Kaoru Okada

Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer

The aim of this study was to evaluate the safety and efficacy of vaccination with human leukocyte antigen (HLA)-A24-restricted human vascular endothelial growth factor receptor 1 (VEGFR1)-1084 and VEGFR2-169 combined with chemotherapy in patients with advanced gastric cancer. HLA-A 2402-positive patients with advanced or recurrent adenocarcinoma of the stomach were vaccinated with VEGFR1-1084 and VEGFR2-169 combined with S-1 and cisplatin. The study included 22 patients (median age 60.5 years) who received at least one cycle of the combination therapy. No severe adverse effects caused by the vaccine therapy were observed except for an inflammatory reaction at the site of injection in 6 patients. Twelve patients (55%) showed partial response and 10 had stable disease after two cycles of the combination therapy. The disease control rate (partial response and stable disease) was 100% after two cycles. The median time to progression was 9.6 months and median overall survival was 14.2 months. VEGFR1-1084-specific cytotoxic T lymphocyte (CTL) response was induced in 18 (82%) of the 22 patients and VEGFR2-169-specific CTL response was induced in 18 (82%) of the 22 patients. Patients showing CTL response to VEGFR2-169 peptide had significantly better prognosis than those without, as demonstrated by the overall survival (OS) and time to progression (TTP) (OS, p=0.028, TTP, p=0.006). The combination therapy was well tolerated and highly effective in advanced or recurrent gastric cancer. Substantial specific CTL for both peptides was frequently induced even under chemotherapy. Thus, cancer vaccination combined with standard chemotherapy warrants further analysis as a promising strategy for the treatment of advanced cancer.

Oncofetal protein, IMP-3, a potential marker for prediction of postoperative peritoneal dissemination in gastric adenocarcinoma.

The aim of this study was to determine the expression of insulin‐like growth factor‐II messenger RNA (mRNA)‐binding protein‐3 (IMP‐3) and its clinical significance in gastric cancers, as well the prognostic value of its expression in the peritoneal lavage fluid after surgery.

REGIV as a potential biomarker for peritoneal dissemination in gastric adenocarcinoma.

This study examined the clinical significance of regenerating islet‐derived family member 4 (REGIV) in surgically resected gastric tumors. The potential of REGIV as a biomarker in gastric cancer was also assessed including its predictive value for prognosis and recurrence after surgery.

The clinical importance of a transcription reverse-transcription concerted (TRC) diagnosis using peritoneal lavage fluids in gastric cancer with clinical serosal invasion: a prospective, multicenter study.

PURPOSE We have developed a novel molecular method of diagnosis using the technique of transcriptase-reverse transcriptase concerted reaction (TRC) for the detection of cancer micrometastasis. This study prospectively examined the clinical importance of the TRC diagnosis with peritoneal lavage fluids collected from gastric cancer operations at multiple institutes. METHODS TRC amplification targeting carcinoembryonic antigen mRNA was applied to detect gastric cancer cells in peritoneal lavage fluids obtained during gastric cancer resections from nine different hospitals. A total of 137 patients with a clinical diagnosis of serosa-invading neoplasms were enrolled to investigate the correlation between the TRC diagnosis and patient prognosis. RESULTS Of the 137 patients, 27 (20%) were positive by cytologic examination. In contrast, TRC targeting carcinoembryonic antigen mRNA was positive in 59 of 137 (54%) patients. TRC positivity was associated with a poorer overall survival in all patients and in the 104 patients who underwent a curative operation. TRC positivity also was associated with the peritoneal recurrence-free survival rate in the 104 curative cases. Multivariate analysis showed that TRC positivity and the pathologic N factor were prognostic factors for the overall survival time. CONCLUSION Our prospective multicenter study showed that the TRC test using peritoneal lavage fluids could be a potential prognostic factor to predict patient survival and peritoneal recurrence with clinically diagnosed, serosa-invading gastric cancer.

Pilot study of a combination of S-1 and paclitaxel for patients with peritoneal metastasis from gastric cancer

BackgroundThis pilot study was carried out to evaluate the efficacy of chemotherapy for patients with peritoneal dissemination from gastric cancer or positive lavage cytology diagnosed by staging laparoscopy.MethodsSixteen patients were enrolled. Paclitaxel was administered at 120 mg/m2 on day 1 and S-1 was administered orally at 80 mg/m2 for 14 consecutive days, followed by a 1-week rest, as one course. After five courses of this therapy, the primary gastric tumors were evaluated and second-look laparoscopy was performed for patients showing partial response or stable disease with clinical benefit.ResultsPartial response or stable disease with clinical benefit was confirmed in seven and five patients, respectively, and these patients underwent second-look laparoscopy. No viable cancer cells were detected on cytopathological investigation during second-look laparoscopy in 9 patients who underwent surgical treatment. The intent-to-treat response rate for gastric tumor was 44% and the rate of disappearance of peritoneal metastasis was 38% (6 cases) at surgery. The median survival time was 555 days. Leucopenia of grade 3 and neutropenia of grade 3 were recognized in two and three patients, respectively.ConclusionThis chemotherapy regimen may be an acceptable option for patients with peritoneal dissemination. We plan to study this regimen further in gastric cancer patients with peritoneal dissemination.

