Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07.

PURPOSE: The second planned interim analysis (median follow-up 12.5 months) in a phase III trial of postoperative adjuvant chemotherapy for stage III gastric cancer revealed significant improvement in relapse-free survival (RFS) for S-1 plus docetaxel over S-1 alone. Although enrollment was terminated on the recommendation of the independent data and safety monitoring committee, we continued follow-up and herein report on 3-year RFS, the primary endpoint. PATIENTS AND METHODS: Patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive adjuvant chemotherapy with either S-1 plus docetaxel or S-1 alone. In the S-1 plus docetaxel group, S-1 was given orally for 2 weeks followed by 1 week of rest for seven courses, and docetaxel was given intravenously on day 1 of the second to seventh courses. The combination therapy was followed by S-1 monotherapy for up to 1 year. RESULTS: The 3-year RFS rate of the S-1 plus docetaxel group was 67.7%. This was significantly superior to that of 57.4% in the S-1 group (hazard ratio [HR] 0.715, 95% CI 0.587-0.871, P = 0.0008). This translated into a significant benefit in the 3-year overall survival (OS) rate in the S-1 plus docetaxel group (77.7% versus 71.2%, HR 0.742, 95% CI 0.596-0.925, P = 0.0076). CONCLUSION: On 3-year follow-up data, postoperative adjuvant therapy with S-1 plus docetaxel was confirmed to improve both RFS and OS and can be recommended as a standard of care for patients with stage III gastric cancer treated by D2 dissection.

Tumor Location Is Associated With the Prevalence of Braf And Pik3ca Mutations in Patients with Wild-Type Ras Colorectal Cancer: A Prospective Multi-Center Cohort Study in Japan.

BACKGROUND: Primary tumor location is a critical prognostic factor that also impacts the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in wild-type RAS (KRAS/NRAS) metastatic colorectal cancer (CRC). However, the association between the incidence of BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations and primary tumor location remains unclear. METHODS: We prospectively collected tumor samples and clinical data of patients from 15 hospitals between August 2014 and April 2016 to investigate RAS, BRAF, and PIK3CA mutations using a polymerase chain reaction-based assay. According to the primary tumor location, patients were classified to right-sided (from cecum to splenic flexure) and left-sided (from descending colon to rectum) tumor groups. RESULTS: In total, 577 patients with CRC were investigated, 331 patients (57%) had CRC with wild-type RAS; of these 331 patients, 10.5%, 4.8%, and 5.9% patients harbored BRAFV600E, BRAFnon-V600E, and PIK3CA mutations, respectively. BRAF/PIK3CA mutations were more frequent in females, patients with right-sided tumors, and patients with peritoneal metastasis cases and less frequent in patients with liver metastases. The prevalence rates of BRAFV600E and PIK3CA mutations were higher in patients with right-sided tumors than in those with left-sided tumors (32.3% vs. 4.8% and 17.2% vs. 3.6%, respectively). CONCLUSIONS: More than half of the patients with right-sided CRC and wild-type RAS harbored BRAF/PIK3CA mutations, including BRAFnon-V600E, which may contribute to the difference in the anti-EGFR efficacy between the right- and left-sided CRC.

Phase II multi-institutional prospective randomized trial comparing S-1 plus paclitaxel with paclitaxel alone as second-line chemotherapy in S-1 pretreated gastric cancer (CCOG0701).

BACKGROUND: The aim of this study was to explore whether a combination of S-1 and paclitaxel offers any benefit over paclitaxel alone to patients pretreated by S-1. METHODS: Gastric cancer patients who developed progression during S-1-based first-line chemotherapy or had recurrence during postoperative adjuvant chemotherapy by S-1 were randomly assigned to receive second-line treatment either by weekly administration of paclitaxel at 80 mg/m(2) three times every 4 weeks or daily oral S-1 (80 mg/m(2)) for 2 weeks plus paclitaxel (50 mg/m(2)) given on days 1 and 8, every 3 weeks (S-1 plus paclitaxel). The primary endpoint was progression-free survival (PFS) at 4 months after the initiation of treatment. RESULTS: A total of 78 patients were eligible for efficacy analyses-40 were assigned to the paclitaxel group and 38 to the S-1 plus paclitaxel group. PFS at 4 months was similar between the groups (50 % for paclitaxel vs 55 % for S-1 plus paclitaxel, P = 0.641). There were no differences between the groups either in progression-free survival (4.6 vs 4.6 months, respectively, P = 0.526), overall survival (10.0 vs 10.0 months, respectively, P = 0.464), or overall response rate (27 vs 22 %, respectively, P = 0.767). The incidences of grade 3 or 4 hematological and non-hematological toxicities were also equivalent between the two groups (25 vs 26 % and 24 vs 26 %, respectively). CONCLUSIONS: No benefit of S-1 administration beyond progression was shown when paclitaxel was selected as the key drug for second-line chemotherapy.

Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft.

Breast cancer is one of the most common and feared cancers faced by women. The prognosis of patients with advanced or recurrent breast cancer remains poor despite refinements in multimodality therapies involving chemotherapeutic and hormonal agents. Multimodal therapy with more specific and effective strategy is urgently needed. The oncolytic herpes simplex virus (HSV) has potential to become a new effective treatment option because of its broad host range and tumor selective viral distribution. Bevacizumab is a monoclonal antibody against VEGFA, which inhibits angiogenesis and therefore tumor growth. Our approach to enhance the antitumor effect of the oncolytic HSV is to combine oncolytic HSV HF10 and bevacizumab in the treatment of breast cancer. Our results showed that bevacizumab enhanced viral distribution as well as tumor hypoxia and expanded the population of apoptotic cells and therefore induced a synergistic antitumor effect. HF10 is expected to be a promising agent in combination with bevacizumab in the anticancer treatment.

Transumbilical Hidden-Scar High Anterior Resection for Sigmoid Colon Cancer Using GelPOINT® Through an Umbilical Zigzag Skin Incision.

Introduction: Hidden-scar surgery is a new method by which surgeons perform abdominal operations through one incision made in the folds of the patient's umbilicus. However, with a straight incision in the umbilicus, the maximal opening of the fascia is 2 cm. The 2-cm fascial opening is not enough to allow for the triangulation of instruments, the removal of specimens, and the performance of anastomosis, particularly during gastrectomy and colectomy. To overcome this problem, we developed an umbilical zigzag skin incision with a 6-cm opening of the fascia and peritoneum in collaboration with plastic surgeons and used Gelport® to maintain pneumoperitoneum, which resulted in a scarless wound.1 Plastic surgeons modified this technique from umbilicoplasties for umbilical deformities.2,3 We have performed gastrectomies, colectomies, cholecystectomies, and transabdominal preperitoneal hernia repairs using this method without any complications and have succeeded in hiding scars in the umbilicus. GelPOINT® is a newly developed device for minimally invasive surgery that provides a flexible, air-tight fulcrum to facilitate the triangulation of standard instrumentation. By offering an increased range of motion and maximum retraction and exposure, the GelPOINT platforms assure maximum versatility and access for a wide range of abdominal procedures. We report herein a video (559 seconds) describing a new method of transumbilical hidden-scar surgery using GelPOINT through an umbilical zigzag skin incision. Materials and Surgical Technique: A 64-year-old woman underwent laparoscopic sigmoidectomy for sigmoid colon cancer. The procedure was performed as previously described1; after marking a zigzag skin incision in the umbilical region, the skin was incised along this line. Then, a GelPOINT double-ring wound retractor was inserted through the incision, which enlarged the diameter of the fascial opening to 6 cm. The GelPOINT was latched to the wound retractor ring, and the pneumoperitoneum was then inflated using CO2. One additional port was inserted in the right-lower abdomen for safety. Laparoscopic high anterior resection with lymph node dissection was performed in the standard fashion. The specimen was easily extracted from the abdomen through the umbilical zigzag incision, and the double-staple technique was used for anastomosis without any complications. The wound in the umbilical region was virtually hidden in the bottom of the umbilicus after surgery. Results and Conclusion: We performed an umbilical zigzag skin incision technique using GelPOINT for laparoscopic high anterior resection without any complications. We consider that this zigzag skin incision technique is one way to lessen the technical difficulties of laparoscopic surgery, resulting in a hidden scar in the umbilicus. The authors have no conflicts of interest or financial ties to disclose. Runtime of video: 9 mins 19 secs.

Combination of the tumor angiogenesis inhibitor bevacizumab and intratumoral oncolytic herpes virus injections as a treatment strategy for human gastric cancers.

