Phase II Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 and Cisplatin for Gastric Cancer with Peritoneal Metastasis.

BACKGROUND: Intraperitoneal chemotherapy is promising for gastric cancer with peritoneal metastasis. Although a phase III study failed to show a statistically significant superiority of intraperitoneal paclitaxel combined with S-1 and intravenous paclitaxel, the sensitivity analysis suggested clinical efficacy. Thus, attempts to combine intraperitoneal paclitaxel with other systemic therapies with higher efficacy have been warranted. We sought to explore the efficacy of intraperitoneal paclitaxel with S-1 and cisplatin. PATIENTS AND METHODS: Gastric cancer patients with peritoneal metastasis were enrolled in the phase II trial. In addition to the established S-1 and cisplatin regimen every 5 weeks, intraperitoneal paclitaxel was administered on days 1, 8, and 22 at a dose of 20 mg/m2. The primary endpoint was overall survival rate at 1 year after treatment initiation. Secondary endpoints were progression-free survival and toxicity. RESULTS: Fifty-three patients were enrolled and fully evaluated for efficacy and toxicity. The 1-year overall survival rate was 73.6% (95% confidence interval 59.5-83.4%), and the primary endpoint was met. The median survival time was 19.4 months (95% confidence interval, 16.1-24.6 months). The 1-year progression-free survival rate was 49.6% (95% confidence interval, 34.6-62.9%). The incidences of grade 3/4 hematological and non-hematological toxicities were 43% and 47%, respectively. The frequent grade 3/4 toxicities included neutropenia (25%), anemia (30%), diarrhea (13%), and anorexia (17%). Intraperitoneal catheter and implanted port-related complications were observed in four patients. There was one treatment-related death. CONCLUSIONS: Intraperitoneal paclitaxel combined with S-1 and cisplatin is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Prognostic significance of NY-ESO-1 antigen and PIGR expression in esophageal tumors of CHP-NY-ESO-1-vaccinated patients as adjuvant therapy.

The aim of this study was to determine the efficacy and the biomarkers of the CHP-NY-ESO-1 vaccine complexed with full-length NY-ESO-1 protein and a cholesteryl pullulan (CHP) in patients with esophageal squamous cell carcinoma (ESCC) after surgery. We conducted a randomized phase II trial. Fifty-four patients with NY-ESO-1-expressing ESCC who underwent radical surgery following cisplatin/5-fluorouracil-based neoadjuvant chemotherapy were assigned to receive either CHP-NY-ESO-1 vaccination or observation as control. Six doses of CHP-NY-ESO-1 were administered subcutaneously once every two weeks, followed by nine more doses once every four weeks. The endpoints were disease-free survival (DFS) and safety. Exploratory analysis of tumor tissues using gene-expression profiles was also performed to seek the biomarker. As there were no serious adverse events in 27 vaccinated patients, we verified the safety of the vaccine. DFS in 2 years were 56.0% and 58.3% in the vaccine arm and in the control, respectively. Twenty-four of 25 patients showed NY-ESO-1-specific IgG responses after vaccination. Analysis of intra-cohort correlations among vaccinated patients revealed that 5% or greater expression of NY-ESO-1 was a favorable factor. Comprehensive analysis of gene expression profiles revealed that the expression of the gene encoding polymeric immunoglobulin receptor (PIGR) in tumors had a significantly favorable impact on outcomes in the vaccinated cohort. The high PIGR-expressing tumors that had higher NY-ESO-1-specific IgA response tended to have favorable prognosis. These results suggest that PIGR would play a major role in tumor immunity in an antigen-specific manner during NY-ESO-1 vaccinations. The IgA response may be relevant.

Up-regulation of FOXO1 and reduced inflammation by ß-hydroxybutyric acid are essential diet restriction benefits against liver injury.

