A novel rat model to determine interaction between reflux oesophagitis and bronchial asthma.

BACKGROUND: Several studies have shown a strong association between reflux oesophagitis (RO) and bronchial asthma (BA). The precise mechanisms of interaction between RO and BA are uncertain, possibly due to lack of animal models. AIMS: We established a novel rat model and examined pathogenic interaction of RO and BA. METHODS: RO and BA were induced in Brown-Norway rats by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus, and by ovalbumin (OVA) sensitisation and challenge with OVA aerosol. Rats were divided into four groups: control, RO, BA, and RO+BA. OVA-induced airway inflammation was assessed by the number of infiltrating cells and cytokine levels in bronchoalveolar lavage fluid (BALF). Oesophageal lesion index, histology and expression of cytokine mRNA, as determined by real-time RT-PCR, were also examined. RESULTS: Significant increases in the number of cells, especially eosinophils, and IL13 but not IFN-gamma concentration in BALF were observed in the RO+BA group compared with the BA group. These enhancements of OVA-induced airway inflammation were prevented by treatment with rabeprazole. Although the oesophagitis lesion index in the RO+BA group did not differ from that in the RO group, eosinophilic infiltration in the oesophageal submucosa and levels of mRNA expression of cytokines such as IL5, IL10, IL13, and RANTES were significantly increased. CONCLUSION: We established a novel rat model of RO and BA, and found significant interactions of the two diseases. This model thus appears to be useful for examining the association between gastro-oesophageal reflux disease and bronchial asthma.

A simplified method for measuring fetal hemoglobin.

Despite confirmation of the placental location by ultrasound examination, bloody tap during diagnostic and therapeutic amniocentesis may occur. If the blood originates from the fetus, such unfavorable complications as fetomaternal transfusion or maternal sensitization may result. Thus, it is necessary to determine immediatley the origin of the blood by the presence of fetal hemoglobin (HbF) in the specimen. To meet an urgent demand for a simpler and faster method for measuring HbF within a few minutes at bedside without requiring complicated procedures or instrumentation, a method has been developed which uses the alkali denaturation technic.

The prognostic value of serum immunosuppressive effect in patients with ovarian cancer.

Sixteen patients who underwent surgery and postoperative chemotherapy for carcinoma of the ovary were studied. Eleven survived more than 18 months without evidence of recurrence, and 5 died more than 5 months after surgery. Serial determinations were made preoperatively and postoperatively of the immunosuppressive effect of the serums of these patients on the response of normal lymphocytes to phytohemagglutinin stimulation. These determinations were plotted for each patient; the shapes of the curves for patients who survived are markedly different from those of patients who died. The prognostic value of these findings is discussed.

Immunosuppressive effect of serum in patients with ovarian carcinoma.

Cell-mediated immune response was measured in 23 patients with ovarian cystadenocarcinoma, 38 patients with benign ovarian tumor, and 44 healthy volunteers. The method used two indexes: the lymphocyte response per unit volume of peripheral blood to phytohemagglutinin (PHA) and the immunosuppressive effect of serum on the response of normal lymphocytes to PHA stimulation. The lymphocyte response per 50 microliter peripheral blood did not differ significantly between patients with ovarian cancer and healthy volunteers. The serum effect, in contrast, differed significantly between malignant and benign ovarian tumors, and was found to increase significantly even when the cancer masses were as small as about 5 x 5 x 5 cm in size, ie, in FIGO Stage I. It is our belief that the measurement of the serum effect in patients with any ovarian tumor enables the early detection of ovarian cancer.

[Fundamental and clinical studies on aztreonam in the field of obstetrics and gynecology].

