Eradication of HPV post-surgical treatments, its correlation with specific types, types of surgery and the physical status.

Low-risk human papillomaviruses (HPVs) will be completely eradicated as long as most visible lesions are treated. However, it is uncertain whether this is also the case for high-risk HPVs that are capable of causing cervical cancer. Many recent studies have demonstrated a high incidence of HPV persistence during post-conization or loop electrosurgical excision (LEEP) due to high-grade cervical intraepithelial neoplasia (CIN). In this report, we correlated the post-operative HPV status with pre-operative HPV type, types of surgery and HPV's physical status. Post-operative HPV E6 amplification by nested PCR was carried out for 157 female patients with positive pre-operative HPV. They underwent LEEPs, therapeutic laser conizations, and simple or radical hysterectomies. We found that high-risk types of HPVs were eradicated in 26.4% (42/159) of patients after extirpation of the lesions. The clearance rate of HPVs increased to 39.2% (40/102), excluding patients with other high-risk (OHR) kinds of type 31, 52b and 58, since OHR persisted after almost all surgeries. Eradication of HPV after radical hysterectomies are highly expected for patients with invasive cancer (70.0%, when excluding OHR), while more than half of them with CIN continue to carry pre-operative types of HPV or some different types from before treatment. Type 33 is most frequently persistent among types 16, 18 and 33. Persistent high-risk HPVs increase the risk for recurrence of post-surgical treatments of CIN, but the incidence is not high as long as the lesion is completely removed.

Heparanase messenger RNA expression in epithelial ovarian tumor.

Endoglycosidic heparanase degrades heparan sulfate glycosaminoglycans, and may be important in cancer invasion and metastasis, although its expression in human epithelial ovarian cancer has not been characterized. Heparanase association with clinicopathological features regarding prognostic significance was examined in patients presenting with epithelial ovarian tumor. Gene expression of heparanase was assessed by reverse transcription-PCR in 5 borderline and 31 malignant epithelial ovarian tumors. Heparanase mRNA expression was high in 16 of 31 malignant epithelial ovarian tumors. In contrast, there was no specimen presenting high heparanase mRNA expression in five borderline epithelial ovarian tumors. Heparanase expression was significantly higher in tumors with massive ascites and high grade (p=0.049 and p=0.006, respectively). There was no association between heparanase expression and patient outcome. These findings provide evidence that heparanase expression may be associated with a high grade phenotype in this class of neoplasm.

In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by E6 siRNA.

Human papillomavirus type 16 (HPV16), a causative agent of cervical cancers, encodes the E6 and E7 oncogenes, whose simultaneous expression is pivotal for malignant transformation and maintenance of malignant phenotypes. In the hope of developing a gene-specific therapy for HPV-related cancer, we examined the effects of E6 short-interfering RNA (siRNA) on the expression of these oncogenes and on the cell growth of HPV16-related cervical cancer cells. Using SiHa cervical cancer cells, we demonstrated that E6 siRNA decreased the levels of mRNA encoding E6 as well as that encoding E7 protein and also induced nuclear accumulation of p53, the most important target of E6. E6 siRNA suppressed monolayer and anchorage-independent growth of SiHa cells, which was associated with p21(CIP1/WAF1) induction and hypophosphorylation of retinoblastoma protein. Further, SiHa cells treated with E6 siRNA formed tumors in NOD/SCID mice that were significantly smaller than in those treated with control siRNA. Our results show HPV E6 siRNA as a candidate for gene-specific therapy for HPV-related cervical cancer.

Regression of esophageal papillomatous polyposis caused by high-risk type human papilloma virus.

Esophageal squamous papilloma is an uncommon benign squamous epithelial polypoid tumor and is usually identified as a solitary lesion in the lower esophagus. Chronic mucosal irritation and infection with human papilloma virus (HPV) are two proposed etiologies. However, the natural history of esophageal squamous papilloma is unknown, and whether it can develop to esophageal cancer is also controversial. The authors report a case of esophageal papillomatous polyposis in which the presence of high-risk HPV DNA was proven by type-specific polymerase chain reaction (PCR). The patient was an 83-year-old man referred to our hospital with complaints of nausea and dysphagia. Esophago-gastroduodenoscopy (EGD) was carried out, and diffuse polyposis of the entire length of the esophagus and stenosis in the antrum of the stomach were revealed. Histological examination of the tissue confirmed the diagnosis of squamous papilloma of the esophagus and poorly differentiated adenocarcinoma of the stomach. Furthermore, HPV type-specific PCR was carried out in the biopsied specimens, and HPV type-16 and type-33 were detected. One month after total gastrectomy performed for the treatment of gastric cancer, follow-up EGD was carried out, and complete regression of the esophageal polyps was noted. This case is rare and supports the evidence that esophageal squamous papilloma is caused by infection with HPV. Furthermore, this case also reflects a unique aspect of the natural history of esophageal papillomatous polyposis.

[Paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients].