Liver ischemia and reperfusion injury (IRI) is a major challenge in liver surgery. Diet restriction reduces liver damage by increasing stress resistance; however, the underlying molecular mechanisms remain unclear. We investigated the preventive effect of 12-h fasting on mouse liver IRI. Partial warm hepatic IRI model in wild-type male C57BL/6 mice was used. The control ischemia and reperfusion (IR) group of mice was given food and water ad libitum, while the fasting IR group was given water but not food for 12 h before ischemic insult. In 12-h fasting mice, serum liver-derived enzyme level and tissue damages due to IR were strongly suppressed. Serum ß-hydroxybutyric acid (BHB) was significantly raised before ischemia and during reperfusion. Up-regulated BHB induced an increment in the expression of FOXO1 transcription factor by raising the level of acetylated histone. Antioxidative enzyme heme oxigenase 1 (HO-1), a target gene of FOXO1, then increased. Autophagy activity was also enhanced. Serum high-mobility group box 1 was remarkably lowered by the 12-h fasting, and activation of NF-κB and NLRP3 inflammasome was suppressed. Consequently, inflammatory cytokine production and liver injury were reduced. Exogenous BHB administration or histone deacetylase inhibitor administration into the control fed mice ameliorated liver IRI, while FOXO1 inhibitor administration to the 12-h fasting group exacerbated liver IRI. The 12-h fasting exerted beneficial effects on the prevention of liver IRI by increasing BHB, thus up-regulating FOXO1 and HO-1, and by reducing the inflammatory responses and apoptotic cell death via the down-regulation of NF-κB and NLRP3 inflammasome.

The evaluation of the postoperative quality of life in patients undergoing radical gastrectomy for esophagogastric junction cancer using the Postgastrectomy Syndrome Assessment Scale-45: a nationwide multi-institutional study.

PURPOSE: This retrospective nationwide survey investigated the quality of life (QOL) of patients with esophagogastric junction cancer after gastrectomy using the Postgastrectomy Syndrome Assessment Scale-45. METHODS: The Postgastrectomy Syndrome Assessment Scale-45 comprises 45 questions classified into symptoms, living status, and QOL domains. A total of 1950 gastrectomized patients with upper-third gastric or esophagogastric junction cancer returned the completed forms. Among them, 224 eligible patients with esophagogastric junction cancer were selected, including 86, 120, and 18 patients who underwent total gastrectomy, proximal gastrectomy (reconstruction-esophagogastrostomy: 56; double-tract method: 51), and other procedures, respectively. RESULTS: The postoperative period was significantly shorter (47 ± 30 vs. 34 ± 30 months, p = 0.002), and the rates of early-stage disease and minimally invasive approaches significantly higher (both p < 0.001) in the proximal gastrectomy group than in the total gastrectomy group. Despite advantageous background factors for proximal gastrectomy, the postoperative QOL did not differ markedly between the groups. Compared to patients who underwent reconstruction with the double-tract method, patients who underwent esophagogastrostomy had significantly larger remnant stomachs but a similar QOL. CONCLUSION: Even with total gastrectomy, a postoperative QOL comparable to that with proximal gastrectomy can be maintained. Clarifying the optimal reconstruction methods for proximal gastrectomy for esophagogastric junction cancer is warranted. TRIAL REGISTRATION: This study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; registration number: 000032221).

The lectin-like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice.

Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin-like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion-induced liver damage in a dose-dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage.

Randomized phase II study of CPT-11 versus PTX versus each combination chemotherapy with S-1 for advanced gastric cancer that is refractory to S-1 or S-1 plus CDDP: OGSG0701.

BACKGROUND: To compare irinotecan-alone, paclitaxel-alone, and each combination chemotherapy with S-1 in patients with advanced gastric cancer (AGC) that is refractory to S-1 or S-1 plus cisplatin (SP). METHODS: Patients with AGC after first-line chemotherapy with S-1 or SP, or patients during adjuvant chemotherapy or within 26 weeks after adjuvant chemotherapy completion with S-1 with confirmed disease progression were eligible. Patients were randomly divided into four groups based on treatment: irinotecan-alone (irinotecan; 150 mg/m2, day 1, q14 days), paclitaxel-alone (paclitaxel; 80 mg/m2, days 1, 8, 15, q28 days), S-1 plus irinotecan (irinotecan; 80 mg/m2, days 1, 15, S-1; 80 mg/m2, days 1-21, q35 days), and S-1 plus paclitaxel (paclitaxel; 50 mg/m2, day1, 8, S-1; 80 mg/m2, days 1-14, q21 days). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS), response rate, and safety. RESULTS: From July 2008 to March 2012, 127 patients were enrolled. No difference in median OS was observed in the irinotecan vs. paclitaxel groups or in the monotherapy groups vs. the S-1 combination therapy groups. Median PFS was longer in the paclitaxel group compared with the irinotecan group (4.1 vs. 3.6 months, p = 0.035), although no difference was observed when comparing monotherapy vs. S-1 combination. The most common grade 3 to 4 hematological adverse events were neutropenia with no difference in incidence rate across the treatment groups. CONCLUSIONS: There was no difference in OS between irinotecan and paclitaxel no in OS prolongation of S-1 combination therapy in second-line chemotherapy.

