Repeated intracyclic clomiphene citrate therapy can be more effective than hMG therapy in inducing ovulation: case report.

PURPOSE OF INVESTIGATION: When clomiphene citrate is ineffective in the treatment of anovulation, hMG administration is typically selected. However, high-dose hMG therapy is associated with a variety of adverse events. We describe the use of a modified clomiphene citrate regimen that was successful in increasing the effectiveness of ovulation induction. CASE REPORT: A patient who did not initially respond to clomiphene citrate therapy required a total dose of 2400 IU hMG to prodeuce mature follicles. However, because of the physical and emotional burdens on the patient, and the possibility of multiple pregnancy and ovarian hyperstimulation syndrome, re-treatment with clomiphene citrate was then selected. Two courses of clomiphene citrate administered at a fixed interval during the same cycle safely induced ovulation. After initial induction of ovulation, her ovulatory failure improved and natural ovulation occurred. CONCLUSIONS: Repeated intracycle clomiphene cirate therapy may be more effective than hMG therapy in inducing ovulation in some patients.

[A patient with recurrent breast cancer whose liver metastasis regressed following combined use of weekly docetaxel and MPA.5'-DFUR].

A 28-year-old woman who was 10 months pregnant was diagnosed with left breast cancer. She received preoperative chemotherapy and underwent mastectomy after parturition. Endocrine therapy and adjuvant CMF and CAF was administered, but a bone metastasis appeared 2 years later and a liver metastasis 3 years later. Weekly docetaxel and MPA plus 5'-DFUR combination therapy were successively and simultaneously administered. The liver tumor regressed, and the survival time was prolonged by 1 year and 6 months. This case suggests that the combined use of both therapies was safe for the patient in serious bad condition and had a strong antitumor effect.

[Effect of weekly docetaxel in patients with recurrent breast cancer].

A pilot trial was conducted to assess the tolerability and efficacy of a regimen with weekly docetaxel (TXT) in patients with metastatic breast cancer. The chemotherapy regimen consisted of a 30-minute weekly intravenous infusion of docetaxel (22-33 mg/m2/wk). Each 8-week cycle included 6 weekly treatments, followed by two weeks of rest. Thirteen patients were treated. All patients were evaluable for response: 0 CR (0%), 7 PR (53.8%), 3 NC (23.1%), 3 PD (23.1%). These results are almost the same as those with the administration of TXT (60 mg/m2) q3 wks. Toxicities observed were mild (< or = grade 2) and reversible, and included fatigue, nausea, neutropenia, and alopecia. This preliminary experience suggests a high level of clinical activity and excellent tolerability of the chemotherapy regimen at the given dose and schedule in patients with metastatic breast cancer.

[A case of recurrent breast cancer successfully treated with docetaxel].

A 53-year-old female underwent mastectomy for left breast cancer in April, 1993. She was given oral tamoxifen but this had to be discontinued due to its side effects. In March, 1998, she developed bone and lung metastases, in spite of treatment with combination chemotherapy (CEF). We thus treated here with docetaxel 90 mg three times and 40 mg six times. After the chemotherapy, she achieved complete remissions of the lung metastases and a decrease in serum CEA, CA 15-3, NCC-ST439, and BCA225. Adverse reactions to docetaxel were grade 2 alopecia, grade 4 neutropenia, dysgeusia, and fluid retention. All were tolerable. This new agent may play an important future role in chemotherapy for recurrent breast cancer.

A comparison of prosthetic materials used to repair abdominal wall defects.

Large abdominal wall defects may require a prosthesis for closure. The aim of our study was to identify the best material for abdominoplasty in pediatric patients. One hundred twenty-eight Wistar KY strain male rats (3 weeks old) were used. All animals underwent celiotomy via a midline skin incision. They were divided into seven groups as follows: the animals in groups 1 through 6 underwent full-thickness abdominal wall excision 3 cm in diameter. The animals in group 1 underwent primary closure. In groups 2 through 6 the defect was closed with prosthetic material. In Group 7, a sham operation was performed. Daily weights were measured. The animals were killed after 3 and 9 weeks. Adhesion scores were assigned for each group. Vicryl mesh resulted in the fewest adhesions and had no effect on weight gain in the developing rats.

[Toremifene sensitized the effect of adriamycin on human breast cancer cell lines].

