藤井 多久磨

BACKGROUND: It has been suggested that micronutrients such as alpha-tocopherol, retinol, lutein, cryptoxanthin, lycopene, and alpha- and beta-carotene may help in the prevention of cervical cancer. Our aim was to investigate whether serum concentrations and/or dietary intake of micronutrients influence the regression or progression of low-grade cervical abnormalities. METHODS: In a prospective cohort study of 391 patients with cervical intraepithelial neoplasia (CIN) grade 1-2 lesions, we measured serum micronutrient concentrations in addition to a self-administered questionnaire about dietary intake. We evaluated the hazard ratio (HR) adjusted for CIN grade, human papillomavirus genotype, total energy intake and smoking status. RESULTS: In non-smoking regression subjects, regression was significantly associated with serum levels of zeaxanthin/lutein (HR 1.25, 0.78-2.01, p = 0.024). This benefit was abolished in current smokers. Regression was inhibited by high serum levels of alpha-tocopherol in smokers (p = 0.042). In progression subjects, a significant protective effect against progression to CIN3 was observed in individuals with a medium level of serum beta-carotene [HR 0.28, 95 % confidence interval (CI) 0.11-0.71, p = 0.007), although any protective effect from a higher level of serum beta-carotene was weaker or abolished (HR 0.52, 95 % CI 0.24-1.13, p = 0.098). Increasing beta-carotene intake did not show a protective effect (HR 2.30, 95 % CI 0.97-5.42, p = 0.058). CONCLUSIONS: Measurements of serum levels of carotenoids suggest that regression is modulated by smoking status. Maintaining a medium serum level of beta-carotene has a protective effect for progression; however, carotene intake is not correlated with serum levels of carotenoids.

Background: Previous studies of human papillomavirus (HPV) 16/18 genome methylation have concluded that methylation status of the L1 gene might act as a biomarker for cervical intraepithelial neoplasia (CIN). Objectives: We investigated the correlation between methylation status in the L1 gene and the long control region (LCR) of HPV52/58 and CIN. Study design: Exfoliated cervical cells were taken from 54 HPV52-positive and 41 HPV58-positive women. The HPV genome was examined using bisulfite modification, polymerase chain reaction amplification, and sequencing. Results: The CpGs were unmethylated or hypomethylated in the HPV52/58 LCR. In contrast, the methylation status of the HPV52 L1 gene was correlated with the severity of cervical neoplasia, with average percentages of 15%, 34%, and 52% for cervicitis/CIN1, CIN2, and CIN3, respectively (P < 0.05). Methylation status of the HPV52 L1 gene was also correlated with the prognosis of CIN1/2, with median percentages of 15% and 35% for regression and persistence/progression, respectively (P < 0.05). The methylation status of the HPV58 L1 gene was correlated with the severity of cervical neoplasia, with average percentages of 12%, 38%, and 61% for cervicitis/CIN1, CIN2, and CIN3, respectively (P < 0.05). Conclusions: The increased methylation at the CpG sites in the HPV52/58 L1 gene was correlated with the severity of cervical neoplasia, similar to HPV16/18 in previous studies. These data suggest that HPV methylation status of the L1 gene is a candidate biomarker of CIN for detecting CIN2 and CIN3. (C) 2013 Elsevier B. V. All rights reserved.

What are the reproductive and obstetric outcomes in patients undergoing radical abdominal trachelectomy (RAT) for early-stage cervical cancer? When RAT was performed before a pregnancy achieved with fertility treatments, pregnancy rate of 36.2 was obtained and 71.4 of these women gave birth at 32 weeks of gestation. Reproductive and obstetric outcomes after radical vaginal trachelectomy (RVT) are well documented; however, these outcomes after RAT have not been well studied. This is a retrospective cohort study of patients at a single institution who underwent RAT and became pregnant. Reproductive and obstetric outcomes of 114 patients who had undergone RAT from September 2002 to December 2010 were investigated. Women of reproductive age with early-stage cervical cancer who wished to preserve their fertility were documented. Patients median age was 33 years (2540 years). A total of 31 pregnancies were achieved in 25 patients and 6 patients had 2 pregnancies. Eighteen of 25 patients (72.0) had infertility problems; 17 patients conceived with IVF-embryo transfer and 1 patient with intrauterine insemination. The pregnancy rate among patients who wished to conceive was 36.2 (25/69). Among 31 pregnancies in 25 patients, 4 patients had first trimester miscarriage and 1 patient had second trimester miscarriage. Excluding the five patients who miscarried and the five ongoing pregnancies, all the 21 patients had deliveries by Cesarean section. Four patients had a preterm birth in the second trimester and 17 patients delivered in the third trimester. Of the 17 pregnancies that reached the third trimester, 2 (11.8) were preterm births between 29 and 32 weeks, 11 (64.7) were delivered between 32 and 37 weeks and 4 (23.5) at 37 weeks of gestation. Because of the retrospective data collection, not all pregnancies may have been recorded. Prospective multicenter studies are needed to determine if the results shown in this retrospective cohort can be generalized to all patients with early-stage cervical cancer who wish to undergo the fertility-sparing RAT procedure. There was no funding for this study. No conflicts of interest.

The medical liquid crystal display (LCD) monitor is a conventionally used imaging device for diagnosis and during endoscopic surgery. Recently, a medical organic electroluminescence panel, the organic light-emitting diode (OLED) monitor, was made available commercially. The advantages of the OLED monitor include good color reproducibility, high contrast, and high video responsiveness. In this nonclinical study, we compared the clinical usefulness and image quality of the OLED monitor and those of the LCD monitor using videos of gynecologic endoscopic surgeries. Monitors were set for blind evaluation. Five evaluators with varying experience in endoscopic surgery evaluated 21 surgery videos played simultaneously on an OLED monitor and two LCD monitors for 2 to 3 minutes twice. Evaluators judged 13 clinical usefulness indices and 11 image quality indices using a 5-point scale (1, very good; 5, very poor) for each video. The mean scores of clinical usefulness indices of the OLED monitor and the LCD monitors 1 and 2 were 2.2 to 2.7, 2.1 to 3.3, and 3.0 to 3.2, respectively. Of seven indices measured, five including motion response, the ability to differentiate organs, recognize lesions, and reproduce actual images, and the general impression of picture quality were statistically superior with use of the OLED monitor compared with the LCD monitor 1, and two including ability to distinguish blood vessels and the ureters were statistically superior with use of the LCD monitor 1 compared with the OLED monitor. The mean scores of image quality indices of the OLED monitor and the LCD monitors 1 and 2 were 1.8 to 3.2, 2.6 to 3.6, and 2.8 to 4.0, respectively. Each index of the OLED monitor was superior to or comparable with those of the LCD monitors. We conclude that the OLED monitor is superior to the LCD monitors insofar as several video presentation characteristics required in gynecologic endoscopic surgery. These findings suggest that the OLED monitor is expected to contribute detailed assessment of organs and the operative field. Journal of Minimally Invasive Gynecology (2013) 20, 522-528 (C) 2013 AAGL. All rights reserved.