[A case of metastatic gastric cancer showing long-term control with nivolumab after pseudoprogression].

The Japanese guidelines for the treatment of gastric cancer recommend nivolumab as third-line chemotherapy for metastatic gastric adenocarcinoma. We report a case in which long-term control of metastatic gastric adenocarcinoma was achieved with nivolumab after pseudoprogression. A man in his late 70s with advanced HER2-negative gastric cancer and liver metastasis underwent total gastrectomy to control tumor bleeding. He then underwent chemotherapy with S-1 plus oxaliplatin, followed by S-1 alone. After metastases in the liver and para-aortic and hilar lymph nodes regrew, the patient received ramucirumab plus paclitaxel as second-line chemotherapy, followed by third-line therapy with nivolumab. After four cycles of nivolumab, these metastases showed progression;however, the treatment was continued because levels of CA19-9 were decreased, and performance status was good. After five more cycles of nivolumab, the liver metastasis shrank, and CA19-9 levels decreased;therefore, we confirmed pseudoprogression. The patient suffered no immune-related adverse events and survived for 50 months after gastrectomy with 34 cycles of nivolumab treatment. Thus, at the beginning of treatment with an immune checkpoint inhibitor, oncologists must consider the possibility of pseudoprogression in cases of tumor growth associated with decreasing tumor marker levels and good performance status.

MAGE-A4, NY-ESO-1 and SAGE mRNA expression rates and co-expression relationships in solid tumours.

BACKGROUND: Cancer testis (CT) antigens are promising targets for cancer immunotherapies such as cancer vaccines and genetically modified adoptive T cell therapy. In this study, we evaluated the expression of three CT antigens, melanoma-associated antigen A4 (MAGE-A4), New York oesophageal squamous cell carcinoma 1 (NY-ESO-1) and sarcoma antigen gene (SAGE). METHODS: MAGE-A4, NY-ESO-1 and/or SAGE antigen expression in tumour samples was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Informed consent was obtained from individuals prior to study enrolment. RESULTS: In total, 585 samples in 21 tumour types were evaluated between June 2009 and March 2018. The positive expression rates of these CT antigens were as follows: MAGE-A4, 34.6% (range, 30.7-38.7); NY-ESO-1, 21.0% (range, 17.2-25.1); and SAGE, 21.8% (range, 18.5-25.4). The MAGE-A4 antigen was expressed in 54.9% of oesophageal cancers, 37.5% of head and neck cancers, 35.0% of gastric cancers and 34.2% of ovarian cancers; the NY-ESO-1 antigen was expressed in 28.6% of lung cancers, 25.3% of oesophageal cancers and 22.6% of ovarian cancers; and the SAGE antigen was expressed in 35.3% of prostate cancers, 32.9% of oesophageal cancers and 26.3% of ovarian cancers. The most common tumour type in this study was oesophageal cancer. MAGE-A4, NY-ESO-1 and SAGE antigen expression were assessed in 214 oesophageal cancer samples, among which 24 (11.2%) were triple-positive, 58 (27.1%) were positive for any two, 59 (27.6%) were positive for any one, and 73 (34.1%) were triple negative. CONCLUSIONS: Oesophageal cancer exhibited a relatively high rate of CT antigen mRNA expression positivity.