BACKGROUND/AIMS: Advanced gastric cancer is difficult to treat due to the frequency of liver metastases and peritoneal dissemination. A combination of two new strategies, including the anti-angiogenesis inhibitor bevacizumab and an oncolytic herpes virus is a promising treatment for advanced cancer. METHODOLOGY: The effects of bevacizumab on oncolytic herpes virus replication and viral cytotoxicity were examined at varying bevacizumab concentrations and viral titers. In addition, the ability of these two new promising anticancer agents to inhibit tumor growth was studied. Histological examinations of CD31 and LacZ were used to assess angiogenesis and virus distribution within the tumor, respectively. RESULTS: Bevacizumab did not affect viral replication or viral cytotoxicity in vitro. The combination of bevacizumab and the oncolytic herpes virus hrR3 significantly reduced tumor growth in vivo in an experimental gastric cancer model. Bevacizumab inhibited angiogenesis caused by local injection of hrR3 and induced virus spread. Bevacizumab increased the distribution of the intratumorally injected oncolytic herpes virus within the tumor. CONCLUSIONS: Combination therapy consisting of bevacizumab and an oncolytic herpes virus is a promising new treatment strategy for gastric cancer.

Oncolytic herpes virus induces effective anti-cancer immunity against murine colon cancer.

UNLABELLED: BACK GROUND/AIMS: Oncolytic virus therapy is becoming a promising anti-cancer therapy and oncolytic viruses have been shown to elicit anti-cancer immunity. We evaluated the anti-tumor immune responses elicited by the herpes oncolytic virus R3616 compared to a representative chemotherapy drug, 5-FU. METHODOLOGY: R3616 or 5-FU was directly injected into subcutaneous tumors of non-immunized mice. Additionally, complete adjuvant, R3616-infected MC26 cells or 5-FU plus MC26 cells were frozen, thawed and used to immunize mice. After 21 days of immunization, the adaptive immune response suppressed implanted tumor growth and prolonged survival rate. We monitored differences in the number of infiltrating CD8- and CD4-positive lymphocytes in implanted tumors by immunofluorescence. RESULTS: R3616 induced a statistically greater number of infiltrating T cells (Thy1.2), macrophages (CD68) and dendritic cells (CD83) in injected tumors than 5-FU. The group immunized with R3616-infected MC26 cells had greater tumor suppression and longer survival rate than non-immunized mice and mice treated with 5-FU plus MC26 cells with statistically significant differences between these groups. The mice immunized with R3616-infected MC26 cells had a statistically greater number of infiltrating T cells in the implanted tumor than non-immunized and mice treated with 5-FU plus MC26 cells. CONCLUSIONS: These results indicate that oncolytic herpes virus R3616 can elicit more effective host anti-tumor immune responses than 5-FU against murine colon cancer model.

High therapeutic potential for systemic delivery of a liposome-conjugated herpes simplex virus.

PURPOSE: Oncolytic viral therapy is a newly developed modality to treat tumors. Many clinical trials worldwide have examined the efficacy of locally injected oncolytic viruses. However, systemic intravascular injections are limited by the humoral immune response, which dramatically decreases the level of infection. To overcome this limitation, we encapsulated the oncolytic virus in liposomes. METHODS: The infectious properties of the herpes simplex virus type 1 (HSV-1) mutant, hrR3, with or without liposomes in the presence of neutralizing antibodies were evaluated using replication and cytotoxicity assays in vitro. To evaluate the efficacy of intravascular virus therapy with liposomes in the presence of neutralizing antibodies, immunized mice bearing multiple liver metastases were intraportally or peritoneally administered hrR3 or hrR3 complexed with liposomes. RESULTS: Anti-HSV antibodies attenuated the infectiousness and cytotoxicity of hrR3, whereas hrR3/liposome complexes were not attenuated by these anti-HSV antibodies. Although the survival rate of non-immunized mice treated with hrR3 alone was similar to that of mice treated with the hrR3/liposome complexes, the survival rates of immunized mice treated with hrR3 alone were significantly reduced compared to mice treated with the hrR3/liposome complexes. CONCLUSIONS: This systemic intravascular delivery of hrR3/liposome complexes in the presence of pre-existing neutralizing antibodies is effective to treat multiple liver metastases.

[A very elderly case of recurrent gastric cancer with peritoneal dissemination effectively treated by combination chemotherapy of docetaxel (DOC) and S-1].