Intraperitoneal administration of paclitaxel and oral S-1 for a patient with peritoneal dissemination and hydronephrosis due to advanced gastric cancer

We report a patient with type 3 gastric cancer with peritoneal dissemination and hydronephrosis who was successfully treated with intraperitoneal infusion of paclitaxel and oral administration of S-1. He was diagnosed with unresectable gastric cancer with severe peritoneal dissemination by staging laparoscopy. We selected combined chemotherapy with both paclitaxel and S-1. Paclitaxel at 60 mg/m2 was administered intraperitoneally on days 1 and 8, and S-1 at 100 mg/body was administered orally for 14 days, followed by 7 days’ rest, as one course. After five courses, primary tumor reduction was confirmed and no cancer cells were detected on pathocytological investigation at second-look laparoscopy. The patient underwent total gastrectomy with lymph node dissection. He died from liver metastasis 29 months after the initial treatment, but he had not suffered from peritoneal metastases and had kept a good quality of life (QOL) since that treatment. This chemotherapy can be applied as one of the promising candidates for the treatment of patients with peritoneal metastasis of gastric cancer.

Pilot study of intraperitoneal administration of paclitaxel and oral S-1 for patients with peritoneal metastasis due to advanced gastric cancer

BackgroundThere is no standard treatment for peritoneal dissemination from gastric cancer. A novel combination chemotherapy has been introduced for patients with advanced gastric cancer with peritoneal metastasis.MethodsThis pilot study was performed on four patients to confirm safety and efficacy. They were diagnosed with unresectable gastric cancer with severe peritoneal dissemination by staging laparoscopy, or with metastasis to the transverse colon. We selected combined chemotherapy with both paclitaxel and S-1. Paclitaxel at 60 mg/m2 or 60 mg/body was administered intraperitoneally on days 1 and 8 and S-1, at 80–120 mg/body, was administered orally for 14 days followed by 7 days’ rest, as one course. After five courses of this therapy, the primary gastric tumors were evaluated by conventional examinations, and second-look laparoscopy was performed to assess the efficacy of the treatment against the peritoneal metastases.ResultsAfter five courses, primary tumor reductions were confirmed, and no cancer cells were detected on pathocytological investigation during second-look laparoscopy in any of the patients. Three patients underwent total gastrectomy with lymph node dissection and one underwent left upper abdominal evisceration. Final histological staging showed two stage 3 and two stage 4 patients. The intraperitoneal administration of paclitaxel and the oral administration of S-1 were well tolerated. Three patients died, at 8, 15, and 29 months, respectively, after the initial treatment, and one has been alive for 54 months without recurrence.ConclusionThis chemotherapy can be used in the treatment of patients with peritoneal metastasis of gastric cancer.

Expression of insulin-like growth factor-II mRNA-binding protein-3 as a marker for predicting clinical outcome in patients with esophageal squamous cell carcinoma

Insulin-like growth factor-II mRNA-binding protein-3 (IMP3) is an important factor in carcinogenesis, although its clinical significance in esophageal squamous cell carcinoma (ESCC) remains unknown. The present study investigated the associations between IMP3 expression and the clinicopathological parameters. IMP3 expression was assessed in 191 resected ESCC specimens, and the associations between IMP3 expression in ESCC, the clinicopathological parameters and patient prognosis were examined. Using immunohistochemistry, 113 (59.2%) tumors were identified as IMP3-positive. IMP3 positivity correlated significantly with high pathological (p)Stage, pT stage and pN stage. The IMP3-positive patients exhibited a poorer prognosis compared with the IMP3-negative patients. In univariate analyses, histology [hazard ratio (HR), 1.94; 95% confidence interval (CI), 1.18–3.49; P=0.0082], pT (HR, 2.34; 95% CI, 1.55–3.62; P<0.0001), pN (HR, 2.85; 95% CI, 1.81–4.69; P<0.0001), lymphatic invasion (HR, 2.08; 95% CI, 1.26–3.70; P=0.0036), venous invasion (HR, 1.79; 95% CI, 1.21–2.64; P=0.0039), neoadjuvant chemotherapy (NAC) (HR, 2.01; 95% CI, 1.35–3.00; P=0.0005) and IMP3 expression (HR, 2.12; 95% CI, 1.40–3.29; P=0.0003) were significantly associated with overall survival. Using multivariate analyses, histology (HR, 1.87; 95% CI, 1.13–3.29; P=0.014), pN (HR, 2.19; 95% CI, 1.36–3.66; P=0.0010), NAC (HR, 1.88; 95% CI, 1.24–2.86; P=0.0028) and IMP3 expression (HR, 1.84; 95% CI, 1.18–2.93; P=0.0064) were significant prognostic factors. IMP3 may therefore be a prognostic factor for patients with ESCC who have undergone a curative resection.

Prognostic information derived from RT-PCR analysis of peritoneal fluid in gastric cancer patients: results from a prospective multicenter clinical trial.

The purpose of this study is to define the clinical significance of the molecular analysis of peritoneal lavage fluid in patients with gastric cancer in a multicenter prospective trial.

A case of esophageal cancer with chronic renal failure undergoing hemodialysis treatment showing long-term complete response with docetaxel chemotherapy and salvage endoscopic treatment

Chemotherapy for hemodialysis patients is not yet well codified, and the selection of individual patients remains difficult. We report the case of a 71-year-old hemodialyzed man who was successfully treated with docetaxel for squamous cell carcinoma of the esophagus. He had received radiotherapy for squamous cell carcinoma of the esophagus 6 years earlier. Metachronous esophageal cancer had developed at the upper third of the esophagus. He was treated tri-weekly with docetaxel at a dose of 60 mg/body in combination with hemodialysis three times a week. He achieved complete response after five cycles of chemotherapy. A small elevated lesion was diagnosed at the anal edge of the scar 26 months after initial treatment, and endoscopic mucosal resection and ablation was performed. Chemotherapy with docetaxel was continued up to 50 months without significant toxicity. The patient died of infection resulting from diabetic gangrene at 60 months after the initial chemotherapy, but no signs of recurrence have been observed until then. Docetaxel may be an effective anticancer agent for patients undergoing hemodialysis.