Circadian rhythm-modulated chemotherapy with high dose 5-fluorouracil against gastrointestinal cancers: evaluation and case report.

Circadian variations in chemotherapy toxicity and antitumor effects were investigated in experimental and clinical studies. In the experimental study, Balb/c mice bearing murine colon carcinoma Colon 26 were treated with 4 injections of 5-fluorouracil (5-FU) (80 mg/kg) at 0000 Hours After Light On (HALO), 0600 HALO, 1200 HALO and 1800 HALO. The antitumor effect of treatment at 0000 HALO (early resting phase) group was significantly better with lower toxicity than the 1200 HALO (early activity phase) group, resulting in significantly longer survival (p < 0.05). In the clinical study, the effect of circadian rhythm-modulated 5-FU plus leucovorin therapy was evaluated in an end-stage patient with recurrent gastric carcinoma. After continuous weekly infusion of 5-FU (1000 mg/m2/day x 2) was stopped because of its gastrointestinal toxicity, circadian rhythm-modulated chemotherapy (CRMC) was performed changing the dose of 5-FU to 666 mg/m2/day during the daytime (0500 to 1700) and to 1333 mg/m2/day from evening to night (1700 to 0500). The patient persevered with the 23 CRMC course without any signs of severe side effects and survived for nearly a year, suggesting the potential effect of CRMC in minimizing toxicity and prolonging survival.

Large vestibular aqueduct syndrome treated by hyperbaric oxygen.

We report the case of a 14-year-old girl with a large vestibular aqueduct (LVA) in whom hyperbaric oxygen (HBO) therapy was effective for the treatment of sensorineural hearing loss. The patient was referred to Nagoya University Hospital for the treatment of hearing loss on 14 September, 1998, because her right hearing level had declined abruptly on 22 August, 1998, and had not changed for 3 weeks since then in spite of steroid and prostaglandin therapy. Her audiogram revealed bilateral profound deafness of more than 110 dB. She had had profound hearing loss on the left side since she was 9 years old. HBO therapy was performed on 22 occasions from 17 September until 19 October, 1998. During the HBO therapy, her right hearing ability returned almost to the level determined prior to the abrupt loss, 60 dB. We therefore recommend HBO therapy for the treatment of sensorineural hearing loss associated with large vestibular aqueduct syndrome if the hearing ability does not recover following conventional treatment.

[Surgery and multidisciplinary treatment for colorectal cancer].

Evaluation of surgery and multidisciplinary treatment for colorectal cancer was performed based on the review of the results of clinical trials. Although most improvement in prognosis for colorectal cancer patients was obtained by the development of surgical techniques until the mid-70's, further extended surgery could not have demonstrated the obvious improvement in survival after the 80's. In this regard, various multidisciplinary treatments were evaluated by a meta-analysis of clinical trials. Among those modalities, preoperative irradiation for rectal cancer, postoperative adjuvant chemotherapy for resected colorectal cancer and biochemical modulation of 5-fluorouracil by methotrexate or leucovorin for advanced colorectal cancers proved to be significantly effective for improvement of prognosis. Clinical trials of immunochemotherapy using either levamisole or PSK for resected colorectal cancers, a trial of hepatic artery infusion for liver metastasis, and a trial of an adjuvant monoclonal antibody treatment, were also reported to demonstrate significant effects. For further progress in multidisciplinary treatment for colorectal cancers, standardization of the appropriate surgical technique for each stage of the disease is much anticipated.

Germ cell tumors of the basal ganglia and thalamus.

The clinicopathological findings in 6 patients with germ cell tumors originating in the basal ganglia and thalamus are presented. Clinical, biological and diagnostic features were somewhat different from germ cell tumors in the pineal region. Early and comprehensive treatment is recommended because of the possible presence of nongerminomatous germ cell components.

[A randomized controlled trial of surgical adjuvant therapy with mitomycin C, 5-fluorouracil and OK-432 in patients with gastric cancer].

The effect of postoperative immunochemotherapy with mitomycin C (MMC), 5-fluorouracil (5-FU) and OK-432 was evaluated as an adjuvant therapy after curative resection for gastric cancer. Immediately after surgery, patients were randomly allocated to the following three treatments: (A) chemotherapy with MMC and 5-FU (32 cases); (B) chemoimmunotherapy with MMC, 5-FU and OK-432 (33 cases); and (C) surgery alone as control (34 cases). There were no significant differences in the background factors influencing survival time among the groups, and there was no dose-distribution of chemotherapeutic agents between groups A and B. While the differences were not statistically significant, the survival rate and disease-free interval of group B were better than those of groups A or C. Side effects such as gastroenteric disorder, leukopenia (less than 3,000/mm3), thrombocytopenia (less than 7 X 10(4)/mm3) and increase of serum transaminase level (GPT greater than or equal to 100 units) were less frequently observed in group B than in group A. The results of the present study seemed to indicate that chemoimmunotherapy with OK-432 may be effective for surgical adjuvant therapy.

[Influence of immunopotentiators on the activation of 5-FU derivatives].