Aztreonam (SQ 26,776, AZT), a new monobactam antibiotic, was fundamentally and clinically studied with the following results. Uterine and adnexal concentrations of AZT after intravenous injection of 1 g were highest 3 hours after administration in the ranges of between 18.6-23.4 micrograms/g 16.5-28.2 micrograms/g, respectively, and and rapidly decreased thereafter. Penetration of AZT into the pelvic dead space exudate was quickly recognized after intravenous injection of 1 g and its concentration 30 minutes after administration was 14.08 +/- 7.08 micrograms/ml and highest (22.35 +/- 5.85 micrograms/ml) 2 hours after administration. It gradually decreased to 8.50 +/- 2.07 micrograms/ml 6 hours after administration. Clinical effect was studied by administering 1-3 g of AZT twice a day for 3-16 days by intravenous drip infusion for 18 patients with various infections in the field of obstetrics and gynecology. Efficacy of AZT for 9 genital infection cases were excellent for 4 cases, good for 4 cases and poor for 1 case, with an overall efficacy rate of 88.9%. For 2 UTI cases, it was excellent for one case and good for the other, and for 4 pelvioperitonitis cases, excellent for 3 cases and good for 1 case. For 2 inflammation cases of the pelvic dead space, efficacy of AZT was excellent for both of them. With regard to side effect, there was only one rash case experienced. It was considered from the above results that AZT is sufficiently useful for the infections in the field of obstetrics and gynecology and also useful for various gynecologic surgery cases.

[Gestagen treatment of endometrial carcinoma--theoretical and practical application].

Since Kistner in 1959 took up the gestagen therapy for endometrial hyperplasia and endometrial carcinoma with a view to inhibiting cellular proliferation, many clinical reports on that therapy have been published. It has been clarified by cell-biological studies that progesterone inhibit the DNA synthesis of endometrial cells followed by the discontinuance of cell division. At dichophase , prior to the onset of the S-stage in cell division cycle, under conjugation of progesterone with a certain specific type of protein (hormone receptor) the cells are induced toward the development of secretory function, i.e. toward differentiation, resulting in no synthesis of DNA. On the basis of the consideration mentioned above, when hormone treatment will be applied to endometrial carcinoma it is required that those cancer cells have the gene activated by administered hormone or have specific type of protein produced by hormone dependent gene in cytoplasm. When cancer cells have still retained the traits of the normal epithelial cells of endometrium, they were believed still possess the character to show the specific reaction to progesterone. However, not all the cancer cells can be considered to have a uniform character (the degree of differentiation), so gestagen therapy cannot be interpreted to be able completely to bring about the fundamental cure of endometrial carcinoma.

[Differing progress patterns in cancer of the uterine cervix and variant effects of adjuvant chemotherapy based on histological type].

Clinical features of 644 surgically treated cases of cancer of the uterine cervix were analyzed according to their histological type. Large cell non-keratinizing carcinomas (L) showed node metastasis proportional to the grade of invasion in the cervix, and the lowest recurrence rate. Small cell non-keratinizing carcinomas (S) tended to have widely spread metastasis from an early stage of the primary lesion. Lateral recurrence from metastatic foci was common in this type. Keratinizing carcinomas (K) were localized in the cervix until the primary tumor became enlarged to a certain size. Central recurrence from invasive foci in the surrounding tissue or organ occurred more often than lateral recurrence in this type. Metastasis pattern of pure adenocarcinomas (A) was similar to that of S, but recurrence was delayed. Adenosquamous carcinomas (AS) showed a similar metastasis pattern to that of K, but recurrence was rapid and the ratio high. Prophylactic maintenance chemotherapy with Tegafur (800 mg/day) or Carboquone (0.5 mg/day) was performed in 187 cases for a period of 2 years after surgery. The effect of maintenance chemotherapy depended on the histological type. A marked effect was obtained in the groups of S and A, in which no recurrence has appeared so far. The recurrence rate of L dropped to 1/5 that of the control. However, unsatisfactory results were shown in the groups of K and AS including the keratinizing cell component. It is of significance that maintenance chemotherapy showed the highest effectiveness in S and A on which conventional adjuvant therapy, i.e. postoperative radiotherapy, has had the least effect. This has led us to consider that a proper selection of adjuvant therapies would contribute toward improving the postoperative prognosis of patients with cancer of the uterine cervix.

