Published papers

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.

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.

31歳女。不正性器出血持続、大量性器出血で緊急入院となった。貧血に対し輸血が施行され、.経腟エコーで右卵巣腫瘍が疑われ、MRが施行された。骨盤内には子宮と一塊となった内部構造不均一な腫瘤病変を認めた。子宮後面には異常な腔があり、内部には出血信号を示す液体貯留が存在した。CTでは非常に血流に富み内部不均一な骨盤内腫瘤、大量の腹腔内出血、骨盤内右側には高濃度血腫を認めた。造影で腫瘍腹側は強く濃染され、腫瘍左側に造影剤の血管外漏出が疑われた。経皮的塞栓術施行のため血管造影を施行、骨盤血管造影を行うと右内腸骨動脈が欠損し、代わりに左内腸骨が代償性に拡張していた。左子宮動脈をジェルフォーム細片、ボルテックスコイル2本で塞栓した。

我々が経験した臨床的絨毛癌および臨床的侵入奇胎の症例を報告する。症例1は39歳0経妊0経産。胞状奇胎の掻爬術後、経過順調型であったが術後8ヵ月目に血中hCGβ値が再上昇した。子宮に病巣はなく、肺に病巣を認めたため絨毛癌診断スコアにより臨床的絨毛癌と診断し、さらにWHO予後スコアによって低リスク症例と判定した。当初、アクチノマイシンDの単剤投与を行ったが、治療期間中にhCGβ値が上昇したため、EMA療法に変更し寛解となった。しかし寛解後8ヵ月で血中hCGβ値の再上昇認め、EMA療法を再開して再度寛解となった時点で肺病巣切除と子宮全摘術を行った。症例2は34歳0経妊0経産。胞状奇胎の掻爬術後、4週目に血中hCGβ値が上昇した。子宮筋層に原発巣を認め、同時に肺転移巣と思われる腫瘤を認めた。絨毛癌診断スコアにより臨床的侵入奇胎と診断し、WHO予後スコアによって中等度リスク症例と判定した。MAC療法を行って寛解となった。絨毛性疾患の治療にあたってはその厳密な診断および治療の選択が重要であると考えられた。(著者抄録)

2000年4月〜2012年12月に健康維持外来受診した初診患者で、頭痛に対して呉茱萸湯エキス製剤が処方された有経・閉経68例を抽出し、これらのうち初診時の症状に対する問診票への記載が確認できた40例の回答状況の相違について検討した。その結果、1)40例中、有効は32例、無効は8例であった。また、片頭痛と診断されたのは有効例では12例、無効例では1例であり、両群間の平均年齢・BMI・閉経例の割合は有意差は認められなかった。2)問診票の項目で有意差が認められた項目は「動悸」「意欲がわかない」「腟の痒み」であった。3)呉茱萸湯の投与目標としての「頭痛」「嘔気」「手足の冷え」「肩こり」は有効例と無効例においてどちらも有意差は認められなかった。4)重症度別で比較すると「動悸」は有効例では重症度2と3が合計37%であったのに対し、無効例では重症度2と3は認められなかった。一方、「意欲がわかない」は有効例では症状ありが70%であったのに対し、無効例では47%であった。更に「腟の痒み」は有効例では症状なしと重症度1しか認めず、無効例では重症度2が25%であった。以上より、「動悸」「意欲がわかない」は呉茱萸湯の奏功例を見分ける指標となり得ることが示唆された。

Fertility preservation is important for women of reproductive age with cervical cancer. The underlying reasons behind suboptimal reproductive results after successful fertility-preserving surgery have not yet been fully revealed.|The objective of this study was to explore the experience of fertility preservation with radical trachelectomy from the perspective of women with cervical cancer.|We conducted interviews with women with cervical cancer who underwent radical trachelectomy using a Grounded Theory methodology with a theoretical framework of symbolic interactionism.|Our findings articulate a process in which feminine identity is first threatened by a diagnosis of cancer, then repaired by fertility preservation with radical trachelectomy, and finally reconstructed after the surgery, through interactions with self, others, and external events in women with cervical cancer. Feeling incomplete as a woman because of the loss of the uterus was a critical factor in the women's feeling that their feminine identity was threatened. Thus, fertility preservation was significant for these women. The meaning of fertility preservation varied among the women, and their life perspectives were therefore distinct after the surgery.|Women with cervical cancer who undergo radical trachelectomy experience an identity transformation process, and child bearing is not the only expected outcome of fertility preservation.|Nurses should coordinate care through the cancer trajectory. Understanding the identity transformation process helps nurses to assess patients' needs and provide appropriate individual care.

