bluuebunny/crossref_metadata_2025 huggingface dataset:
Laparoscopy and endoscopy cooperative surgery for gastric tumor.
Authors: Hiroki Ozawa , Kawakubo Hirofumi , Mayanagi Shuhei , Fukuda Kazumasa , Goto Osamu , Nakamura Rieko , Suda Koichi , Wada Norihito , Yahagi Naohisa , Kitagawa Yuko
Published: January 2019

168

Background: Laparoscopic wedge resection is widely performed for managing gastric submucosal tumors (SMTs) that measure ≤5 cm in diameter. Laparoscopy and endoscopy cooperative surgery (LECS) is performed to ensure a sufficient margin while avoiding deformation or stenosis. Methods: We conducted a retrospective review of the data of 76 patients who underwent LECS for SMTs or early gastric cancers at our institution between April 2012 and July 2017. While Non-exposed Endoscopic Wall-inversion Surgery (NEWS) was performed for tumors with a major axis diameter of ≤5 cm and minor axis diameter of ≤3 cm, for other tumors, we adopted classical LECS or used the combination of laparoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET). Results: The tumor was located in the upper-/middle-/lower-third of the stomach in 49/20/7 cases. The mean operation time was 201.7 ± 66.2 min, and the mean blood loss was 4.7 ± 12.8 ml. The mean tumor size was 28.6 ± 11.6 mm. The histological tumor types included GIST (n = 38), leiomyoma (n = 14), schwannoma (n = 6), early gastric cancer (n = 8) and others (n = 10). The surgical procedure consisted of classical LECS/CLEAN-NET/NEWS in 17/15/44 cases; all early gastric cancers were treated by NEWS. The mean length of postoperative hospital stay was 8.7 ± 3.9 days. The mean serum levels of C-reactive protein on POD1 and POD3 were 3.2 ± 1.9 and 4.4 ± 3.4 mg/dl, respectively. The postoperative complications were anastomotic stenosis (n = 1), delayed gastric emptying (n = 3), pneumonia (>Grade II by the Clavien-Dindo classification) (n = 1) and exacerbation of GERD (>Grade II by the Clavien-Dindo classification) (n = 3). In the patient group that developed complications, the postoperative resumption of water intake was later, and the postoperative hospital stay was longer as compared to the group without complications (p = 0.04, 0.028). No relationship was observed between the likelihood of development of complications and the tumor location. Conclusions: Use of minimally invasive surgical procedures such as LECS could minimize the extent of gastric resection without deformation, stenosis. We consider that for surgical complications the LECS approach can be employed, regardless of the tumor location.
The prognostic role of neutrophil-to-lymphocyte ratio trends during therapy in esophageal cancer.
Authors: Al Lawati Yaseen , Ramirez-Garcialuna Jose Luis , Molina Franjola Juan Carlos , Pham Donavan , Skothos Elena , Mueller Carmen L. , Spicer Jonathan D. , Alcindor Thierry , Ferri Lorenzo
Published: January 2019

17

Background: Neutrophil-to-lymphocyte ratio (NLR) has been identified as a biomarker for a number of malignancies, with higher ratios being associated with poorer oncologic outcomes. Rather than purely an indicator of advanced disease there is emerging evidence that neutrophils are directly implicated in facilitating cancer progression, and thus alterations and trends of neutrophil counts and NLR during different phases of treatment may reflect a change in oncologic outcome that is as important, or more so, as the absolute count or NLR at baseline. The aim of this study is to investigate the prognostic role of neutrophil-to-lymphocyte ratio trends during the treatment trajectory of patients with esophageal adenocarcinoma. Methods: This is a retrospective study of patients who underwent esophagectomy for esophageal adenocarcinoma between 2005-2016. NLR was measured at three time points: baseline, during neoadjuvant chemotherapy (NAC), and in the late postoperative period. Primary outcomes were overall (OS) and disease-free survival (DFS). Results: 333 patients met our inclusion criteria. Mean age was 65.6 years and 82% of patients were males. The majority of patients had locally advanced disease; 75% had clinical T3 disease and 59% had clinical N-positive disease. NAC was administered in 65.6% of patients. Increasing NLR trends between baseline and late postoperative periods was associated with worse OS (3-year OS 56.1% vs. 71.9%, p=0.045). Patients in the high NLR group before and after treatment did worse than those who moved from high to low groups (3-year OS 42.8% vs. 69.2%, p=<0.0001, 3-year DFS 32.3% vs. 61.8%, p=0.0001). High NLR at baseline and in the postoperative stage is associated with worse OS (3-year OS: 57% vs. 75.7% for baseline and 44.1% vs. 74.9% for postoperative NLR; p=0.0038 and <0.0001, respectively) and DFS (3-year DFS: 52.4% vs. 60.9% for baseline and 34.9% vs. 59.9% for postoperative NLR; p=0.03 and <0.0001, respectively). Patients with complete pathological response to NAC had lower mean baseline NLR (3.2 vs. 4.9 p=0.009). Conclusions: Changes in NLR during treatment may provide a clearer picture about survival outcomes and the role of neutrophils in cancer progression.
Intraperitoneal chemotherapy for gastric cancer with peritoneal dissemination: A single center retrospective analysis of 82 cases.
Authors: Yoshida Masahiro , Tsuji Yasushi , Oiwa Syutaro , Takayama Toshizo , Okamura Naoka , Sugiyama Junko , Sumiyoshi Tetsuya , Hirayama Michiaki , Kondo Hitoshi , Okushiba Syunichi
Published: January 2019