We report a case of a 77-year-old man with gastric cancer of Borrmann type 3, pyloric stenosis and liver invasion. Distal gastrectomy with liver film resection was performed. Pathological staging was IV(sig, pT4, pN2, H0, P0, CY0, M0, ly3, v3). We recommended adjuvant chemotherapy but the patient refused. He was diagnosed with a recurrence of peritoneal dissemination 4 months after the operation. He received docetaxel(DOC)at a starting dose of 40 mg/m2 by iv infusion on day 1 and S- 1 at a full dose of 100 mg/body daily for two weeks every three weeks. After 5 cycles of this combination therapy, the gastric cancer with peritoneal dissemination completely disappeared. He was recognized to have grade 2 hematologic toxicity, hand foot syndrome and stomatitis, and all treatment-related toxicities were resolved. No re-growth of gastric cancer has been seen for 9 months with this chemotherapy.

Middle pancreatectomy: safety and long-term results.

BACKGROUND: Pancreaticoduodenectomy and distal pancreatectomy for lesions of the neck or body of the pancreas sacrifice a large amount of normal pancreatic tissue. Middle pancreatectomy (MP) is a parenchyma sparing technique that reduces the risk of postoperative endocrine and exocrine insufficiency. This study aims to evaluate the perioperative and long-term results of MP and to clarify whether MP can be performed with outcomes comparable with traditional pancreatectomies. METHOD: Twenty-six patients who underwent MP for benign or low-grade malignant tumor of the pancreas between 1991 and 2006 at the Department of Surgery II, Nagoya University Graduate School of Medicine, were identified. Their outcomes were compared with 2 separate control groups, 35 left-side pancreatectomies (LSP) and 60 right-side pancreatectomies (RSP). RESULTS: The mean operating time of the MP group was 295 minutes, which was significantly shorter than that for RSP (P=.0001). The rate of pancreatic fistula formation was higher in the MP group than in the 2 control groups, although the differences did not reach statistical significance. After a mean follow-up of 71 months, postoperative endocrine function was equivalent to the pre-operative values in the MP group, and none of the patients developed diabetes mellitus postoperatively. Only 1 patient in the MP group required enzyme substitution postoperatively for exocrine insufficiency. The MP group was inclined to be superior to the other 2 control groups in terms of postoperative nutritional status. CONCLUSION: Middle pancreatectomy is a reasonable technique that is indicated for selected patients with benign or low malignant tumors in the neck and body of the pancreas. Middle pancreatectomy seems to result in better preservation of exocrine and endocrine functions as well as in better nutritional status postoperatively.

Considerations for intravascular administration of oncolytic herpes virus for the treatment of multiple liver metastases.

PURPOSE: Oncolytic viral therapy is a newly developed modality for treating tumors. Many clinical trials using oncolytic virus have been performed worldwide, but most of them have used local injection in the tumor. Determination of the effect and safety of intravascular virus injection instead of local injection is necessary for clinical use against multiple liver metastases and systemic metastases. METHODS: To evaluate the efficacy and safety of intravascular virus therapy, mice bearing multiple liver metastases were treated by intraportal or intravenous administration of the herpes simplex virus type 1 (HSV-1) mutant, hrR3. Mice treated with hrR3 were killed and organs were harvested for lacZ staining and PCR analysis. Inactivation of oncolytic virus in bloodstream was assessed by neutralization assay in vitro. Infectious activity of hrR3 with vascular endothelial cells was evaluated by replication and cytotoxicity assay. RESULTS: The survival rate of animals treated by hrR3 was significantly improved compared with the untreated group. lacZ staining and PCR analysis demonstrated detectable virus in the tumor but not in normal tissue or other organs except for the adrenal glands. We also showed that vascular endothelial cells allowed virus replication, while normal hepatocytes did not, and human anti-HSV antibody revealed attenuation of the infectious activity of hrR3. CONCLUSIONS: Intravascular delivery of hrR3 is effective in treating multiple liver metastases, however, several points must be kept in mind at the time of human clinical trials using intravascular virus administration in order to avoid critical side effects.

Cystic lymphangioma of the gallbladder: report of a case.

