Anticancer effects of gallic acid isolated from Indonesian herbal medicine, Phaleria macrocarpa (Scheff.) Boerl, on human cancer cell lines.

The natural antioxidant gallic acid (GA) was isolated from fruits of a medicinal Indonesian plant, Phaleria macrocarpa (Scheff.) Boerl. The structure was identified on the basis of spectroscopic analysis and comparison with authentic compound. GA demonstrated a significant inhibition of cell proliferation in a series of cancer cell lines and induced apoptosis in esophageal cancer cells (TE-2) but not in non-cancerous cells (CHEK-1). Observation of the molecular mechanism of apoptosis showed that GA up-regulated the pro-apoptosis protein, Bax, and induced caspase-cascade activity in cancer cells. On the other hand, GA down-regulated anti-apoptosis proteins such as Bcl-2 and Xiap. In addition, GA also induced down-regulation of the survival Akt/mTOR pathway. In non-cancerous cells, we observed delayed expression of pro-apoptosis related proteins. Our results suggest that GA might be a potential anticancer compound. However, in depth in vivo studies are needed to elucidate the exact mechanism.

Closed continuous hyperthermic peritoneal perfusion model in mice with peritoneal dissemination of colon 26.

An original model of closed continuous hyperthermic peritoneal perfusion (CHPP) in mice is presented and was found to support the efficacy of intraperitoneal hyperthermia. Closed CHPP was performed after intraperitoneal inoculation of transplantable colon 26 cells into a mouse. Colon 26 cells (5 x 10(4)) were injected into 18 mice. The mice were then allocated to six groups of three each and subjected to peritoneal perfusion over time. Peritoneal washings from each mouse were sampled and counted by the cytosmear method. On day 10 after inoculation, colonies of the disseminated tumour were seen on the mesentery by staining with 0.1% methylene blue for 5 min. The number of tumour nodules on the mesentery was counted. The number of washed-out tumour cells decreased the most at 24 h after inoculation, and 76% of the inoculated cells did not wash out during the peritoneal perfusion procedure. CHPP was performed after 24 h when colon 26 cells were injected into the peritoneal cavity because this status may represent micrometastasis. The total number of nodules on the mesentery in the CHPP group was significantly smaller than that in the control (p < 0.02). In conclusion, because this treatment model is similar to the clinical CHPP, the biostaining model might be useful for the evaluation of peritoneal dissemination and it was unique and valuable in demonstrating an effective treatment for the prevention of peritoneal dissemination.

Spasmolytic effect of peppermint oil in barium during double-contrast barium enema compared with Buscopan.

AIM: To evaluate the efficacy of peppermint oil in barium as a spasmolytic agent during a double-contrast barium enema (DCBE). MATERIALS AND METHODS: A total of 383 DCBEs with positive results from occult blood tests were assessed. Patients were assigned to one of four groups: peppermint in barium (n=91), peppermint in tube (n=90), Buscopan (n=105), or no treatment (n=97). After a screening sigmoidoscopy, the DCBEs were performed using air as a distending gas. In the Buscopan group, the DCBE was performed with an intramuscular injection of 20mg Buscopan at the start of the examination. Patients in the no-treatment group underwent DCBE without any spasmolytic agent. A peppermint oil preparation (30ml) was mixed in the barium solution for patients in the peppermint-in-barium group, and the same dose of peppermint oil was included in the enema tube in the peppermint-in-tube group. The presence of spasm on a series of spot films was evaluated without information about the type of spasmolytic agent used. RESULTS: The percentage of patients in the four groups (no treatment, Buscopan, peppermint in tube, and peppermint in barium) with absence of spasm in the entire colon on the series of spot films was 13.4, 38.1, 41.8, and 37.8%, respectively. In the group using peppermint oil or Buscopan, the rate of patients with non-spasm examination was higher than that in no-treatment group (p<0.0005). Peppermint oil had the same spasmolytic effect as the systemic administration of Buscopan in the transverse and descending colon. Peppermint oil had a stronger effect in the caecum and the ascending colon than a Buscopan injection (p<0.005). There was no advantage to placing peppermint oil in the enema tube over mixing it in the barium solution. A total of 157 polyps were found during the DCBE procedures, and no differences were observed in the number of lesions among the four groups. Peppermint oil did not impair image quality. CONCLUSION: Barium solution mixed with peppermint oil was safe and effective for the elimination of colonic spasm during the DCBE procedure, and it could be used instead of Buscopan.