170

Background: The prognosis of gastric cancer with peritoneal metastases remains dismal. Ishigami et al. have recently published a phase III study (PHOENIX-GC) aimed at clinical efficacy of intraperitoneal paclitaxel (PTX), which established intraperitoneal chemotherapy as a decent option for gastric cancer with peritoneal dissemination. According to this report, we have used various regimens of intraperitoneal chemotherapy, adjusted mainly based on previous treatments. Methods: Data from 82 patients with gastric cancer with peritoneal metastases who underwent intraperitoneal chemotherapy in our institute from February 2012 to July 2017 were retrospectively analyzed. The progression free survival (PFS), the overall survival (OS) and the 1-year survival rate were stratified by prior treatments. Results: Of the 82 patients, 38 (46.3%) were chemotherapy-naïve. The intraperitoneal regimens were assigned mainly according to the prior treatment: intraperitoneal PTX plus S-1/PTX was the most frequent (39 cases), followed by intraperitoneal PTX plus intravenous PTX (17 cases), intraperitoneal PTX only (6 cases), and the rest. The median PFS for the chemotherapy-naïve group and the previously treated group was 6.9 and 4.1 months, and the median OS was 12.8 and 7.9 months, and the 1-year survival rate was 72.2% and 34.4%, respectively. 10 patients (12.2%) achieved conversion surgery after confirmed complete response in the peritoneal metastases. Among these 10 patients, the median survival time is 22.7 months (7.6+-47.7). Adverse events were also analyzed for each regimen, as for intraperitoneal PTX plus S-1/PTX, leukopenia, neutropenia and anemia occurred frequently. All regimens were comprehensively tolerable, and there were no treatment-related deaths. Conclusions: Intraperitoneal chemotherapy is a promising and feasible option for gastric cancer with peritoneal dissemination. There were several cases with long-term prognosis where conversion surgery was achieved.
Results of neoadjuvant chemoradiotherapy with docetaxel, cisplatin, and 5-fuluorouracil for advanced esophageal cancer.
Authors: Emi Manabu , Hamai Yoichi , Ibuki Yuta , Okada Morihito
Published: January 2019

171

Background: We previously reported a phase I study of neoadjuvant chemoradiotherapy (CRT ) with docetaxel, cisplatin, and 5-fuluorouracil (DCF) for advanced esophageal cancer. After that, we continued to conduct neoadjuvant CRT with DCF as phase II study and here, we report the results of this study including phase I. Methods: We performed neoadjuvant CRT with DCF chemotherapy and concurrent radiation therapy (40Gy including irradiation field) in patients with advanced esophageal squamous cell carcinoma. Dose of chemotherapy were as follows: docetaxel 25mg/m2 (level 1 n=17), or 30mg/m2 (level 2 n=4) on day 1,15,29 and 43 and cisplatin 70mg/m2 on day 1,29 and 5-fuluorouracil on day 1-4 and 29-32. The tumors were resected during weeks 10-13. Results: From Dec 2009 to Aug 2012, 21patients were enrolled and 19 patients underwent thoracic surgery. There were 17 male and four female subjects of ages ranging from 38 to 72 years (median, 61 years). Of these, 6 patients had stage IIIA esophageal cancer and two had stage IIIB esophageal cancer. All the patients had squamous cell carcinoma. Pathological complete response of primary tumor was achieved in 12 patients (63%) and complete pathological response of both primary tumor and lymph node was seen in eight patients (42%). During CRT, the most common grade 3/4 non-hematological toxicity were anorexia (29%) and esophagitis (29%). During CRT, septic shock caused by infection via catheter was observed and re-operation was performed in one patient with reconstructed gastric tube necrosis.One patient developed recurrent gastric tube ulcer in the anastomotic part 4years after esophagectomy. 10 patients are alive more than 5 years and 5-year overall survival is 47.6% and three of them were level II cases. Conclusions: This preoperative CRT regimen using triplets result in favorite prognosis, but treatment plan should be reconsidered because of relative high toxicity. Because high complete response rate of primary tumor were observed and long-term survival has been obtained at a high rate in the case of level II, we planned new phase I/II study of CRT with DCF without preventive irradiation field. Clinical trial information: R000002555.
Phase Ib/II trial of durvalumab and chemoradiation (CRT) with carboplatin/paclitaxel for esophageal and gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Greally Megan , Molena Daniela , Sihag Smita , Wu Abraham Jing-Ching , Shah Pari M. , Fein Carly , Capanu Marinela , Kelsen David Paul , Janjigian Yelena Yuriy , Ilson David H. , Ku Geoffrey Yuyat
Published: January 2019

