The role of the replication error-positive (RER+) phenotype in the development of specific subtypes of sporadic ovarian carcinomas was examined by screening for the presence of microsatellite instability (MI) in 47 tumors. The overall frequency of ovarian MI was 17% only. However, MI occurred in 50% of the ovarian endometrioid-type tumors, which was significantly more often than in all the other histological subtypes combined (8%). Five of the 8 RER+ tumors exhibited most marked type I instability, possibly representing a different mechanism than for the remaining type 2 tumors. The cDNA of the mutation suppression gene hMSH2, the gene most often associated with MI, was screened for alterations in 8 MI-positive and 5 MI-negative ovarian tumors. Only 3 changes were found. Complete loss of hMSH2 mRNA expression was detected in I tumor, while another expressed only an abnormal transcript containing a deletion of exon 3. One additional RER+ serous adenocarcinoma contained a rare polymorphism with a non-conservative amino acid change. One of 8 RER+ tumors showed loss of heterozygosity at the hMSH2 loci. Genetic instability, caused in part by alterations in the hMSH2 gene, may play an important role in the sporadic endometrioid subtype of ovarian tumors. Other mutator-phenotype genes may be responsible for the remaining cases of RER+ ovarian tumors.
Simultaneous involvement of the endometrium and the ovary by carcinoma is a familiar problem in the routine practice of surgical pathology. Such cases may be considered either examples of a single primary carcinoma with metastasis or as synchronous primary neoplasms. The distinction between these two possibilities is made based on clinicopathologic observations, and therefore may not be definitive. In the present study, the authors used molecular techniques to analyze the clonal composition of five cases of concurrent adenocarcinomas of the endometrium and ovary that were clinicopathologically diagnosed as synchronous primary tumors. Patterns of X-chromosome inactivation, Cases of concurrent carcinomas of the endometrium and the ovary are not uncommonly encountered in the routine practice of surgical pathology. The incidence of endometrial carcinoma in patients with endometrioid ovarian cancer has been reported to range from more than 5% to nearly 70%, and in most series has averaged about 20% '~4 Simultaneous carcinomas of the endometrium and ovary may represent a diagnostic dilemma and the clinical management of such cases may be problematic.3 ' 5,6 Such cases could be considered alternatively FIGO (International Federation of Gynecologists Obstetricians) stage III adenocarcinoma of the endometrium, FIGO stage II ovarian carcinoma, or synchronous primary neoplasms. 6 Various studies have shown that if tumors in both the endometrium and the ovary are of an endometrioid morphology, then the patient prognosis is better than ex- From the
Immunosuppressive acidic protein (IAP) was determined in sera of patients with gynecologic tumors using the single radial immunodiffusion method. The normal limit of IAP of 490 μg/ml was derived from the mean value + 2 SD of IAP in 150 healthy females. Among 141 patients with gynecologic cancers, serum IAP was elevated in 87 patients (62%). Among 190 patients with benign tumors (98 uterine myoma, 92 benign ovarian tumors) serum IAP was elevated in 14 patients (7%). Elevated levels of IAP were recognized in 43% of 77 patients with cervical cancer, in 55% of 11 endometrial cancer patients, and in 91% of 53 ovarian cancer patients. The frequency of elevated levels showed a tendency to increase with advancing stage of disease. In ovarian cancer elevation of IAP was observed even in early stages. All of 13 patients with recurrent cervical cancer had elevated IAP while only 6 of 35 (17%) previously treated patients without evidence of recurrence had elevated IAP. Immunosuppressive acidic protein determinations may be useful in monitoring the recurrence of cervical cancer. The measurement of serum IAP as a marker for gynecologic cancer is recommended as an addition to diagnostic procedures.
The effect of immunotherapy using sizofiran (SPG) on the prognosis of patients with ovarian cancers was prospectively studied in a total of 68 patients, who were randomly assigned to either a cisplatin, adriamycin and cyclophosphamide (PAC) therapy group or a PAC plus SPG combination therapy group. The survival rate was significantly higher in patients with stage Ic, II or III cancers treated with the PAC plus SPG combination, compared with the patients treated with PAC alone. In the SPG-receiving patients with stage Ic or more advanced cancers who were treated with four cycles or more of PAC, the outcome was improved (Cox-Mantel, p = 0.074; generalized Kruskal-Wallis, p = 0.032). Similar improvement was also observed in the patients with non-serous adenocarcinomas (Cox-Mantel, p-0.076; generalized Kruskal-Wallis, p = 0.045). No side effects attributable to SPG were recorded. The present results suggest that the use of SPG in combination with long-term chemotherapy improves the postoperative prognosis in ovarian cancer patients.
Utilizing vaccinia virus (VV), a tumor-specific immunotherapy model was established in which a growing tumor regressed. C3H/HeN mice were primed with VV after low dose irradiation to generate amplified VV-reactive T cell activities. Then 4 weeks later, the mice were inoculated i.d. with syngeneic MH134 hepatoma cells, and 6 days after the tumor cell inoculation, live VV was injected into the tumor mass 3 times at 2-day intervals. Of 10 mice which had received VV priming and subsequent VV injection into the tumor mass, 8 exhibited complete tumor regression. On the contrary, mice which had received only intratumoral VV injection without VV priming failed to exhibit appreciable tumor regression. Mice whose tumor had completely regressed following the VV immunotherapy were shown to have acquired systemic antitumor immunity, which was confirmed by a challenge with syngeneic tumor cells after immunotherapy. In vitro analysis of these immune mice revealed that potent tumor-specific antibody responses were preferentially induced, but with no detectable antitumor cytotoxic T lymphocyte (CTL) responses. Such a potent tumor-specific immunity was not observed in mice which had received intratumoral VV injection in the absence of VV priming. Thus, the results clearly indicate that tumor regression was accompanied by the concurrent generation of a potent tumor-specific immunity, suggesting that cellular cooperation between VV-reactive T cells and tumor-specific effector cells might be functioning in this VV immunotherapy protocol. Therefore, the present model provides an effective maneuver for tumor-specific immunotherapy. This system is, in principle, applicable to the human situation.
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