Prognostic significance of lymphocyte infiltration following preoperative chemoradiotherapy and hyperthermia for esophageal cancer.

PURPOSE: Lymphocyte infiltration (LI) around cancerous lesions is an important immune response. The purpose of this study is to evaluate the prognostic significance of LI after preoperative treatment for esophageal cancer. METHODS AND MATERIALS: Preoperative chemoradiotherapy (CR therapy), either bleomycin 30 mg or cisplatin 120 mg/m(2) plus radiation 30 Gy, was performed on 51 cases with esophageal cancer, while hyperthermo-chemoradiotherapy (HCR therapy) was also indicated in 71 cases. Using resected specimens, both the histopathologic effectiveness and degree of LI to cancerous lesions were evaluated. RESULTS: The incidences of the cases in which preoperative treatment was effective were 56% and 92.3% in LI (-) and LI (++) group (p < 0.05). The presence of LI resulted in favorable prognosis; the 5-year survival rates of LI (++) and LI (+) patients were 75.5% and 46.1%, both of which were significantly better than LI (-) (27.8%, p < 0.05 and p < 0.01, respectively). Especially among cases whose preoperative treatment was moderately effective, a multivariate analysis revealed LI to be a favorable prognostic factor independent of other clinicopathologic factors (p = 0.0171). Regarding the preoperative treatment, the incidence of LI (++) was higher in the HCR group (16.9%) than in the CR group (2.0%, p < 0.01). CONCLUSIONS: LI appears to be a prognostic predictor after preoperative CR therapy while, in addition, simultaneous hyperthermia may stimulate LI in cases with esophageal cancer.

An easy method for the intraluminal administration of peppermint oil before colonoscopy and its effectiveness in reducing colonic spasm.

BACKGROUND: Systemic administration of a cholinergic blocking agent or glucagon is used to reduce spasms, but it is inconvenient and sometimes causes side effects. This study is an evaluation of the intracolonic administration of peppermint oil during colonoscopy for the control of colonic spasm. METHODS: Each patient in the treated group (n = 409) was given approximately 200 mL of the solution (a mixture of 8 mL of peppermint oil and 0.2 mL of Tween 80 per 1 L of water with 0.04% indigo carmine) by using a hand pump attached to the accessory channel of the colonoscope. Changes in patient posture were made to distribute the solution. The patients in the control group (n = 36) were given the solution without peppermint oil. RESULTS: A satisfactory spasmolytic effect was seen in 88.5% of the treated patients and in 33.3% of those in the control group (p<0.0001). No adverse effect was observed. The mean time to onset was 21.6 +/- 15.0 seconds, and the effect continued for at least 20 minutes. In patients with irritable bowel syndrome, efficacy was significantly lower (p < 0.0001). CONCLUSIONS: The intraluminal administration of peppermint oil by using a hand pump is a simple, safe, and convenient alternative to the systemic injection of a cholinergic blocking agent or glucagon during colonoscopy.

[Postoperative adjuvant therapies for esophageal carcinoma].

Recent studies have focused on biochemical modulation with the combined use of CDDP and 5-FU for esophageal cancer. The combination of chemo- and radiotherapy is one of the most effective regimens for esophageal carcinoma. This combination therapy led to complete clinical remission in up to 30% of the cases in a prospective randomized study. We introduce many trials about postoperative adjuvant therapy after surgical treatment for esophageal carcinoma. The development and investigation of more effective chemotherapy regimens, as well as precise assessments of the response to preoperative treatment, is the challenge for randomized trials in the future.

