Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study.

BACKGROUND: Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC). METHODS: Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee. RESULTS: From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. CONCLUSIONS: The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. TRIAL REGISTRATION: ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).

Human papillomavirus as a risk factor for head and neck cancers--a case-control study.

A retrospective, case-control study was conducted to examine the relationship between the presence of human papillomavirus types 16 and 18 (HPV16/18) DNA and the risk of head and neck cancers. Twelve out of 74 (16.2%) head and neck cancers contained HPV16/18 DNA, while 3 out of 70 (4.2%) non-cancer controls showed HPV16/18 positivity by polymerase chain reaction. The presence of HPV16/18 DNA was associated with an increased risk of head and neck cancer formation, showing an odds ratio of 4.32, with a 95% confidence interval of 1.26-14.78. Although its epidemiological impact might be smaller than that of other factors like cigarette smoking, the presence of HPV16/18 DNA in the aerodigestive tract is suggested to be a risk factor for human head and neck cancers.

Clinicopathological features of early gastric cancer: results of 100 cases from a rural general hospital.

OBJECTIVE: To evaluate 100 patients with early gastric cancer from the point of view of early detection, clinicopathological variables, and long term results. DESIGN: Retrospective study. SETTING: Rural general hospital, Japan. SUBJECTS: 100 patients with early gastric cancer (confined to the epithelium, lamina propria, or submucosa) out of a total of 197 who had gastric cancers resected for cure between May 1986 and April 1996. INTERVENTIONS: Subtotal gastrectomy (n = 87), total gastrectomy (n = 8), proximal gastrectomy (n = 2), and local wedge resection (n = 3). MAIN OUTCOME MEASURES: Histopathological features and outcome. RESULTS: The mean annual incidence of early gastric cancer was 51% (range 35%-70%). 16/59 patients with mucosal cancer (37%) and 18/41 with submucosal cancer (44%) presented with symptoms of the disease. The diagnosis was made in 62 by endoscopy, and in only 2 by upper gastrointestinal radiographic examination. None of the 59 with mucosal cancer had lymphatic invasion, and only 1 had a lymph node metastasis. Among the 41 with submucosal cancer, however, 15 had lymphatic invasion (37%), 13 had venous invasion (32%), and 2 had lymph node metastases (5%). 83 patients were alive with no sign of recurrence at the time of writing (median follow up 62 months, range 12-136). One patient with a tumour that produced alpha-fetoprotein died of hepatic metastases 23 months after subtotal gastrectomy. 9 patients developed second cancers, and 6 died of these with no signs of recurrence of early gastric cancer. The overall 5 and 10 year survival rates were 82% and 66%, and the corresponding disease-specific survival rates for 85 patients were both 98%. CONCLUSIONS: Excellent long term results can be achieved in the treatment of early gastric cancer, even in a non-specialist centre. Patients with early gastric cancer should have their alpha-fetoprotein concentration measured, and be examined for the presence of other malignant disease both before and after treatment of the gastric cancer.

nm23 in the primary and metastatic sites of gastric carcinoma. Relation to AFP-producing carcinoma.

Tumor metastasis is the major cause of treatment failure and death in cancer patients. The present study was designed to extrapolate the association of nm23 expression with acquisition of metastatic potential of gastric carcinoma with special reference to the alpha-fetoprotein-producing gastric carcinoma (APGC). The primary tumor with surrounding normal mucosa and metastatic lymph nodes of 30 patients with APGC and 29 randomly selected matched controls of non-AFP gastric carcinoma (NAGC) were immunostained for nm23 and an image analyzer system was used for quantitative evaluation. Overexpression of nm23 was noted in 71% (42/59) of the primary tumors and 18% (10/55) of the metastatic tumors and there was no difference between the APGC and NAGC groups. The overexpression of nm23 in the primary tumors correlated with tumor invasion, metastasis and progression in all cases and similar results were obtained in the APGC and NAGC groups except for the tumor stage which was insignificant in the APGC group. The patient survival was adversely affected by the overexpression of nm23 in the primary sites and downregulation in the metastatic sites in all cases but lost their significance in the multivariate analysis. However, nm23 status did not affect patient survival in the APGC group.

The role of P-glycoprotein in human gastric cancer xenografts in response to chemotherapy.

