p=0.066), respectively. The 2-year DSS for S100A4-negative patients in the 5FU treatment arm was 26%, and 39% for S100A4-positive patients. In the gemcitabine treatment arm, 2-year DSS for S100A4-negative patients was 59% and 37% for S100A4-positive patients.

Conclusions: The association with improvement in survival for S100A4-negative patients treated with gemcitabine, although not statistically significant, supports the hypothesis that S100A4 expression predicts for chemoresistance to gemcitabine. The small number of unique samples available from RTOG 9704, especially in subgroups of interest, was a limiting factor in this study. This project was supported by RTOG grant U10 CA21661, U24 CA114734, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and the RTOG Translational Research Program.

[Table: see text]
Is laparoscopy still needed for staging resectable pancreatic cancer?
Authors: Santoro Peter Michael , Abdel-Misih Raafat Z. , Petrelli Nicholas J. , Bennett Joseph J.
Published: February 2017

168

Background: Imaging for pancreatic cancer has demonstrated increased accuracy in staging patients before resection. Many propose diagnostic laparoscopy is therefore unnecessary before laparotomy and resection. Pancreatic cancer still has a high incidence of peritoneal and liver metastases that may be radiographically occult. Our hypothesis is that laparoscopy is still necessary to detect occult disease and avoid non-curative laparotomy in cases of peri-pancreatic malignancy.

Methods: Patient data were collected at a large, academic community-based tertiary care center with a specialized pancreatic team. Retrospective chart review was performed for patients surgically treated for peri-pancreatic neoplasms between the years 2005-2011. Patients with adenocarcinoma were the focus of this study. All patients had triple phase CT imaging for staging and to assess resectability. Patients who had laparoscopy (group 1) were identified and compared to those who did not (group 2).

Results: Two hundred and two patients from 2005-2011 with pancreatic neoplasms were identified as radiographically resectable. Of these, 107 had pancreatic adenocarcinoma (53%). In the first group, 80 patients underwent diagnostic laparoscopy (75%) and metastatic disease was identified in 8 cases (10%). Laparotomy for resection was performed for the remaining 72 patients and 6 were found to have metastatic disease that was missed during laparoscopy. The overall prevalence of metastatic disease in this group was 17.5%. In the second group, 27 patients underwent laparotomy without laparoscopy. Four of these patients(15%) were found to have metastatic disease. The sensitivity of laparoscopy to detect radiographically occult metastases was 70%. Laparoscopy still missed 43% (6/14) of patients ultimately found to have metastatic disease in this group.

Conclusions: Occult metastases were still found in 15%-17.5% of patients despite modern CT scan imaging. Even though laparoscopy missed some metastases when compared to laparotomy, our results show that 10% of patients were spared an unnecessary laparotomy. Laparoscopy should still play a role in staging patients with radiographically resectable pancreatic cancer.
Association of high histone H3K4 trimethylation level and prognosis of patients with low-TNM-stage hepatocellular carcinoma.
Authors: Xu Junyao , He Chuanchao , Zhang Jianlong , Wang Jie
Published: February 2017

171

Background: Along with genetic events, tumor associated epigenetic alterations including DNA methylation and post-translational histone modifications are important determinants in the initiation and progression of hepatocellular cancer (HCC) and represent promising biomarkers and therapeutic targets. Locus-specific trimethylation of histone H3 lysine 4 (H3K4me) is a well-known modification linked to the enhanced transcriptional expression of many genes activated in HCC. However its expression and association with prognosis of HCC patients remain unclear. Our aim was to assess the cellular expression pattern of H3K4me3 in HCC and its association with clinicopathologic variables and outcome.

Methods: Expression of H3K4me3 and the histone methyltransferase SMYD3 was studied by western blotting and immunohistochemistry in human HCC cell lines and tumor tissue micmicroarray, which is from a well–characterized series of HCC patients(n=168). Tissue staining were assessed using blinded semiquantitative scoring. The optimal cut-point of H3K4me3 expression for prognosis was determined by the X-tile program. The prognostic significance was evaluated using Kaplan-Meier survival estimates and log-rank tests. Tumor tissue micmicroarray from another independent HCC patients cohort(n=147) was used for validation studies.