This study was designed to evaluate the Clinichip HPV test, a new DNA test that detects carcinogenic human papillomavirus (HPV) rapidly by loop-mediated isothermal amplification and performs genotyping of all 13 carcinogenic types using automated DNA chip technology with an assay time 2.5 h. Using this test, 247 Japanese women (109 with normal cytology, 43 with cervical intraepithelial neoplasia grade 1, 60 with cervical intraepithelial neoplasia grade 2/3 and 35 with invasive cervical cancer) were tested for carcinogenic HPV genotypes. The results were compared to those obtained by the polymerase chain reaction-amplified DNA sequencing using 13 type-specific primers. Overall, there was very good agreement for the detection of carcinogenic HPV between the Clinichip test and direct sequencing, with 95.5% total agreement and a kappa value of 0.91. Comparison of the detection of individual HPV types shows that the overall agreement was also high (range: 96.8-100%). In women with cervical intraepithelial neoplasia grade 2 or worse, the detection rate of carcinogenic HPV was 95.7% by both the Clinichip test and the direct-sequencing method, indicating complete agreement between the two methods. In conclusion, it was found that the Clinichip test is a promising new laboratory method for genotyping of carcinogenic HPV. (C) 2012 Elsevier B.V. All rights reserved.

Objective: In cervical intraepithelial neoplasia (CIN), p16INK4a immunohistochemistry has been reported to be a useful diagnostic biomarker. However, limited information is available about the association between the p16INK4a immunohistochemistry and the outcomes of CIN. Here, we report p16INK4a immunohistochemistry as an effective biomarker to predict the outcomes of CIN. Methods: p16INK4a immunohistochemistry was performed in patients with CIN from January 2000 to August 2009. Among these patients, we have performed a retrospective analysis of the medical records to evaluate the outcome of CIN 1-2 and performed statistical analysis to determine the correlation between p16INK4a expression and the outcomes. We also performed HPV genotyping and analyzed the relation between the infecting human papillomavirus (HPV) genotype and the outcomes. Results: A total of 244 patients, including 82 with CIN 1, 60 with CIN 2, and 102 with CIN 3, were examined. The rate of p16INK4a overexpression increased with increasing CIN grade, 20.7% for CIN 1, 80.0% for CIN 2, and 89.2% for CIN 3, with significant differences between CIN 1 and CIN 2-3 group. In the 131 CIN 1-2 patients, the progression rate was significantly higher for the patients showing p16INK4a overexpression than for those not showing p16INK4a overexpression (p=0.005) the regression rate was also found to be significantly lower for the patients showing p16INK4a overexpression (p=0.003). High-risk HPV genotypes were detected in 73 patients (73.7%). Both progression and regression rates were not significantly different between the high-risk HPV-positive and HPV-negative groups (p=0.401 and p=0.381, respectively). Conclusion: p16INK4a overexpression was correlated with the outcome of CIN 1-2, and p16INK4a is considered to be a superior biomarker for predicting the outcome of CIN 1-2 compared with HPV genotyping. © 2013. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

Lower limb lymphedema is difficult to prevent and diagnose early because its natural history is unclear. Therefore, the aim of this study was to clarify its pathogenesis and to identify risk factors that may lead to early diagnosis. In 29 patients, aged 25 to 74 years with cervical, uterine, or ovarian cancer who underwent pelvic lymphadenectomy, indocyanine green fluorescence lymphangiography was performed with an infrared camera system, and lymph pumping pressure was measured indirectly preoperatively, and one, two, three, and six months postoperatively. Of these 29 patients, 22 (75.9%) completed the examinations. In the non-lymphedema group, the average lymph pumping pressure did not change significantly at postoperative follow-up compared with preoperative values. On the other hand, lymph pumping pressure increased at various time points in five patients who developed early lymphatic changes with dermal diffusion at the level of the proximal femur. An increase in lymph flow path resistance due to pelvic lymphadenectomy resulted in an initial increase in lymph pumping pressure, followed by a subsequent decrease, in the early lymphatic changes group. This trend in the pressure change signifies that the lymph vessels became dysfunctional as they were overwhelmed by the overload condition and this feature may be a clinically useful signal for the early diagnosis of developing lymphedema.

To determine the role of neutralizing antibody generated by human papillomavirus (HPV) infections, baseline levels of serum neutralizing antibodies directed against HPV 16 and cervical HPV DNA were determined in 242 unvaccinated women with low-grade cervical abnormalities, who were then monitored by cytology and colposcopy every 4 months. In women infected with HPV 16 (n?=?42), abnormal cytology persisted longer in those positive for HPV 16-specific neutralizing antibodies at baseline (median time to cytological regression: 23.8 vs. 7.2 months). Progression to cervical precancer (cervical intraepithelial neoplasia grade 3) within 5 years occurred only among women carrying HPV 16-specific neutralizing antibodies (P?=?0.03, log-rank test). In women infected with types other than HPV 16 (n?=?200), detection of HPV 16-specific neutralizing antibodies was not correlated with disease outcome. In conclusion, development of specific neutralizing antibodies following natural HPV 16 infection did not favor a better outcome of low-grade cervical lesions induced by HPV 16 or by other types; rather, detection of neutralizing antibodies generated by current infection may reflect viral persistence and thus help identify those who are at high risk of disease progression. J. Med. Virol. 84: 11281134, 2012. (C) 2012 Wiley Periodicals, Inc.