Five-year outcomes of a phase II study of adjuvant chemotherapy with S-1 plus docetaxel for stage III gastric cancer after curative D2 gastrectomy (OGSG1002).

BACKGROUND: Adjuvant S-1 monotherapy is standard of care for stage II and III gastric cancer (GC), but there is still a need to improve the efficacy of treatment for stage III disease. We conducted phase II study of eight cycles of S-1 plus docetaxel (DS) followed by S-1 monotherapy for up to 1 year after D2 gastrectomy for stage III GC. PATIENTS AND METHODS: Sixty-two patients with stage III GC were enrolled. They received oral S-1 (80 mg/m2/day) for 2 consecutive weeks and intravenous docetaxel (40 mg/m2) on day 1, repeated every 3 weeks for 8 cycles, followed by S-1 until 1 year postgastrectomy. Treatment safety, tolerability, and survival were evaluated. RESULTS: The completion rate for eight cycles of DS therapy was 77.4% [95% confidence interval (CI) 65.0-87.1%]. Subsequent S-1 monotherapy for 1 year was feasible in 71.0% (95% CI 58.1-81.8%) of patients. The incidence of neutropenia, leukopenia, anorexia, and fatigue of grade 3 or higher was 10% or higher. There were no treatment-related deaths. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 72.4% (95% CI 62.1-84.5%) and 60.0% (95% CI 48.8-73.9%), respectively. Subgroup analyses by disease stage showed 5-year OS and DFS rates of 74.5% (95% CI 60.7-91.5%) and 59.3% (95% CI 43.8-80.2%) for stage IIIA and 70.0% (95% CI 55.4-88.5%) and 60.0% (95% CI 44.8-80.4%) for stage IIIB, respectively. CONCLUSIONS: Adjuvant eight cycles of DS therapy might be safe and manageable and has promising OS and DFS for stage III GC.

A Phase 2 Study of Induction Chemotherapy Using Docetaxel, Cisplatin, and S-1 for Gastric Cancer with Peritoneal Metastasis (KUGC06).

BACKGROUND: The authors previously showed the significant efficacy of S-1 plus cisplatin for gastric cancer with limited peritoneal metastasis. They conducted a phase 2 study to evaluate the safety and efficacy of induction chemotherapy using a docetaxel, cisplatin, and S-1 (DCS) triplet regimen to treat gastric cancer with peritoneal metastasis. METHODS: The key eligibility criteria were gastric cancer with peritoneal metastasis or positive peritoneal cytology but no other distant metastases and capability of oral administration. The patients received three 28-day cycles of DCS (60 mg/m2 of cisplatin, 40 mg/m2 of docetaxel on day 1, and 80 mg/m2 of S-1 from day 1 to day 14), then underwent D2 gastrectomy if R0 was possible. The primary end point was the R0 resection rate. The sample size was determined to have 80% power for detecting a 20% improvement in the R0 resection rate over a 45% baseline for a one-tailed alpha of 0.1. RESULTS: Among 30 enrolled patients, 24 completed three cycles of DCS. The most frequent grade 3 or 4 toxicity was neutropenia (60%). A complete response of peritoneal metastasis was observed in 16 patients, and 14 patients achieved R0 resection (47%; 95% confidence interval 28-66%). When the extent of peritoneal metastasis was classified as P0CY1, P1, P2, and P3 according to the Japanese classification, the R0 resection rates were respectively 63%, 60%, 46% and 0%. CONCLUSIONS: Induction chemotherapy with DCS is safe and can achieve R0 resection for some patients with limited peritoneal metastasis or positive peritoneal cytology. The efficacy, however, appears similar to that of S-1 plus cisplatin.

A phase II study of neoadjuvant chemotherapy with S-1 and cisplatin for stage III gastric cancer: KUGC03.