A experimental study was reported here to clarify the chemosensitizing effect of Toremifene (Tor) on human breast cancer cell lines. MCF7, estrogen dependent adriamycin (ADM) resistant cell, and MDA-MB231, estrogen independent cell, were preincubated for 8 hours with Tor 0, 4 or 10 microM, then with ADM 0-10 micrograms/ml for one hour. After that, cells were cultured for 24 hours, and their cell cycle and growth were analyzed with flow-cytometry and MTT assay, respectively. Furthermore, the ADM concentrations of these cells were measured by high-performance liquid chromatographic assay (HPLC). Although flowcytometric analysis showed the enhancement of Gz block only in MCF7 at the ADM concentration with 5 micrograms/ml, the sensitizing effect was revealed by MTT assay, and the elevation of ADM concentration was found in HPLC assay in both cells. The chemosensitizing effect of Toremifene was observed in estrogen dependent and independent cell lines.

[Analysis for predicting the prognostic factors of gastrointestinal tract leiomyosarcoma using MIB-1 and DNA flow cytometry].

PURPOSE: The present study was undertaken to investigate the possibility of determining a prognosis for gastrointestinal tract leiomyosarcoma with the use of DNA analysis and MIB-1 staining. SUBJECTS AND METHODS: Malignant tumors originating in smooth muscle of the gastrointestinal tract, surgically excised from 23 lesions in 17 patients (stomach; 8 cases, 12 lesions; small intestine: 6 cases, 8 lesions; colon: 3 cases, 3 lesions) and embedded in paraffin, were examined. DNA was analyzed using flow cytometry to produce a DNA histogram, and aneuploidy and diploidy were found. MIB-1 staining was done in conformity with the ABC method. RESULTS: 1. An investigation of prognoses using the Kaplan-Meier method revealed a tendency for more favorable prognoses in patients determined to be aneuploid through DNA analysis. However, this was not significantly better than those exhibiting diploidy. 2. All patients who died had a MIB-1 staining positivity rate of over 10%, while all patients who had no recurrence within one year or survived had a MIB-1 staining positivity of less than 10%. 3. No consistent trends were observed between MIB-1 positivity rate and DNA analysis, MIB-1 positivity rate and size of tumor, or DNA analysis and size of tumor. 4. The MIB-1 positivity rate of patients with remote metastases was significantly greater than that of patients with no remote metastases. CONCLUSION: From the fact that patients with MIB-1 positivity rates of greater than 10% had a poor prognosis, while those with rates of less than 10% had a favorable prognosis, we conclude that a MIB-1 positivity rate of 10% is an important value in determining the prognosis of patients with gastrointestinal tract leiomyosarcomas.

Prognostic and Therapeutic Implications of the MIB-1 Labeling Index in Breast Cancer.

BACKGROUND: Assessment of tumor proliferative activity is considered to be the most powerful prognostic factor aside from axillary lymph node status. The purpose of this study is to assess the clinical value of measurement of proliferative activity using the MIB-1 labeling index in patients with breast cancer. METHODS: Surgical specimens from 36 patients with benign breast disorders and146 patients with breast cancer were investigated. The MIB-1 labeling index wasdetermined on the specimens stained by immunohistochemical methods as much as possible. Clinical factors associated with the MIB-1 labeling index were reviewed. RESULTS: The MIB-1 labeling index for non-proliferative disorders, proliferative disorders, and breast cancer was 3.4 +/-1.9%, 8.9 +/-6.2% and 20+/-12%, respectively. The MIB-1 labeling index and tumor size, lymph node metastasis status, and clinical stage according to the TNM classification correlated significantly. Survival rate was inversely correlated with the MIB-1 labeling index. No patientwith an MIB-1 labeling index of less than 10% had lymph node metastases, and all are alive without recurrence. Patients with an MIB-1 labeling index of over 30% had an extremely poor prognosis. CONCLUSION: The MIB-1 labeling index is very useful for predicting both either extremely good or extremely poor prognosis, and axillary lymph node metastasis

[Immunomodulatory effect of daily low-dose cisplatin treatment].

Immunomodulatory effects of daily low-dose cisplatin treatment were investigated on compromised patients with advanced or recurrent gastrointestinal cancer. One case of esophageal cancer, 7 of gastric cancer, 2 of colorectal cancer, 1 of carcinomatous peritonitis from unknown origin, and 1 of hepatocellular carcinoma, were treated by daily low-dose cisplatin combined with 5-FU or tegafur, and their ECOG Performance Status Score (PS), number of lymphocytes, and CD3 zeta chain expression of peripheral blood lymphocytes were studied to compare with the effects of treatment. Seven patients with esophageal cancer and gastric cancer showed a partial response and their PS was improved, and the number of lymphocytes and CD3 zeta chain expression of lymphocytes was increased. However, in two patients with progressive disease, a decreased number of lymphocytes and less expression of CD3 zeta chain were seen.

Lack of interleukin-2 (IL-2) expression and selective expression of IL-10 mRNA in human renal cell carcinoma.

