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.

Propionic Acid, Induced in Gut by an Inulin Diet, Suppresses Inflammation and Ameliorates Liver Ischemia and Reperfusion Injury in Mice.

Liver ischemia and reperfusion injury (IRI) is one of the obstacles in liver surgery such as liver resection and transplantation. In this study, we investigated the preventive effect on mouse liver IRI by feeding mice with inulin, which is a heterogeneous blend of indigestible fructose polymer. Mice were fed either a control ordinary diet (CD) or an inulin diet (ID) containing 5% inulin in the CD, for 14 days before the ischemia and reperfusion (IR) maneuver. IR induced-liver damages were significantly ameliorated in the ID group, compared with those in the CD group. Feeding mice with an ID, but not a CD, elevated levels of Bacteroidetes among gut microbiota, and especially increased Bacteroides acidifaciens in mouse feces, which resulted in significant elevation of short-chain fatty acids (SCFAs) in the portal vein of mice. Among SCFAs, propionic acid (PA) was most significantly increased. The microbial gene functions related to PA biosynthesis were much higher in the fecal microbiome of the ID group compared to the CD. However, the action of PA on liver IRI has not been yet clarified. Direct intraperitoneal administration of PA alone prior to the ischemia strongly suppressed liver cell damages as well as inflammatory responses caused by liver IR. Furthermore, PA suppressed the secretion of inflammatory cytokines from peritoneal macrophages stimulated in vitro through TLR-4 with high-mobility group box 1 protein (HMGB-1), known to be released from apoptotic liver cells during the IR insult. The present study shows that PA may play a key role in the inulin-induced amelioration of mouse liver IRI.

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.

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).

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.

Randomized phase II study of docetaxel versus paclitaxel in patients with esophageal squamous cell carcinoma refractory to fluoropyrimidine- and platinum-based chemotherapy: OGSG1201.

BACKGROUND: There is no standard chemotherapy for esophageal squamous cell carcinoma (ESCC) refractory to first-line fluoropyrimidine- and platinum-based chemotherapy. We therefore performed a randomized, selection-design phase II trial to compare docetaxel (DTX) and paclitaxel (PTX) in this setting. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive either DTX (70 mg/m2 on day 1 of each 21-day cycle) or PTX (100 mg/m2 on days 1, 8, 15, 22, 29 and 36 of each 49-day cycle). The primary end-point was overall survival (OS), and secondary end-points included progression-free survival (PFS), time to treatment failure (TTF), response rate (RR) and safety. RESULTS: Seventy-eight eligible patients (N = 39 in each group) were included for efficacy analysis. OS was significantly longer in the PTX group than in the DTX group (median, 8.8 versus 7.3 months; hazard ratio [HR], 0.62; P = 0.047). A significant benefit of PTX over DTX was also apparent in PFS (median, 4.4 versus 2.1 months; HR, 0.49; P = 0.002) and TTF (median, 3.8 versus 2.1 months; HR, 0.45; P < 0.001). RR (25.6% versus 7.7%, P = 0.065) were higher in the PTX group than in the DTX group. Compared to the PTX group, neutropenia (28% versus 80%) and leukopenia (28% versus 76%) of grade ≥3 as well as febrile neutropenia (0% vs. 46%, P < 0.0001) occurred more frequently in the DTX group. CONCLUSION: PTX showed a significantly better efficacy as well as a more manageable toxicity compared with DTX. CLINICAL TRIAL REGISTRATION: UMIN000007940.

[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.

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.

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.

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.

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.

Preventive Effect of Antioxidative Nutrient-Rich Enteral Diet Against Liver Ischemia and Reperfusion Injury.

BACKGROUND: Liver ischemia and reperfusion injury (IRI) is a major problem associated with liver surgery. This study is aimed to compare the preventive effect of an antioxidative nutrient-rich enteral diet (Ao diet) with an ordinal enteral diet (control diet) against liver IRI. METHODS: The Ao diet was an ordinary diet comprising polyphenols (catechin and proanthocyanidin) and enhanced levels of vitamins C and E. Male C57BL/6 mice were fed the Ao or control diet for 7 days before ischemic insult for 60 minutes, followed by reperfusion for 6 hours. The levels of inflammatory cytokines, chemokines, and antioxidant enzymes and oxidative stress were evaluated. RESULTS: After 7 days of pretreatment with the Ao diet, the serum levels of vitamins C and E in mice were markedly elevated. The levels of serum aspartate aminotransferase and alanine aminotransferase, as well as the scores of liver necrosis caused by ischemia and reperfusion, were significantly lower in the Ao diet group than in the control diet group. The gene expression levels of inflammatory cytokines and chemokines, such as interleukin-6 and CXCL1, were significantly lower in the Ao diet group. In the liver, the levels of antioxidant enzymes superoxide dismutase 1 (SOD1) and SOD2 were significantly higher and the malondialdehyde levels were significantly lower in the Ao diet group. Cell adhesion molecule expression was significantly lower, and neutrophil and macrophage infiltration was less in the Ao diet group. CONCLUSIONS: Antioxidative nutrient supplementation to an ordinary enteral diet may mitigate liver IRI by causing an antioxidant effect and suppressing inflammation.