OBJECTIVES: A multi-center phase II study was conducted to evaluate the safety and efficacy of neoadjuvant chemotherapy (NAC) with S-1 plus cisplatin for advanced gastric cancer. METHODS: The eligibility criteria were clinical T3/T4 or N2, not Stage IV. Patients received two 35-day cycles of S-1 plus cisplatin, and then underwent D2 gastrectomy. The primary endpoint was 3-year progression free survival (PFS). Secondary endpoints were ratio of R0 resection, response rate, adverse events, and overall survival. A sample size of 49 was determined to have 80% power for detecting 15% improvement in the 3-year PFS over 55% at a one-sided alpha of 0.1. RESULTS: Among 53 patients enrolled, 44 patients completed two cycles of NAC (83%), and 48 patients underwent R0 resection (91%). Postoperative complications occurred in 13 patients (26%). A pathological response was confirmed in 24 patients (45%), including four complete responses. The 3-year PFS was 50.7%, while the 3-year OS was 74.9%. CONCLUSIONS: Although the observed 3-year PFS rate was worse than expected, NAC with S1 plus cisplatin was safe and led to a high rate of R0 resection. A randomized controlled trial is needed to make conclusions about the effectiveness of NAC in Japanese patients undergoing D2 resection.

Long-term quality-of-life comparison of total gastrectomy and proximal gastrectomy by postgastrectomy syndrome assessment scale (PGSAS-45): a nationwide multi-institutional study.

BACKGROUND: Although proximal gastrectomy (PG) is widely accepted as a function-preserving operation for early upper-third gastric cancer, postoperative disorders, such as reflux or gastric stasis, have often been pointed out. From the perspective of postoperative disorder, the choice of total gastrectomy (TG) or PG for such cancers is still controversial. By using the newly developed Postgastrectomy Syndrome Assessment Scale (PGSAS)-45, the quality of life after TG and PG was compared. METHODS: The PGSAS-45 consists of 45 items composed of the SF-8 and GSRS scales and 22 new items. The main outcomes are measured by seven subscales (SS) covering symptoms, physical and mental component summary (SF-8), meals (amount and quality), ability to work, dissatisfaction for daily life, and change in body weight. A total of 2,368 eligible questionnaires were acquired from 52 institutions. From these, 393 patients with TG and 193 patients with PG were selected and compared. RESULTS: The PG was better than TG in terms of body weight loss (TG 13.8% vs. PG 10.9%; p = 0.003), necessity for additional meals (2.4 vs. 2.0; p < 0.001), diarrhea SS (2.3 vs. 2.0; p = 0.048), and dumping SS (2.3 vs. 2.0; p = 0.043). There were no differences in the other main outcome measures. CONCLUSIONS: Proximal gastrectomy appears to be valuable as a function-preserving procedure for early upper-third gastric cancer.

[Case report of disseminated carcinomatosis of the bone marrow originating from gastric cancer with cancer-related disseminated intravascular coagulation successfully treated with recombinant human soluble thrombomodulin].

A 62-year-old man, who underwent distal gastrectomy due to gastric cancer, was diagnosed with disseminated carcinomatosis of the bone marrow 8 years later. Chemotherapy was administered following treatment with recombinant human soluble thrombomodulin (rTM), and as a result, he successfully recovered from his disseminated intravascular coagulation (DIC) status and experienced improvement of his severe cancer-related pain. The use of rTM may enable the safe continuation of chemotherapy, and rTM may also be a useful treatment for DIC associated with solid cancer, such as gastric cancer.

Overcoming regulatory T-cell suppression by a lyophilized preparation of Streptococcus pyogenes.

Cancer vaccines have yet to yield clinical benefit, despite the measurable induction of humoral and cellular immune responses. As immunosuppression by CD4(+) CD25(+) regulatory T (Treg) cells has been linked to the failure of cancer immunotherapy, blocking suppression is therefore critical for successful clinical strategies. Here, we addressed whether a lyophilized preparation of Streptococcus pyogenes (OK-432), which stimulates Toll-like receptors, could overcome Treg-cell suppression of CD4(+) T-cell responses in vitro and in vivo. OK-432 significantly enhanced in vitro proliferation of CD4(+) effector T cells by blocking Treg-cell suppression and this blocking effect depended on IL-12 derived from antigen-presenting cells. Direct administration of OK-432 into tumor-associated exudate fluids resulted in a reduction of the frequency and suppressive function of CD4(+) CD25(+) Foxp3(+) Treg cells. Furthermore, when OK-432 was used as an adjuvant of vaccination with HER2 and NY-ESO-1 for esophageal cancer patients, NY-ESO-1-specific CD4(+) T-cell precursors were activated, and NY-ESO-1-specific CD4(+) T cells were detected within the effector/memory T-cell population. CD4(+) T-cell clones from these patients had high-affinity TCRs and recognized naturally processed NY-ESO-1 protein presented by dendritic cells. OK-432 therefore inhibits Treg-cell function and contributes to the activation of high-avidity tumor antigen-specific naive T-cell precursors.

