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Abdominal radical trachelectomy has been identified as a surgical option for fertility preservation in cervical cancer patients, particularly in pregnant women who strongly desire to continue their pregnancy. Since this procedure requires operating in the uterus, the hardness of the uterus can affect the ease of surgery. Generally, sevoflurane is used for anesthesia in non-obstetric surgery for pregnant women because uterine relaxation is advantageous for uterine blood flow maintenance. However, the use of sevoflurane during radical trachelectomy has not been thoroughly evaluated. Here, we report on anesthesia use in three cases of abdominal radical trachelectomy during pregnancy. Propofol enabled maintenance of uterine tension while not significantly affecting fetal growth. It is important to consider maintenance of uterine tension and fetal circulation in anesthesia management. During the operation, we performed an ultrasound examination every 30 min to confirm fetal well-being. Although frequent fetal heart rate monitoring of the pre-viable fetus is not recommended, if fetal bradycardia is detected, sevoflurane may then be used to improve fetal circulation. Additionally, if the fetal heartbeat stops, a radical hysterectomy would then be required. Therefore, we consider that fetal heart rate monitoring during this procedure is necessary, and propofol is suitable as an anesthetic for this surgery during pregnancy., Author(s): Jun Terukina [sup.1] , Misako Takamatsu [sup.1] , Takayuki Enomoto [sup.2] , Hiroshi Baba [sup.3] Author Affiliations: (1) 0000 0004 0639 8670grid.412181.fDepartment of Anesthesiology, Niigata University Medical and Dental [...]

In 2013, the Ministry of Health, Labor, and Welfare (MHLW) in Japan announced a suspension of the governmental recommendation for routine HPV vaccinations. In 2020, MHLW started individual notifications of HPV vaccine to the targeted girls. In April 2022, the governmental recommendation was restarted, and catch-up vaccinations started. We evaluated the benefits and limitations of the MHLW's new vaccination strategies by estimating the lifetime risk for cervical cancer for each birth FY under different scenarios to suggest a measure for the vaccine suspension generation. It was revealed that catch-up immunization coverage among the unvaccinated must reach as high as 90% in FY2022, when the program begins, in order to reduce the risk of the females already over the targeted ages to the same level or lower than that of women born in FY1994-1999 who had high HPV vaccination rates. For women whose vaccination coverage waned because of their birth FYs, strong recommendations for cervical cancer screening should be implemented. [ABSTRACT FROM AUTHOR]

Japanese girls aged 12–16 years are offered free human papillomavirus (HPV) vaccination and cervical cancer screening is conducted with cytology and not HPV testing from the age of 20 years. So far, no study has analyzed the effect of HPV vaccination against cervical precancers considering HPV infection status and sexual activity. We aimed to analyze the vaccine effectiveness (VE) against HPV infection and cytological abnormalities, adjusted for sexual activity. This study comprised women aged 20–26 years who underwent cervical screening in Niigata. We obtained HPV vaccination status from municipal records and a questionnaire along with information concerning sexual activity. Of 5194 women registered for this study, final analyses included 3167 women in the vaccinated group (2821 vaccinated women prior to sexual debut) and 1386 women in the unvaccinated group. HPV 16/18 (0.2% vs 3.5%), 31/45/52 (3.4% vs 6.6%), and 31/33/45/52/58 (5.0% vs 9.3%) positive rates were significantly lower in the vaccinated group (P < 0.001). No women vaccinated before sexual debut had HPV 16/18‐related cytological abnormalities. VE for HPV 16/18 infection and high‐grade cytological abnormalities in women vaccinated prior to sexual debut were 95.8% (95% CI 81.9–99.0%; P < 0.001) and 78.3% (95% CI 11.3–94.7%; P = 0.033), respectively, in multivariate analyses adjusted for age and number of sexual partners. However, analyses of all vaccinated women did not show significant effectiveness against cytological abnormalities. Our results showed the effectiveness of HPV vaccine against high‐grade cervical cytological abnormalities and the importance of the vaccination before sexual debut. [ABSTRACT FROM AUTHOR]

In Japan, public funding for HPV vaccination began in 2010 for girls aged 13–16 years (birth cohort years 1994–1997) and women born in 1994 who turned 25 in 2019. We aimed to verify the long‐term effectiveness of the bivalent HPV vaccine in women aged 25 years. Subjects were women aged 25–26 years who underwent cervical cancer screening and HPV testing in Niigata from 2019 to 2020 (birth cohort years 1993–1994). Information on vaccination status and sexual behavior was obtained from a questionnaire and municipal records. We compared the HPV infection rates of the vaccinated and unvaccinated groups. Of the 429 registrants, 150 (35.0%) and 279 (65.0%) were vaccinated and unvaccinated, respectively. The average period from HPV vaccination to HPV testing was 102.7 months (8.6 years), with a median of 103 months (range 92–109 months). The HPV high‐risk infection rate was 21.3% (32/150) in the vaccinated group and 23.7% (66/279) in the unvaccinated group (P = 0.63). The HPV16/18 infection rate was 0% (0/150) in the vaccinated group and 5.4% (15/279) in the unvaccinated group, showing a significant difference (P = 0.0018), and the vaccine effectiveness was 100%. The cross‐protective type HPV31/45/52 infection rate in the vaccinated group was significantly lower than that in the unvaccinated group (3.3% vs. 10.0%, P = 0.013). There was no significant difference in the mean age at sexual debut and the number of previous sexual partners between the two groups. We have demonstrated the long‐term 9‐year effectiveness of the bivalent vaccine against HPV infection for the first time in Japan. [ABSTRACT FROM AUTHOR]

In Japan, the age‐adjusted incidence of cervical cancer has been increasing constantly and rapidly among younger women. We set out to accurately confirm the effectiveness of the HPV vaccine in Japan. Data were collected for women born in the fiscal year (FY) 1990 to 1997, who became eligible for their 20‐y‐old cervical cancer screening between the FY 2010 to 2017. The adjusted incidence of cervical intraepithelial neoplasia (CIN)1+ in women born in FY 1990 to 1993, that is those who reached the national vaccination target age prior to the introduction of publicly subsidized HPV vaccinations, referred here after as "the pre‐introduction generation", was 1.42% (242/17 040). The incidence in the "vaccination generation" (women born in FY 1994 to 1997, that is those who were heavily vaccinated as a group when they were of the nationally targeted age of 13‐16) was 1.66% (135/8020). There was no significant difference between these incidence rates. However, our FY birth year‐by‐year analysis revealed that the incidence of CIN1+ was obviously lower than that predicted based on just the trend for CIN1+ seen in the pre‐introduction generation. Our analysis revealed that the incidence of CIN3+ was obviously lower in the vaccination generation than in the pre‐introduction generation (P =.0008). The incidence of CIN was already tending to increase in both the pre‐introduction and vaccination generations. The changes in CIN incidence by individual birth FY must be examined to accurately determine the actual effects of the HPV vaccine for reducing mild cervical lesions. [ABSTRACT FROM AUTHOR]