Sonographic features of acute colonic diverticulitis: the "dome sign".

PURPOSE: This study was performed to clarify the sonographic features of acute colonic diverticulitis to enable its differentiation from appendicitis. METHODS: Of 119 patients who were referred to our hospitals for lower abdominal pain between June 1997 and December 1998 and underwent sonography, 12 patients had a definitive diagnosis of acute colonic diverticulitis and 4 patients a tentative diagnosis. Seventy-eight patients were diagnosed as having acute appendicitis, confirmed by appendectomy. In the 16 patients with diagnoses of diverticulitis, the sonographic and clinical features of acute colonic diverticulitis were studied. RESULTS: Among the 12 patients with definitive diagnoses of acute colonic diverticulitis, sonographic findings included localized thickening of the colonic wall (100%) and a hemispheric mass (the "dome sign") protruding at the thickened colonic wall (100%) and consisting of a hypoechoic wall (100%) and a central echogenic area (66%). The presence of diverticula was confirmed by barium-enema x-ray study in all 12 patients. The 4 patients with tentative diagnoses of acute colonic diverticulitis all had colonic wall thickening but no dome sign. Colonoscopy revealed colitis in 3 of these patients. All 16 patients recovered with conservative treatment, without laparotomy. CONCLUSIONS: Sonography was useful for differentiating acute colonic diverticulitis from appendicitis. The sonographic finding of the dome sign seems to be specific for acute colonic diverticulitis.

Antiemetic effect of ramosetron during hyperthermo-chemo-radiotherapy for esophageal cancer.

BACKGROUND: The antiemetic effects of serotonin receptor antagonists during chemoradiotherapy for solid tumors have never been reported. We have developed hyperthermo-chemo-radiotherapy (HCR) for esophageal cancer. However, with this treatment, the more potent the chemotherapy was, the more frequently emesis was experienced. MATERIALS AND METHODS: Fifteen patients with esophageal cancer underwent HCR (6 courses of hyperthermia, cisplatin 20 mg/m2 x 6, 5-FU 300 mg/m2 x 15 and radiation 1.5 Gy x 30). Ramosetron was administered intravenously (0.3 mg x 15). The emesis inhibition rate was defined as the rate of patients having neither vomiting nor severe nausea. RESULTS: The incidence of patients without nausea gradually decreased to 60% at the end of chemotherapy. However, vomiting was completely avoided except in one patient for two days. The emesis inhibition rates of weeks 1, 2, 3 and 4 were 100.0, 93.3, 89.5 and 95.2%, respectively. The overall inhibition rate was 94.5% and the rate of "well inhibited" was 79.0%. There were no ramosetron-related adverse reactions. CONCLUSIONS: These findings suggest that ramosetron is a useful antiemetic agent for nausea and vomiting induced by chemoradiotherapy for solid tumors.

Relationship between the expression of HLA-DR antigen and the effectiveness of preoperative hyperthermo-chemo-radiotherapy in oesophageal cancer.

Based on the hypothesis that tumour cells expressing HLA-DR antigen would easily be damaged by the local immune response during preoperative treatments, the relationship was investigated between the expression of HLA-DR antigen in the oesophageal cancer and the effectiveness of the preoperative treatment. Immunohistochemical staining for the detection of HLA-DR antigen in cancer cells from biopsy specimens obtained before undergoing preoperative hyperthermo-chemo-radiotherapy (HCR therapy) in patients with oesophageal squamous cell carcinoma was performed, and the relationship between the expression of HLA-DR antigen and the effectiveness of HCR therapy was evaluated according to a histopathologic examination of resected specimen. A total of 35 cases were examined in which 14 showed strongly positive staining (+2), 14 weakly positive staining (+) and seven negative staining (-). No significant differences in the clinicopathologic factors between the groups were observed. In the 14 strongly positive HLA-DR antigen cases, nine were markedly effective (grade 3) (64.3%), four were moderately effective (grade 2) (28.6%) and one was slightly effective or ineffective (grade 1, 0) (7.1%). In the 14 weakly positive HLA-DR antigen cases, the markedly, moderately and slightly or ineffective cases numbered four (28.6%), eight (57.1%) and two (14.3%), respectively. On the other hand, in the seven patients showing no HLA-DR expression, the markedly, moderately and slightly effective cases numbered one (14.3%), two (28.6%) and four (57.1%), respectively. A statistical difference was observed between the cases of strongly positive and negative staining for HLA-DR antigen (p < 0.05). The expression of HLA-DR antigen in oesophageal cancer cells is thus considered to potentially be a valuable factor for predicting the effectiveness of preoperative treatment.