Freshly isolated tumor-infiltrating lymphocytes (TIL) are often functionally deficient. Since one of the key functional parameters of an immune response is the local production of cytokines, we studied the expression of cytokine genes in freshly isolated renal cancer tissue. Using a PCR-assisted mRNA amplification assay, the constitutive expression of mRNA for 10 different cytokines was assessed in renal cancer tissue. We compared the cytokine mRNA expression in freshly isolated samples of renal carcinomas, renal cancer cell lines established from the tumor samples, peripheral blood mononuclear cells (PBMC) and non-tumor kidney tissue isolated from the same patients. IL-10 mRNA expression was detected only in tumor samples, while renal cancer lines, PBMC and non-tumorous kidney tissues were devoid of this cytokine. One-third of the tumor samples but none of the normal kidney samples also expressed G-CSF mRNA. IL-6, TNF-alpha and IFN-gamma mRNA were expressed non-selectively in tumors, PBMC and normal rental tissue. Expression of IL-2, IL-3 and IL-4 mRNA was not detected in any of the tissues analyzed. Established renal cancer lines exhibited expression of IL-1 alpha, IL-6, TNF-alpha and GM-CSF. Culture of tumor-derived T cells with anti-CD3 monoclonal antibody (MAb) resulted in expression of IL-2, IL-3 and IL-4 mRNA. In contrast, none of these cytokines was detected in culture with recombinant human IL-2 alone. Since IL-10 is known to suppress antigen presentation, these findings have important implications for the possible in vivo role of IL-10 as a suppressor of local anti-tumor response.

The Epstein-Barr virus latent membrane protein-1 (LMP1) induces interleukin-10 production in Burkitt lymphoma lines.

Human interleukin-10 (h-IL-10) is a pleiotropic cytokine with stimulatory activity on B-lymphocytes. Recent evidence indicates that infection with Epstein-Barr virus (EBV) induces h-IL-10 production in B-cells and that this cytokine may contribute to EBV-induced B-cell transformation. It is not known whether h-IL-10 induction by EBV correlates with distinct phenotypic features of the infected cells or with the expression of particular viral genes. We have approached these questions by investigating the expression of h-IL-10 mRNA in a panel of B-cell lines including: in vitro EBV-transformed lymphoblastoid cell lines (LCLs), EBV-carrying Burkitt lymphoma (BL) lines, EBV-negative BL lines and their sublines infected with different EBV strains, or transfected with the transformation-associated viral gene. h-IL-10 mRNA was detected by reverse-transcriptase-assisted (RT)-PCR in a subset of EBV-negative BLs and in all EBV-positive BL lines and LCLs investigated except Daudi. This cell line carries an EBV nuclear antigen (EBNA)-2 gene-defective virus strain. h-IL-10 mRNA was induced by conversion of 3 EBV-negative and h-IL-10-negative BL lines (BL41, BL47 and BL49) with the transforming, B95.8-derived EBV strain. P3HR-I virus convertants that do not express the viral EBNA-2 and the EBV latent membrane protein (LMP)-1, and fail to progress towards a LCL-like cell phenotype, showed no evidence of h-IL-10 up-regulation. Expression of LMP1 was sufficient to induce h-IL-10 mRNA in transfected sublines of the EBV-negative DG75 and BL41 cell lines, whereas expression of EBNA1, 2, 5, or 6 had no effect. h-IL-10 was detected in the culture supernatants of the LMP1 transfectants by specific ELISA assays. The present findings confirm the role of LMP1 in the transactivation of a wide variety of cellular genes which may be involved in EBV-induced B-cell transformation.

Decreased expression of the signal-transducing zeta chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma.

An impaired immune response is frequently observed in cancer patients and tumor-bearing mice. T-cells from mice with an experimental colon carcinoma were recently shown to express T-cell receptors that completely lacked the signal-transducing molecule CD3 zeta. Here, we have investigated the expression of the signal-transducing molecule zeta on lymphocytes from 14 patients with colorectal carcinomas using flow cytometric analysis of permeabilized cells with a monoclonal antibody (TIA-2; IgG1) specific for the cytoplasmic domain of the zeta chain as well as with immunoprecipitation and analysis on diagonal gel electrophoresis. We demonstrate that T-cells isolated from the tumors of the patients express significantly less CD3 zeta than T-cells in the peripheral blood of the same patients and that the peripheral blood of the patients express decreased levels of zeta chains, as compared to the levels found in lymphocytes from healthy controls. This decreased expression was also observed on zeta chains associated with the low affinity Fc receptor for IgG found in tumor-infiltrating NK cells (Fc gamma RIIIA alpha; CD16).

Cytotoxic activity and T cell receptor repertoire in tumor-infiltrating lymphocytes of adrenal cell carcinomas.