Aim: In the recent years, the number of cervical conization procedures performed for diagnostic or therapeutic purposes is increasing, accompanied by increased cervical neoplasia among young women. This study aimed to analyze the clinical data of patients who underwent conization in Japan. Methods: Among the 14 832 cases of conization registered in 205 facilities over 2 years (2009–2011), the data of 2409 and 12 417 patients who underwent conization for diagnostic and therapeutic purposes, respectively, were retrospectively analyzed. Results: The median age of the patients in diagnostic and therapeutic conization groups was 44 and 37 years, respectively. When comparing the diagnostic and therapeutic groups, 25.5% of the patients in the former were suspected with invasive cancer preoperatively, which is higher than that in the latter (2.7%). About 25.7% in the diagnostic and 14.1% in the therapeutic group had positive margin in the conization specimens. Additional treatment was required for 36.0% and 5.5% of the patients in the diagnostic and therapeutic groups, respectively, which are high figures for both. The risk factors of pathological upgrade in the conization specimens were diagnostic purpose, postmenopausal status and glandular lesion. Additional hysterectomy was performed in 1304 patients after conization, and pathological diagnosis was upgraded in 550 cases. Multivariate analysis revealed that postmenstrual status was an independent risk factor. Conclusion: This study revealed that cervical lesions of glandular lineage and patients with postmenopausal status benefit from diagnostic conization. However, in postmenopausal patients, the underlying disease cannot be excluded in the preserved uterus even by diagnostic conization. [ABSTRACT FROM AUTHOR]

Aim: The human papillomavirus (HPV) vaccination rate in Japan fell to nearly 0% following widespread coverage of possible adverse events. Developing a next approach to promote the effective prevention of HPV‐related diseases including cervical cancer (CC) in Japan requires comprehensive understanding of knowledge and attitudes regarding CC prevention, HPV infection and HPV vaccination among the population including laypersons and medical professions in Japan. Methods: A questionnaire survey was administered in a wide variety of settings in Japan. The questionnaire contained items on knowledge about CC, HPV infection and HPV vaccination; awareness of the HPV vaccine's effectiveness and associated adverse events; and attitudes toward the HPV vaccination for their daughters and for men/boys. Results: Of 3033 targeted people, complete survey responses were received from 1182 men and 1602 women (total: 2784). The male laypersons' group had significantly lower knowledge than did the female laypersons' group (adjusted odds ratio, aOR = 3.86, P < 0.001). Compared with the male laypersons' group, the female laypersons' group tended to have less positive attitudes toward HPV vaccination for their daughters (aOR = 0.78, P = 0.006), but the female laypersons' group showed more positive attitudes toward vaccinating men/boys (aOR = 1.93, P < 0.001). Conclusion: The survey results indicated that men in Japan generally lacked knowledge and awareness of HPV‐related diseases and their prevention. However, women had more negative attitudes toward HPV vaccination for their daughters than did men. Increasing male involvement in HPV prevention and changing women's perceptions of the HPV vaccine are essential steps to increase the HPV vaccination rate. [ABSTRACT FROM AUTHOR]

Aim: To provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2015 and the Annual Treatment Report for 2010 on the outcomes of patients who started treatment in 2010. Methods: The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment was initiated in 2015 were analyzed retrospectively. Survival of the patients who started treatment in 2010 was analyzed by using the Kaplan–Meier, log‐rank and Wilcoxson tests. Results: Treatment was initiated in 2015 for 7527 patients with cervical cancer, 10 119 with endometrial cancer, 6424 with ovarian cancer and 2181 with ovarian borderline tumors. This clinicopathological information was summarized as the Patient Annual Report. Prognoses were analyzed across 4309 patients with cervical cancer, 5054 with endometrial cancer and 3423 with ovarian cancer, whose treatment was initiated in 2010. The 5‐year survival rates of the patients with cervical cancer were 92.1%, 74.2%, 52.0%, and 29.8% for stages I, II, III, and IV, respectively. The 5‐year survival rates for the patients with endometrial cancer were 94.3%, 88.8%, 74.0% and 26.6% for stages I, II, III and IV, respectively. The 5‐year survival rates for the patients with ovarian cancer (surface epithelial‐stromal tumors) were 88.5%, 80.1%, 46.3% and 36.2% for stages I, II, III and IV, respectively. Conclusion: The annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan. [ABSTRACT FROM AUTHOR]

Background: Proactive recommendations for human papillomavirus (HPV) vaccines in Japan have been suspended for 5 years because of safety concerns. While no scientific evidence exists to substantiate these concerns, one reason given for not reinstating recommendations is the lack of reliable vaccine effectiveness (VE) data in a Japanese population. This study reports the VE of the bivalent HPV vaccine in Japanese women aged 20-22 years.Methods: During cervical screening between 2014 and 2016, women had Papanicolaou smears and HPV tests performed and provided data about their sexual history. Estimates of VE for vaccine-targeted HPV type 16 (HPV16) and 18 and cross-protection against other types were calculated.Results: Overall, 2197 women were tested, and 1814 were included in the analysis. Of these, 1355 (74.6%) were vaccinated, and 1295 (95.5%) completed the 3-dose schedule. In women sexually naive at vaccination, the pooled VEs against HPV16 and 18 and for HPV31, 45, and 52 were 95.5% (P < .01) and 71.9% (P < .01), respectively. When adjusted for number of sex partners and birth year, pooled VEs were 93.9% (P = .01) and 67.7% (P = .01) for HPV16 and 18 and HPV31, 45, and 52, respectively.Conclusions: The bivalent HPV vaccine is highly effective against HPV16 and 18. Furthermore, significant cross-protection against HPV31, 45, and 52 was demonstrated and sustained up to 6 years after vaccination. These findings should reassure politicians about the VE of bivalent HPV vaccine in a Japanese population. [ABSTRACT FROM AUTHOR]