Clinicopathologic features of patients with oesophageal cancer obtaining a histological complete response for preoperative hyperthermo-chemo-radiotherapy.

From 1979 to 1993, 151 patients with resectable oesophageal cancer underwent preoperative hyperthermo-chemo-radiotherapy (HCR) followed by a subtotal esophagectomy. All resected specimens were histopathologically evaluated, and then were classified into two groups according to the efficacy of the preoperative HCR. Group A included 33 patients whose resected oesophagus was free of any cancer cells (grade 3). Group B included 118 patients, in which viable cancer cells remained in the resected specimens to various degrees (grade 1,2). The incidence of patients with well differentiated squamous cell carcinoma, node negative cases, or TNM stage I/II was significantly higher in group A than in group B (27.3% versus 9.3%, 72.7% versus 50.8%, 72.7% versus 50.8%, respectively). The recurrence rate was 33.3% (11/33) in group A, while it was 65.3% (77/118) in group B (p < 0.005). There was no case with any local recurrence in the former, while it was 8.5% (10/118) in the latter. The 1-, 3- and 5-year survival rates were 87.2%, 65.9% and 46.1% in group A, while they were 54.8%, 26.7% and 18.8% in group B (p < 0.005), respectively. Preoperative HCR may be expected of decreasing in the recurrence rate, including regional relapse when a grade 3 is obtained. Complete local control would further positively influence the prognosis.

[Long-term results of preoperative hyperthermo-chemo-radiotherapy (HCR) for patients with esophageal carcinoma invading neighboring structures (T4)].

PATIENTS: A total of 180 patients with esophageal carcinoma invading the neighboring structures (T4) were surgically treated by esophagectomy and reconstruction in the Department of Surgery II, Kyushu University from January 1965 to April 1997. Any of these cases with distant node metastasis and demonstrating organ metastasis or a combined resection of adjacent structures were excluded from this study. As a result, twenty-six patients treated with preoperative hyperthermo-chemo-radiotherapy (HCR Group), 39 treated either with preoperative radiotherapy or preoperative chemo-radiotherapy (R or CR Group) and 23 non-treated patients (Non-tx Group) were thus entered in this study. RESULTS: The 3-year survival rates after esophagectomy in HCR Group, R or CR Group and Non-tx Group were 26.5%, 0% and 9%, respectively, while the 5-year survival rate of the HCR group was 15.9%. The group with preoperative HCR thus showed a significantly more favorable outcome than R or CR Group and Non-tx Group. (p < 0.05). DISCUSSION: The significant difference observed in the prognosis was thought to be due to the reinforced effect of local regulation due to hyperthermia. Our data thus suggest that preoperative HCR contributes to the prolonged post-operative survival for carcinoma of the esophagus invading the neighboring structures.

The clinical and histopathological contributing factors influencing the effectiveness of preoperative hyperthermo-chemo-radiotherapy for the patients with esophageal cancer.