172

Background: Pre-op CRT with carboplatin (C)/paclitaxel (P) and radiation (RT) for locally advanced esophageal cancer is a standard of care, based on the CROSS trial (NEJM 2012;366:2074). However, outcomes remain poor. Early data suggest activity of durvalumab (D) in GEJ/gastric cancer [Ann Oncol 25:iv361-372; 2014]. In a pilot study, we assessed safety of D + C/P + RT as pre-op therapy. Methods: Patients (Pts) had TanyN+ or T3-4NanyM0 esophageal and Siewert Type I/II GEJ adenocarcinoma staged by EUS, PET/CT and CT. Pts received D 1500mg x 1 dose and 4 weeks later C AUC2 and P 50mg/m2 weekly x 5 with RT (1.8Gy daily fractions to 50.4Gy). Pts also received D 1,500mg at first dose of C/P and RT. PET/CT was repeated 21-27 days post D and 4-6 weeks post CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts who had R0 resections received adjuvant D 1,500mg 4 weekly x 6 doses. Initially, 6 patients were treated and followed for 30 days after surgery to assess for unacceptable toxicities. Results: 6 pts were enrolled: 3 Siewert I (50%), 2 Siewert II (33%), 1 esophageal (17%); 5 T3N1-2, 1 T4aN1. 5 pts (83%) underwent sx. 1 pt was retrospectively assessed to have metastases after induction D and taken off-study. Pathologic response was 60% in 2 pts, 90% in 1 pt, 80% in 1 pt and 40% in 1 pt; no complete response was seen. Significant grade 3/4 toxicity observed during D and CRT was neutropenia in 1 pt (17%). Adverse events (AEs) of any grade in ≥20%: lymphopenia (5 pts), thrombocytopenia (5 pts), leucopenia (4 pts), fatigue (3 pts), anemia (3 pts), neutropenia (3 pts) and abdominal pain (2 pts). Immune-related AEs were hypothyroidism (grade 2; 1 pt) and nephritis (grade 2; 1 pt). Surgical complications: 2 esophageal strictures, 1 pneumonia and 1 anastomotic leak with airway fistula, successfully treated with a stent. Immune correlative analyses from tumor blocks and whole blood are ongoing and will be reported in the poster. Conclusions: The addition of D to pre-op CRT in esophageal and GEJ adenocarcinoma appears feasible and safe. We observed no unacceptable toxicity. The study is being modified to incorporate use of induction chemo and PET (based on CALGB 80803 results) and expanded to a multicenter setting. Clinical trial information: NCT02962063.
A dose-escalation study of docetaxel, oxaliplatin and S-1 (DOS) as a first-line therapy for patients with unresectable metastatic gastric cancer.
Authors: Sato Yasushi , Sagawa Tamotsu , Takahashi Yasuo , Ohnuma Hiroyuki , Hamaguchi Kyoko , Hirakawa Masahiro , Fujikawa Koshi , Okamoto Koichi , Miyamoto Hiroshi , Muguruma Naoki , Takayama Tetsuji
Published: January 2019

174

Background: Although the triplet regimen of docetaxel/cisplatin/S-1 (DCS) has shown promising activity and conversion rate in patients with unresectable metastatic gastric cancer (UMGC) in Japan, it was accompanied by severe adverse events. Recent studies suggested that oxaliplatin was almost as active, and relatively less toxic, than cisplatin in combination regimens for UMGC and can therefore replace cisplatin. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended dose (RD), and preliminary efficacy of docetaxel/oxaliplatin/S-1 (DOS) instead of DCS in patients with UMGC. Methods: Previously untreated 16 patients with histologically proven UMGC were enrolled. Docetaxel and oxaliplatin were administered intravenously on day 8. S-1 was administered orally twice a day on days 1-14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first cycle of treatment. Three dose-escalations of DOS were used in this study namely, level 1 (50/100/80 mg/m2), level 2 (50/130/80 mg/m2), and level 3 (60/130/80 mg/m2). Results: Among the six patients, one patient each experienced DLTs (febrile neutropenia and diarrhea) at level 1 and 2 doses, respectively. While two more patients experienced DLTs (febrile neutropenia and diarrhea) after administration of level 3 doses. Therefore, two additional patients were enrolled into the study at level 2. However, both these patients subsequently exhibited DLTs (febrile neutropenia and diarrhea). Therefore, we concluded that the MTD and RD with this regimen were level 2 and level 1, respectively, and that the DLT were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) of the patients with measurable lesions, consisting of two complete response and five partial responses. Five patients underwent conversion surgery. Conclusions: The RD of the 3-weekly DOS regimen in patients with UMGC was docetaxel at 50 mg/m2 and oxaliplatin at 100 mg/m2 on day 8 and S-1 at 80 mg/m2 on days 1-14. The efficacy and ease of administration make the regimen a promising alternative to DCS. A phase II study using this RD regimen is currently underway. Clinical trial information: 000015849.
Preoperative prognosis predictors for patients with gastric stump cancers.
Authors: Tokunaga Masanori , Sugita Shizuki , Watanabe Masahiro , Kaito Akio , Kinoshita Takahiro
Published: January 2019

179

Background: The incidence of GSC is expected to increase as the survival outcome following gastrectomy for gastric cancer improves. Considering poor tolerability to postoperative adjuvant chemotherapy after completion of total gastrectomy, neoadjuvant chemotherapy (NAC) is a plausible treatment strategy for GSC, but it is unclear which clinical factors should make patients candidates for NAC, due to the lack of studies investigating the relationship between clinical factors and survival outcome. The aim of this study was to review preoperative prognostic factors and identify suitable candidates for NAC. Methods: A total of 71 patients with GSC who underwent curative completion total gastrectomy between 1998 and 2015 were included. Preoperative clinical factors and survival outcomes were investigated, and independent prognostic factors were analyzed by Cox proportional hazards model. Results: Median age (range) was 68 (42-82) years, and male-female ratio was 6.0:1. Initial surgery was for benign disease in 21 and for malignant disease in 49 patients. Preoperative diagnosis was cT2-4 in 30 (43%), and cN+, which was defined as lymph node ≥10mm in diameter, in 7 patients (10%). The 3-year recurrence free survival (RFS) rate was 79%. Multivariable analysis revealed cT2-4 as an independent prognostic factor (HR, 2.86; 95% C.I., 1.03-8.64), but clinical N+ was not (HR, 0.64; 95% C.I., 0.10-2.31). When survival curves were stratified by cT, 3-year RFS of cT2-4 (60%) was significantly worse than cT1 (92%, p=0.024) Conclusions: Survival outcomes of patients with cT2-4 seem worse enough for them to be selected as candidates for NAC. On the contrary, cN+ was not associated with worse survival outcome. NAC could be a treatment option for cT2-4 GSC patients irrespective of nodal status.
Validation of the 8th AJCC TNM staging system for gastric cancer: Survival analysis with high volume Asian centers and SEER database by comparing with 7th TNM staging system.
Authors: Son Taeil , Sun Jiyu , Kim Hyoung-Il , Cheong Jae-Ho , Choi Seung Ho , Noh Sung Hoon , Woo Yanghee , Fong Yuman , Park Sohee , Hyung Woo Jin
Published: January 2019