The cytotoxic activity and T cell receptor (TCR) V beta repertoire in tumor-infiltrating lymphocytes (TIL) of three primary adrenal cell carcinomas were analyzed. Fresh, non-cultured TIL from two of the three tumors showed low but significant lysis of the autologous tumor, and for one of the patients this activity was strongly enhanced upon culture in interleukin-2. An allogeneic adrenal cell carcinoma line and the K562 or Daudi targets included as controls were not killed. Phenotypic analysis of freshly isolated TIL demonstrated that the cells from the two patients that demonstrated cytolytic capacity mainly consisted of CD45RO+ T cells. In vitro cultured TIL lines from these patients demonstrated a high percentage of CD8+ cells expressing either the V beta 6 gene or the V beta 8 gene product, as measured with a panel of mAb specific for TCR V alpha and V beta gene products. Analysis of the TCR V beta gene mRNA expression in freshly isolated non-cultured TIL, using a polymerase-chain-reaction-assisted cDNA-amplification assay, confirmed the strong expression of the genes coding for the TCR V beta 6 or the V beta 8. This assay also demonstrated a more restricted TCR V beta gene usage in the TIL as compared to peripheral blood lymphocytes from the same patient.

[Studies on fibrinopeptide A, fibrinopeptide B beta 15-42 and inhibitors of blood coagulation and fibrinolysis during use of oral contraceptives].

PIP: To examine a change occurring in the coagulation-fibrinolytic system during oral contraceptive (OC) administration, the author measured fibrinopeptide A and Bbeta15-42 (FPA and FPBbeta15-42) over a long period of time. These are sensitive indicators of coagulation and fibrinolytic activity as well as coagulation fibrinolysis inhibiting factor plasma antithrombin III (AT III) and alpha2 plasmin inhibitor (alpha2 PI). The interesting results are listed as follows. 1) FPA showed almost no change during OC administration, nor was thrombin observed to have been produced. 2) FPB15-42 increased when the drug was administered 3-5 times and 11-12 times (p0.05) but showed significant difference when the drug was administered for the 18th and 24th times. 3) Plasma AT III activity decreased significantly (p0.05) when the drug was given for the 1st time but showed no change when the drug was administered 3-5 times. When administered 11-12 times, AT III was observed to decrease again, but repeat administrations did not cause AT III to decline; this was probably due to inurement. A similar change in immune activity concentration was observed but the change was slight. 4) When the drug was given 3-5 times following the 1st administration, a slight decrease (p0.1) occurred in alpha2 PI levels, but no change worth of mention was noted to occur thereafter. 5) In patients who received norethisterone 5 mg alone, no particular change was seen to occur in FPA, FPBbeta15-42, AT III, or alpha2 PI. Judging from the above results, especially that there was an increase in FPA, the decrease in AT III levels may be attributed not to a reduction in consumption but to a decrease in the AT III itself, due to estrogens. It is possible also that an increase in FPBbeta 15-42 led to plasmin production which was the reason so few thromboses were observed to form. (author's modified)^ieng

[Effects of acid-base balance and Apgar score on fibrinopeptide A and fibrinopeptide B beta 15-42 in umbilical cord blood].

Previous studies on asphyxia neonatorum show that the infant's blood is in a state of hypercoagulability at such a time. In the present study, we determined the amount of fibrinopeptide A (FPA) and fibrinopeptide B beta 15-42 (FPB beta), new sensitive indicators of the coagulation-fibrinolytic system, in the newborn, and examined their relationship to the acid-base balance in umbilical artery blood in elective cesarean section and vaginal delivery, as well as to the Apgar score (Ap. S). In addition, the findings in umbilical cord blood were then compared with those in the blood of normal adults. The results were as follows: In vaginal delivery, infants with Ap. S at 5-7, pH, had significantly lower HCO-3 and BE readings lower while PCO2 was significantly increased, which indicated respiratory and metabolic acidosis. In the vaginal delivery group, FPA was significantly increased in infants with pH under 7.24, PCO2 over 50 mmHg, BE under -8 and Ap. S at 5-7, and as well as in infants in the elective cesarean section group with Ap. S at 5-7. This suggests that the production of thrombin is accelerated if the fetus is asphyxiated. FPB beta was not significantly different among groups. However, FPB beta was significantly higher in various vaginal delivery groups than in the elective cesarean section group (Ap. S greater than or equal to 8), which implies acceleration of the production of plasmin and fibrinolysis in vaginal delivery. FPA and FPB beta were markedly increased in umbilical cord blood as compared with the blood of normal adults. This suggests that blood coagulation and fibrinolysis were accelerated in umbilical cord blood.