BACKGROUND/AIMS: The effectiveness of hyperthermic treatment combined with irradiation and chemotherapy for patients with esophageal cancer on local response as well as on long-time survival has been reported. In order to investigate the contributing factors influencing the effectiveness of preoperative hyperthermo-chemo-radiotherapy (HCR therapy), this study was performed. MATERIALS AND METHODS: One hundred nineteen patients with esophageal cancer who underwent preoperative HCR therapy followed by esophagectomy were reviewed in this retrospective study. The rate of effectiveness of preoperative HCR therapy was then compared in resected tissue specimens with regard to such factors as age, sex, the location of the tumor, the longitudinal diameter of the esophagogram, the radiographic type of tumor, the histological type and the histological depth of invasion using univariate and multivariate analyses. RESULTS: Both univariate and multivariate analyses showed that the clinical and histopathological factors which had the greatest effect on preoperative HCR therapy were well differentiated squamous cell carcinoma regarding the histological type and tumorous type regarding the radiographic types. CONCLUSION: We thus conclude that preoperative HCR therapy shows great promise for the treatment of patients with esophageal cancer, especially in instances of well differentiated and radiographic tumorous type squamous cell carcinoma.

Oesophageal cancer coexisting with colorectal lesions.

OBJECTIVE: To investigate the incidence of colorectal lesions in patients who present with oesophageal cancer. DESIGN: Prospective open study. SETTING: University hospital, Japan. SUBJECTS: 135 of 218 patients who presented with squamous cell carcinoma of the oesophagus during the seven year period 1988-1994 were randomly allocated to have a barium enema examination. INTERVENTIONS: Barium enema examinations, and if colorectal lesions were found, colonoscopy and biopsy. MAIN OUTCOME MEASURE: Incidence of coexistent colorectal lesions. RESULTS: No abnormal findings were found in 52 (39%), diverticula were present on 37 (27%), benign polypoid lesions in 51 (38%), and malignant lesions in 6 (4%). We examined the clinical and histopathological details of all patients to see if it was possible to distinguish the patients at high risk of developing oesophageal and colorectal cancer but could find no differences among the groups. CONCLUSION: Asymptomatic colorectal lesions are relatively common in patients with squamous cell carcinoma of the oesophagus in Japan.

Hyperthermia combined with chemotherapy and irradiation for the prolongation of the postoperative prognosis in the patients with esophageal carcinoma invading neighbouring structures.

Preoperative hyperthermo-chemo-radiotherapy (HCR) has been performed on patients with esophageal carcinoma, especially in advanced cases with invasion to the neighbouring structures (a3 carcinoma), and is considered to have contributed to the favorable postoperative prognosis. 163 patients with operated locally advanced esophageal carcinoma with invasion to the neighbouring structures (a3 carcinoma) were analyzed. 40 cases were treated with preoperative HCR (HCR group), while 85 cases were treated with other preoperative adjuvant therapies including 35 with chemo-radiotherapy (CR group) and 42 with radiotherapy (R group), and the remaining 38 were operated on without any preoperative treatments. The effectiveness of the therapies and the prognosis were investigated. The survival rates of the HCR group were significantly better than those of the CR group (p < 0.05). The prognosis of cases with Grade 3 effectiveness was significantly better than those of others, moreover, in 5 cases with Grade 3 effectiveness in the HCR group, there was no case of early recurrence or metastasis after resection, while in addition, three patients have since survived for 4, 5, and 7 years, respectively. Our data showed that for the patients with locally advanced esophageal carcinoma with invasion to the neighbouring structures (a3 carcinoma), hyperthermia combined with chemotherapy and irradiation has demonstrated a favorable influence on the prognosis.

Prospective randomized study of hyperthermia combined with chemoradiotherapy for esophageal carcinoma.