[Management of vulvar cancer].

In the treatment of vulvar malignancy surgery, chemotherapy, irradiation therapy and so on can be used. Actually, it was rarely performed only by a single method. For treatment by the stage of cancer progression, the superficial cancer was treated by wide local resection for the patients except old women who were done simple vulvectomy. For the invasive cancer, stage 1 or 2, the pre-operative bleomycin (BLM) was administered to reduce the tumor mass, thereafter, radical vulvectomy with inguinal lymph node resection was performed. If inguinal lymph nodes metastasis was found, area of resection was extended to pelvic lymph nodes. Recently, micro-invasive carcinoma was defined that the foci was below 2 cm and interstitial invasion below 1 mm. In this condition, it was needless to remove the lymph nodes. For the stage of 3 or 4 which was inoperable, chemotherapy (mainly BLM) combined with irradiation therapy was done. In the cases of good general condition, it was chosen by super-radical vulvectomy.

[Phase II study of cisplatin in cervical and endometrial carcinomas].

A phase II group study of cisplatin for cervical and endometrial carcinomas was carried out in 19 institutes throughout Japan. The patients entered consisted of 62 women with cervical and 7 with endometrial carcinoma of whom 39 and 4 were evaluable, respectively. Cisplatin was administered in either of two regimens; 10-20 mg/m2 i.v., on days 1-5, or 50-100 mg/m2 i.v., on day 1, every 3 to 4 weeks. The responders comprised 4 CRs and 10 PRs for cervical carcinoma and 1 CR and 2 PRs for endometrial carcinoma, and the response rates were 35.9% and 75.0%, respectively. The response rates by histological classification were 39.4% (13/33) for squamous cell carcinoma and 16.7% (1/6) for non-squamous cell carcinoma. Response rates analysed by lesion site were 33.3% for primary tumors, 36.8% for local lesions and 33.3% for metastases. Furthermore, the response rate among patients without any prior chemotherapy was 44.4% vs. 16.7% for those with prior chemotherapy. Adverse effects included nausea and vomiting (95.3%), anorexia (93%), anemia (72.1%), leucopenia (60.5%) and elevation of BUN (16.3%). Adverse effects were tolerable. We concluded from these results that cisplatin is among the most efficacious and useful drugs against cervical (and endometrial) carcinoma(s).

[Study of the clinical background and therapeutic method in patients with vulvar cancer].

Forty-two cases of vulvar cancer were reviewed with regard to clinical condition and therapeutic method, especially the efficacy of local administration of BRM. By histological examination, koilocytosis was found in 45%. Furthermore, there was 90% positive koilocytosis rate in immunohistological study using anti-human papilloma virus antibody and in situ hybridization method by HPV DNA probe (type 6, 11, 16, 18). The HPA was mostly type 16. Therefore, vulvar cancer was considered to occur in close relation with HPV type 16. Some 12% of vulvar cancer was complicated with other gynecologic cancer. In these cases, NK activity was low. Thus, cancer may be considered to occur in association with low immunological status. With regard to the therapeutic method, surgery and radiotherapy were usually used after chemotherapy in our institute. At stage 3-4, combination therapy using surgery and radiotherapy were found to be most effective. In regard to local immunotherapy using OK-432 and LAK cell and IL-2, local administration of OK-432 was effective. Therefore, surgery and radiotherapy with local immunotherapy after chemotherapy were considered to be the most effective therapeutic method for vulvar cancer.

[Studies of prognostic factor and chemotherapeutic effect of epithelial ovarian cancer using Cox's proportional hazard model].