BACKGROUND: To clarify the contribution of P-glycoprotein (P-GP) to drug resistance of gastric cancer, the correlation between chemosensitivity of the tumor and expression of P-GP was examined using human gastric cancer xenografts in nude mice. METHODS: Two strains, P-GP-positive and -negative, were established using primary explants from patients who had not received chemotherapy. Their stable growth was obtained by serial passages as subcutaneous tumors in nude mice. Mitomycin C (MMC, 3.25 mg/kg), adriamycin (ADR, 6mg/kg), or cisplatin (CDDP, 6mg/kg) was administered intraperitoneally once a week for 3 weeks. RESULTS: In the P-GP-negative strain, all three drugs significantly suppressed the tumor growth, while in the P-GP-positive strain, only MMC did so. However, the growth inhibition of MMC was apparently greater in the P-GP-negative strain than in the positive tumor. The expressions of metallothionein (MT), glutathione-S-transferase-pi (GST-pi), and p53 were not different between the strains. Bcl-2 was expressed only in the P-GP-negative strain. Induction of P-GP expression was observed in some specimens after treatment with MMC and with CDDP. CONCLUSIONS: P-GP might affect inherent and acquired resistance against chemotherapeutic agents in gastric cancer.

Overexpression of transforming growth factor-beta1 in scirrhous carcinoma of the stomach correlates with decreased survival.

A retrospective study of 50 patients with scirrhous carcinoma of the stomach who had undergone surgery was performed to elucidate whether immunohistochemical overexpression of transforming growth factor-beta1 (TGF-beta1) could predict the patients' survival. To evaluate the proliferative activity of the tumor, the proliferating cell nuclear antigen (PCNA) index was used. Expression of TGF-beta1 was low in 27 patients and high in 23. Clinicopathological characteristics were not significantly different between the two groups with high and low TGF-beta1 expression. Tumors with higher TGF-beta1 expression had higher PCNA indices (p = 0.0467, unpaired Student's t test). The 5-year survival rate was 40.4% for the low TGF-beta1 group and 28.7% for the high TGF-beta1 group (p = 0.0388, log rank test). By multivariate analysis, pT, residual tumor, and TGF-beta1 were the independent prognostic factors. These results suggest that immunohistochemical expression of TGF-beta1 is one of the useful predictors for estimating the patients' survival in scirrhous carcinoma of the stomach particularly of the T3 and T4 stages.

Prognostic factors and rational approach in the treatment of submucosal cancer of the stomach.

In early gastric cancer, lymph node metastasis is known to be a prognostic factor. A retrospective study of 134 patients with submucosal gastric cancer (SMGC) who had undergone gastrectomy with lymph node dissection was performed to evaluate the prognostic factors and indication of postoperative chemotherapy. Five-year disease-free survival rate for 121 patients without nodal metastasis was 100% with (n = 62) or without postoperative chemotherapy (n = 59). On the other hand, it was 72.9% for 13 patients with nodal metastases, although all patients had undergone D2 or D3 resection and received postoperative chemotherapy. Tumor recurrence occurred only in three patients (n = 3) with alpha-fetoprotein (AFP) producing cancer and lymph node metastasis. Multivariate analysis with the Cox's proportional hazard model revealed AFP positivity to be a new independent prognostic factor in addition to lymph node metastasis in the patients with SMGC. Our findings suggest that routine use of postoperative chemotherapy does not appear rational for the patients without nodal metastasis and that new modalities of operation and chemotherapy may be necessary for the patients with AFP producing SMGC with nodal metastasis. The necessity of chemotherapy in conventional-type SMGCs with nodal involvement remains to be studied in future.

Prognostic significance of the expressions of metallothionein, glutathione-S-transferase-pi, and P-glycoprotein in curatively resected gastric cancer.

Although experimental studies indicate that overexpression of metallothionein (MT), glutathione-S-transferase-pi (GST-pi), or P-glycoprotein (P-GP) is related to the drug resistance of cancer cells, the clinical significance of the overexpression remains to be elucidated. The expressions of MT, GST-pi, and P-GP wre evaluated immunohistochemically in 74 specimens of gastric adenocarcinoma in T1-3N1-2 stages which were resected with curative intent. Fluorinated pyrimidines, mitomycin C, and Adriamycin were prescribed in 73, 54, and 2 patients, respectively. The staining characteristics were investigated in relation to the clinical results. The cell-proliferative activity was studied with anti-proliferating cell nuclear antigen antibody. Expressions of GST-pi and P-GP correlated with the staining intensity of normal mucosa. Five-year disease-free survival rates (DFSRs) of GST-pi-negative and GST-pi-positive groups were 75.0 and 49.0%. The 5-year DFSRs of P-GP-negative and P-GP-positive groups were 68.2 and 38.6%. Concurrent expression among the three proteins was associated with the survival: 5-year DFSR of no- or one-protein-positive group was 75.0%, while those of 2- and 3-protein-positive groups were 56.0 and 38.9%, respectively. Tumors concurrently expressing 2 or 3 proteins have a high proliferative activity. Expressions of MT, GST-pi, and P-GP by the tumor are associated with a poorer prognosis of the patients.