From January 1988 to June 1992, 66 patients with resectable squamous cell carcinoma of the thoracic esophagus underwent preoperative adjuvant therapy. These patients were prospectively divided into two treatment groups; 32 were treated with radiofrequency wave local hyperthermia combined with chemoradiotherapy (hyperthermochemoradiotherapy; HCR), while the remaining 34 patients were treated with chemoradiotherapy alone (CR). There were no procedural complications in either group and the postoperative mortality was zero. In the HCR group, no viable cancer cells were found within the entire 5 mm-width slices of the resected specimen in eight patients (25%), while only two (5.9%) in the CR group (P < 0.05) demonstrate no viable cancer cells. The cumulative 3-year survival rate was 50.4% in the HCR group and 24.2% in the CR group. The present prospective trial demonstrated that the addition of hyperthermia to chemoradiotherapy resulted in a better local control and an improved long-term survival when treating patients with advanced esophageal carcinoma.

The long-term results of pre-operative hyperthermo-chemo-radiotherapy for oesophageal carcinoma--a comparison with preoperative radiation therapy alone.

The long-term results of patients with oesophageal carcinoma treated with pre-operative hyperthermo-chemo-radiotherapy (HCR) and pre-operative radiation therapy alone were compared. Twenty-six patients treated with pre-operative hyperthermo-chemo-radiotherapy (HCR Group) and 25 treated with radiation therapy alone (R Group), which demonstrated histopathologically marked effective results (Grade 3), were entered into the study. The 3-year survival rates after oesophagectomy in the HCR Group and the R Group were 67.4% and 41.8%, respectively, while the 5-year survival rates were 50.5% and 34.9%, respectively. Thus post-operative prognosis in the HCR Group was significantly more favourable than that in the R Group (P < 0.05). The local recurrence and distant metastasis rate in the HCR Group was significantly less than in the R Group (P < 0.01). This significant difference in prognosis was thought to be due to the reinforced effects of local regulation by hyperthermia and the systemic control of micrometastasis by chemotherapy in addition to radiation. Our data suggest that for carcinoma of oesophagus, pre-operative hyperthermo-chemo-radiotherapy contributes to prolonged post-operative survival while reducing both local recurrence and micrometastasis.

Hyperthermochemoradiotherapy is effective for small cell carcinoma of the esophagus.

Esophageal small cell carcinoma is a highly aggressive disease, and no effective treatment has yet been reported. We present here two cases of esophageal small cell carcinoma preoperatively treated with a combination of hyperthermia, irradiation, and an intravenous infusion of cis-diammine-dichloroplatinum (CDDP). The first case concerned a 67-year-old Japanese woman. Hyperthermochemoradiotherapy (HCR) was performed before surgical treatment. A histopathologic study of the resected specimen showed no residual viable cancer cells either in the esophagus or in the dissected lymph node. The second case involved a 59-year-old Japanese man who received HCR therapy before surgical treatment. This patient survived for 33 months, the longest known period of survival for small cell carcinoma of the esophagus. These cases indicate that preoperative hyperthermochemoradiotherapy may be considered one promising adjuvant therapy alternative for this aggressive disease.

Effect of dietary vitamin A on forestomach tumorigenesis during the total and postinitiation stages in mice treated with high- or low-dose benzo(a)pyrene.

The effects of dietary vitamin A on forestomach tumorigenesis during the total stage of the initiation and postinitiation periods and during the postinitiation stage were evaluated in ICR/Jcl mice treated with either high or low doses of benzo(a)pyrene (B(a)P). In experiment 1, the animals were initiated with a high carcinogenic dose of B(a)P to a total of 20 mg, while in experiment 2 the animals were treated with a low dose of B(a)P to a total of 2 mg. A control group of animals received no carcinogens. Five different dietary levels of vitamin A supplements were used in each experiment and in the control study. In experiment 1, a high incidence of tumorigenesis was observed in every group, with 74% to 96% developing papilloma and 19% to 46% developing carcinoma. In experiment 2, the incidence of tumorigenesis in the high-dose vitamin A groups, including those given during the total and postinitiation stages, was found to be significantly reduced at 7.4%, compared with that in the low-dose vitamin A group of 57.7% (P < 0.05). These results suggest that a high dietary level of vitamin A can reduce the incidence of tumorigenesis when low carcinogenic dose levels of B(a)P are given in both the total and postinitiation stages.