18

Background: Recently, the 8th AJCC TNM staging system for estimating prognosis for patients with gastric cancer was revised with new subgroups. There are little number of studies have shown its validation with other datasets. We aimed to validate the new TNM staging system by using various datasets with large number of gastrectomies. Methods: We retrospectively reviewed data of 17160, 11324 and 1500 patients treated for gastric cancer in Yonsei University Severance Hospital (SH), The Surveillance, Epidemiology, and End Results (SEER) and Gangnam Severance Hospital (GSH), respectively. Survival curves were plotted and the performance of tumor staging defined by the 7th and 8th TNM staging was compared based on the log-rank test, Concordance index (C-index) and Akaike information criterion (AIC). Results: The performance of predicting survival using the 8th TNM staging system is superior to that of the previous version in SH by evaluating log-rank, C-statistics, and AIC (8444.5 vs. 9263.8, 0.796 vs. 0.798, 104152 vs. 103909), respectively. It is also superior in a data with SEER and GSH (log-rank, C-statistics, and AIC; 3342 vs. 3527, 0.7064 vs. 0.709, 100931 vs. 100820 in SEER, 973 vs. 1031, 0.8021 vs. 0.8038, 7173 vs. 7154 in GSH), respectively. In subgroup analysis of each subclassification, IA, IB, IIA, IIB, IIIA, IIIB, IIIC, and IV in SH, the 8th TNM staging system shows similar or more homogenous survival (0.0324 vs. < 0.001 in Stage IIB, 0.020 vs. < 0.0001 in Stage IIIB, 0.0004 vs. < 0.0001 in Stage IIIC, respectively) in each subclassification than that of the 7th TNM staging system by measuring log-rank p values. Conclusions: The 8th TNM staging system provides more accurate prediction of prognosis of gastric cancer patients than the previous one. In addition, each subgroup in the same stage is relatively homogenous with respect to survival than the previous staging system. It is also applicable to Eastern and Western patients with various backgrounds.
The utility of PET-CT after preoperative chemoradiation in predicting treatment outcomes in locally advanced esophageal cancer.
Authors: Lewis Gary , Teh Bin S. , Dalwadi Shraddha , Chiang Stephen , Butler Edward Brian , Farach Andrew M , Bernicker Eric , Kim Min
Published: January 2019

182

Background: In the treatment of gastroesophageal junction (GEJ) cancer, trimodality treatment with preoperative chemoradiation followed by surgery is the standard of care. However, predicting patient survival outcomes remains difficult. One possible means of predicting outcomes is comparing pre-treatment PET-CT with post-treatment PET-CT to see if a favorable response on imaging correlates with survival outcomes. Methods: We conducted a retrospective chart review of locally advanced GEJ cancer patients who underwent preoperative chemoradiotherapy followed by esophagectomy with negative margins. All patients underwent two PET-CT scans (before and after preoperative chemoradiation). We compared PET-CT imaging results and pathology results with survival outcomes. Values such as pre-treatment max SUV, post-treatment max SUV, change in max SUV, percent residual max SUV, complete response on PET-CT, and pathologic complete response were analyzed for potential impacts on recurrence rates and survival outcomes. Results: Forty patients had sufficient data to be included in our study. The median follow-up was 22.5 months. The majority of patients were male (82.5%), Caucasian (84.2%) and had adenocarcinoma histology (97.5%). Altogether, 75% of patients had stage III disease and 67.5% had locoregional nodal involvement. The majority (90%) of patients received some form of taxane and platinum based chemotherapy. Pre-treatment max SUV, post-treatment max SUV, change in max SUV, percent residual max SUV, and complete response on PET-CT were not associated with local recurrence, regional recurrence, disease-free survival, or overall survival. Pathologic complete response was associated with a decrease in the rate of distant metastasis ( P= 0.021) but not disease-free survival ( P= 0.411) or overall survival ( P= 0.878). Conclusions: Response on PET-CT after preoperative chemoradiation is not a predictive factor for recurrence, disease-free survival, or overall survival. Pathologic complete response predicted for a decrease in the rate of distant metastasis but not disease-free survival or overall survival.
The feasibility and safety of laparoscopy-assisted distal gastrectomy that was performed by trainee supervised by a technically qualified surgeon.
Authors: Yamada Takanobu , Hayashi Tsutomu , Nakazono Masato , Hara Kentaro , Osakabe Hiroaki , Nagasawa Shinsuke , Kumazu Yuta , Ogata Takashi , Yoshikawa Takaki
Published: January 2019