To make clear the prognostic factor and chemotherapeutic effect of epithelial ovarian cancer, a multiple-center study involving 22 hospitals in Japan was conducted using Cox's proportional hazard model. A total of 1,181 cases were reviewed. Clinical stage, histologic type, and residual tumor diameter were significant prognostic factors, but the degree of tissue differentiation was not. The effect of remission induction chemotherapy was assessed with or without CDDP, and a distinct prognostic difference was noted. Among the patients receiving CDDP + ADM + other chemotherapeutic agents (PA group), CDDP + other chemotherapeutic agents (PO group) and CDDP only (P group), the prognosis of the PO group was better than for the P group. The long-term prognosis improving effect of chemotherapy was assessed. Neither maintenance chemotherapy based on oral administration of pyrimidine fluoride nor immunotherapy had any long-term prognosis improving effect, while intermittent chemotherapy based on CDDP resulted in improved prognosis.

[Phase II study of UFT in cancer of the uterine cervix].

UFT Phase II study was undertaken as a joint research project at 6 institutions on 36 patients with cancer of the uterine cervix. Results showed that, in the 25 of 36 cases in whom results and conclusions were feasible, there was an effectiveness of 16% (CR 3 cases, PR 1 case, NC 17 cases, PD 4 cases). Histologically, there was 25% effectiveness with large-cell, non-keratinizing, epidermoid carcinoma, against 16.7% with small-cell type. Considerable effect was noted as to metastasis effect in terms of location: Virchow 50%, and lungs 33.3%. CR effectiveness was noted in one case of local recurrence following irradiation. In 10 (37%) of the 27 evaluable cases some side effects were observed. Virtually all involved the digestive organs, and serious bone-marrow problems, hepatic or renal impairment were not evident. The findings suggested that UFT is an effective chemotherapeutic agent against carcinoma of the uterine cervix.

[Long-term administration of carmofur as a post-operative adjuvant chemotherapy for cervical adenocarcinoma. Cervical Adenocarcinoma Cooperative Research Association].

Cervical adenocarcinoma and adenosquamous cell carcinoma are low in radiation sensitivity, and the prognosis is said to be inferior to that of squamous cell carcinoma. Eleven facilities nationwide participated in the historical control study on the recurrence prevention effect of carmofur (HCFU) administered at 300 mg/day for more than two years postoperatively as an adjuvant chemotherapy to patients with cervical adenocarcinoma or adenosquamous cell carcinoma for which radical operation is possible. Registered for the study was a total of 252 patients: 77 patients for whom administration of carmofur was begun during the period from January 1987 and March 1989, 71 patients (control 1) who were treated for the cancer after January 1982 but did not receive adjuvant chemotherapy, and 104 patients who received adjuvant chemotherapies with other than carmofur (control 2). In analyses with the Kaplan-Meier method, the carmofur administration group demonstrated a better cumulative survival rate and disease free rate than control 1 (no adjuvant chemotherapy), suggesting carmofur was effective in preventing the recurrence of cervical adenocarcinoma and adenosquamous cell carcinoma.

[An early phase II study of CPT-11 in gynecologic cancers. Research Group of CPT-11 in Gynecologic Cancers].

An early Phase II study of CTP-11, a new derivative of Camptothecin, in gynecologic cancers was carried out by a cooperative study group of 9 institutions. Forty-six patients were enrolled, and there were 14 cases of ovarian cancers, 7 of cervical cancer, 6 of uterine body cancers and 1 of endometrial stromal sarcoma which satisfied study criteria. The response rate in ovarian cancers was 21.4%, and in cervical cancers 42.9%, among an overall rate of 21.4%. Three out of 6 patients with objective response had undergone previous chemotherapies including cisplatin, suggesting that CPT-11 was effective for patients with no response or refractory to these therapies. Leukopenia was a major adverse reaction with an incidence of 60.0% (grade 2 or more). Gastrointestinal symptoms such as nausea vomiting, anorexia and diarrhea were frequently observed (grade 2 or more; 13.3-43.3%). These were generally tolerable except in a few cases. Besides these reactions, alopecia was also observed (33.3%), but severe adverse reactions such as nephropathy were not. These results suggested that CPT-11 was effective against ovarian cancer and cervical cancer. The recommended dose regimen for a late phase II study is considered to be 100 mg/m2 once weekly and 150 mg/m2 once every 2 weeks.