NY-ESO-1 antigen expression and immune response are associated with poor prognosis in MAGE-A4-vaccinated patients with esophageal or head/neck squamous cell carcinoma.

MAGE-A4 antigen is a cancer-testis antigen that is frequently expressed in tumor tissues. 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 a CHP-MAGE-A4 vaccine. Twenty-two patients with advanced or metastatic cancer were enrolled, and were subcutaneously vaccinated with either 100 µg or 300 µg of CHP-MAGE-A4. Seven and 15 patients, respectively, were repeatedly vaccinated with 100 µg or 300 µg of CHP-MAGE-A4; patients in both groups received a median of 7 doses. No serious adverse events related to the vaccine were observed. Of 7 patients receiving the 100 µg dose, 2 (29%) showed immune responses, compared with 3 of the 14 (21%) patients who received the 300 µg dose. In total, MAGE-A4-specific antibody responses were induced in 5 of 21 (24%) patients. No differences in survival were seen between patients receiving the 100 µg and 300 µg doses, or between immune responders and non-responders. Eleven (50%) patients had pre-existing antibodies to NY-ESO-1. In 16 patients with esophageal or head/neck squamous cell carcinoma, the survival time was significantly shorter in those who had NY-ESO-1-co-expressing tumors. Patients with high pre-existing antibody responses to NY-ESO-1 displayed worse prognosis than those with no pre-existing response. Therefore, in planning clinical trials of MAGE-A4 vaccine, enrolling NY-ESO-1-expressing tumor or not would be a critical issue to be discussed. Combination vaccines of MAGE-A4 and NY-ESO-1 antigens would be one of the strategies to overcome the poor prognosis.

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.

Enhanced Expression of Fibroblast Growth Factor Receptor 3 IIIc Promotes Human Esophageal Carcinoma Cell Proliferation.

Deregulated expression of fibroblast growth factor receptors (FGFRs) and their ligands plays critical roles in tumorigenesis. The gene expression of an alternatively spliced isoforms of FGFR3, FGFR3IIIc, was analyzed by RT-PCR in samples from patients with esophageal carcinoma (EC), including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). The incidence of FGFR3IIIc was higher in EC [12/16 (75%); p=0.073] than in non-cancerous mucosa (NCM) [6/16 (38%)]. Indeed, an immunohistochemical analysis of early-stage ESCC showed that carcinoma cells expressing FGFR3IIIc stained positively with SCC-112, a tumor marker, and Ki67, a cell proliferation marker, suggesting that the expression of FGFR3IIIc promotes cell proliferation. We used EC-GI-10 cells endogenously expressing FGFR3IIIc as a model of ESCC to provide mechanistic insight into the role of FGFR3IIIc in ESCC. The knockdown of endogenous FGFR3 using siRNA treatment significantly abrogated cell proliferation and the overexpression of FGFR3IIIc in cells with enhanced cell proliferation. EC-GI-10 cells and ESCC from patients with EC showed endogenous expression of FGF2, a specific ligand for FGFR3IIIc, suggesting that the upregulated expression of FGFR3IIIc may create autocrine FGF signaling in ESCC. Taken together, FGFR3IIIc may have the potential to be an early-stage tumor marker and a molecular target for ESCC therapy.

Adoptive Transfer of MAGE-A4 T-cell Receptor Gene-Transduced Lymphocytes in Patients with Recurrent Esophageal Cancer.

PURPOSE: Preparative lymphodepletion, the temporal ablation of the immune system, has been reported to promote persistence of transferred cells along with increased rates of tumor regression in patients treated with adoptive T-cell therapy. However, it remains unclear whether lymphodepletion is indispensable for immunotherapy with T-cell receptor (TCR) gene-engineered T cells. EXPERIMENTAL DESIGN: We conducted a first-in-man clinical trial of TCR gene-transduced T-cell transfer in patients with recurrent MAGE-A4-expressing esophageal cancer. The patients were given sequential MAGE-A4 peptide vaccinations. The regimen included neither lymphocyte-depleting conditioning nor administration of IL2. Ten patients, divided into 3 dose cohorts, received T-cell transfer. RESULTS: TCR-transduced cells were detected in the peripheral blood for 1 month at levels proportional to the dose administered, and in 5 patients they persisted for more than 5 months. The persisting cells maintained ex vivo antigen-specific tumor reactivity. Despite the long persistence of the transferred T cells, 7 patients exhibited tumor progression within 2 months after the treatment. Three patients who had minimal tumor lesions at baseline survived for more than 27 months. CONCLUSIONS: These results suggest that TCR-engineered T cells created by relatively short-duration in vitro culture of polyclonal lymphocytes in peripheral blood retained the capacity to survive in a host. The discordance between T-cell survival and tumor regression suggests that multiple mechanisms underlie the benefits of preparative lymphodepletion in adoptive T-cell therapy.

[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.

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.