As it has been shown that various kinds of immunopotentiators inhibit the hepatic microsomal drug-metabolizing enzymes and reduce the activation of masked compounds such as tegafur, we investigated the influence of immunopotentiators (OK-432 and PSK) on the activation of carmofur (HCFU), which is known to be transformed spontaneously in to the tumor-active substance, 5-fluorouracil (5-FU), in vivo, and compared the results to those obtained for tegafur. After oral administration of tegafur, the area under the plasma concentration curves of 5-FU in rats pretreated with OK-432 and PSK were 72% and 79% of those in untreated rats, while in the case of HCFU almost similar plasma concentration curves for 5-FU were obtained in both treated and untreated rats. These results show that the activation of HCFU to 5-FU is not influenced by treatment with these immunopotentiators. Furthermore, our clinical investigation showed that the survival curves of cancer patients given combination therapy of tegafur with OK-432 tended to be lower than those given a single therapy of tegafur, supporting the above mentioned basic results.

[A controlled study of surgical adjuvant chemoimmunotherapy with FT-207 and OK-432 for advanced stomach cancer: the fourth study].

A prospective randomized trial of surgical adjuvant chemoimmunotherapy was conducted in patients who had undergone palliative gastrectomy for previously untreated advanced stomach cancer. Immediately after surgery, one hundred and forty-seven patients were randomized to receive either chemoimmunotherapy with FT-207 plus OK-432 (group A) or chemotherapy with only FT-207 (group B). The number of patients subjected to this analysis was 134 cases (group A: 70 cases, group B: 64 cases) because thirteen patients were excluded. FT-207 was administered orally and OK-432 was administered intracutaneously. There were no differences in the background factors influencing survival time between the two groups. While the survival rate of group A patients was higher than that of group B patients, the difference in the survival rate between the two study groups was not statistically significant. However, in patients with less differentiated cancer (poorly differentiated adenocarcinoma, signet-ring cell carcinoma) the survival rate of group A patients was significantly (p less than 0.05) higher than that of group B patients. The results of the present study show that OK-432 administered intracutaneously is effective in elevating the survival rate of patients receiving chemotherapy with FT-207 for advanced stomach cancer (especially for less differentiated cancer).

[Origin of short latency somatosensory evoked potential following median nerve stimulation].

Short latency somatosensory evoked potentials (S-SEP) to median nerve stimulation recorded from scalp-shoulder derivation consisted of four positivities (P1, P2, P3 and P4) and one negativity (N). There is still, however, significant controversy regarding the generators of these peaks. The purpose of the present study is to attempt to solve some of the controversies by comparing the potentials recorded on surface montages with intrasurgical tracing obtained while monitering evoked potentials. This is complemented by analysis of S-SEP in patients with disorders of the cervical cord, brain stem or thalamus. Average latency of each component in normal subjects (N = 17) was as follows; P1: 7.6 +/- 0.6 ms P2: 9.6 +/- 0.7 ms, P3: 11.8 +/- 0.8 ms, P4: 12.9 +/- 0.5 ms, N: 17.7 +/- 0.8 ms. The peak latency of P1 was always shorter than that of negativity recorded over the Erb's point following the median nerve stimulation. The peak latency of P2 corresponded to that of the earliest negativity of spinal evoked potential, recorded from the epidural dorsal surface of the lower cervical cord during the operation, which was considered as the potential of afferent volley at the posterior root or spinal entry portion. In a case with severe spondylotic radiculopathy, P2 and following components were abolished. The peak latency of P3 corresponded to that of negative potential recorded over the high cervical dorsal column or cuneate nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)

[Adjuvant immunochemotherapy combined with OK-432 following surgery of stomach cancer].

Postoperative immunochemotherapy with mitomycin C (MMC), 5-fluorouracil (5-FU) and OK-432 was evaluated as adjuvant therapy for curative resection in the cases of gastric cancer. One hundred and twenty-two patients (28 were excluded) were randomly assigned to 3 groups: Group A-MMC and 5-FU (28 cases); Group B-MMC, 5-FU and OK-432 (33 cases); Group C-control (33 cases). There were no differences in the back ground factors influencing survival time among each group. Group B showed better results in survival rate and disease free interval as compared with Group A or C. Minor and reversible side effects such as enterogastric disorder, leukopenia (less than 3000/mm3), thrombo cytopenia (less than 7 X 10(4)/mm3) and elevation of serum transaminase (S-GPT greater than or equal to 100 unit) were equivalently observed in frequency in each Group A and B, but they were milder in Group B than Group A.

A controlled study of maintenance chemoimmunotherapy vs immunotherapy alone immediately following palliative gastrectomy and induction chemoimmunotherapy for advanced gastric cancer. Tokai cooperative study group for adjuvant chemoimmunotherapy of stomach cancer.

A randomized trial of surgical adjuvant chemoimmunotherapy was conducted in patients who had undergone palliative gastrectomy for previously untreated advanced stomach cancer. First, all patients received the same induction chemoimmunotherapy with MFC (mitomycin C, 5-fluorouracil, and cytosine arabinoside) plus OK-432 for 6 weeks after surgery. The patients were then randomized to receive either chemoimmunotherapy with MFC plus OK-432 (group A) or immunotherapy with OK-432 alone (group B) for maintenance. The survival rate of patients was significantly higher in group B (44 cases) than in group A (39 cases) during the first 9 months after the start of induction therapy (P less than 0.05). A further division of patients in terms of carcinoma histology revealed a difference in survival rate only in patients with an undifferentiated histology (poorly differentiated adenocarcinoma and signet-ring cell carcinoma), and not in those with a differentiated histology (papillary, tubular, and mucinous adenocarcinomas). These results indicate that simple immunotherapy with Ok-432 is better for maintenance than chemoimmunotherapy involving MFC, particularly in patients with undifferentiated gastric carcinomas.