The Japan Society of Gynecologic Oncology (JSGO) Guidelines 2017 for the Treatment of Uterine Cervical Cancer are for the purpose of providing standard treatment strategies for cervical cancer, indicating treatment methods currently considered appropriate for cervical cancer, minimizing variances in treatment methods among institutions, improving the safety of treatment and prognosis of diseases, reducing the economic and psychosomatic burden of patients by promoting performance of appropriate treatment, and enhancing mutual understanding between patients and healthcare professionals. The guidelines were prepared through consensus of the JSGO Guideline Committee, based on careful review of evidence gathered through the literature searches and in view of the medical health insurance system and actual clinical practice situations in Japan. The guidelines comprise eight chapters and five algorithms. The main features of the 2017 revision are as follows: (1) evidence was collected using a search formula and with cooperation of the Japan Library Association. The bibliographical search formula was placed at the end of the book; (2) regarding clinical questions (CQs) where evidence or clinical inspection in Japan was lacking, opinions of the Guidelines Committee were described as "proposals for future directions"; (3) cervical intraepithelial neoplasia (CIN) 3 and adenocarcinoma in situ (AIS) were treated as a cervical precancerous lesion; (4) the CQs of endoscopic surgery, radical trachelectomy, and sentinel node biopsy were newly added in Chapter 3, "primary treatment for stage IB-II cervical cancer"; and (5) the CQ about hormone replacement therapy after cancer treatment was newly established. Each recommendation is accompanied by a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSGO Guidelines 2017 for the Treatment of Uterine Cervical Cancer. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Objectives: Cervical cancer is one of the most frequently diagnosed cancers in pregnancy. Our aim was to evaluate the safety and efficacy of abdominal radical trachelectomy (ART) for pregnant women with early-stage cervical cancer who strongly desire to preserve their pregnancies. Methods/Materials: A retrospective observational study was performed for stage IB1 cervical cancer patients who underwent ART or radical hysterectomy (RH) at our hospital between February 2013 and June 2017. We compared differences in perioperative findings and oncologic outcomes among ART during pregnancy (ART-DP), ART, and RH groups. Results: A total of 38 patients were included in this analysis. Six, 10, and 22 patients were assigned to the ART-DP, ART, and RH groups, respectively. There were no significant differences in the distribution of pathological TNM classifications, histology, tumor size, stromal invasion, and lymph-vascular space invasion among the 3 groups. The patients in the ART-DP group were younger than those in the RH group (P = 0.014). The ART-DP group was associated with more blood loss and prolonged surgery compared with the RH group (P = 0.017 and P = 0.014). The number of total lymph nodes in the ART-DP group was lower than that in the RH group (P = 0.036). However, there were no significant differences in age, surgical time, blood loss, or lymph node count between the ART-DP and ART groups. There were no significant differences in progression-free and overall survival times among the 3 groups, and no recurrence was observed in the ART-DP group. Conclusions: Abdominal radical trachelectomy may be a tolerable treatment option for pregnant women with early-stage cervical cancer who strongly desire a baby. [ABSTRACT FROM AUTHOR]

Cervical cancer constitutes a significant health burden for women globally. While most patients with early-stage disease can be cured with radical surgery or chemoradiotherapy, patients with high-risk locally advanced disease or with recurrent/metastatic disease have a poor prognosis with standard treatments. Immunotherapies are a rational treatment for this HPV-driven cancer that commonly expresses programmed cell death ligand-1. Before 2021, pembrolizumab was the only United States Food and Drug Administration-approved immunotherapy in cervical cancer, specifically for the second-line recurrent or metastatic (r/m) setting. In late 2021, the antibody-drug conjugate tisotumab vedotin was approved for second-line r/m cervical cancer and pembrolizumab combined with chemotherapy ± bevacizumab was approved for first-line r/m disease based on results from KEYNOTE-826. Moreover, with at least 2 dozen additional immunotherapy clinical trials in the second-line and first-line r/m setting, as well as in locally advanced disease, the treatment landscape for cervical cancer may eventually encounter a potential paradigm shift. Pivotal trials of immunotherapies for cervical cancer that were recently approved or with the potential for regulatory consideration through 2024 are reviewed. As immunotherapy has the opportunity to establish new standards of care in the treatment of cervical cancers, new biomarkers to identify the ideal patient populations for these therapies may also become important. However, issues with access, affordability, and compliance in low- and middle-income countries are anticipated. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to analyze the long-term outcome of cervical intraepithelial neoplasia 3 (CIN 3) after treatment with the Shimodaira-Taniguchi conization procedure, based on the status of the resection margins. Methods: In the Osaka University Hospital, conization using the Shimodaira-Taniguchi procedure has been routinely performed for CIN 3. Medical records of patients during the period from 2001 to 2008, whose post-conization diagnosis was CIN 3, were retrospectively analyzed for outcome versus margin status. Results: During the median follow-up period of 565 days (range 34-3,013), CIN disease was again detected in 14 of 243 patients; it was found in 7 patients among 198 margin-negative cases, and in 7 patients among 45 margin-positive cases. There was a significant difference in the reappearance rate demonstrated between the cases with positive and negative margins ( p = 0.0018). Among the patients whose first follow-up post-conization cytology was normal, recurrence-free probability was significantly higher in margin-negative cases than in margin-positive ones (hazard ratio, 5.19; 95% CI, 1.175-22.994; p = 0.0041). Conclusion: For the first time, we demonstrate that after treatment of CIN 3 lesions by Shimodaira-Taniguchi conization the status of the resection margin was a significant predictor for long-term outcome. [ABSTRACT FROM AUTHOR]

We investigated the prognostic significance of multiple pelvic node metastases in cervical cancer patients who were treated with radical hysterectomy plus adjuvant chemoradiotherapy.We retrospectively reviewed the medical records of 311 patients with International Federation of Gynecology and Obstetrics stage IB1-IIB cervical cancer who had been treated with radical hysterectomy plus adjuvant radiotherapy (RT) between January 1998 and December 2008. Of these, 119 received adjuvant RT and 192 received adjuvant concurrent chemoradiotherapy (CCRT) postoperatively. Multivariate analysis for progression-free survival (PFS) was performed using the Cox proportional hazards regression model to investigate the prognostic significance of pelvic node metastases in the 2 treatment groups. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test.Multivariate analysis demonstrated pelvic node metastasis to be an independent prognostic factor for shorter PFS in both treatment groups. When the node-positive patients were analyzed according to the number of positive pelvic nodes, we found that the patients with multiple pelvic node metastases (≥3) displayed significantly shorter PFS than those with 1 or 2 pelvic node metastases in the RT group. In contrast, in the CCRT group, the PFS of the patients with multiple pelvic node metastases (≥3) was similar to that observed of the patients with 1 or 2 pelvic node metastases.The presence of multiple pelvic node metastases was not an independent predictor of shorter PFS in the CCRT group. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate whether nedaplatin-based concurrent chemoradiotherapy (CCRT) using high-dose-rate intracavitary brachytherapy (HDR-ICBT) is superior to radiotherapy (RT) alone in patients with FIGO stage IIIb cervical cancer. Methods: The records of 41 consecutive women treated either with nedaplatin-based CCRT using HDR-ICBT (n = 20) or RT alone (nonrandomized control group, n = 21) for stage IIIb cervical cancer were retrospectively reviewed. The activity and toxicity were compared between the two treatment groups. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. Results: The 5-year overall survival rates in the CCRT and RT groups were 65 and 33.3%, respectively. The median OS of the CCRT and RT groups were 60 and 29 months, respectively. CCRT was significantly superior to RT alone with regard to PFS (p = 0.0015) and OS (p = 0.0364). The frequency of acute grade 3–4 toxicity was significantly higher in the CCRT group than in the RT group. However, no statistically significant difference was observed with regard to severe late toxicity. Conclusions: Nedaplatin-based concurrent chemoradiotherapy was safely performed and significantly improved the prognosis of patients with FIGO stage IIIb cervical cancer. This treatment can be considered as an alternative to cisplatin-based chemoradiotherapy in this patient population. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Cervical intraepithelial neoplasia (CIN) has its highest incidence during women's reproductive years. During 2 sequential 7-year periods, 1994 to 2000 and 2001 to 2007, 3695 and 3894 deliveries were performed, respectively, at Osaka University Hospital. CIN was detected in 21 cases (0.57%) during 1994-2000 and in 43 cases (1.1%) during 2001-2007. By comparison, cervical intraepithelial neoplasia-complicated pregnancies increased significantly in the latter period (P = .015 by Fisher exact test, Odds ratio = 1.95; 95%CI: 1.16-3.30). We observed CIN regression in 34 (76%) of 45 cases of vaginal delivery and in 6 (50%) of 12 cases of cesarean delivery, indicating that the outcome of an initially diagnosed CIN and the delivery routes appeared not to be significantly related. However, a different result was obtained when only those patients whose CIN lesions persisted until the delivery were analyzed. Among the 35 such cases in the vaginal delivery group, 24 cases (69%) regressed after the delivery; in 8 such cases from the cesarean delivery group, only 2 cases (25%) regressed afterward. Our study clearly shows that pregnancy complicated with CIN is increasing rapidly in Japan. We also find that there is a significantly more frequent postpartum regression of biopsy-proven CIN lesions following a vaginal delivery compared to cesarean section (P = .042 by Fisher exact test, Odds ratio = 6.55; 95% CI: 1.13-37.8). [ABSTRACT FROM AUTHOR]