[A case of locally advanced sigmoid colon cancer treated with neoadjuvant chemoradiotherapy].

The patient was a 38-year-old woman who visited our hospital complaining of nausea and abdominal pain. A colonoscopy revealed an advanced cancer in the sigmoid colon. A computed tomography (CT) scan showed left hydronephrosis and lymph node metastasis to the left iliopsoas muscle and left ureter. No distant metastasis was found. Since the surgical margins were likely to be positive with a one-stage resection, 3 cycles of FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin)were administered after creating a transverse loop colostomy. Although the tumor decreased in size, the surgical margins were still suspected to be positive. For further regional tumor control, radiotherapy (1.8 Gy/day for 25 days) to the medial region of the left iliac bone and oral UFT/LV (uracil and tegafur/Leucovorin)were administered. A partial response(PR)was determined in accordance with the Response Evaluation Criteria in Solid Tumors(RECIST). Sigmoidectomy with partial resection of the left ureter was performed by laparotomy. The histologic response was assessed as Grade 2 and all surgical margins were negative. Preoperative chemoradiotherapy may be an effective therapeutic option for locally advanced colon cancer resistant to conventional preoperative chemotherapy.

[Hepatic resection for local recurrence after radiofrequency ablation therapy for colorectal liver metastases].

Patients who underwent hepatic resection of locally recurrent tumors after radiofrequency ablation(RFA)for colorectal liver metastases (CRLM) were retrospectively investigated. Among 12 patients who underwent RFA as first-line treatment for CRLM, 7 experienced local recurrence, 5 of whom (6 nodules) underwent hepatic resection. The mean diameter (range) of the tumors was 9.5(5-16) mm, and they were located at S2, S7 (adjacent to the right hepatic vein), S5/6 (between the root of the anterior and the posterior Glisson's pedicle), S1r (right paracaval portion), S6, and S3. No local recurrence was observed after hepatic resection. In conclusion, hepatic resection must be the initial therapeutic strategy for CRLM, and the indication for RFA must be considered carefully.

Dose-dependent effects of NY-ESO-1 protein vaccine complexed with cholesteryl pullulan (CHP-NY-ESO-1) on immune responses and survival benefits of esophageal cancer patients.

BACKGROUND: Cholesteryl pullulan (CHP) is a novel antigen delivery system for cancer vaccines. This study evaluated the safety, immune responses and clinical outcomes of patients who received the CHP-NY-ESO-1 complex vaccine, Drug code: IMF-001. METHODS: Patients with advanced/metastatic esophageal cancer were enrolled and subcutaneously vaccinated with either 100 µg or 200 µg of NY-ESO-1 protein complexed with CHP. The primary endpoints were safety and humoral immune responses, and the secondary endpoint was clinical efficacy. RESULTS: A total of 25 patients were enrolled. Thirteen and twelve patients were repeatedly vaccinated with 100 µg or 200 µg of CHP-NY-ESO-1 with a median of 8 or 9.5 doses, respectively. No serious adverse events related to the vaccine were observed. Three out of 13 patients in the 100-µg cohort and 7 out of 12 patients in the 200-µg cohort were positive for anti-NY-ESO-1 antibodies at baseline. In the 100-µg cohort, an antibody response was observed in 5 out of 10 pre-antibody-negatives patients, and the antibody levels were augmented in 2 pre-antibody-positive patients after vaccination. In the 200-µg cohort, all 5 pre-antibody-negative patients became seropositive, and the antibody level was amplified in all 7 pre-antibody-positive patients. No tumor shrinkage was observed. The patients who received 200 µg of CHP-NY-ESO-1 survived longer than patients receiving 100 µg of CHP-NY-ESO-1, even those who exhibited unresponsiveness to previous therapies or had higher tumor burdens. CONCLUSIONS: The safety and immunogenicity of CHP-NY-ESO-1 vaccine were confirmed. The 200 µg dose more efficiently induced immune responses and suggested better survival benefits. (Clinical trial registration number NCT01003808).