183

Background: The laparoscopic gastrectomy is becoming widespread. But acquisition of its technique is challenging. We investigated whether supervision by a technically qualified surgeon (QS) affects the feasibility and safety of laparoscopic gastrectomy performed by trainee (TR). Methods: The outcomes of laparoscopy-assisted distal gastrectomy for gastric cancer performed by QS group and TR group between 2013 and 2016 were assessed. A laparoscopic surgeon qualified by the Endoscopic Surgical Skill Qualification System (Japan Society for Endoscopic Surgery) participated in surgeries that ware performed by trainee as the teaching assistant. Results: All patient characteristics were not different between QS group and TR group, except of BMI (median BMI 23.9 vs 22.2, p = 0.01). Although operation time of TR group was longer than that of QS group (median time: 248 min. vs 285 min., p = 0.01), Blood loss and number of harvested lymph nodes were not different. One patient (0.3%) in QS group and two patients (0.4%) in TR group required conversion to open surgery (p = 0.58). Postoperative complication, that was defined by Clavien-Dindo classification grade 3 and more, occurred in four patients (11.4%) in QS group and nine patients (5.4%) in TR group (p = 0.25). Complication in QS group were anastomotic leakage (n = 2) and abdominal abscess (n = 2), whereas that in TR group were anastomotic leakage (n = 3), anastomotic stenosis (n = 2), pancreatic fistula (n = 1), bowel obstruction (n = 1), pneumothorax (n = 1), and cerebral hemorrhage (n = 1). One patient in QS group (2.9%) and four patients in TR group (2.4%) underwent reoperation (p = 1.00). Postoperative mortality occurred in one cases in TR group (0.01%). Conclusions: The laparoscopy-assisted distal gastrectomy of TR group supervised by QS was feasible and safe procedure as well as that of QS group.
Staffing turnover effect of fellowship-trained surgical specialists on oncologic outcomes in community cancer center.
Authors: Franko Jan , Kraemer Soren , Goldman Charles David , Frankova Daniela , Raman Shankar
Published: January 2019

187

Background: Contemporary health care is delivered in highly interdependent team-based environment. Transitions in surgeon complement may be associated with a disturbance of workflow, especially in smaller-sized community cancer centers. Herein we examined the impact of two surgical oncologists turnover in our cancer center. Methods: Survival outcomes of all cases of esophageal, gastric, rectal and pancreatic adenocarcinoma treated in the index cancer center (n = 1,445) were compared to then-contemporary standard derived from Iowa-SEER registry, 2001-2015 (n = 12,617). Period before and after changeover of surgeons was compared using descriptive statistics and regression model. Results: Substantial reduction of annually referred (101.8±9.2 versus 60.5±0.7 case per year, p = 0.026) and operative cases (37.0±4.5 versus 17.5±3.5 cases per year, p = 0.027) was seen during fully-staffed versus on-boarding periods at the index hospital. At the state level, there was no fluctuation of annually referred cases (898.0±19.8 versus 910.5±35.6 cases per year, p = 0.384) and minimal decrease in operated cases (366.2±18.0 versus 335.0±24.1 cases per year, p = 0.020) in early versus late period. New surgical team was able to improve upon survival of resectable esophageal cancer patients in the index hospital and maintain survival of other complex GI malignancies as compared to geographically relevant standard of Iowa-SEER registry. Survival regression model on all 5,795 non-metastatic cases with available data, adjusted for age, stage and primary disease site, demonstrated that being treated in the index hospital did not result is inferior survival comparing early and late period (HR = 1.060, p = 0.237). Conclusions: Loss of surgical cancer specialists was associated with profound & significant loss of referrals to the index cancer center, and likely outmigration of patients from the community seeking advanced care. Quick restoration of surgical services may reinstate overall efficacy of care for resectable cancer cases without negative survival effect.
Prognostic factors for survival in apatinib-treated gastric cancer: Results from a post-marketing phase IV study (Ahead-G201).
Authors: Qin Shukui , Deng Wenying , Wen Lu , Wang Junsheng , Zhang Guifang , Zhong Haijun , Jia Tongfu , Yang Jianwei , Ba Yi , Bai Yuxian , Lin Xiaoyan , Wang Mei , Wang Lin , Liu Likun , He Yifu , Tao Min , Xie Congying , Ye Feng , Wu Xiang-yuan , Li Jin
Published: January 2019

19

Background: Easily detectable and reliable prognostic factors for apatinib response in gastric cancer are of great interest. In this study, 42 characteristics were test for their prognostic value. Methods: Data were collected from the ongoing single-arm phase IV trial in patents (pts) with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction after failure of ≥2 lines of chemotherapy. Kaplan–Meier and multivariable Cox analysis were conducted. Results: As of 2017/7/10, 1037 pts were enrolled. 820 were evaluable for survival. The median progression free survival (PFS) and overall survival (OS) was 4.60 and 6.57 m. Age, metastatic lesions, region, treatment interruption, leucocyte decrease and adverse events (AEs) occurrence were independent prognostic factors for PFS, while ECOG PS, disease duration, metastatic lesions, region, developed city, initial dose, treatment interruption, BMI, AST abnormal, hand-foot-skin reaction (HFSR), leucocyte decrease and AE occurrence for OS (Table). Conclusions: Multiple demographics, baseline clinical and laboratory indexes, treatment related indicators and occurrence of AEs can predict the efficacy of apatinib in gastric cancer. Updated results will be reported to guide the clinical application of apatinib. Clinical trial information: NCT02426034. [Table: see text]
Targeted next-generation sequencing (NGS) of germline DNA to identify genetic predisposition to gastric cancer (GC) in patients with CDH1-mutation negative early-onset (EO) or familial GC (FGC).
Authors: Ku Geoffrey Yuyat , Mukherjee Semanti , Okoro Chizoba , Sharma Medha , Ravichandran Vignesh , Offit Kenneth , Joseph Vijai , Janjigian Yelena Yuriy , Stadler Zsofia Kinga , Kelsen David Paul
Published: January 2019