In Japan, government subsidies for human papillomavirus (HPV) vaccination of girls aged 13–16 commenced in 2010. By early 2013, vaccination had become a widely accepted national immunization program. However, in June of 2013, the Ministry of Health, Labor, and Welfare (MHLW), the government's lead agency, suspended its recommendation for vaccination in response to reports of adverse vaccine events. The rate of HPV vaccination quickly dropped from 70% to almost zero, where it has lingered for eight years. In 2020, a new 9-valent HPV vaccine was licensed in Japan. The momentum seemed to be building for the resumption of HPV vaccinations, yet Japanese mothers remain widely hesitant about vaccinating their daughters, despite the well-proven safety and efficacy of the HPV vaccines. The Japanese government and our educational and medical institutions must work harder as a team to inform our parents and their children about the life-saving benefits of the HPV vaccine, and at the same time, we must respond to all their concerns and questions. The vaccine hesitancy of unvaccinated women born in 2000 and thereafter is a natural consequence of the suspension of the government's recommendation. We must also take every possible measure to reduce the significant risk for cervical cancer these women have. [ABSTRACT FROM AUTHOR]

The CDKN2A locus on human chromosome 9p21 encodes two tumor suppressors, p14ARF and p16INK4A, which enhance the growth-suppressive functions of the retinoblastoma (Rb) and the p53 proteins, respectively. Conversely, the E6 and E7 oncoproteins of the high-risk human papillomaviruses (HPVs) causally associated with carcinogenesis of the uterine cervix contributes to tumor development by inactivating p53 and Rb. Nevertheless, a correlation between expression of p14ARF/p16INK4A and HPV infection in uterine cervix is less clear. To clarify this, we examined 25 cervical cancers and 11 normal uterine cervixes. HPV was detected in 21 of 25 cervical cancers (84%) and their subtype was determined by PCR-RFLP. Quantitative real-time RT-PCR assays showed overexpression of p14ARF mRNA in all 21 HPV-positive cases (100%). p16INK4A mRNA was overexpressed in 17 cases of the HPV-positive cases (81%). In four HPV-negative cancers, reduced expression of p14ARF mRNA was detected in two cases (50%) and reduced p16INK4A mRNA in three cases (75%). Our data indicate that the overexpression of p14ARF and p16INK4A strongly associates with HPV-positive cervical cancers and that reduced expression of p14ARF and p16INK4A correlates with HPV-negative cervical cancers. These findings may indicate that impaired p14ARF and p16INK4A mRNA expression contribute to tumor development in HPV-negative cervical cancers by failure to support p53 and Rb instead of their inactivation by HPV E6 and E7. [Copyright &y& Elsevier]

Recommendations for HPV vaccines were suspended in 2013 due to unfounded safety fears in Japan. We aimed to clarify the differences between vaccinated and unvaccinated females in their awareness, knowledge, and behaviors toward cervical cancer, HPV vaccination and sex. Questionnaires were administered online to women aged 16 to 20. We conducted investigations for the following: awareness, knowledge, and actions for cervical cancer, HPV vaccination, and sexual activity, as well as items related to participants' social background. The survey in 828 girls revealed three points. The first is that more than half of the surveyed Japanese girls had poor knowledge about cervical cancer screening, HPV, or HPV vaccines. The second is that those in the unvaccinated group had a particularly poor knowledge of the subject and tended to have higher sexual activity. The final is that only 0.5% of the girls experienced changes in awareness about sexual activity after vaccination. In conclusion, this is the first large-scale survey analyzing the association between HPV vaccination and sexual activity in Japanese girls. Not only do unvaccinated girls not benefit from vaccines, but they also tend to engage in high-risk sexual behavior, and thus it is even more important to provide information on the effectiveness of vaccines and the usefulness of cancer screening. [ABSTRACT FROM AUTHOR]

In 2013, recurrent reports of diverse symptoms occurring in girls after receiving HPV vaccination appeared in Japanese media. The Ministry of Health, Labor and Welfare quickly responded by announcing a temporary suspension of its recommendation for the vaccine. The HPV vaccination rate soon fell to almost zero. In the present study, we calculated the potential future numbers of cervical cancer incidence and death that will be increased by this policy decision. We have assumed that the number of yearly vaccinations is evenly distributed across a daily basis. Future incidence and death increased in females born in FY2000 are estimated to be 3651 and 904, respectively, 4566 and 1130 for those born in FY2001, 4645 and 1150 for those born in FY2002, and 4657 and 1153 for those born in FY2003. In FY2020, the large increase of risks to females born in FY2004 amounts to 12.0 females per day who will now be at a higher risk for acquiring of cervical cancer in their future, and 3.0 females per day newly at risk for future death from that disease in its progressive form. No one should be able to accept this situation. We sincerely ask the government to resume its recommendation for the vaccine as soon as possible. [ABSTRACT FROM AUTHOR]

Organized human papillomavirus vaccination (OHPV) in Japan was introduced in 2010 for girls aged 12–16 years who were born in 1994 or later. The rate of OHPV coverage was 70–80%. However, after suspension of the government vaccination recommendation, the coverage dramatically decreased. We aim to investigate the change in prevalence of HPV infection after the initiation of HPV vaccination. We recruited females aged 20–21 years attending public cervical cancer screening from 2014 to 2017 fiscal years (April 2014 to March 2018). Residual Pap test specimens were collected for HPV testing. We compared the prevalence of HPV type-specific infection between women registered in 2014 (born in 1993–1994, including the pre-OHPV generation) and registered in 2015–2017 (born in 1994–1997, the OHPV generation). We collected 2379 specimens. The vaccination coverage figures were 30.7%, 86.6%, 88.4% and 93.7% (p < 0.01) from 2014 to 2017, respectively. The prevalence of HPV16/18 infection significantly decreased from 1.3% in 2014 to 0% in 2017 (p = 0.02). The three most prevalent types were HPV52, 16 and 56 in 2014, and HPV52, 58 and 56 in 2015–2017, respectively. HPV16 and 33 infection rates decreased. On the other hand, the HPV58 infection rate was obviously increased after OHPV from 0.3% to 2.1%. Our study demonstrates that the prevalence of HPV16/18 infection dramatically decreased and the profile of type-specific HPV infection was changed after OHPV. [ABSTRACT FROM AUTHOR]