Objective: The aim of this study was to investigate the risk and recurrence of early invasive adenocarcinoma of the cervix, and to determine whether non-radical methods of management could be performed. Methods: The medical and histopathological records of 50 patients with early invasive adenocarcinoma of the cervix treated at Keio University Hospital between 1993 and 2005 were reviewed, and compared with the literature. Results: The median follow-up period was 64.3 months. The depth of stromal invasion was mm in <= 33 cases and >3 mm, but <= 5 mm in 17 cases. The horizontal spread was <= 7 mm in 25 cases and >7 mm in 25 cases. One of the 33 cases that had tumor volumes of <= 500 mm(3), and three of the 17 cases with tumor volumes of >500 mm(3) were positive for lymph node metastasis. When our data were combined with previously reported results, statistically significant differences were observed between the tumor volume and the frequency of pelvic lymph node metastasis/the rate of recurrence (p<0.0001). The frequency of pelvic lymph node metastases was significantly higher in the lymphovascular space invasion (LVSI)-positive group than in the LVSI-negative group (p=0.02). No adnexal metastasis or parametrial involvement was noted. Conclusion: Assessment of the depth of stromal invasion, tumor volume, and LVSI is critical for selecting an appropriate therapeutic modality. Non-radical methods of management are considered suitable for patients with LVSI-negative adenocarcinoma of the cervix exhibiting a stromal invasion depth of mm and a tumor volume of 500 mm(3).

To investigate the natural course of low-grade squamous intraepithelial lesions (LSILs) that cannot be histologically confirmed by colposcopy-directed biopsy. In a multicenter, prospective, cohort study of Japanese women with LSILs, we analyzed the follow-up data from 64 women who had a negative biopsy result at the initial colposcopy (biopsy-negative LSIL) in comparison with those from 479 women who had a histologic diagnosis of cervical intraepithelial neoplasia grade 1 (LSIL/CIN1). Patients were monitored by cytology and colposcopy every 4 months for a mean follow-up period of 39.0 months, with cytologic regression defined as two consecutive negative smears and normal colposcopy. In women with biopsy-negative LSILs, there were no cases of CIN3 or worse (CIN3+) diagnosed within 2 years; the difference in the 2-year risk of CIN3+ between the two groups was marginally significant (0 vs. 5.5%; P = 0.07). The cumulative probability of cytologic regression within 12 months was much higher in the biopsy-negative LSIL group (71.2 vs. 48.6%; P = 0.0001). The percentage of women positive for high-risk human papillomaviruses (hrHPVs) was significantly lower in the biopsy-negative LSIL group than in the LSIL/CIN1 group (62.1 vs. 78.4%; P = 0.01); however, the 12-month regression rate of biopsy-negative LSIL was similar between hrHPV-positive and -negative women (67.3 vs. 74.4%, P = 0.73). In women with biopsy-negative LSILs, the risk of CIN3+ diagnosed within 2 years was low; furthermore, approximately 70% underwent cytologic regression within 12 months, regardless of HPV testing results. Biopsy-negative LSILs may represent regressing lesions rather than lesions missed by colposcopy.

Notch is a transmembrane receptor functioning in the determination of cell fate. Abnormal Notch signaling promotes tumor development, showing either oncogenic or tumor suppressive activity. The uncertainty about the exact role of Notch signaling, partially, stems from inconsistencies in descriptions of Notch expression in human cancers. Here, we clarified basal-cell dominant expression of NOTCH1 in squamous epithelium. NOTCH1 was downregulated in squamous neoplasms of oral mucosa, esophagus and uterine cervix, compared with the normal basal cells, although the expression tended to be retained in cervical lesions. NOTCH1 downregulation was observed even in precancers, and there was little difference between cancers and high-grade precancerous lesions, suggesting its minor contribution to cancer-specific events such as invasion. In culture experiments, reduction of NOTCH1 expression resulted in downregulation of keratin 13 and keratin 15, and upregulation of keratin 17, and NOTCH? knockdown cells formed a dysplastic stratified epithelium mimicking a precancerous lesion. The NOTCH1 downregulation and the concomitant alterations of those keratin expressions were confirmed in the squamous neoplasms both by immunohistochemical and cDNA microarray analyses. Our data indicate that reduction of NOTCH1 expression directs the basal cells to cease terminal differentiation and to form an immature epithelium, thereby playing a major role in the histopathogenesis of epithelial dysplasia. Furthermore, down regulation of NOTCH1 expression seems to be an inherent mechanism for switching the epithelium from a normal and mature state to an activated and immature state, suggesting its essential role in maintaining the epithelial integrity. Laboratory Investigation (2012) 92, 688-702; doi:10.1038/labinvest.2012.9; published online 13 February 2012

Objective: Genetic variations in human leukocyte antigens (HLA) class II regions may influence the risk of cervical cancer by altering the efficiency of the immune responses to human papillomavirus antigens. This prospective study was designed to evaluate the effects of HLA class II alleles on the natural course of cervical precursor lesions. Methods: We followed a total of 454 Japanese women with cytological low-grade squamous intraepithelial lesion (LSIL) and histological cervical intraepithelial neoplasia grades 1 to 2 (CIN1-CIN2). Patients were tested for HLA class II alleles and cervical human papillomavirus DNA at the time of entry and then monitored by cytology and colposcopy every 4 months for a mean follow-up of 39.0 months. We analyzed cumulative probabilities of cytological regression to at least 2 consecutive negative Papanicolaou tests and histological progression to biopsy-positive CIN3. Results: During the follow-up period, 39 lesions progressed to CIN3, and 282 lesions regressed to normal cytology. Progression to CIN3 did not occur in DRB1*1302-positive women, and this protective effect of DRB1*1302 was statistically significant (P = 0.03). Low-grade squamous intraepithelial lesion regressed to normal cytology more quickly in DRB1*1302-positivewomen than in DRB1*1302-negativewomen (median time, 8.9 months vs 14.2 months), although the differencewas not statistically significant (P = 0.16). The risk of LSIL persistence or progression to CIN3 within 5 years was not affected by any other HLA class II alleles. Conclusion: By using a prospective study design, we demonstrated the protective effect of the DRB1*1302 allele against progression to CIN3 among Japanese women with LSIL.