20

Background: While GC arises as part of several hereditary cancer syndromes, a genetic etiology is not identified for most FGC kindreds and EOGC patients. We hypothesize that NGS of germline DNA may reveal previously unsuspected genomic alterations that predispose to EOGC/FGC. Methods: We identified 42 Pts from a prospective GC registry with CDH1-mutation negative EOGC (≤50 years old) and/or with FGC. Germline DNA was analyzed by MSK-IMPACT, a 468-gene targeted NGS panel that includes > 70 genes associated with known cancer predisposition syndromes. GATK HaplotypeCaller (HTC) was used to call SNVs and Indels simultaneously from the sequence read data and joint calling of all samples was used to generate VCF files. We annotated the VCF with public annotators and public allele frequencies from large sequencing studies. Manual variant curation was performed and were classified by ACMG criteria (Genet Med 2015;17:405), with only likely pathogenic and pathogenic variants included. Results: 41 Pts (98%) had early onset and 11 Pts (26%) had FGC (9 had ≥1 1st or 2nd degree relatives with GC). Median age was 40 (range, 18 to 55) and 23 (55%) were men. Ethnicities were 21 (50%) White, 13 (31%) Black, 6 (14%) Asian and 2 (5%) unknown. 40 (95%) had poorly differentiated and/or diffuse histology. Pathogenic mutations were diagnosed in 4 Pts (10%). 1 Pt had a BRCA2 mutation; his father had prostate CA and a paternal aunt had breast CA but he did not meet current NCCN criteria for BRCA testing. Three additional pathogenic mutations were FGFR1, SOX17 and KMT2D; none has previously been described in GC susceptibility but are associated with GC carcinogenesis. All 3 Pts had EOGC. None had FGC but all 3 had ³1 1st-degree relative with CA ( FGFR1: breast, uterine, appendix; SOX17: breast; KMT2D: osteosarcoma). Further functional work of these variants and segregation analysis is on-going. Conclusions: MSK-IMPACT identified germline mutations in 10% of Pts; most are previously not known GC predisposition genes. NGS can be an important clinical tool for screening multiplex families and also a research tool for discovering genes that predispose to GC.
Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial.
Authors: Abou-Alfa Ghassan K. , Meyer Tim , Cheng Ann-Lii , El-Khoueiry Anthony B. , Rimassa Lorenza , Ryoo Baek-Yeol , Cicin Irfan , Merle Philippe , Park Joong-Won , Blanc Jean-Frédéric , Bolondi Luigi , Klümpen Heinz Josef , Chan Stephen Lam , Dadduzio Vincenzo , Hessel Colin , Borgman-Hagey Anne E. , Schwab Gisela , Kelley Robin Kate
Published: January 2019

207

Background: C, an inhibitor of MET, VEGFR, and AXL, has previously shown clinical activity in pts with advanced HCC. This phase 3 trial (NCT01908426) evaluated C vs P in previously treated pts with advanced HCC. Methods: In this double-blind, global, phase 3 trial, pts were randomized 2:1 to receive C (60 mg qd) or matched P stratified by disease etiology (HBV, HCV, other), geographic region (Asia, other), and presence of extrahepatic spread and/or macrovascular invasion (EHS/MVI). Eligible pts had pathologic diagnosis of HCC, Child-Pugh score A, ECOG PS ≤1, and must have received prior sorafenib. Pts received up to two lines of prior systemic therapy for HCC and must have progressed following at least one. The primary endpoint was overall survival (OS). Secondary endpoints were investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per RECIST 1.1. The study was designed to detect a hazard ratio (HR) for OS of 0.76 (90% power, 2-sided α = 0.05) at the final analysis with two prespecified interim analyses at 50% and 75% of the planned 621 events. Results: As of 1 Jun 2017, 707 pts were randomized, and 484 deaths had occurred (317 out of 470 for C; 167 out of 237 for P). Baseline characteristics were balanced between the two arms: median age was 64 years, 82% were male, 38% had HBV, 24% had HCV, 25% enrolled in Asia, 78% had EHS, 30% had MVI, 85% had EHS/MVI, and 27% had received two prior systemic therapy regimens for advanced HCC. The study met the primary endpoint at the second planned interim analysis with median OS 10.2 mo for C vs 8.0 mo for P (HR 0.76, 95% CI 0.63-0.92; p = 0.0049). Median PFS was 5.2 mo for C vs 1.9 mo for P (HR 0.44, 95% CI 0.36-0.52; p < 0.001), and ORR was 4% vs 0.4% (p = 0.0086). The most common grade 3/4 adverse events (predominantly grade 3) with higher incidence in the C vs P arm included hand-foot skin reaction (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%). Conclusion: C significantly improved OS and PFS vs P in previously treated pts with advanced HCC. Adverse events were consistent with the known safety profile of C. Clinical trial information: NCT01908426.
Evaluation of systemic inflammation based prognostic scores in patients with advanced oesophageal cancer receiving palliative radiotherapy.
Authors: Dolan Ross , Tilling Elliot , Kong Chia Y , MacLeod Nicholas James , McSorley Stephen Thomas , Park James Hugh , Glen Paul , Horgan Paul G. , Laird Barry , McMillan Donald C
Published: January 2019