The Japanese government suspended proactive recommendations for the HPV vaccine in June 2013. The suspension is now in its seventh year, despite all the data pointing to the safety of the HPV vaccine. We reported a high vaccine effectiveness in the group of women vaccinated before their first intercourse (93.9%). The prevalence of cross-protected types of HPV 31/45/52 was also lower in the vaccinated group, and the vaccine effectiveness was 67.7%. Furthermore, prevalence of HPV16, 31 and 52 infection rates in the vaccinated group were obviously lower than that in the unvaccinated group, and no one had HPV18 or 45 infection in the vaccinated group. The addition of a cross-protective effect toward HPV types 31/45/52 to HPV types 16/18, which is the direct target of the bivalent HPV vaccine, may possibly prevent around 82% of invasive cervical cancer cases in Japan. With regard to the preventive effect of histological abnormalities, we also reported significant reduction in incidence of cervical intraepithelial neoplasia (CIN)3 or worse. Thus, the efficacy of the vaccine has been demonstrated for precancerous disease, and the diverse symptoms after HPV vaccination are likely functional somatic. For the future of Japanese girls, there is a need to resume the proactive recommendation of HPV vaccination and for immediate action to be taken by the Japanese government. [ABSTRACT FROM AUTHOR]

(1) Background: This study examined the use of a two-tier system in grouping cervical adenocarcinoma for survival discrimination. (2) Methods: A nationwide retrospective observational cohort study was conducted using the Japan Society of Gynecologic Oncology tumor registry database from 2001 to 2015 (n = 86,754). Adenocarcinoma subtypes were grouped as type 1 (endocervical usual type and endometrioid) or type 2 (serous, clear, mucinous, and not otherwise specified), based on their relative survival compared with that of squamous tumors. (3) Results: The majority of the adenocarcinoma cases were type 1 (n = 10,121) versus type 2 tumors (n = 5157). Type 2 tumors were more likely to be old and have stage IV disease than those with squamous tumors. The number of type 2 tumors increased from 2001 to 2014 (106.1% relative increase, p < 0.001). Type 2 tumors had disproportionally poorer survival compared to other types (5-year survival rates: 68.9% for type 2, 75.4% for type 1, and 78.0% for squamous; p < 0.001). On multivariate analysis, type 2 tumors remained an independent prognostic factor associated with decreased survival compared with squamous (adjusted hazard ratio 2.00, 95% CI 1.84–2.15, p < 0.001). (4) Conclusion: The survival of cervical adenocarcinoma varies largely across the histological subtypes, and the proposed two-tier grouping may be useful for survival discrimination. [ABSTRACT FROM AUTHOR]

Background: Trachelectomy is the treatment of choice for reproductive-aged women with early-stage cervical cancer who desire future fertility. Comprehensive population-based statistics have been missing to date.Objective: We sought to compare characteristics and survival of reproductive-aged women who underwent trachelectomy for early-stage cervical cancer to those who had hysterectomy.Study Design: This is a retrospective observational study examining the Surveillance, Epidemiology, and End Results program from 1998 through 2014. Women <45 years of age with stage IA and IB1 (tumor size ≤2 cm) cervical cancer who underwent trachelectomy were compared to those who underwent hysterectomy. Multivariable models were used to identify clinicopathological factors associated with trachelectomy. Survival was compared between the 2 groups after propensity score matching.Results: Among 6359 women, 190 (3.0%; 95% confidence interval, 2.6-3.4) underwent trachelectomy. The median age of the trachelectomy group was 31 years (interquartile range, 28-34). The proportion of women who underwent trachelectomy significantly increased during the study period (1.2% in 1998 through 2002, 3.0% in 2003 through 2008, and 4.5% in 2009 through 2014, P < .001). Younger age, nonblack race, single marital status, eastern registry area, recent disease diagnosis, nonsquamous histology, and higher stage were independent factors associated with trachelectomy use (all, adjusted P < .05). After propensity score matching, 5-year cause-specific survival (96.9% vs 96.6%; hazard ratio, 0.73; 95% confidence interval, 0.23-2.30; P = .59) and overall survival (96.1% vs 96.6%; hazard ratio, 0.76; 95% confidence interval, 0.26-2.20; P = .61) were similar between the trachelectomy group and the hysterectomy group.Conclusion: Our study found that there was a significant increase in the proportion of reproductive-aged women with stage IA or IB1 (≤2 cm) cervical cancer who underwent trachelectomy in recent years. Survival with trachelectomy was similar to those who had hysterectomy in this population. [ABSTRACT FROM AUTHOR]

Background: Prior research about the sexual and reproductive health of young women has relied mostly on self-reported survey studies. Thus, participant recruitment using Web-based methods can improve sexual and reproductive health research about cervical cancer prevention. In our prior study, we reported that Facebook is a promising way to reach young women for sexual and reproductive health research. However, it remains unknown whether Web-based or other conventional recruitment methods (ie, face-to-face or flyer distribution) yield comparable survey responses from similar participants.Objective: We conducted a survey to determine whether there was a difference in the sexual and reproductive health survey responses of young Japanese women based on recruitment methods: social media-based and conventional methods.Methods: From July 2012 to March 2013 (9 months), we invited women of ages 16-35 years in Kanagawa, Japan, to complete a Web-based questionnaire. They were recruited through either a social media-based (social networking site, SNS, group) or by conventional methods (conventional group). All participants enrolled were required to fill out and submit their responses through a Web-based questionnaire about their sexual and reproductive health for cervical cancer prevention.Results: Of the 243 participants, 52.3% (127/243) were recruited by SNS, whereas 47.7% (116/243) were recruited by conventional methods. We found no differences between recruitment methods in responses to behaviors and attitudes to sexual and reproductive health survey, although more participants from the conventional group (15%, 14/95) chose not to answer the age of first intercourse compared with those from the SNS group (5.2%, 6/116; P=.03).Conclusions: No differences were found between recruitment methods in the responses of young Japanese women to a Web-based sexual and reproductive health survey. [ABSTRACT FROM AUTHOR]