Expression of a therapeutic gene in the skeletal muscle is a practical strategy to compensate a patients' insufficient circulating factor. Its clinical application requires a muscle-targeting vector capable of inducing a continuous high-level transgene expression. We modified an adeno-associated virus serotype 2 (AAV2) vector expressing luciferase from the mouse muscle creatine kinase gene promoter-enhancer (Ckm). First, AAVS1 insulator was inserted into the vector genome for transcriptional enhancement. This increased transduction of mouse quadriceps muscle by 11-fold at 4 weeks after intramuscular injection. Second, two capsid modifications were combined (21F capsid): incorporation of a segment of AAV1 capsid to produce a hybrid capsid and substitution of a tyrosine with a phenylalanine. Use of 21F capsid increased muscle transduction further by 18-fold, resulting in 200-fold higher efficacy than that of the unmodified vector. Compared with a vector having human elongation factor 1 alpha promoter which showed similar efficacy in the muscle, this vector having Ckm transduced non-muscle organs less efficiently after intravenous administration. The AAV2 vector composed of the modified genome and capsid provides a backbone to develop a clinical vector expressing a therapeutic gene in the muscle.

To compare two MR sequences at 1.5 T-T2-weighted and contrast-enhanced T1-weighted images-by using macroscopic sections to determine which image type enables the most accurate assessment of cervical carcinoma. Forty consecutive patients (mean age, 39.2 years) with biopsy-proven cervical carcinoma were included. Each MR sequence was assessed for tumour localisations, tumour margins, and cancer extent with the consensus of two readers, and tumour margins were rated on a five-point scale. MR findings were correlated with histopathological findings. Contrast-to-noise ratios (CNRs) obtained with each image were compared using nonparametric tests. Thirty-one of 40 patients underwent hysterectomies and nine of 40 underwent trachelectomies. In 36 patients, lesions were identified on at least one sequence. The tumours at stage 1B or higher were detected in 94.7% on contrast-enhanced T1-weighted images and in 76.3% on T2-weighted images (P < 0.05). Tumour margins appeared significantly more distinct on contrast-enhanced T1-weighted images than on T2-weighted images (P < 0.001). The CNRs obtained using contrast-enhanced T1-weighted images were significantly higher (P < 0.001) than those obtained using T2-weighted images. Contrast-enhanced T1-weighted imaging is more useful for assessing cervical carcinoma than T2-weighted imaging.

Only a subset of cervical precursor lesions progress to cervical cancer and because of the lack of the predictive markers, it cannot be ascertained which lesions will progress or not. To estimate the risk of disease progression associated with human papillomavirus (HPV) genotypes, we followed 570 Japanese women with cytological LSIL (low-grade squamous intraepithelial lesion) and histological CIN (cervical intraepithelial neoplasia) grade 1-2 lesions (479 CIN 1; 91 CIN 2) at 3 to 4 month intervals for a mean follow-up period of 39.1 months. At entry, we detected HPV DNA in cervical samples by polymerase chain reaction-based methodology. Over the period of follow-up period, 46 lesions progressed to CIN 3 while 362 regressed to normal cytology. Women with multiple HPV infections were more likely to have persistent lesions (hazard ratio [HR] for regression, 0.65; 95% confidence interval [CI], 0.42-1.02; p = 0.07); however, multiple infections did not increase the risk of progression (HR for progression, 1.04; 95% CI, 0.37-2.94; p = 0.94). After adjusting for CIN grade and women's age, HRs for progression to CIN 3 (vs. women with low-risk types or negative for HPV DNA) varied markedly by HPV genotype: type 16 (11.1, 95% CI: 1.39-88.3); 18 (14.1, 0.65-306); 31 (24.7, 2.51-243); 33 (20.3, 1.78-231); 35 (13.7, 0.75-251); 52 (11.6, 1.45-93.3); 58 (8.85, 1.01-77.6); other high-risk types (4.04, 0.47-34.7). HPV 45 was not detected in our study subjects. The cumulative probability of CIN 3 within 5 years was 20.5% for HPV 16, 18, 31, 33, 35, 52 and 58; 6.0% for other high-risk types; 1.7% for low-risk types (p = 0.0001). In conclusion, type-specific HPV testing for women with LSIL/CIN 1-2 lesions is useful for identifying populations at increased or decreased risk of disease progression.

The role of tobacco smoking in the multistage carcinogenesis at the cervix is not fully understood because of a paucity of prospective data. To assess the relationship between smoking and spontaneous regression of cervical precursor lesions, a total of 516 women with low-grade squamous intraepithelial lesion (LSIL) were monitored by cytology and colposcopy every 4 months. Probability of LSIL regression within 2 years was analyzed in relation to smoking behaviors, with regression defined as at least two consecutive negative Pap smears and normal colposcopy. Women's age, initial biopsy results, and human papillomavirus (HPV) genotypes were included in the multivariate models for adjustments. Our study subjects included 258 never-smokers and 258 smokers (179 current and 79 former smokers). During a mean follow-up time of 39.8 months, 320 lesions regressed to normal cytology. Probability of regression within 2 years was significantly lower in smokers than in never-smokers (55.0% vs 68.8%, P = 0.004). The risk of LSIL persistence increased with smoking intensity and duration and with younger age at starting smoking (P = 0.003, P < 0.001, and P = 0.03, respectively). Smokers had twice as high a risk of persistent HPV infection compared to never-smokers (odds ratio, 2.50; 95% confidence interval, 1.30-4.81; P = 0.006). In young women, passive smoking since childhood reduced probability of regression within 2 years (56.7% vs 85.9%, P < 0.001). Further adjustments for a wide range of cervical cancer risk factors did not change the findings. In conclusion, tobacco smoking may interfere with regression of cervical precursor lesions. Childhood exposure to second-hand smoke may increase a risk of persistent cervical abnormalities among young women. (Cancer Sci 2010).

