Ryohei Kawabata

Antibody response against NY‐ESO‐1 in CHP‐NY‐ESO‐1 vaccinated patients

NY‐ESO‐1 specific humoral responses are frequently observed in patients with various types of NY‐ESO‐1 antigen expressing tumors. In a large proportion of NY‐ESO‐1 antibody‐positive patients of NY‐ESO‐1‐specific CD8 T‐cells can also be detected suggesting that monitoring of the NY‐ESO‐1 specific humoral immune response may be a relevant and more practical surrogate for estimating the overall immune response against NY‐ESO‐1 in clinical vaccine studies. We have immunized 9 cancer patients with full length NY‐ESO‐1 protein formulated with cholesterol‐bearing hydrophobized pullulan (CHP‐NY‐ESO‐1) and investigated the humoral immune responses against NY‐ESO‐1. Seven patients were NY‐ESO‐1 antibody‐negative and 2 patients were positive prior to vaccination. Vaccination with CHP‐NY‐ESO‐1 resulted in the induction or increase of NY‐ESO‐1 antibody responses in all 9 patients immunized. Epitope analysis revealed 5 regions in the NY‐ESO‐1 protein molecule that were recognized by antibodies induced after vaccination. The 5 regions were also recognized by antibodies present in nonvaccinated, NY‐ESO‐1 antibody‐positive cancer patients. A peptide spanning amino acids 91–108 was recognized in 6 out of 9 vaccinated patients and in 8 out of 9 nonvaccinated, sero‐positive patients, being the most dominant antigenic epitope in NY‐ESO‐1 for antibody recognition in cancer patients. In conclusion, we showed that CHP‐NY‐ESO‐1 protein vaccination had a potent activity for inducing humoral immune responses against NY‐ESO‐1 antigen in cancer patients. The antigenic epitopes recognized by antibodies in the vaccinated patients were similar to those recognized in cancer patients with spontaneous humoral immunity against NY‐ESO‐1.

NY-ESO-1 antibody as a novel tumour marker of gastric cancer.

Background:NY-ESO-1 antibodies are specifically observed in patients with NY-ESO-1-expressing tumours. We analysed whether the NY-ESO-1 humoral immune response is a useful tumour marker of gastric cancer.Methods:Sera from 363 gastric cancer patients were screened by enzyme-linked immunosorbent assay (ELISA) to detect NY-ESO-1 antibodies. Serial serum samples were obtained from 25 NY-ESO-1 antibody-positive patients, including 16 patients with curative resection and 9 patients who received chemotherapy alone.Results:NY-ESO-1 antibodies were detected in 3.4% of stage I, 4.4% of stage II, 25.3% of stage III, and 20.0% of stage IV patients. The frequency of antibody positivity increased with disease progression. When the NY-ESO-1 antibody was used in combination with carcinoembryonic antigen and CA19-9 to detect gastric cancer, information gains of 11.2% in stages III and IV, and 5.8% in all patients were observed. The NY-ESO-1 immune response levels of the patients without recurrence fell below the cutoff level after surgery. Two of the patients with recurrence displayed incomplete decreases. The nine patients who received chemotherapy alone continued to display NY-ESO-1 immune responses.Conclusion:When combined with conventional tumour markers, the NY-ESO-1 humoral immune response could be a useful tumour marker for detecting advanced gastric cancer and inferring the post-treatment tumour load in seropositive patients.

Analysis of peripheral and local anti-tumor immune response in esophageal cancer patients after NY-ESO-1 protein vaccination.

NY‐ESO‐1 antigen is a prototype of a class of cancer/testis antigens. We carried out a clinical trial using NY‐ESO‐1 whole protein as a cancer vaccine for 13 advanced cancer patients. We have recently reported that vaccine elicited humoral and cellular immune responses in 9 cancer patients including 4 esophageal cancer patients, and clinical responses were also observed in 4 of 5 evaluable patients. In this study, we analyzed the responses in 8 esophageal cancer patients including 4 newly enrolled patients. Patients were injected subcutaneously at biweekly intervals with NY‐ESO‐1 recombinant protein formulated with cholesterol‐bearing hydrophobized pullulan. Induction of antibody, and CD4 and CD8 T‐cell responses were observed in 7, 7 and 6 patients, respectively, out of 8 patients. 1 PR, 2 SD and 2 mixed clinical responses were observed in 6 evaluable patients. No significant adverse events were observed. Furthermore, we analyzed NY‐ESO‐1 and MHC class I expression and the infiltration of immune cells into tumor samples obtained before and after vaccination from 4 patients by immunohistochemistry. The results showed 2 patients with disappearance of CD4 and CD8 T‐cell infiltration, 1 patient with increase in the number of CD68+ macrophages and 1 patient with tumor antigen loss in the progressive tumors following vaccinations. The induction of NY‐ESO‐1 immunity and some preferable clinical outcomes were observed in esophageal cancer patients by vaccination with NY‐ESO‐1. However, the tumors grew eventually by various mechanisms after vaccination.