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Background: The presence of a systemic inflammatory response (SIR) in patients with advanced cancer is an increasingly recognised prognostic domain and is commonly assessed by the Glasgow Prognostic Score (GPS) and modified Glasgow Prognostic Score (mGPS). However, little work has been carried out to evaluate their role in palliative radiotherapy. The aim of the present study was to compare the prognostic value of the GPS/mGPS in patients with advanced oesophageal cancer receiving palliative radiotherapy. Methods: Those patients receiving palliative radiotherapy for oesophageal cancer between 2010 and 2015 were examined (n=194). After exclusions the following demographic data was recorded sex, age, indication for radiotherapy, time from treatment to death/last clinic visit, medical comorbidities, tumour and radiotherapy location/dose, CRP, albumin, and differential blood counts. GPS, mGPS, NLR, PLR and LMR were all calculated and Cox regression analysis carried out in SPSS. Results: Patients who had undergone non-oesophageal/neoadjuvant radiotherapy (n=2) or died within 30 days of treatment administration were excluded (n=22). Of the remaining 170 analysed, 112 (66%) were male and the median age was 72 (Range: 43-91). The most common clinical indications for radiotherapy were dysphagia (n=142), weight loss (n=81) and pain (n=50). Medical comorbidities varied with the most common being hypertension (n=83), ischaemic heart disease (n=46) and COPD (n=42). At the time of analysis, 170 (100%) of the patients were dead with median survival of 6 months (Range: 1-81 month). On univariate six month cancer specific survival analysis, TNM stage (p=0.028), GPS (p<0.001) and mGPS (p<0.001) were significantly associated with poor survival. On multivariate analysis of the significant variables, only mGPS (HR: 2.28, 95%CI 1.29-4.01, p=0.004) and TNM stage (HR: 1.71 95%CI 1.09-2.69, p=0.020) remained independently associated with survival. Conclusions: In the palliative radiotherapy setting, systemic inflammation based scores (GPS/mGPS) had prognostic value and the mGPS had independent prognostic value.
Effect of transarterial chemoembolization plus external beam radiotherapy on survival of patients with hepatocellular carcinoma showing macroscopic vascular invasion compared with sorafenib: A randomized trial.
Authors: Yoon Sang MIN , Lee So Jung , Kim Jong Hoon , Shin Ji Hoon , An Jihyun , Lee Han Chu , Ryoo Baek-Yeol , Lim Young-Suk
Published: January 2019

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Background: Sorafenib is the sole treatment option for advanced stage hepatocellular carcinoma (HCC) with macroscopic vascular invasion (MVI) with unsatisfactory response rate and survival benefit. Combined transarterial chemoembolization (TACE) plus external beam radiotherapy (RT) has shown promising results in these patients by observational studies. Here, we report the efficacy and safety of TACE plus RT compared to sorafenib in patients with advanced HCC and MVI. Methods: This study was a randomized, open-label trial at an academic tertiary care center. Between 2013 and 2016, 90 treatment-naive patients with liver-confined HCC showing MVI were randomly assigned to receive sorafenib (400 mg twice-daily; n = 45; sorafenib group) or TACE (every 6 weeks) plus RT (within 3 weeks after the first TACE; n = 45; TACE+RT group). Primary endpoint was 12-week the progression-free survival (PFS) rate by intention-to-treat analysis. Radiologic response was assessed by independent review according to Response Evaluation Criteria in Solid Tumors (version 1.1). Crossover of treatment was permitted after confirming disease progression. Results: All patients had portal vein invasion of HCC and Child-Pugh class A liver function. The median maximal tumor diameter was 9.7 cm. At week 12, the PFS rate was significantly higher in the TACE+RT group than the sorafenib group (77.8% vs. 26.7%; P< 0.001). The TACE+RT group showed significantly higher radiologic response rate (33.3% vs. 2.2% at 24 weeks; P< 0.001), significantly longer median time to disease progression (30 weeks vs. 8 weeks; P< 0.001), and significantly longer overall survival (55 weeks vs. 43 weeks; P= 0.04), compared with the sorafenib group. No patients in the TACE+RT group discontinued treatment due to hepatic decompensation. Conclusions: In patients with advanced HCC showing MVI, first-line treatment with TACE+RT was well-tolerated and provided improved progression-free survival, objective response rate, time to disease progression, and overall survival, compared with sorafenib treatment. Clinical trial information: NCT01901692.
Defining the role of lymphadenectomy for pancreatic neuroendocrine tumors: An eight institution study of 695 patients from the U.S. Neuroendocrine Tumor Study Group.
Authors: Lopez-Aguiar Alexandra G , Zaidi Mohammad , Dillhoff Mary , Beal Eliza W , Poultsides George A. , Makris Eleftherios , Rocha Flavio G. , Kanji Zaheer S. , Idrees Kamran , Marincola Smith Paula , Cho Clifford , Beems Megan , Weber Sharon M. , Fisher Alexandra V. , Fields Ryan C , Krasnick Bradley A. , Cardona Kenneth , Maithel Shishir
Published: January 2019

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Background: Preoperative factors that reliably predict lymph node (LN) metastases in pancreatic neuroendocrine tumors (PanNETs) are unclear. The number of LNs needed to accurately stage PanNETs has not been defined. Methods: Patients who underwent curative-intent resection of primary non-functional PanNETs at 8 institutions from 2000-2016 were analyzed. Tumors with poor differentiation and Ki-67 > 20% were excluded. Preoperative factors associated with LN metastases were identified. A procedure specific target for LN retrieval to accurately stage patients was determined. Results: Of 2182 pts with GI NETs, 695 underwent resection of PanNETs. 33% of tumors were proximal (head/uncinate), and 67% were distal (neck/body/tail). 26% of pts (n = 158) had LN+ disease, which was associated with worse 5-yr recurrence-free survival (RFS) (60% vs 86%; p < 0.001). Increasing number of +LNs was not associated with worse RFS. Preoperative factors associated with +LNs included tumor size ≥2 cm (OR 6.6; p < 0.001), proximal location (OR 2.5; p < 0.001), moderate vs well differentiation (OR 2.1; p = 0.006), and Ki-67≥3% (OR 3.1; p < 0.001). LN metastases were also present in tumors without these risk factors: < 2cm (9%), distal location (19%), well differentiated (23%), and Ki-67 < 3% (16%). Median LN retrieval was 13 for pancreatoduodenectomy (PD), but only 9 for distal pancreatectomy (DP). Given that PD routinely includes a complete regional lymphadenectomy, a minimum number of LNs to accurately stage pts was not identified. For DP, however, removal of < 7 LNs failed to discriminate 5-yr RFS between LN (+) and (-) pts ( < 7 LNs: 72% vs 83%, p = 0.198; ≥7 LNs: 67% vs 86%, p = 0.002). Conclusions: Tumor size ≥2 cm, proximal location, moderate differentiation, and Ki-67≥3% are preoperative factors that predict LN positivity in resected non-functional PanNETs. Given the 9-23% incidence of LN metastases in patients without such risk factors, routine regional lymphadenectomy should be considered. Pancreatoduodenectomy inherently includes sufficient LN retrieval, while distal pancreatectomy should aim to remove ≥7 LNs for accurate staging.
Multiomic molecular comparison of primary versus metastatic pancreatic tumors.
Authors: Brar Gagandeep , Blais Edik , Bender R Joseph , Brody Jonathan , Sohal Davendra , Madhavan Subha , Picozzi Vincent J. , Hendifar Andrew Eugene , Chung Vincent M. , Halverson David , Mikhail Sameh , Matrisian Lynn McCormick , Rahib Lola , Petricoin Emanuel , Pishvaian Michael J.
Published: January 2019