Introduction: Although the colposcopic features of cervical glandular disease and cervical adenocarcinoma are not widely well known, unique microvascular patterns are reportedly useful for identifying such diseases. The narrow band imaging (NBI) system used in endoscopy can be used to obtain high-contrast vascular images. Therefore, we examined the utility of NBI colposcopy and compared the results with those of conventional colposcopy. Methods: Twenty-one patients with adenocarinoma in situ or early invasive adenocarcinomas were examined using digital NBI colposcopy, and the photo records were compared with those of conventional colposcopy. The histological examination and immunohistochemistry with anti-CD31 antibody confirmed the microvascular pattern. Results: Digital NBI colposcopy depicted the fine vascular texture on the surface of the cervix more clearly than conventional colposcopy. The vascular pattern was depicted in 86% (18/21) of glandular disease cases. The characteristic fine vascular patterns were critical for identifying cervical glandular diseases. Conclusions: Digital NBI colposcopy was useful for identifying early cervical adenocarcinoma as well as adenocarcinoma in situ. This system yields cervical glandular disease-related colposcopic findings that may be useful for both clinical and educational purposes.

Objectives: Incidence of lymph node metastasis is relatively high even in early-stage epithelial ovarian cancers (EOC). Lymphadenectomy is important in the surgical treatment of EOC; however, the exact role of lymphadenectomy in the management of EOC remains unclear. In this study, we evaluated lymph node metastasis in stages I and II EOC patients. Patients and Methods: Seventy-nine patients with stage I/II EOC underwent initial surgery, and 68 patients received adjuvant platinum and taxane chemotherapy after surgery at Keio University Hospital. The patients were evaluated with respect to age at diagnosis, clinical stage, histology, histological grade, and tumor laterality. Results: Of the 79 patients, 10 (12.7%) had lymph node metastasis. Of these, 4 (5.1%) had lymph node metastasis in paraaortic lymph node (PAN) only, 1 (1.3%) in pelvic lymph node (PLN) only, and 5 (6.3%) in both PAN and PLN. The incidence of serous-type lymph node metastasis in PAN, PAN + PLN, and total was higher than nonserous type (25% vs 1.5%, P < 0.0001; 25% vs 3.0%, P = 0.001; 50% vs 5.9%, P < 0.0001). However, there was no significant difference between lymph node status and T factor or histological grade. In 78% of patients (7/9), metastases in contralateral lymph nodes were present (contralateral, 2; bilateral, 5). There was no significant difference in progression-free survival between node-positive and node-negative groups (P = 0.47). Conclusions: Based on diagnostic value, the result suggests that the role of lymphadenectomy might differ by histological type, as its therapeutic effect might be unclear. A multicenter analysis is essential for confirmation.

Integration of human papillomavirus DNAs into the host genome is crucial to the development of cervical cancer. Overexpression of the P16 protein has been reported in cervical intraepithelial neoplasia (CIN) as well as cervical cancer. Such molecular biomarkers have been utilized for ancillary testing of liquid-based cytology specimens; however, their clinical application remains controversial. To detect CIN 2 or more advanced lesions, 153 liquid-based cytology (LBC) specimens were investigated to determine the physical status of the human papillomavirus (HPV) DNA by in situ hybridization (ISH) and to detect overexpression of the P16 protein by immunocytochemistry combined with HPV genotyping by polymerase chain reaction. The combination of ISH, P16 immunocytochemistry, and LBC showed high sensitivity (89.3%) as well as high specificity (92.6%). We confirmed the usefulness of P16 immunocytochemistry combined with ISH and HPV genotyping as ancillary molecular-biological tests of LBC specimens for identifying patients at high risk of cervical cancer.

Uterine cervical and endometrial cancers are common malignant solid neoplasms for which there are no useful prognostic markers. In this study, we evaluate the relationship between ATP-binding cassette superfamily F2 (ABCF2) expression and clinical factors including clinical stage, histologic type, grade and prognosis in uterine cervical and endometrial cancer. Two hundred and sixty seven cervical and 103 endometrial cancers were studied. ATP-binding cassette superfamily F2 cytoplasmic expression was detected by immunohistochemical staining and scored as positive or negative. Among cervical cancer cases, 149 (55.8%) expressed ABCF2. The overall survival was longer in ABCF2-negative than ABCF2-positive cases (P=0.0069). Statistically significant prognostic factors for survival were ABCF2 positivity ( risk ratio (rr) = 1.437), old age (rr = 1.550) and advanced stage (rr = 2.577). ATP-binding cassette superfamily F2 positivity was an independent prognostic factor by multivariate proportional hazard test (P=0.0002). Among endometrial cancer cases, 72 (69.9%) were cytoplasmic ABCF2 positive. However, there was no significant relationship between ABCF2 expression and age, clinical stage, histologic type, histologic grade, oestrogen receptor status or prognosis. ATP-binding cassette superfamily F2 expression may be a useful prognostic marker in cervical but not endometrial cancer. The role of ABCF2 protein may differ depending on the type of cancer.

Purpose: To prospectively determine if semiquantitative assessment of R2* images and T1-weighted magnetic resonance (MR) images of leiomyomas correlates with the efficacy of gonadotropin-releasing hormone (GnRH) agonist treatment for volume reduction. Materials and Methods: Internal review board approval and informed consent were obtained for this study. Twenty women (mean age, 36.3 years) with intramyometrial leiomyomas were enrolled in this study. Single-section double-echo dynamic MR imaging was performed before GnRH agonist administration. T2-weighted images were obtained before and after two or three GnRH agonist injections (1.88 mg leuprorelin acetate). The steepest signal intensity (SI) upslope on T1-weighted images and the area under the curve (AUC) on R2* images were determined by using a 16 x 16-voxel matrix that was placed in the center of a leiomyoma. Pearson correlation analysis was performed to compare the percentage of volume reduction with SI upslope and AUC. Unpaired t test was performed to evaluate the difference between leiomyomas with AUC and SI upslope values that were less than or greater than the mean. Results: Percentage of volume reduction ranged from 6.2% to 51.1%. The mean AUC and mean SI upslope were 39.2 and 9.83% per second, respectively. There was a significant correlation between the AUC and the percentage of volume reduction (r = 0.81, P < .001), although no significant correlation was observed between the SI upslope and the percentage of volume reduction. A significant difference in percentage of volume reduction was observed in leiomyomas by using mean AUC as a cutoff value (P = .003). Conclusion: AUC on R2* images correlates with the efficacy of GnRH agonist before initiation of treatment for volume reduction of leiomyoma. (C) RSNA, 2008.

A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.