Surgically curable and incurable scirrhous carcinomas of the stomach.

BACKGROUND AND OBJECTIVES: The purpose of this study was to identify a subgroup of patients with scirrhous carcinoma of the stomach who are more suitable for surgery by analysis of their clinicopathologic characteristics. METHODS: Seventy-three patients with scirrhous gastric carcinoma who underwent gastrectomy between 1979 and 1994 were included in the study. Clinicopathological characteristics of 5-year survivors and nonsurvivors were compared. A multivariate analysis of various prognostic factors was performed. RESULTS: The 5-year survival rate was 31.4%; 78% (28/36) of nonsurvivors died of malignant ascites and only 8% (3/36) died of hepatic or lung metastasis. When clinicopathologic parameters of 5-year survivors and nonsurvivors were compared, age, tumor size, macroscopic appearance, pT, pN, pM, stage, peritoneal lavage cytology, residual tumor, extent of gastric resection, operation time, volume of blood loss, and transfusion were significantly different. By the multivariate analysis, residual tumor, pathological depth of tumor infiltration, blood transfusion, and histological type were the independent prognostic factors. CONCLUSIONS: The prognosis of scirrhous carcinoma of the stomach is mainly determined by the depth of penetration and curability. In order to obtain better survival, early detection of tumor while it is limited to T2 stage appeared most important. Aggressive surgery would be indicated for T3 tumors, but in the case of T4 tumors, extent of operation should be determined by other factors such as extent of nodal metastasis or presence of distant metastasis.

Clinicopathological features of superficial squamous cell carcinoma of the esophagus.

BACKGROUND: The depth of penetration is the crucial factor determining the prognosis of esophageal carcinoma patients. Patients with superficial esophageal carcinoma have a significantly favorable clinical course compared with those with advanced cancers. The outcome for patients with mucosal cancer is excellent with a 5-year survival rate exceeding 80%. On the other hand, submucosal cancer often metastasizes to lymph nodes or other organs, and the prognosis of these patients is far from satisfactory. METHODS: Among 165 patients with squamous cell carcinoma of the esophagus, surgically resected between December 1979 and April 1995, 30 patients (18.2%) had superficial esophageal carcinoma (SEC) confined to the epithelium, lamina propria mucosa, or submucosa. Disease profile and clinicopathological characteristics of these 30 patients were studied. RESULTS: The incidence of SEC has increased from 6.3% (2 of 32) in the first 5-year period (1979 to 1984) to 27.4% (20 of 73) in the recent 5-year period (1991 to 1995). Subjective symptoms were present in 2 (13.3%) with 15 mucosal cancers and in 4 (26.7%) with 15 submucosal cancers. The remaining 24 patients (80%) had no subjective symptoms. Twenty-two patients (73.3%) were diagnosed to have the lesions by endoscopic examination at the time of screening for gastric problems, and only 3 were detected by gastrointestinal series. None of the 15 patients with mucosal cancer had lymphatic invasion, venous invasion, or lymph node metastasis. On the other hand, in those with submucosal cancers, 9 (60%) had lymphatic invasion, 5 (33.3%) venous invasion, and 8 (53.3%) lymph node metastases. Twenty-two patients are alive without recurrence. The 3- and 5-year survival rates are 86.7% and 86.7% for patients with mucosal cancer and 72.2% and 65.0% for those with submucosal cancer, respectively. CONCLUSION: Esophagectomy with wide lymphadenectomy should be carried out for submucosal cancer, whereas esophagectomy with moderate lymphadenectomy can be preferred for mucosal cancer.

Overexpression of metallothionein correlates with chemoresistance to cisplatin and prognosis in esophageal cancer.

