Yoshinobu Hayashi

Expression of ras Oncogene Product and EGF Receptor in Cervical Squamous Cell Carcinomas and Its Relationship to Lymph Node Involvement

The expression of ras oncogene product p21 and epidermal growth factor (EGF) receptor was studied immunohistochemically in tissues obtained from 52 patients with squamous cell carcinoma of the uterine cervix. We examined the relationship between p21 and EGF receptor expression and lymph node metastasis in cervical cancer. The data demonstrate that the patients with positive staining for ras p21 in cervical carcinomas have a higher incidence of lymph node metastasis than the patients with negative staining for p21 (P = 0.027). Although the levels of p21 expression in the metastatic sites were reduced compared to those in the primary sites, tumor cells in metastatic lymph nodes also expressed p21. No relationship was found between EGF receptor expression and lymph node metastasis. These results suggest that expression of ras oncogene product may be associated with the biological aggressiveness of cervical carcinomas.

Interferon γ treatment for cervical intraepithelial neoplasia

Eight patients with cervical intraepithelial neoplasia (CIN) were administered perilesional injections of human recombinant interferon gamma (IFN-gamma), and the response was evaluated by colposcopy and exfoliative cytology and then by histopathology. In all patients, colposcopic and cytologic findings improved after two to four injections of IFN-gamma and the cytologic findings reverted to normal in five of these eight patients. All five were free of dysplastic lesions. The other three patients with positive cytology and positive colposcopy after completion of IFN-gamma treatment underwent hysterectomy or laser conization, and histopathologic examination revealed residual dysplastic lesions. On the other hand, a control study revealed that only one of eight patients showed spontaneous regression during the 3-month observation period. During the course of these treatments, keratinizing cells were often present in the cervical smears and isolated cell keratinization was often evident in the residual dysplastic lesions of the surgical specimens. These observations suggest that IFN-gamma treatment is an effective therapeutic method for CIN lesions and that IFN-gamma has the potential to differentiate nonkeratinizing squamous cells into keratinizing cells.

‘Hit and run’ oncogenesis by human papillomavirus type 18 DNA

Transfection of an immortalized cell line (AE), derived from Syrian hamster embryo cells, with human papillomavirus type 18 (HPV 18) DNA induced morphological transformation and these transformed cells were tumorigenic in nude mice. Southern blot analysis revealed that the transfected viral DNA was retained in all the cell lines tested, however, all these transformed cells contained only less than one copy per cell of viral genome. Eleven cloned cell lines were established from a tumor cell line obtained after explantation of a tumor into a nude mouse. Two lines revealed no viral sequences by both Southern blot hybridization and polymerase chain reaction, whereas the nine others contained the remaining viral sequences. These results are highly suggestive of a ‘hit and run’ oncogenesis by this virus.

Malignant pericardial effusion in endometrial adenocarcinoma

A case of endometrial adenocarcinoma in a 62-year-old woman with malignant pericardial effusion is presented. The patient underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic node dissection, and paraaortic node biopsy. Postoperatively, she was placed on a combination chemotherapy regimen of cisplatin, doxorubicin, and cyclophosphamide. The patient developed cardiac tamponade during the course of chemotherapy. Although we first suspected cardiotoxic effect of doxorubicin, cytologic examination revealed adenocarcinoma cells in the pericardial fluid. A review of the literature revealed no other cases of cardiac metastasis from endometrial carcinoma diagnosed during life.

Antitumor effects of human recombinant interferon-γ and tumor necrosis factor on five cervical adenocarcinoma cell lines, in vivo and in vitro

We examined the antitumor effects of recombinant interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) on cervical adenocarcinoma cell lines, in vitro and in vivo. Four of five cell lines showed a high sensitivity to IFN-gamma, in vitro. One of five cell lines showed a remarkable sensitivity to TNF, in vitro. Only one cell line resistant to both IFN and TNF was derived from a well-differentiated adenocarcinoma of endocervical type. Experiments using nude mice bearing transplanted tumors revealed that these cytokines were also effective against tumors in vivo. All these observations suggest that IFN-gamma or TNF can have positive effects in the treatment of patients with adenocarcinoma of the uterine cervix.