Human papillomavirus (HPV) 18 is related not only to squamous cell carcinoma of the cervix, but also to adenocarcinoma and small cell carcinoma of the cervix, in which prognosis is known to be poor. Small interfering RNA (siRNA) that targets HPV18 E6 and E7 was tested in HPV18-positive cell lines to investigate its effect and investigate its mechanism of action. Nude mice were also tested in a combination of siRNA and atelocollagen to determine whether it might be useful as a new molecule-targeting therapy for cervical cancer. siRNAs targeting HPV18 E6 and E7 were transfected into cervical cancer cells in vitro and they were investigated for cell growth inhibition, expression of E6 and E7 mRNA, expression of retinoblastoma protein, and senescence-associated B-galactosidase staining. Sequence-specific siRNA inhibited cell growth. Decreased expression of E6 and E7 mRNA followed with E7 protein was observed in the transfected cells, but the expression of retinoblastoma protein and the beta-galactosidase staining increased, suggesting cell growth inhibitory effect through senescence. Treatment of xenografts established from SKG-II cells with siRNA specific for E6 and E7 obviously suppressed tumor growth in vivo. These results indicate that atelocollagen-mediated delivery of siRNA HPV 18 E6 and E7 can be used as a novel therapeutic approach for cervical cancer.

To identify the predictive markers for spontaneous regression of cervical intraepithelial neoplasia (CIN), we examined whether IgG antibody responses to common human papillomavirus (HPV) L1-capsids correlate with CIN regression. In a cohort study, a total of 116 Japanese women with CIN grade I/II were tested for cervical HPV DNA and serum IgG antibodies to HPV16/52/58/6 L1-capsids. Our data suggest that baseline IgG reactivities to HPV L1-capsids do not serve as a predictive marker of CIN regression, in contrast to histological CIN grades and HPV DNA status. © 2005 Elsevier Ireland Ltd. All rights reserved.

Overexpression of p16INK4a has been observed when retinoblastoma protein is inactivated by high-risk human papillomavirus (HPV) oncoprotein E7. We investigated overexpression of p16INK4a and HPV infection in cervical squamous neoplasia to evaluate the oncogenic potential among various HPV subtypes. The high-risk HPV was detected by PCR in 69.8% (37/53), 97.5% (39/40), 91.7% (44/48), and 100% (16/16) of cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, and squamous cell carcinoma (SCC), respectively. The p16INK4a overexpression was investigated immunohistochemically using a p16INK4a-specific monoclonal antibody (clone E6H4). In high-risk HPV positive cases, 32.4% (12/37) of CIN1, 82.1% (32/39) of CIN2, 93.2% (41/44) of CIN3, and all (16/16) SCC showed p16INK4a overexpression. The incidence of p16INK4a overexpression was significantly different between CIN1 and CIN2, suggesting that the disorder of cell cycle regulation by HPV frequently occurred from CIN2. As for CIN1 cases, p16INK4a overexpression was observed more frequently in HPV16 and HPV52 than in HPV51 and HPV35. Using p16INK4a as a bio marker of HPV oncogenic activity, we demonstrate that the level of pRb dysfunction by high-risk HPV varied from subtypes and was getting more frequent from CIN2. © 2006, IGCS.

Aims: To determine the safety of uterine-preserving operations for adenocarcinoma in situ of the cervix. Methods: Fifteen cases of adenocarcinoma in situ (AIS) were diagnosed using neodymium:yttrium aluminum garnet (Nd:YAG) laser conization. The accuracy of preconization histology or cytology was evaluated in 15 AIS cases. In these AIS cases, we investigated how far the tumor was located from the squamocolumnar junction (SCJ) and the endocervix. Fourteen cases of the 15 AIS-affected patients were treated using laser conization alone. These patients were closely followed up. Results: Precise agreement between preconization diagnosis and conization histology was seen in 46.7% (7/ 15) of the AIS cases. In 14 of the 15 cases of AIS (93.3%), the tumor was adjacent to the transitional zone, within 3 mm of the SCJ, and in the other case (6.7%), the tumor was between 0 and 5 mm away from the SCJ. In all subjects, cone height was 8-18 mm (mean 13.1 mm). None of the 15 patients showed any recurrence of AIS during follow up ranging from 15 to 75 months (43.1 months on average). Conclusions: Women with AIS who want to preserve their fecundity might be treated with laser conization alone.

Integration of the human papillomavirus (HPV) genome is thought to be one of the causes of cancer progression. However, there is controversy concerning the physical status of HPV 16 in premalignant cervical lesions, and there have been no reports on the concordance between detection of the integrated form of HPV16 by real-time PCR and by in situ hybridization. We investigated specimens of cervical intraepithelial neoplasia (CIN) and invasive carcinomas for the physical status of HPV 16 by real-time PCR and in situ hybridization. The presence of the integrated form was detected by both real-time PCR and in situ hybridization in zero of four cases of CIN1, three of six cases of CIN2, nine of 27 cases of CIN3, and two of six cases of invasive carcinomas. Integrated HPV 16 was present in some premalignant lesions but was not always present in carcinomas. The concordance rate between the two methods for the detection of the presence of the integrated form was 37 of 43 (86%) cases. Real-time PCR and in situ hybridization were found to be complementary and convenient techniques for determining the physical status of the HPV genome. We conclude that a combination of both methods is a more reliable means of assessing the physical status of the HPV genome in cervical neoplasia. Copyright © 2005 by Lippincott Williams & Wilkins.

Objective. Human papillomavirus (HPV) infection is reported to be related to carcinogenesis in the uterine cervix. In Japan, screening for cervical cancer by cytology is performed in women over 30 years old. The purpose of this study was to determine whether there is an association between patient age and cervical neoplasia or HPV infection in Japanese women. Methods. Specimens from 881 randomly selected patients who came to our clinic were tested for HPV DNA by using Hybrid Capture II, whereas specimens from a 204-patient randomly selected subset diagnosed with cervical neoplasia were tested for HPV DNA by using polymerase chain reaction (PCR). HPV typing was performed in all the PCR-positive cases. Results. The HPV-positive rate in the 20- to 29-year-old patients (29.0% in the normal cytology/histology group and 85.5% in the abnormal group) was higher than in the 30- to 59-year-old patients, and the rate declined until age 60 when age increased. While HPV 18, HPV 52, other HPV types, and HPV types as a whole were frequently detected in 30- to 49-year-old patients, HPV 16 was detected more frequently in the younger group than the other HPV types (P = 0.03). Among the HPV 16-positive patients with cervical neoplasia, the proportion of cervical intraepithelial neoplasia (CIN) 3 cases was high (44%) in the 20- to 29-year-old group. Conclusions. Screening for cervical neoplasia by cytology should also be performed in women under 30 years old in Japan. The HPV typing could be a tool to strictly follow-up younger women who were diagnosed with CIN. © 2004 Elsevier Inc. All rights reserved.