The aim of this study was to determine the correlation of metallothionein (MT) expression with resistance to cisplatin and to identify prognostic factors in esophageal cancer. Immunostaining for MT was performed on the specimens of squamous cell carcinoma of the esophagus resected from 68 patients with curative intent. The expression of MT was evaluated in terms of clinicopathologic variables, effect of cisplatin, and the patients' survival. Overexpression of MT in the tumor was found in 70.6% of the patients. Stage III and IV tumors were more common in MT-positive tumors (p = 0.0282) but there was no difference in other clinicopathologic variables between MT-positive and MT-negative groups. Stage, cisplatin therapy, and tumor length were the independent prognostic indicators by multivariate analysis. Among 43 patients treated with cisplatin, the 5-year survival rate was 56% for MT-negative and 26% for MT-positive patients (p = 0.0277). In the MT-negative patients, multivariate analysis revealed that curability, stage, cisplatin therapy, and tumor length were the independent prognostic factors. These findings suggest that MT expression in squamous cell carcinoma of the esophagus is a major determinant of the chemoresistance to cisplatin and may be a predictor of poor prognosis.

Quantitative analysis of cyclin D1 messenger RNA expression in head and neck squamous cell carcinomas.

Cyclin D1 is thought to play a critical role in the G1/S phase transition of the cell cycle. Amplification of this gene has been reported in several types of human neoplasms including breast, lung, esophageal, and head and neck tumors. In this study, we have analyzed the relative level of expression of cyclin D1 messenger RNA (mRNA) in fresh specimens of head and neck squamous cell carcinoma (HNSCC), and investigated the concordance of the overexpression of cyclin D1 mRNA with gene amplification. Levels of cyclin D1 mRNA were analyzed by a modified method of competitive reverse transcription-polymerase chain reaction and levels of cyclin D1 gene amplification were evaluated by Southern blot hybridization in a series of 23 matched normal mucosas and HNSCC. Overexpression of cyclin D1 mRNA was observed in 10 of 23 cases (43.5%) of HNSCC, ranging from 2 to 50-fold higher than the normal control. Twelve of 23 cases could be evaluated by Southern blot hybridization, and gene amplification was found in only 2 of 12 cases (16.7%). These findings suggest that cyclin D1 plays an important role in tumorigenesis of HNSCC, and gene amplification is not one of the major mechanisms for overexpression of cyclin D1.

Prognostic significance of proliferating cell nuclear antigen (PCNA) in squamous cell carcinoma of the esophagus.

Proliferating cell nuclear antigen (PCNA) has been shown to be of prognostic significance in some gastrointestinal tumors. Immunohistochemical analysis was performed to determine whether PCNA is useful for predicting the outcome of patients with squamous cell carcinoma of the esophagus. Using a mouse monoclonal antibody, PC 10, the expression of PCNA was studied in resected squamous cell carcinomas of the esophagus from 59 patients who had undergone curative esophagectomy. None had received any preceding therapy. The proliferation rate was assessed in terms of the percentage of the PCNA-positive nuclear area relative to the total area of cancer nuclei using a cell analysis system (CAS). Clinicopathological variables including PCNA staining were assessed in relation to prognosis. Survival rate was obtained by the Kaplan-Meier method. The PCNA indices (percentage of the positive nuclear area) of the tumors varied from 4.4% to 96.2%. Among the clinicopathological variables, only tumor size (5 cm) and depth of invasion were correlated significantly with PCNA index (P<0.05). Microscopically, PCNA was stained in non-keratinized cells but not in keratinized cells. However the histological grade was not correlated with PCNA index. The survival rate was significantly worse in patients with high PCNA indices (> or = 40%) than in those with low indices (<40%) (P<0.05). However, multivariate analysis revealed that PCNA index was not an independent prognostic factor.

Long-term results of operation for carcinoma of the stomach in T1/T2 stages: critical evaluation of the concept of early carcinoma of the stomach.