Survival outcomes for cervical cancer differ between countries and world regions. Locally advanced cervical cancer (LACC) is associated with poorer outcomes than early-stage disease. Country-specific variations in diagnostic and treatment recommendations might contribute to differences in LACC outcomes among countries. We compared international and country-specific guidelines for LACC diagnostic imaging and treatment recommendations. A systematic literature review and targeted search were used to identify cervical cancer treatment guidelines published between January 1999—August 2021. Guidelines were identified via literature databases, health technology assessment databases, disease-specific websites, and health organization websites. The targeted search included guidelines from countries in regions known to have high cervical cancer prevalence or mortality. Non-English guidelines were translated by native speakers or online translation services. Forty-six guidelines from 31 countries, regions, and international organizations were compared (41/46 using staging criteria, 27 of which used 2009 FIGO). Most guidelines recommended imaging tests for diagnosis and staging. Chest X-ray, intravenous pyelogram, CT, and MRI were commonly recommended for diagnosis and staging while MRI and PET-CT were recommended for the assessment of lymph node status and distant metastases, with a preference for PET-CT over MRI. There was global consensus for cisplatin-based concurrent chemoradiation as primary treatment for stages IIB to IVA, with few exceptions. Treatment recommendations for stages IB2 to IIA2 varied. Most guidelines agreed on adjuvant concurrent chemoradiation after radical hysterectomy when there is a high recurrence risk, and adjuvant radiotherapy when there is an intermediate recurrence risk. Recommendations for other adjuvant and neoadjuvant therapies varied among the guidelines. Differences among treatment guidelines by LACC stage might be influenced by staging criteria used, resource availability, and prevention program effectiveness. Addressing these areas may unify guidelines and improve global outcomes. Review and update of guidelines will be important as novel LACC therapies become available. • We identified 46 global diagnostic imaging and treatment recommendations for locally advanced cervical cancer (LACC). • Chest X-ray, CT, MRI, and/or PET-CT were recommended by most guidelines for diagnosis or staging. • Concurrent chemoradiotherapy was the consensus recommendation for stage IIB-IVA LACC. • Treatment recommendations varied for early-stage LACC and neoadjuvant/adjuvant therapies varied. • Differences between guidelines may be due to varying staging criteria and/or resource availability between countries. [ABSTRACT FROM AUTHOR]

Objective: To evaluate timing and a prediction model for pregnancy in early-stage cervical cancer patients who underwent fertility-sparing trachelectomy.Design: Retrospective cohort.Setting: Academic multicenter.Patient(s): Women ages <45 years with clinical stage I-II cervical cancer were enrolled between 2009 and 2013 (n = 393).Intervention(s): Planned fertility-sparing trachelectomy.Main Outcome Measure(s): Cumulative incidences and clinicopathological characteristics of those who developed subsequent pregnancy were examined.Result(s): There were 77 (21.6%) women who had subsequent pregnancies after fertility-sparing trachelectomy with 1-, 2-, and 5-year cumulative pregnancy rates of 2.8%, 6.2%, and 17.4%, respectively. The median time to develop subsequent pregnancy was 3.2 years. In a competing risk analysis, women had a higher risk of recurrent cancer than conception during the first 11 months postsurgery. On multivariable analysis, younger age, being married, and postoperative reproductive treatment were independently associated with an increased chance of developing a subsequent pregnancy. The subsequent pregnancy index (SPI) score to predict the likelihood of having pregnancy was proposed, and it was calculated based on age, marital status, and reproductive treatment (2, 2, and 4 points, respectively). Women with a higher SPI score had significantly higher subsequent pregnancy rates (5-year pregnancy rate; the score was 3 in 4.7% of cases; 4 to 5 in 11.3%; 6 to 7 in 27.4%; and 8 in 50.8%), but they had similar recurrence rates (5.0%).Conclusion(s): The SPI score proposed in our study is useful in predicting subsequent pregnancy in women with early-stage cervical cancer undergoing fertility-sparing trachelectomy. [ABSTRACT FROM AUTHOR]

To propose an ideal patient candidate with early-stage cervical cancer for undergoing fertility-sparing trachelectomy. This nationwide, multicenter, retrospective study was conducted by the Japan Society of Obstetrics and Gynecology involving women aged <45 years with clinical stage I-II cervical cancer who had planned fertility-sparing trachelectomy and pelvic lymphadenectomy between 2009 and 2013 (n = 393). Ideal candidates were defined to have a tumor size of ≤2 cm, no lymph node metastasis, no deep stromal invasion, and no high-risk histology (n = 284, 69.6%). Less-ideal candidates were defined to have any one of these four characteristics (n = 109, 30.4%). Propensity score inverse probability of treatment weighting was used to assess survival outcomes. Less-ideal candidates were more likely to undergo hysterectomy conversion (22.9% versus 3.2%), receive postoperative radiotherapy (11.9% versus 0.4%), or chemotherapy (32.1% versus 3.2%) compared with ideal candidates (all, P < 0.05). The weighted model revealed that among those who underwent trachelectomy (ideal candidates, n = 275 and less-ideal candidates, n = 84), less-ideal candidates had significantly decreased disease-free survival (5-year rates: 85.5% versus 95.5%; HR 3.93, 95% CI 1.99–7.74; P < 0.001) and cause-specific survival (92.5% versus 98.6%; HR 5.47, 95% CI 1.68–17.8, P = 0.001) compared with ideal candidates. Similarly, less-ideal candidates were significantly associated with decreased disease-free survival compared with ideal candidates among those who were young age, had small tumors or squamous histology, and underwent surgery alone (all, P < 0.05). Less-ideal candidates had approximately four-fold higher recurrence risk and cancer mortality compared with ideal candidates. Ideal candidates for fertility-sparing trachelectomy for early-stage cervical cancer proposed in our study may be useful as the future framework for developing guidelines for fertility-sparing trachelectomy in Japan. • A retrospective study was performed for 393 women underwent fertility-sparing trachelectomy for stage I-II cervical cancer. • Women without tumor size>2cm, deep stromal invasion, nodal metastasis, or high-risk histology may be ideal candidates. • Less-ideal candidates had approximately four-fold higher recurrence risk and mortality compared with ideal candidates. • Adjuvant chemotherapy for women with large tumors may have benefit for the purpose of fertility preservation. [ABSTRACT FROM AUTHOR]

Objective This multicenter phase II Japanese Gynecologic Oncology Group study (JGOG1067) was designed to evaluate the efficacy and safety of postoperative chemotherapy in patients with node-positive cervical cancer. Methods Patients with stage IB–IIA squamous cervical cancer who underwent radical hysterectomy and were confirmed to have pelvic lymph node metastasis were eligible for this study. The patients postoperatively received irinotecan (CPT-11; 60 mg/m 2 intravenously on days 1 and 8) and nedaplatin (NDP; 80 mg/m 2 intravenously on day 1). Chemotherapy administration commenced within 6 weeks after surgery and was repeated every 28 days for up to 5 cycles. The primary endpoint of this study was the 2-year recurrence-free survival (RFS) rate. The secondary endpoints were the 5-year overall survival (OS) rate, 5-year RFS rate, and adverse events such as complications of chemotherapy and lower-limb edema. Results Sixty-two patients were analyzed according to our protocol, among whom 55 (88.7%) completed 5 cycles of scheduled treatment. The median follow-up period was 66.1 months (range, 16.8–96.6 months). The 2-year and 5-year RFS rates were 87.1% (95% confidence interval [CI]: 75.9–99.3) and 77.2% (95% CI: 64.5–85.8), respectively. Fourteen patients (22.5%) experienced recurrence during the follow-up period, 8 of whom died of the disease. The 5-year OS rate in this study was 86.5% (95% CI: 74.8–93.0). Only 9.7% of the patients experienced lymphedema in their legs. Conclusion Postoperative chemotherapy without radiotherapy was found to be very effective in high-risk patients with node-positive cervical cancer. [ABSTRACT FROM AUTHOR]