Results: Expression of H3K4me3 and the histone methyltransferase SMYD3 were enhanced in HCC cell lines.In clinical tumor specimens, enhanced expression of H3K4me3 was correlated with reduced overall survival (P < 0.0001), especially in early-stage HCC patients(TNM I/II).Furthermore,both univariate and multivariate analysis revealed that H3K4me3 level was a significant and independent predictor of poor survival (hazard ratio,3.592; 95% CI, 2.302-5.605). In addition, H3K4m3 expression was positively correlated with SMYD3 expression in both testing and validation cohorts (P<0.0001).

Conclusions: H3K4me3 level defines previously unrecognized subsets of HCC patients with distinct epigenetic phenotype and clinical outcome, thus can be a novel predictor for poor prognosis of HCC patients, especially within TNM I/IIstage.
Pancreatic neuroendocrine tumors: Twenty years’ experience of 100 patients at a single center.
Authors: Shiba Satoshi , Morizane Chigusa , Kondo Shunsuke , Ueno Hideki , Ikeda Masafumi , Yamaguchi Tomohiro , Okusaka Takuji , Shimada Kazuaki , Kosuge Tomoo , Hiraoka Nobuyoshi
Published: February 2017

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Background: Pancreatic neuroendocrine tumors (NETs) are rare neoplasms that exhibit a variety of diverse morphological, functional and behavioral characteristics. However, only a few reports have evaluated large case series of pancreatic endocrine tumors.

Methods: We conducted a retrospective review of 100 consecutive patients with pancreatic NETs diagnosed pathologically and treated at the National Cancer Center Hospital between 1991 and 2010.

Results: The characteristics of the 100 patients were as follows: male, 49; female, 51; median age, 55 years. Fourteen patients gave a history of endocrine symptoms at the time of diagnosis. The primary tumors arose in the head, body and tail of the pancreas in 54, 25 and 21 patients, respectively. According to the 2010 grading classification of the World Health Organization, 11 patients were classified as having NET G1, 44 as having NET G2 and 29 as having NEC. The five-year survival rates of the patients with NET G1, NET G2 and NEC were 91%, 78% and 12%, respectively. The five-year survival rates of the patients with stage I, II and III, and IV disease classified according to the American Joint Committee on Cancer (AJCC) were 100%, 68% and 9%, respectively. Distant metastases occurred in 18% percent of the NET G1 patients, 39% of the NET G2 patients and 83% of the NEC patients. Treatment was undertaken by surgical resection in 82%, 59% and 24% of patients with NET G1, NET G2 and NEC, respectively. The five-year survival rates of the patients with NET G1, NET G2 and NEC after radical surgery were 100%, 91% and 36%, respectively. Among the 33 patients treated by systemic chemotherapy, the median survival period was 22.9 months in the patients with NET G1/G2 and 6.6 months in those with NEC. A multivariate analysis identified lower age, good performance status (PS) and lower histopathologic grade as independent favorable prognostic factors.

Conclusions: Patients with NET G1, G2 treated by surgical resection had a good prognosis. Most patients with NEC exhibited distant metastases and had a poor prognosis. Histopathologic grade is an important factor for selecting the appropriate treatment strategy and predicting the prognosis in patients with pancreatic NETs.
Additional primary malignancies in patients with pancreatic cancer.
Authors: Allamaneni Shyam S. , Sharma Rohit , Miller Austin , Yendamuri Saikrishna S. , Gibbs John F.
Published: February 2017

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Background: Rates of second primary malignancy have been increasing with increased cancer survivorship. The published literature on second primaries in patients with pancreatic adenocarcinoma is sparse. We addressed this question utilizing the SEER database.

Methods: 99,614 patients of primary pancreatic adenocarcinoma diagnosed between 1973-2006 were identified from SEER database. Of these, 8,889 (8.93%) had another primary diagnosed before pancreatic cancer (BPC) and 1813 (1.82%) a second primary diagnosed after pancreatic cancer (APC). SAS was used for statistical analysis and P-value <0.05 was determined to be significant.

Results: The most common non-pancreatic primary identified were prostate, breast, lung, colorectal, and urinary bladder. The median age at presentation was 75 and 71 years in the BPC and APC groups respectively. APC patients had higher odds of developing primary cancers of embryonic gut origin (esophagus, stomach, small intestine, hepatobiliary, lung, and thyroid) compared to PBC patients (p<0.05). Patients of BPC compared to APC were more likely to be older than 70 yrs (70.5% vs. 65.3% p=0.01), less likely to undergo surgery for pancreatic cancer (11.2% vs.5.87% p=<0.05) and with decreased median survival (7 vs.3 months). With each passing decade, increasing second primaries were diagnosed, presumably reflecting better overall survival from cancer diagnosis.