To evaluate the validity of administration of paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with gynecologic cancer, we explored the efficacy and safety of these regimens. From October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin with or without THP-ADR pursuant to the chart we prepared originally as first line chemotherapy in patients with gynecologic cancer. Eleven elderly patients (age > 70 years) and 62 younger patients (age < 70 years) were entered into the present study. Paclitaxel was administered as a 3-hour intravenous (i.v.) infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over 60 minutes at dosages of area under the curve (AUC) 3 to 5, administered intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p = 0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin with THP-ADR. The overall response rates were equivalent among elderly and younger patients (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin without THP-ADR was applied safely to elderly patients.

[The effect of L-Glutamine and Shakuyaku-Kanzo-to for paclitaxel-induced myalgia/arthralgia].

Myalgia/arthralgia is a crucial side effect of paclitaxel, and may become the major dose-limiting side effect. However, this is a situation where there is little effective preventive treatment. L-Glutamine was reported as a neuroprotective agent for vincristine-induced neurotoxicity. In Japan, there have been reports on steroid and Shakuyaku-Kanzou-to (a herbal medicine) for paclitaxel-induced myalgia/arthralgia. This study aimed to compare the effect of L-Glutamine and Shakuyaku-Kanzou-to, and to discuss the validity of these agents for the paclitaxel-induced myalgia/arthralgia. Our results suggested that Shakuyaku-Kanzou-to showed no remarkable effects against paclitaxel-induced myalgia/arthralgia as had been reported before; however, both L-Glutamine and Shakuyaku-Kanzou-to decreased the duration of grade 2 toxicity (CALGB Expanded Common Toxicity Criteria) in comparison with those who were not treated. L-Glutamine and Shakuyaku-Kanzou-to might therefore a preventive effect against moderate or severer myalgia/arthralgia during paclitaxel-treated chemotherapy. Further trials are needed to confirm the value of these drugs.

Rapid and sensitive detection of physical status of human papillomavirus type 16 DNA by quantitative real-time PCR.

A rapid quantitative real-time PCR method was employed to quantify the copy number of E2 and E6 genes for analysis of the physical status of human papillomavirus type 16 (HPV-16) DNA. Significant differences with respect to both copy numbers were found when more than 40% of HPV-16 DNA was integrated with disruption of the E2 gene in an experimental model. The physical status of HPV-16 DNA in 50 clinical samples was exclusively episomal in 21 cases (42%), concomitant in 14 cases (28%), and integrated in 15 cases (30%). The prevalence of integrated and/or concomitant forms of HPV-16 DNA increased with progression of cervical disease. Four of 11 cervical intraepithelial neoplasia involved integrated forms of HPV-16 DNA partially or exclusively. This rapid, sensitive technique is useful in the analysis of the physical status of HPV DNA.

Neoadjuvant treatment with docetaxel and the effects of irradiation for human ovarian adenocarcinoma and cervical squamous cell carcinoma in vitro.

The in vitro radiosensitizing effects of docetaxel have been reported, but the DNA damage caused by the irradiation after docetaxel exposure has not been investigated. In this study, the authors attempted to evaluate the radiosensitizing effects in terms of cell survival and DNA single-strand breaks in a human ovarian adenocarcinoma cell line (known as line BG-1) and a human cervical squamous cell carcinoma cell line (known as line SiHa). The cell lines were exposed to various concentrations of docetaxel (from 2.27 x 10(-3) to 2.27 microg/ml) to investigate the cytocidal effects by colony-formation assay. DNA single-strand breaks after exposure to 2.27 microg/ml of docetaxel for 30 min or 100 min were measured by the alkaline-elution assay. The remarkable cytotoxicity of docetaxel followed by irradiation was observed when concentrations were greater than 2.27 x 10(-2) microg/ml in both cell lines. The combination of docetaxel and irradiation appears to be supraadditive. The DNA single-strand breaks induced by the irradiation were enhanced in both cell lines (BG-1; P < 0.01, SiHa; P < 0.05). The synergistic cytocidal effect cannot be explained quantitatively only by the single-strand breaks.

Optimal surgery and diagnostic approach of stage IA2 squamous cell carcinoma of the cervix.

BACKGROUND: Most patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA2 squamous cell carcinoma of the cervix, opt for radical surgery at present. OBJECTIVE: To review surgical and diagnostic approaches in such patients. STUDY DESIGN: Our patient population consisted of 394 patients with a diagnosis of stage I squamous cell cervical carcinoma (with depth of stromal invasion 10mm or less) according to the 1995 FIGO definition. Biopsy and surgical specimen slides were reassessed retrospectively in all cases. The findings of T2-weighted MR imaging were available from the individual medical charts. RESULTS: None of the patients with stromal invasion of 5mm depth or less showed pelvic lymph node metastasis. However, metastasis to the parametrial connective tissue was found in one case with stage IA1 exhibiting marked lymph-vascular space involvement. There were no deaths due to disease in cases with stromal invasion of 5mm depth or less. The lesions were detected in all 20 cases exhibiting stromal invasion of greater than 5mm in depth. In contrast, the lesions were not detected with T2 imaging in four of six cases (67%) with stage IA2. CONCLUSION: Simple or modified radical hysterectomy with pelvic lymph node dissection may be sufficient for cases of stage IA2 cervical squamous cell carcinoma where lymph-vascular space involvement is absent. T2-weighted MR imaging with no detectable tumor would prove beneficial in the selection of these patients.