Abdominal lymphangioma is usually diagnosed within the first 2 years of life and is extremely rare in adults. The most common location of abdominal lymphangioma is the mesentery, but there are sporadic reports of its development in the gallbladder. A 66-year-old woman was found to have a cystic lesion near the gallbladder. Preoperative studies, including endoscopic ultrasonography, computed tomography, and magnetic resonance imaging, showed a tumor with multilocular cystic structure, originating in the gallbladder fossa. The patient underwent exploratory laparotomy, and the mass was resected en bloc with the gallbladder, as there was no evidence of malignancy on intraoperative ultrasonography. Macroscopically, the tumor was a multilocular cystic mass, 6 x 3 x 2 cm in size, with a rough, sponge-like appearance. Histologically, the cystic tumor was diagnosed as a lymphangioma, originating in the gallbladder. To our knowledge, only three other cases of a cystic lymphangioma originating in the gallbladder have been reported in the medical literature of the world.

Effects of tumor selective replication-competent herpes viruses in combination with gemcitabine on pancreatic cancer.

PURPOSE: Pancreatic cancer still has a poor prognosis, even if aggressive therapy is pursued. Currently, new modalities of oncolytic virus therapy are being tested against this cancer. The combination of one of two representative mutant herpes simplex viruses (R3616: gamma(1)34.5 inactivated, hrR3: UL39 inactivated) with a standard anti-pancreatic cancer chemotherapy drug (gemcitabine), was investigated in this study. EXPERIMENTAL DESIGN: The intracellular concentration of ribonucleotide reductase was estimated by Western blotting. The effect of gemcitabine on viral replication and the total cytotoxic effect of the combination therapy were investigated on pancreatic cancer cell lines. We compared the results of two oncolytic viruses, R3616 and hrR3. A mouse model of pancreatic cancer with peritoneal dissemination was used to evaluate the in vivo effect of the combination therapy. RESULTS: Although the replication of both viruses was inhibited by gemcitabine, the combination caused more tumor cell cytotoxicity than did virus alone in vitro. The results with R3616 were more striking. Although the difference was not statistically significant, R3616 with gemcitabine had a greater effect than did R3616 alone, while hrR3 with gemcitabine had a weaker effect than did hrR3 alone in vivo experiments. CONCLUSION: The combination of oncolytic virus with gemcitabine is a promising new strategy against advanced pancreatic cancer. Each virus has different functional characteristics, and can affect the results of the combination of viruses and chemotherapy drugs. The results indicate that there is a complicated interaction among viruses, cells, and chemotherapy drugs and that the best combination of oncolytic virus and chemotherapeutic agents should be studied more extensively before embarking on a clinical trial.

Hyperlactemia can predict the prognosis of liver resection.

Although hyperlactemia is known to accompany hepatic failure and metabolic acidosis, few reports examined the relationships between lactate concentrations and outcome after liver resection. We examined the ability of arterial plasma lactate concentration to predict the patient outcome after hepatectomy. The relationships of arterial lactate and base excess (BE) measured on admission to the intensive care unit (ICU) after hepatectomy to postoperative outcome were investigated in 151 consecutive patients. Lactate level was significantly higher in nonsurvivors than in survivors (P < 0.001), and in patients with postoperative complications than in those without complications (P < 0.001). Base excess was significantly reduced in nonsurvivors (P < 0.001) and in patients with postoperative complications (P = 0.004). The area under the receiver-operator curve of lactate to mortality was 0.86, whereas that of BE to the mortality was 0.82. Moderate correlation was observed between the lactate level at ICU admission and the highest total bilirubin concentration measured within 14 days after the surgery (r = 0.61), whereas the correlation between BE and bilirubin levels was lower (r = 0.35). Using multivariate analysis, the lactate level independently predicted mortality (P = 0.008) and morbidity (P = 0.013). Lactate (P < 0.001) and BE (P = 0.0068) levels both independently predicted the highest bilirubin concentration. The arterial plasma lactate concentration measured on admission to ICU seemed an excellent predictor of patient outcome after liver resection.

[Two cases of advanced gastric cancer with peritoneal dissemination acquired long-term response three years or more by postoperative treatment with oral anticancer drug TS-1].

The first patient is a 60-year-old man who underwent total gastrectomy and splenectomy for type-3 gastric cancer after neoadjuvant chemotherapy. The second patient is a 69-year-old woman who underwent distal gastrectomy for type-2 gastric cancer and pyloric stenosis after neoadjuvant chemotherapy. Some peritoneal dissemination was observed in these two cases. No re-growth of peritoneal dissemination was seen for three years or more from treatment with the oral anticancer drug TS-1. Treatment on an outpatient basis, therefore, greatly contributed to their quality of life. We consider TS-1 as a first-line anti-cancer drug for advanced gastric cancer.