Purpose: Human papillomavirus (HPV) infections are associated with cervical neoplasia. Cellular and viral proteins are known to interact with the papillomavirus E2 protein to initiate transcription and DNA replication in the HPV life cycle. Our aim was to identify peptides that bind to the HPV16 E2 protein and thereby inhibit its ability to alter the transcriptional activity of other genes. Experimental Design: The HPV16 E2 protein was expressed and purified to near homogeneity in bacteria. We screened a phage display library of random peptides for ones that bound to HPV16 E2 protein. Among the isolated phage clones, we found that tryptophan-rich peptide sequences appeared repetitively in successive cycles of phage library panning. Replacement of the tryptophan amino acids in these dodecapeptides reduced the degree to which these peptides bound to the E2 protein. These E2-binding peptides were tested for their ability to inhibit the transcriptional regulatory function of E2 in a test cell line, which contained an E2 gene and a luciferase reporter gene driven by an E2-dependent transcriptional promoter. Results: Delivery of four of the E2 binding peptides into the intracellular compartment of the test cell line resulted in suppression of the E2-dependent luciferase expression. Deletion of the tryptophan residues from these peptides reduced their E2 binding and their ability to suppress E2-dependent luciferase expression in the test cell line. Conclusions: These results suggest a strategy for the development of chemical inhibitors of E2-dependent transcription of viral genes in HPV-infected cells as an approach to the therapy of chronic HPV infections.

As human papillomavirus (HPV) infection is the main risk factor for squamous cell carcinoma of the cervix and overexpression of p16INK4a occurs when retinoblastoma protein is inactivated by high-risk HPV, the authors studied the association of HPV infection and expression of p16INK4a in cervical adenocarcinomas. Specimens of cervical glandular neoplasias were immunostained with a p16INK4a-specific monoclonal antibody (clone E6H4). Approximately 80% of glandular neoplasms showed overexpression of p16INK4a. Exfoliated cells from 14 adenocarcinomas were further examined by p16INK4a-specific immunocytochemistry, and 12 cases showed overexpression of p16INK4a, suggesting that immunostaining for p16INK4a may be a useful diagnostic tool for cervical adenocarcinomas. The authors further examined HPV DNA in cervical adenocarcinomas with the polymerase chain reaction method. Overexpression of p16INK4a was positive in 94% of cases in which HPV16 or 18DNA was positive, a finding suggesting that HPV16 or 18 may play an important role in cervical adenocarcinomas. Overexpression of p16INK4a may be an indicator of pathogenic activity of high-risk HPVs.

Carcinogenesis of cervical cancer has been investigated, and p16 INK4a overexpression in squamous cell carcinoma of the cervix has been reported as a result of infection by human papillomavirus (HPV) (eg, HPV 16), and the consequence of the retinoblastoma (Rb) protein inactivation by HPV E7 protein. However, to our knowledge, there have been no studies on the relation between p16INK4a overexpression associated with HPV and small cell carcinoma of the cervix, which behaves more aggressively clinically than squamous cell carcinoma. The purpose of this study was to determine whether p16INK4a is overexpressed in small cell carcinoma, and if p16INK4a is overexpressed, the types of HPV that are related to this cancer. We reviewed 10 cases of small cell carcinoma and examined them for p16INK4a overexpression by immunohistochemistry. We also performed HPV typing with polymerase chain reaction (PCR)-sequencing analysis and in situ hybridization and found that p16INK4a was overexpressed in every case. PCR-sequencing analyses revealed that all cases were HPV-positive and that 9 cases were positive for HPV 18. Five of the 9 cases positive for HPV 18 were also positive by in situ hybridization and yielded a punctate signal, considered to represent the integrated form. In conclusion, p16INK4a was overexpressed and HPV 18 was frequently detected in an integrated form in small cell carcinoma. Therefore, inactivation of Rb protein by HPV 18 E7 protein may be associated with carcinogenesis of small cell carcinoma the same as inactivation of Rb protein by HPV 16 E7 protein is associated with carcinogenesis of squamous cell carcinoma. © 2003 Elsevier Inc. All rights reserved.

A fluid-based Papanicolaou test has been established to improve sample collection and preparation. This study was the first largescale investigation in Japan to examine the feasibility of using fluid-based Papanicolaou specimens to detect human papillomavirus (HPV) using Hybrid Capture II and polymerase chain reaction (PCR). Three thousand patients who visited Keio University Hospital between October 2000 and February 2001 were enrolled in the study. The results of the fluid-based Papanicolaou tests corresponded well with those of conventional Papanicolaou smears (96.8% concordance). The sensitivities of cervical neoplasia detection using the fluid-based Papanicolaou test (73.9%) and Hybrid Capture II (76.3%, P=0.55) were not significantly different. Among the cervical intraepithelial neoplasia 3 and squamous cell carcinoma specimens, HPV 16 and HPV 52 were predominantly detected using the PCR method. Although some DNA samples extracted from the fluid-based specimens were degradaded, PCR and direct sequencing could be performed without difficulty even after 1 year of specimen storage. We conclude that fluid-based Papanicolaou specimens can be applied to investigate HPV infection. © 2003 Cancer Research UK.

Background: To clarify the pathogenicity of multiple human papilloma virus (HPV) infection, we applied SSCP (single-strand DNA conformation polymorphism) analysis for cervical neoplastic lesions. Materials and Methods: Two hundred and sixty-six cervical swab specimens from normal cervix (n=64), cervical dysplasia (n=95), carcinoma in situ (n=79) and cervical cancer (n=28), were studied by nested PCR-SSCP analysis using L1 consensus primers. Results: In 95 samples of cervical dysplasia, HPV infection was detected in 98.9% (94 out of 95), multiple HPV infection was detected in 38.3% (36 out of 94). In 19 squamous cell carcinomas (SCC) and 9 adenocarcinomas, the detection rate of HPV infection was 84.2% (16 out of 19) and 55.6% (5 out of 9), respectively, and all HPV-positive cases showed infection of a single HPV, among which HPV 16 occupied 68.6% (11 out of 16) in SCC and HPV 18 occupied 100% (5 out of 5) in adenocarcinoma. Conclusion: Multiple HPV infections may be concerned with pathogenicity in cervical dysplasia; however, the single infection with only a few HPV types, such as type 16 in SCC and type 18 in adenocarcinoma, may play a role in cervical carcinogenesis.