The incidence of cervical cancer has been increasing, especially in younger generation, in Japan. The females born between 1994 and 1999, who achieved rates of HPV vaccination approaching 70%, have become the target of cervical cancer screening programs. Here, we have analyzed the cervical cancer screening rates among the vaccinated and unvaccinated women. The survey data for cervical cancer screening at age 20 in FY 2015 was derived from two cities, Toyonaka and Iwaki. Among 2,727 females, in Toyonaka and Iwaki, who were born in FY 1995 and targeted in FY 2015 at age 20 for cervical cancer screening, their HPV vaccination rate was 64.2% (1,753/2,727). The screening rate was 6.4% (112/1,753) in the vaccinated and 3.9% (38/974) in the unvaccinated. This difference was statistically significant (p < 0.01). We have demonstrated that HPV-vaccinated females tended to be effectively protected from future cervical cancer than the unvaccinated. [ABSTRACT FROM AUTHOR]

In 2013, following the Ministry of Health, Labor and Welfare (MHLW)'s announced suspension of its vaccine recommendation due to media reports of "adverse events", HPV vaccination dropped to almost 0%. Here, we analyzed, by birth year, the cumulative vaccinations for girls up to age 16 (maximum age for public subsidies) and the results of cervical cancer screening in Matsuyama City. The incidence of CIN3 or worse was 0.09% (7/7872) for these unvaccinated generation born between 1991 and 1993, and 0.00% (0/7389) for the vaccination generation born between 1994 and 1996. This study is the first to show the significant reduction in incidence of CIN3+depending on birth year in Japan. We must keep in mind that the unacceptable high risk for cervical cancer has already begun for an entire new generation of unvaccinated girls born in or after 2000. This data encourages a resumption of MHLW's recommendation for HPV vaccination. [ABSTRACT FROM AUTHOR]

Objectives A phase II study was conducted to evaluate the efficacy and toxicity of carboplatin plus paclitaxel (TC)-based postoperative concurrent chemoradiotherapy (CCRT) followed by TC-based consolidation chemotherapy in surgically-treated early-stage cervical cancer patients. Methods Women with surgically-treated early-stage cervical cancer with positive pelvic lymph nodes were eligible for this study. The patients were postoperatively treated with pelvic intensity modulated radiotherapy (50.4 Gy) and concurrent weekly carboplatin (AUC: 2) and paclitaxel (35 mg/m 2 ) (TC-based CCRT). Three cycles of consolidation chemotherapy involving carboplatin (AUC: 5) and paclitaxel (175 mg/m 2 ) were administered after TC-based CCRT. Results Thirty-one patients were enrolled and treated. Overall, the treatment was well tolerated, and 26 patients (83.9%) completed the planned TC-based CCRT. The most frequently observed acute grade 3/4 hematological toxicities were leukopenia and neutropenia, and diarrhea was the most common acute grade 3/4 non-hematological toxicity. After a median follow-up period of 36.5 months, 2 patients (6.5%) had developed recurrent disease. The patients' estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 88.5% and 93.8%, respectively. In comparisons with historical control groups, TC-based CCRT followed by TC-based consolidation chemotherapy was found to be significantly superior to CCRT involving a single platinum agent in terms of PFS ( p = 0.026) and significantly superior to extended-field radiotherapy in terms of both PFS ( p = 0.0004) and OS ( p = 0.034). Conclusions In women with surgically treated early-stage cervical cancer, pelvic TC-based CCRT followed by TC-based consolidation chemotherapy is feasible and highly effective. Future randomized trials are needed to verify the efficacy of this regimen. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To evaluate the significance of adenocarcinoma (AC) compared with squamous cell carcinoma (SCC) with regard to the survival of surgically-treated early stage cervical cancer patients. Methods: We retrospectively reviewed the medical records of 520 patients with FIGO stage IA2–IIB cervical cancer who were treated with radical hysterectomy with or without adjuvant radiotherapy between January 1998 and December 2008. The patients were classified according to (i) pathological risk factors (low-, intermediate-, or high-risk group) and (ii) adjuvant radiotherapy (concurrent chemoradiotherapy [CCRT group] or radiotherapy alone [RT group]). Survival outcomes were examined by Kaplan–Meier method and compared with Log-rank test. Multivariate analysis for disease-specific survival (DSS) was performed using Cox proportional hazards regression model to investigate the prognostic significance of histological subtype. Results: AC histology was associated with significantly decreased DSS compared with SCC histology in the intermediate- and high-risk groups (hazard ratio: 3.06 and 2.88, respectively, both P<0.05) while there was no survival difference in the low-risk group (P=0.1). Among patients who received any types of adjuvant radiotherapy, DSS of AC histology patients were significantly poorer than SCC histology. Multivariate analysis demonstrated AC histology to be an independent predictor of decreased DSS in both CCRT and RT groups. Moreover, pelvic nodal metastasis significantly predicted the poor survival of patients with AC histology who received CCRT in multivariate analysis Conclusions: Adenocarcinoma is an independent prognostic indicator of poor survival in early stage cervical cancer patients with intermediate- and high-risk factors, regardless of the type of adjuvant radiotherapy after radical hysterectomy. [Copyright &y& Elsevier]

Abstract: Objective: An effective salvage chemotherapy for advanced and recurrent non-squamous carcinoma of the uterine cervix has not yet been established. The aim of the present study was to analyze the safety and efficacy of a combination chemotherapy for this disease using taxane, anthracycline, and platinum. Study design: This was a retrospective analysis of advanced and recurrent non-squamous cervical cancers treated at the Osaka University Hospital and the Osaka Medical Center for Cancer and Cardiovascular Diseases during a 10 year study period from 2000 to 2009. Single agent chemotherapies and combination chemotherapies for advanced and recurrent cervical cancer cases of non-squamous histology which were reported in the English literature were also reviewed. Results: Salvage chemotherapy, using taxane, anthracycline and platinum, was performed for 5 advanced and 14 recurrent cases. Prior to the salvage chemotherapy, 15 (79%) of the 19 patients had already received either radiation or chemotherapy. A complete or partial tumor response was achieved in 8 (42%) of the 19 cases. The response rate for recurrent disease in a previously irradiated field was 40%. The median progression-free survival (PFS) and overall survival (OS) were 8 months (1–108) and 13 months (5–108), respectively. Grade 4 and febrile grade 3 neutropenia was observed in 6 cases (32%), but there was no case in which salvage chemotherapy had to be cancelled due to toxicity. According to previous reports, the cumulative response rate of combination chemotherapy (35%) was significantly higher than that of single agent chemotherapy (17%) (p <0.001). OS tended to be longer in the combination chemotherapy cases (8.7 months to 18 months) than that of single agent chemotherapy cases (7.3+ months to 9.1+ months). Conclusion: Combination chemotherapy of taxane, anthracycline, and platinum was found to have a survival benefit for advanced and recurrent cervical cancer patients of non-squamous carcinoma histology, with a tolerable toxicity. [Copyright &y& Elsevier]