Conclusions: Approximately 11% of pancreatic adenocarcinoma patients have another cancer in their life time. Identifying common genetic and risk factors in these patients with multiple malignancies may provide the new therapeutic opportunities for patients with pancreatic cancer.
Methodology to screen and evaluate cost/survival of anticancer drugs in advanced/metastatic gastrointestinal cancers.
Authors: Guirgis Helmy M.
Published: February 2017

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Background: There is a paucity of methods to screen cost/survival of anticancer drugs in 1st-line advanced/metastatic (adv/met) gastrointestinal (GI) cancers.

Methods: Average whole prices (AWP) in United States dollars (US $) of evaluated drugs for the entire course were divided by previously reported median survival gain in days. Generic drugs were given flat total costs of up to $750. A 100% crude score was assigned to cost/survival/day < $25 and 0% to cost/survival/day $750. Results were expressed as % scores of cost/progression-free-survival (cost/PFS) or cost/overall survival (cost/OS). Guidelines were suggested for corrections; lack of OS - 10%, adverse effects (AEs) - 0 -15%, Quality of life (QoL) - 0-10% and administration and preparation (A and P) - 0-10%.

Results: Generic drugs scored 80%-90% in pancreatic and biliary followed by Trastuzumam 60% in gastric and Bevacizumab 0-40% in colon cancers (Table 1).

Conclusions: Methodology based on limits on cost/survival/day was developed to screen anticancer drugs in GI cancers. Generic drugs in bilary and pancreatic cancers scored the highest.

[Table: see text]
Phase I randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib as first-line treatment in patients with metastatic pancreatic cancer (SWOG-0727).
Authors: Philip Philip Agop , Goldman Bryan H. , Ramanathan Ramesh K. , Lenz Heinz-Josef , Lowy Andrew M. , Whitehead Robert P. , Iqbal Syma , Gaur Rakesh , Benedetti Jacqueline K. , Blanke C. D.
Published: February 2017

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Background: Targeting a single pathway in pancreatic adenocarcinoma (PAC) did not impact the natural history of this molecularly complex disease. Epidermal growth factor receptor (EGFR) targeting with erlotinib marginally improved the outcome of patients with advanced disease. We tested the hypothesis that if the EGFR and IGF-1R pathways are simultaneously blocked then progression free survival (PFS) would be significantly improved by abrogating reciprocal signaling.

Methods: S0727 was a phase I/randomized phase II (RP2) study testing the anti-IGF-1R monoclonal antibody cixutumumab combined with erlotinib and gemcitabine in patients with metastatic PAC. The control arm was erlotinib plus gemcitabine. The primary endpoint of the RP2 portion of the study was PFS. Eligibility included patients with untreated metastatic disease, performance status 0/1, fasting blood glucose less than institutional upper limit of normal, and willingness to provide tissue and blood specimens for correlative studies.

Results: In Phase I portion (n=10) safety of cixutumumab 6 mg/kg IV/wk, erlotinib 100 mg/day orally and gemcitabine 1000 mg/m2 IV D 1,8, and 15 of a 28-day cycle was established. In the RP2 portion (n=124) 114 eligible patients (median age 63) were included. On the cixutumumab arm, 59% of patients were female vs. 41% on control arm. Median PFS and overall survival were 4 and 7 months, respectively, in both arms. Four patients on cixutumumab remain on treatment; sensitivity analyses show no impact on the conclusions. Major grade 3 and 4 toxicities were (cixutumumab/control) elevation of transaminases (12%/6%), fatigue (24%/21%), gastrointestinal (35%/28%), and hematologic (53%/39%). Grade 3/4 hyperglycemia was seen in 27% of patients on cixutumumab. Grade 3 or 4 kin toxicity was similar in both arms of the study (< 5%). Five treatment-related deaths were reported: 2 cardiac on each arm, 1 pulmonary on cixutumumab.