BACKGROUND: The significance of nodal metastasis in patients with early gastric cancer (ECG) (T1) is unknown. It has been suggested that patients with T2, N0 carcinoma of the stomach have a comparable survival rate to patients with T1 carcinoma of the stomach. STUDY DESIGN: A retrospective review and survival analysis of 321 patients with T1/T2 adenocarcinoma of the stomach treated between 1979 to 1991 were performed. RESULTS: Patients were divided into four groups: group 1, 214 patients with node-negative EGC (T1, N0); group 2, 13 patients with node-positive EGC (T1, N+); group 3, 49 patients with node-negative T2 disease (T2, N0); and group 4, 45 patients with node-positive T2 disease (T2, N+). Excluding deaths from causes other than recurrence, the survival rate for patients in groups 1 and 3 was 100 percent, in contrast to the ten-year survival rate of 72.7 percent for group 2 and 62.5 percent for group 4 patients (p < 0.001, groups 1 versus 2, groups 3 versus 4). The ten-year survival rate for patients with node-negative T2 disease (group 3, 100 percent) was significantly better than that of patients with node-positive EGC (group 2, 72.7 percent) (p < 0.001). Although differences in the survival rates were noted according to lymphatic or venous invasion and whether or not patients had EGC or T2 carcinoma, the most significant factor was lymph node invasion. CONCLUSIONS: The postoperative survival rate for patients with node-positive EGC was poorer than that for those with node-negative T2 carcinomas. Reevaluation of the concept of EGC may be necessary. Post-operative chemotherapy does not appear necessary in patients with T2, N0 disease.

[Pharmacokinetic study of intraperitoneally administered plachitin for non-curative gastrointestinal cancer].

Plachitin is a chemical compound of cis-diammine-dichloroplatinum (CDDP) and chitin. Pharmacokinetics and adverse effects of Plachitin for intraperitoneal chemotherapy (IP) were studied in 11 patients who suffered from non-curative gastrointestinal cancers in comparison with 4 patients who underwent IP of CDDP. Five patients were given 300 mg (100 mg as CDDP) of Plachitin which was cotton type on the residual cancer mass (Group A). Six patients were given IP 300 mg of Plachitin particles (Group B). As the control group, 4 patients were given IP 100 mg of CDDP (Group C). The platinum concentrations of serum, urine and intraperitoneal discharge were observed during 3-4 weeks after the treatments and calculated as the CDDP concentration. The serum CDDP levels were below 0.1 micrograms/ml for 4 weeks in Group A and B. In Group A, urine concentrations of CDDP were significantly lower than in Group B and C at 3 and 5 days after the treatment statistically (p > 0.05). But at 14 days after treatment, the urine concentration of CDDP in Group A was higher than in Group C. In Group A and B, the CDDP concentrations of intraabdominal discharge was lower than in Group C statistically (p > 0.05). Nausea was observed only in one patient of Group B and other adverse effects which contained renal sufficiency were not recognized in the three groups. Thus, Plachitin was considered an effective and safe agent for intraperitoneal chemotherapy.

Curative resection of gastric cancer: limitation of peritoneal lavage cytology in predicting the outcome.

Patients with stage T3N0-2M0 gastric carcinoma (n = 108) were studied for relevant prognostic factors. Peritoneal lavage cytology (PLC) was performed in all. In univariate analysis, 5-year survival rates were better with smaller serosal invasion (diameter < 3.0 cm vs. > or = 3.0 cm, 61% vs. 37%, P < 0.05) and fewer metastatic nodes (< or = 5 vs. > or = 6, 57% vs. 29%, P < 0.05). In multivariate analysis, only these two factors were significant. The predictive value of PLC was not shown in both univariate and multivariate analyses. Peritoneal recurrence occurred in 14 (22%) of 77 patients with negative PLC, and in 3 (18%) of 17 with positive PLC, the difference being not significant. Our results indicate that PLC is insensitive in predicting the development of peritoneal recurrence. Its role in the estimation of survival is limited, as many will die of visceral or locoregional recurrence if not of peritoneal dissemination.

Thermodynamics and kinetics for the helix formation of the P3 region in Tetrahymena ribozyme.

The thermodynamic and kinetic results for the helix formation of the oligonucleotides, GACCGUCA and UGUCGGUC, which correspond to the sequence of the P3 region in Tetrahymena ribozyme are reported. The kinetic result suggested that the melting mechanism of the duplex of the oligonucleotides consisted of at least two steps because of a UU mismatch.

Electrostatic interaction in the reaction between porphyrin and DNA.

The association of tetrakis(4-N-methylpyridyl)porphine with salmon testes DNA in solution has been investigated in the presence of ethanol at 25 degrees C. It was found that the association constant was 1.14 x 10(6) M-1 and it increased with increasing the mole fraction of added ethanol. The behavior was very different from that in the case of usual intercalaters.