Abstract: Objectives: The aim of this study was to compare the treatment outcomes and adverse effects of radical hysterectomy followed by adjuvant radiotherapy with definitive radiotherapy alone in patients with FIGO stage IIB cervical cancer. Methods: We retrospectively reviewed the medical records of FIGO stage IIB cervical cancer patients who were treated between April 1996 and December 2009. During the study period, 95 patients were treated with radical hysterectomy, all of which received adjuvant radiotherapy (surgery-based group). In addition, 94 patients received definitive radiotherapy alone (RT-based group). The recurrence rate, progression-free survival (PFS), overall survival (OS), and treatment-related complications were compared between the two groups. Results: Radical hysterectomy followed by adjuvant radiotherapy resulted in comparable recurrence (44.2% versus 41.5%, p=0.77), PFS (log-rank, p=0.57), and OS rates (log-rank, p=0.41) to definitive radiotherapy alone. The frequencies of acute grade 3–4 toxicities were similar between the two groups (24.2% versus 24.5%, p=1.0), whereas the frequencies of grade 3–4 late toxicities were significantly higher in the surgery-based group than in the RT-based group (24.1% versus 10.6%, p=0.048). Cox multivariate analyses demonstrated that treatment with surgery followed by adjuvant radiotherapy was associated with an increased risk of grade 3–4 late toxicities, although the statistical significance of the difference was marginal (odds ratio 2.41, 95%CI 0.97–5.99, p=0.059). Conclusions: Definitive radiotherapy was found to be a safer approach than radical hysterectomy followed by postoperative radiotherapy with less treatment-related complications and comparable survival outcomes in patients with FIGO stage IIB cervical cancer. [Copyright &y& Elsevier]

Tumor stroma drives the growth and progression of cancers. A heparin-binding epidermal growth factor-like growth factor, HB-EGF, is an EGF receptor ligand that stimulates cell growth in an autocrine or paracrine fashion. While elevated expression of HB-EGF in cancer cells and its contribution to tumor progression are well documented, the effects of HB-EGF expression in the tumor stroma have not been clarified. Here, we show that HB-EGF is expressed in stromal fibroblasts where it promotes cancer cell proliferation. In uterine cervical cancers, HB-EGF was detected immunohistochemically in the stroma proximal to the cancer epithelium. Proliferation of cervical cancer cells was enhanced by coculture with fibroblasts isolated from tumor in vitro tissues of patients with cervical cancer. Inhibition of HB-EGF function or treatment with platelet-derived growth factor (PDGF) inhibitors abrogated cancer cell growth enhanced by cervical cancer-associated fibroblast (CCF) coculture. Furthermore, tumor formation in a mouse xenograft model was enhanced by cotransplantation of CCF or mouse embryonic fibroblasts, but not with embryonic fibroblasts from HB-EGF-deficient mice. Conversely, conditioned medium from cancer cells induced HB-EGF expression in CCF. Mechanistic investigations established that PDGF was the primary factor responsible. Together, our findings indicate that HB-EGF and PDGF reciprocally mediate the interaction of cancer cells with cancer-associated fibroblasts, promoting cancer cell proliferation in a paracrine manner that has implications for novel combinatorial cancer therapies. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of this study was to compare the efficacy of postoperative pelvic radiotherapy plus concurrent chemotherapy with that of extended-field irradiation (EFRT) in patients with FIGO Stage IA2–IIb cervical cancer with multiple pelvic lymph node metastases. Methods: We retrospectively reviewed the medical records of patients with FIGO Stage IA2–IIb cervical cancer who had undergone radical surgery between April 1997 and March 2008. Of these, 55 patients who demonstrated multiple pelvic lymph node metastases were treated postoperatively with pelvic radiotherapy plus concurrent chemotherapy (n=29) or EFRT (n=26). Thirty-six patients with single pelvic node metastasis were also treated postoperatively with pelvic radiotherapy plus concurrent chemotherapy. The recurrence rate, progression free survival (PFS), and overall survival (OS) were compared between the treatment groups. Results: Pelvic radiotherapy plus concurrent chemotherapy was significantly superior to EFRT with regard to recurrence rate (37.9% vs 69.2%, p=0.0306), PFS (log-rank, p=0.0236), and OS (log-rank, p=0.0279). When the patients were treated with pelvic radiotherapy plus concurrent chemotherapy, there was no significant difference in PFS or OS between the patients with multiple lymph node metastases and those with single node metastases. With regards to grade 3–4 acute or late toxicities, no statistically significant difference was observed between the two treatment groups. Conclusions: Postoperative pelvic radiotherapy plus concurrent chemotherapy is superior to EFRT for treating patients with FIGO Stage IA2–IIb cervical cancer displaying multiple pelvic lymph node metastases. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of this study was to evaluate the efficacy of postoperative nedaplatin-based concurrent chemoradiotherapy (CCRT) in patients with FIGO stage IA2–IIB cervical cancer with adverse risk factors. Methods: We retrospectively reviewed the medical records of 183 patients with early-stage cervical cancer who had undergone radical surgery between April 1997 and March 2006. Of these, 68 patients displayed high-risk prognostic factors such as positive pelvic lymph nodes, parametrial involvement, or a positive surgical margin. Fifty-seven patients demonstrated intermediate-risk prognostic factors including deep stromal invasion, capillary lymphatic space involvement, or large tumor diameter. These patients were treated postoperatively with CCRT or radiotherapy alone (RT). Fifty-eight patients showed no risk factors and, therefore, received no adjuvant therapy after surgery. The 3-year recurrence rate, progression free survival (PFS), and overall survival (OS) were compared between the treatment groups. Results: CCRT was significantly superior to RT alone with regard to recurrence rate, PFS, and OS in patients that displayed high-risk and intermediate-risk prognostic factors. The frequencies of acute grade 3–4 toxicities were significantly higher in patients treated with CCRT than in those treated with RT alone. However, no statistically significant difference was observed with regard to severe late toxicities. Conclusions: Postoperative nedaplatin-based CCRT was safely performed and improved the prognosis of FIGO stage IA2–IIB cervical cancer patients displaying high-risk or intermediate-risk prognostic factors. This treatment can be considered as an alternative to cisplatin-based chemoradiotherapy in this patient population. [Copyright &y& Elsevier]