Conclusions: IGF-1R inhibitor cixutumumab did not improve the progression free or overall survival in patients with metastatic PAC treated with erlotinib and gemcitabine in a molecularly unselected population.
The prognostic significance of extra-intestinal tumor location for primary nonmetastatic gastrointestinal stromal tumors.
Authors: Guye Mary Lydon , Nelson Rebecca A. , Arrington Amanda Kathleen , Chen Steven L. , Chow Warren Allen , Kim Joseph
Published: February 2017

2

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the GI tract. Tumor size, tumor location, and mitotic index are established factors that risk stratify recurrence and survival. Extra-intestinal GISTs are infrequently observed and our objective was to investigate the outcomes of patients with primary GISTs found outside the GI tract.

Methods: The Surveillance Epidemiology and End Results registry was used to identify patients with GIST treated with surgery between 1996 and 2008. Patients were evaluated by standard clinical and pathological indices including: age, primary tumor location (extra−intestinal vs. GI tract), tumor size, tumor grade, and extent of disease. Overall survival differences between primary site groups were assessed by Kaplan-Meier method. Univariate and stepwise multivariate Cox proportional hazards analyses were performed.

Results: Of the 2812 patients with surgically treated GIST, 2489 (88.5%) had a primary tumor location in the GI tract and 323 (11.5%) were located in extra-intestinal sites. Comparison of patients by primary tumor location demonstrated more locally advanced cancers with lymph node involvement (40.2% vs. 18.4%; p<.0001) and a higher occurrence of distant metastatic disease (22.3% vs. 16.6%; p<.0001) among the extra-intestinal GISTs. When comparing overall survival, patients with extra-intestinal GISTs had significantly worse 5 year survival (62% vs. 70%, respectively; p=0.002) than patients with primary tumors within the GI tract. Stepwise multivariate analysis showed that non-intestinal site was an independent predictor of poorer survival (HR 1.29, 95% CI [1.05-1.59], p=0.015).

Conclusions: Our data indicates that extra-intestinal location for primary non-metastatic GIST is an independent poor prognostic factor, with worse overall survival, compared to GISTs located within the GI tract. Risk stratification for prognosis should account for these rare GIST locations.
A novel xenograft model of gastrointestinal stromal tumors.
Authors: Sicklick Jason Keith , Leonard Stephanie Yvette , Mose Evangeline , French Randall P , Criscuoli Michele , Jaquish Dawn V , Maruyama Karly , Schwab Richard B. , Cheresh David , Lowy Andrew M.
Published: February 2017

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Background: GIST treatment with imatinib has served as the prototype for targeted molecular therapy. However, patients frequently acquire drug resistance to imatinib and this has prompted the development of additional multi-kinase inhibitors. To date, preclinical testing of novel agents has predominantly been performed using cell line based subcutaneous xenografts that may overestimate drug activity in the clinic. This suggests that novel in vivo models are needed to improve prediction of clinical efficacy. We hypothesized that human GISTs could be intra-peritoneally xenografted into immunodeficient mice in order to better recapitulate the microenvironment and biology of GIST.

Methods: Tumor acquisition was performed under an IRB-approved protocol. Following tumor resection, we anesthetized NOD-scid (NS) or NS gamma (NSG) mice and performed a midline laparotomy. 2′2 mm tumor fragments were sutured into the abdominal viscera of NS (N=10) or NSG (N=15) mice. Tumors were imaged every 3-4 wks with ultrasound (US). 2 mice were also evaluated with PET scan.

Results: We have xenografted GISTs from 3 patients into 25 mice with an 80% success rate and 4% perioperative mortality. We observed tumor progression in the liver (9/10), renal capsule (8/10), lesser sac (2/3), or gastric wall (1/2) of mice. This included 14 primary xenografts and 11 passaged xenografts. At 21-196 d (median 46 d), tumor size averaged 473±736 mm3 (median 104 mm3, range 2.2-2683 mm3) by US. In addition, 30% (6/20) of mice developed metastatic disease based upon US, necropsy, histology and/or KIT immunostaining. We also determined that 2/2 tumors were FDG-avid on PET.

Conclusions: To our knowledge, we report the first intra-peritoneal xenograft model of human GIST using patient-derived tumor tissue. This novel in vivo approach is a reproducible model of human GIST that replicates the tumor microenvironment, heterogeneity, and metastatic potential of a human GI sarcoma. As compared to current research tools/models, this approach may allow researchers to better predict chemotherapeutic responses, further understand the tumor biology of GIST, and serve as a means to propagate additional tumor tissue for subsequent experimental analyses.