The variation of the E6 region of human papillomavirus type 16 (HPV16) is associated with a high risk for cervical carcinogenesis. To see whether the same is the case with HPV33, 52 and 58, known to have high homology with HPV16, we analyzed the E6 sequence variation of these HPVs in 107 Japanese women with cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC: 20 HPV33-positive, 46 HPV52-positive and 41 HPV58-positive cases. HPV33 variants were more frequently observed in CINs MI than in CIN III/ICCs (71% (5/7) versus 15% (2/13), P = 0.02). In HPV52-positive cases, a single E6 variant was detected in 98% of the cases, whereas the prototype accounted for 98% of HPV58-positive cases. In summary, the distribution of E6 variants is different among HPV types tested, suggesting a link between E6 variation and oncogenic potential being type-specific. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

A 2.4-kh truncated L-plastin promoter was inserted either 5′ to the LacZ gene (Ad-Lp-LacZ) or 5′ to the cytosine deaminase (CD) gene (Ad-Lp-CD) in a replication-incompetent adenoviral vector backbone. Infectivity and cytotoxicity experiments with the LacZ and CD vectors suggested that the L-plastin promoter-driven transcriptional units were expressed at much higher levels in explants of ovarian cancer cells from patients and in established ovarian or bladder cancer cell lines than they were in normal peritoneal mesothelial cells from surgical specimens, in organ cultures of normal ovarian cells, or in the established CCD minimal deviation fibroblast cell line. Control experiments showed that this difference was not attributable to the lack of infectivity of the normal peritoneal cells, the normal ovarian cells, or the minimal deviation CCD fibroblast cell line, because these cells showed expression of the LacZ reporter gene when exposed to the replication-incompetent adenoviral vector carrying the cytomegalovirus (CMV)-driven LacZ gene (Ad-CMV-LacZ). The Ovcar-5 and Skov-3 ovarian cancer cell lines exposed to the Ad-Lp-CD adenoviral vector were much more sensitive to the prodrug 5-fluorocytosine (5FC), which is converted from the 5FC prodrug into the toxic chemical 5-fluorouracil, than was the CCD minimal deviation fibroblast cell line after exposure to the same vector. A mouse xenograft model was used to show that the Ad-Lp-CD vector/5FC system could prevent engraftment of ovarian cancer cells in nude mice. Finally, injection of the Ad-Lp-CD vector into s.c. tumor nodules generated a greater reduction of the size of the tumor nodules than did injection of the Ad-CMV-LacZ vectors into tumor nodules. The Ad-Lp-CD vectors were as suppressive to tumor growth as the Ad-CMV-CD vectors. These results suggest that an adenoviral vector carrying the CD gene controlled by the L-plastin promoter (Ad-Lp-CD) may be of potential value for the i.p. therapy of ovarian cancer.

The papillomavirus E2 protein plays an important role in viral transcriptional regulation and replication. We chose to study the cottontail rabbit papillomavirus (CRPV) E2 protein as a transcriptional regulator because of the availability of an animal model for papiloma formation, which may be relevant for human papillomavirus (HPV) infection and replication. We studied the effect of expression levels of E2 on the long control region, which contains transcriptional promoter and enhancer elements, and synthetic E2-dependent artificial promoters in which the E2 was the dominant factor in the transcriptional activation. These experiments indicated that high levels of E2 were inhibitory and low levels were stimulatory for transactivation. In addition, we showed that the complex formed between CRPV E2 and the cognate binding site was less stable than the complex formed between HPV E2 and the same cognate binding site. Furthermore, we showed that CRPV E2 binding to its transcriptional regulatory sequence was stabilized by other proteins such as El, which produced increments in transcriptional activation of E2-dependent genes. The data may be used to define conditions in which the rabbit model can be used for the screening of drugs which are inhibitory to the HPV and CRPV replication and gene expression.

For the past 50 years, during which chemotherapy has been administered for the treatment of cancer, the paradigm driving the selection of chemotherapeutic agents was their capability to damage the DNA of dividing cells. In addition, chemotherapeutic agents were studied for the selectivity of their toxic effect to the cancer cell versus the normal cell. Because many of the normal cells in the body shared the phenotype of cellular division with the tumor cells, the drugs developed for the treatment of cancer displayed only relative selectivity for the cancer cell. The advent of structural biology and computational chemistry to drug development, and the explosion of information about the molecular and genetic changes acquired in the cancer cell, have now produced the opportunity to design drugs for cancer treatment which specifically block the effects of the signals within cancer cells which drive the evolution of the disease process to unregulated cell growth. The implementation of this new mode of drug design to the field of cancer chemotherapy is the subject of this chapter.

SOX is a family of genes related to the testis-determining gene, SRY. We have isolated and sequenced an hSOX20 cDNA: from a cell line of human embryonic carcinoma. This cDNA contains an open reading frame (ORF) encoding 233 amino acids. The protein encompasses an SRY-type HMG box exhibiting strong homologies to those of mouse Sox15 and Sox16. Various adult and fetal tissues were tested for hSOX20 mRNA by Northern analysis. Its expression is restricted to the fetal testis and the size of the transcript is 1.5 knt. Electrophoretic mobility shift assay indicated that recombinant hSOX20 polypeptide is capable of binding to AACAAT sequence.

Current approaches to the treatment of cancer (radiation and chemotherapy) are limited by the toxicity to normal tissues and the sensitivity of tumor cells to these treatments. The use of gene delivery vector systems for the introduction of genetic elements into normal and neoplastic tissues which code for proteins that protect the normal chemotherapy-sensitive tissues and sensitize the tumor cells to radiation and chemotherapy, may contribute to an overall improvement in the outcome of cancer treatment programs. This chapter will review the clinical trials either completed or about to be initiated which are designed to accomplish these goals.