Effects of rikkunshito, a kampo medicine, on quality of life after proximal gastrectomy.

BACKGROUND: The loss of the gastroesophageal junction after proximal gastrectomy (PG) induces various gastrointestinal symptoms, such as regurgitation, anorexia, and body weight loss, leading to impairment of the postoperative quality of life. In the present study, we investigated the long-term quality of life and the effects of rikkunshito, a traditional Japanese medicine (kampo), on the gastrointestinal symptoms and plasma ghrelin levels in patients with gastric cancer who had undergone PG. METHODS: Nineteen patients who had undergone PG> 6 mo before entry into the present study were enrolled. The plasma ghrelin levels, body weight, appetite, and Gastrointestinal Symptom Rating Scale (GSRS) scores were examined before and after the 4-wk administration of rikkunshito. A subgroup analysis was performed of patients showing a GSRS score of ≥ 2 before treatment, indicating the presence of gastrointestinal symptoms. RESULTS: The patients' body weight increased significantly after the administration of rikkunshito. Neither their appetite nor plasma acylated and deacylated ghrelin levels were significantly affected. In the subgroup analysis, the mean total GSRS score improved significantly from 2.6 ± 0.6 before the administration of rikkunshito to 1.9 ± 0.7 after administration because of the significant improvement in the subscale scores for abdominal pain, acid reflux, diarrhea, and constipation. CONCLUSIONS: The long-term quality of life was well preserved in the patients who had undergone PG at our hospital. In the patients with a baseline GSRS score of ≥2, rikkunshito significantly improved the symptoms of postgastrectomy syndrome, and its effect was possibly independent of the plasma ghrelin levels.

Phase II trial of combined treatment consisting of preoperative S-1 plus cisplatin followed by gastrectomy and postoperative S-1 for stage IV gastric cancer.

BACKGROUND: To improve the poor prognosis in patients with stage IV (StIV) gastric cancer (GC), we conducted a multicenter phase II study of preoperative S-1 plus cisplatin followed by gastrectomy and postoperative S-1 for StIV GC (the protocol is registered at the clinical trial site of the National Cancer Institute; KYUH-UHA-GC03-01, NCT00088816). METHODS: Eligibility criteria included histologically proven StIVGC. Patients received S-1 (80 mg/m(2)/day, days 1-21) plus cisplatin (60 mg/m(2) on day 8) for 2 courses. After preoperative chemotherapy (CTx), radical gastrectomy was performed. Postoperative S-1 (80 mg/m(2)/day, days 1-14) was administered every 3 weeks for 1 year. RESULTS: Fifty-one patients were enrolled and all patients were followed for more than 2 years. The 2-year overall survival and progression-free survival rates were 43.1% (95% confidence interval [CI] 29.4-56.1%) and 33.3% (95% CI 20.9-46.2%), respectively. Preoperative chemotherapy was accomplished in 44 patients (86.3%). These 44 patients underwent surgery and R0 resection was achieved in 26. The rate of R0 resection for GC with a single StIV factor (n = 24) was 79.2% and that for GC with multiple StIV factors (n = 27) was 25.9%. All patients with cancer cells in peritoneal washings (cytology [Cy] 1) alone (n = 12) became Cy0 after preoperative chemotherapy. Postoperative chemotherapy was completed in 11 patients, including 8 with Cy1 alone. No treatment-related death was recorded. Recurrences were observed in 14 patients after R0 resection. The most frequent recurrence site was the peritoneum. Patients who underwent R0 resection and those with Cy1 alone had a better survival. CONCLUSIONS: This perioperative treatment was safe and feasible for StIVGC but failed to show a survival benefit. In patients with StIVGC with Cy1 alone this treatment resulted in a better prognosis.