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Background: Pancreatic cancer metastasizes very early, as evidenced by the fact that > 70% of patients with operable disease ultimately develop metastases. Thus, it is likely that the molecular characteristics of primary pancreatic tumors are similar to metastatic lesions. We compared the frequency of genetic alterations and protein expression from primary vs. metastatic pancreatic tumors, and from metastases from different sites. By focusing on actionable genetic and proteomic information, we sought to explore whether targeted therapies could be tailored to patients at metastatic progression based on primary surgical material. Methods: Next generation DNA sequencing (NGS) data of 208 genes and a limited set of protein markers were analyzed from pancreatic tumors of 431 patients enrolled in the Know Your Tumor initiative. Of the 208 genes tested, mutations in 70 were considered potentially actionable based on preclinical and clinical evidence. We compared 146 primary pancreatic tumors against 285 metastatic lesions, and examined subgroups for liver vs. lung vs. other metastatic lesions. Molecular alterations were compared between independent groups for each gene/protein using Fisher’s exact test. Significance was assessed using a false discovery rate adjusted q-value threshold of 0.05. Results: No differences in the specific mutation or expression pattern were observed between primary vs. metastatic lesions, nor across the site of metastasis after correcting for multiple hypotheses. Even the proportion of actionable alterations (including mutations in the homologous recombination DNA repair pathway) was similar across subgroups. Conclusions: Comparison of the muli-omic profile of primary vs. metastatic pancreatic adenocarcinoma reveals that the molecular architecture is very similar, and that actionable alterations are identified at the same frequency. This is unlike the data observed from other solid tumors, (e.g. colon and breast cancer), in which substantial molecular discordance and heterogeneity exists between primary tumors and metastatic sites, but is consistent with the belief that primary pancreatic cancers metastasize early and thus are molecularly indistinguishable from metastatic lesions.
Association of preoperative monocyte-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with overall survival after resection of pancreatic neuroendocrine tumors.
Authors: Panni Roheena Z. , Davidson Jesse T , Krasnick Bradley A. , McGilvray Martha , Zarate Rodriguez Jorge , Lopez-Aguiar Alexandra G , Dillhoff Mary , Poultsides George A. , Winslow Emily , Rocha Flavio G. , Idrees Kamran , Hammill Chet , Cho Clifford , Doyle Maria Majella , Chapman William C. , Hawkins William G. , Strasberg Steven M. , Trikalinos Nikolaos A , Maithel Shishir , Fields Ryan ,   US-NETSG Group
Published: January 2019

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Background: Neutrophil, monocyte and lymphocyte counts are important biomarkers of the tumor-induced systemic inflammatory response. A lower monocyte-to-lymphocyte ratio (MLR) and neutrophil-to-lymphocyte ratio (NLR) is associated with a favorable prognosis for certain tumors. However, this association has not yet been demonstrated in resected pancreatic neuroendocrine tumors (PNETs). The aim of this study was to investigate the prognostic significance of MLR and NLR in patients with resectable PNETs with regards to overall survival (OS). Methods: Eligible patients undergoing surgery for PNETs between 2000 and 2016 were identified using a national multi-center cohort dataset. Their pre-operative neutrophil, monocyte and lymphocyte counts were imported and NLR and MLR were calculated. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut offs for NLR and MLR. Univariate analyses were used to compare patient factors and tumor characteristics in different groups. The difference in OS between high and low groups was explored with the use of Kaplan Meier curves and compared using log-rank tests. Results: A total of 635 patients were analyzed. Univariate analysis revealed that higher lymphocyte, low monocyte and low neutrophil counts were associated with improved OS (P = 0.0002, 0.014 and 0.011 respectively). The mean NLR and MLR level was 4.11 ± 0.219 and 0.4295 ± 0.0196, respectively. Lower NLR ( < 4) and lower MLR ( < 0.25) were significantly associated with improved OS (p < 0.001 & p < 0.0001). Median survival was 141 months in the low NLR group (n = 474) and 119 months in the high NLR group (n = 161). The median survival in the high MLR group (n = 464) was 120 months and has not been reached in the low MLR group (n = 171). On multivariate analysis, low MLR was independent predictor of improved OS when controlling for age, race and comorbidities (p < 0.001). Conclusions: For resectable PNETs, low pre-operative NLR and MLR levels are significantly associated with improved survival. NLRs and MLRs may serve as valuable markers to stratify PNET patients for subsequent therapies and clinical trial enrollment.