Clinical Trial of the Intratumoral Administration of Labeled DC Combined With Systemic Chemotherapy for Esophageal Cancer

Esophageal cancer is a highly aggressive disease, and improved modalities for its treatment are needed. We performed chemoimmunotherapy involving the intratumoral administration of 111In-labeled dendritic cells (DC) in combination with preoperative chemotherapy in 5 esophageal cancer patients. Mature DC were generated and traced by scintigraphy after their administration. No adverse events that were directly related to the intratumoral DC administration were observed. Delayed-type hypersensitivity skin tests against keyhole limpet hemocyanin, which was added to the culture medium, detected a positive response in 3 patients, and keyhole limpet hemocyanin antibody production was observed in 4 patients, suggesting that intratumorally administered DC migrate to the lymph nodes, where they function as antigen-presenting cells. However, scintigraphic images obtained after the DC administration demonstrated that the DC remained at the esophageal tumor injection sites in all cases, and no DC accumulation was observed elsewhere. The accumulation of CD83+ cells in the primary tumor was also observed in 2 out of 4 patients in an immunohistochemical analysis using surgically resected specimens. Although the induction of tumor-specific immune responses during chemoimmunotherapy was also analyzed in enzyme-linked immunosorbent assay against 28 tumor antigens, none of the antibodies against the antigens displayed enhanced titers. No changes of NY-ESO-1-specific cellular immune response was observed in a patient who displayed NY-ESO-1 antibody production before the DC administration. These results suggest that the intratumoral administration of 111In-labeled mature DC during chemotherapy does not lead to detectable DC migration from the primary tumor to the draining lymph nodes, and therefore, might not achieve an optimal clinical response.

Living-related liver transplantation with renoportal anastomosis for a patient with large spontaneous splenorenal collateral.

Background. A large splenorenal collateral must be interrupted during liver transplantation to secure adequate portal perfusion. However, this process increases the complexity of the operative procedure and may cause hazardous bleeding. Recently, renoportal anastomosis in portal reconstruction was reported in cadaveric liver transplantation for patients with surgically created splenorenal shunts. We used this technique in a living-related liver transplantation. Methods. A 29-year-old female with a large spontaneous splenorenal collateral and a portal venous thrombus underwent a living-related liver transplantation. At surgery, the left renal vein was divided and the distal stump was anastomosed to the portal vein of the graft without interrupting collaterals. Results. Adequate portal venous blood flow was maintained throughout the postoperative course. The patient was discharged 9 weeks after transplantation and remains well. Conclusion. The renoportal anastomosis could be used for portal reconstruction in living-related liver transplantation for patients with a large splenorenal collateral. It provides adequate portal perfusion without interrupting collateral circulation.

A suspected [18F]fluorodeoxyglucose positron emission tomography-negative metastatic lymph node successfully diagnosed by laparoscopic staging in esophageal cancer: Report of two cases

An accurate preoperative staging is important for selecting an appropriate therapy for esophageal cancer. In particular, diagnosis of lymph node metastases influences the indication for radical surgery. [18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) has been widely applied primarily as a useful tool for initial staging of esophageal cancer. However, false-negative cases sometimes make it difficult to select the appropriate treatment. We report two patients with esophageal cancer and PET-negative enlarged lymph node successfully diagnosed by laparoscopic sampling. This procedure did not only allow accurate histopathological staging, but also helped to select the optimal minimally invasive management. This technique can be recommended for patients with esophageal cancer in whom the diagnosis of enlarged lymph node cannot be confirmed by preoperative imaging.

Evaluation of the effects of postoperative oral nutrition support on body weight in gastric cancer patients by using an elemental diet: A randomized study.

110 Background: Postoperative weight loss causes deterioration in the patient’s quality of life and influences long-term prognosis in gastric cancer patients who have undergone gastrectomy. Moreover, recent retrospective studies indicated postoperative weight loss as a risk factor for premature interruption of S-1 adjuvant chemotherapy. We conducted a prospective randomized controlled study to examine whether the early institution of nutritional support comprising an oral elemental diet (ED) prepared for post-gastrectomy patients with depressed digestive/absorptive function would help prevent postoperative weight loss. Methods: After surgery, patients were randomly assigned to the ED or control groups. The groups were divided according to the surgical methods used (total/distal gastrectomy), clinical stage (≤Ia/>Ia), and patients’ body mass index ( 18.5). In patients assigned to the ED group (Elental, 300 kcal) was provided in addition to the regular diet from the day starting soft rice diet or equi...

Multicenter phase II study of combination therapy with paclitaxel, cisplatin, and S-1 for adavanced gastric cancer (OGSG0703).

e14654 Background: A multicenter phaseII study was conducted to evaluate the efficacy and safety of a combination regimen (PCS) with paclitaxel, cisplatin, and S-1 in patients with advanced gastric cancer in an outpatient setting. METHODS Patients with previously untreated metastatic or recurrent gastric cancer received intravenous paclitaxel at 70 mg/m2 and cisplatin at 30 mg/m2 on days 1 and 15, plus oral S-1 at 40 mg/m2 b.i.d. on days 1 to 21,followed by 2 weeks off, in a 35-day cycle. RESULTS A total of 52 patients were enrolled in this study, among whom 49 were assessable for efficacy and 51 assessable for toxicity. The overall response rate was 46.9% (95% CI: 32.5-61.7%). The median progression-free survival and median overall survival were 5.4 months (95% CI:4.1-7.0) and 11.5 months (95% CI:7.3-16.1), respectively. Frequent grade 3/4 toxic effects included neutropenia (51%), leucopenia (25%), anemia (20%), hyponatremia (16%), anorexia (14%), and fatigue (10%). There was no treatment-related death. CONCLUSIONS In this study, the predicted response rate was not achieved employing this combination regimen with paclitaxel, cisplatin, and S-1, although it was found to be well- tolerated.