Treatment of advanced cervical cancer by a combination of peplomycin, vincristine, mitomycin-C, and cisplatin.

Eighteen patients with advanced or recurrent carcinoma of the cervix were treated with a combination of peplomycin, vincristine, mitomycin-C, and cisplatin (POMP). Ten of the 16 evaluable patients (63%) responded, including 4 with a complete response. Median duration of the response was 7 months. Two of 6 with intrapelvic recurrent tumors responded to some extent following intraarterial infusion. The subcutaneous infusion of peplomycin was well accepted by the patients. Toxicity was tolerable. This regimen seemed to be one of the regimens which should be considered for the advanced or recurrent cervical cancer.

Polymerase chain reaction analysis of human papillomavirus in adenocarcinoma and adenosquamous carcinoma of the uterine cervix

Thirty‐two cervical adenocarcinomas and adenosquamous carcinomas were examined to search for human papillomaviruses (HPVs) using the polymerase chain reaction system. Human papillomavirus type 16 (HPV16) and type 18 (HPV18) deoxyribonucleic acid was detected in 22% and 16% of these carcinomas, respectively. HPV16 was the most common type in both adenocarcinoma and adenosquamous carcinoma, and the mean age of the HPV negative patients was significantly higher than that of HP V positive patients. There may be an association between HPVs and the development of certain adenocarcinomas and adenosquamous carcinomas of the cervix.

Human papillomavirus 16 and 18 DNA can solely induce oncogenic transformation of mammalian cells in primary culture

To compare the tumorigenic activity of HPV 6, 11, 16, and 18 DNA in mammalian cells in primary culture, HPV DNAs were transfected to Syrian hamster embryo (SHE) cells. Morphologically transformed foci were observed in all the HPV DNA‐transfected cultures and cells propagated from these foci were immortalized. All these cell lines at early passages were not tumorigenic in nude mice. However, a cell line derived from HPV 16 transfection became tumorigenic after 25 passages and a cell line derived from HPV 18 transfection also revealed tumorigenicity after 48 passages. Overexpression of the Ha‐ras proto‐oncogene occurred in these transformed cell lines. No tumorigenic activity was observed in HPV 6 and HPV 11‐transfected cell lines. All these observations suggest that HPVs 16 and 18 have a higher transforming potential than do HPVs 6 and 11 and can solely induce tumorigenic transformation of cells in primary cultures, with continuous passage.

Treatment of advanced cervical cancer by a combination of peplomycin, vincristine, mitomycin-C, and cisplatin

Eighteen patients with advanced or recurrent carcinoma of the cervix were treated with a combination of peplomycin, vincristine, mitomycin-C, and cisplatin (POMP). Ten of the 16 evaluable patients (63%) responded, including 4 with a complete response. Median duration of the response was 7 months. Two of 6 with intrapelvic recurrent tumors responded to some extent following intraarterial infusion. The subcutaneous infusion of peplomycin was well accepted by the patients. Toxicity was tolerable. This regimen seemed to be one of the regimens which should be considered for the advanced or recurrent cervical cancer.

Interferon gamma treatment for cervical intraepithelial neoplasia

Eight patients with cervical intraepithelial neoplasia (CIN) were administered perilesional injections of human recombinant interferon gamma (IFN-gamma), and the response was evaluated by colposcopy and exfoliative cytology and then by histopathology. In all patients, colposcopic and cytologic findings improved after two to four injections of IFN-gamma and the cytologic findings reverted to normal in five of these eight patients. All five were free of dysplastic lesions. The other three patients with positive cytology and positive colposcopy after completion of IFN-gamma treatment underwent hysterectomy or laser conization, and histopathologic examination revealed residual dysplastic lesions. On the other hand, a control study revealed that only one of eight patients showed spontaneous regression during the 3-month observation period. During the course of these treatments, keratinizing cells were often present in the cervical smears and isolated cell keratinization was often evident in the residual dysplastic lesions of the surgical specimens. These observations suggest that IFN-gamma treatment is an effective therapeutic method for CIN lesions and that IFN-gamma has the potential to differentiate nonkeratinizing squamous cells into keratinizing cells.