Cervical cancer is a female-specific disease with a high incidence and mortality. MicroRNAs (miRNAs) are implicated in posttranscriptional regulation of gene expression and in the pathogenic mechanisms of cancer, suggesting their importance in diagnosis and treatment. miRNAs may have roles in the pathogenesis of cervical cancer based on the increases or decreases in several specific miRNAs found in patients with this disease. The miRNAs implicated in cervical cancer are miR-21, miR-126, and miR-143, and clinical application of these miRNAs for diagnosis and treatment is under investigation. Methods for diagnosis of cervical cancer include analysis of changes in the levels of specific miRNAs in serum and determination of aberrant hypermethylation of miRNAs. Supplementation of miR-143 or inhibition of miR-21 activity in vivo may be therapeutic strategy for cervical cancer. Previous approaches to development of siRNA as a drug have provided information for establishment of therapy based on these approaches, and an anti-miR-21 inhibitor has been developed. miRNAs also have effects on drug resistance and may be useful in combination therapy with other drugs.

Cervical cancer is a female-specific disease with a high incidence and mortality. MicroRNAs (miRNAs) are implicated in posttranscriptional regulation of gene expression and in the pathogenic mechanisms of cancer, suggesting their importance in diagnosis and treatment. miRNAs may have roles in the pathogenesis of cervical cancer based on the increases or decreases in several specific miRNAs found in patients with this disease. The miRNAs implicated in cervical cancer are miR-21, miR-126, and miR-143, and clinical application of these miRNAs for diagnosis and treatment is under investigation. Methods for diagnosis of cervical cancer include analysis of changes in the levels of specific miRNAs in serum and determination of aberrant hypermethylation of miRNAs. Supplementation of miR-143 or inhibition of miR-21 activity in vivo may be therapeutic strategy for cervical cancer. Previous approaches to development of siRNA as a drug have provided information for establishment of therapy based on these approaches, and an anti-miR-21 inhibitor has been developed. miRNAs also have effects on drug resistance and may be useful in combination therapy with other drugs. © 2014 Kouji Banno et al.

We have developed a collaborative hospital-based approach to monitoring the impact of a human papillomavirus vaccine on cervical cancer, its precursor lesions and human papillomavirus type-specific prevalence in Japan. The monitoring will be conducted for a total period of 21 years on women aged <40 who are newly diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia or adenocarcinoma in situ at 21 participating institutes. Women are monitored to determine their vaccine history and will be human papillomavirus-genotyped each year. The primary endpoint is the human papillomavirus16/human papillomavirus18-positive rate in women aged 16-25 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ. The major secondary endpoints are the number of women aged <40 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ, the human papillomavirus type-specific prevalence, and the number of deaths from invasive cervical cancer in women aged <40. Long-term surveillance for human papillomavirus-associated cervical diseases in young females is important for the development of future strategies for cervical cancer prevention in Japan.

Human papillomavirus vaccines are being introduced worldwide and are expected to reduce the incidence of cervical cancer. Here we report a cross-sectional study using a validated human papillomavirus genotyping method to reveal the human papillomavirus prevalence and genotype distribution in Japanese women with cervical intraepithelial neoplasia Grade 2/3 and invasive cervical cancer.|Cervical exfoliated cells were collected from 647 patients with abnormal cervical histology (cervical intraepithelial neoplasia Grade 2, n = 164; cervical intraepithelial neoplasia Grade 3, n = 334; and invasive cervical cancer, n = 149), and subjected to the PGMY-PCR-based genotyping assay. The association between human papillomavirus infection and lesion severity was calculated using a prevalence ratio.|Overall, the prevalence of human papillomavirus deoxyribonucleic acid was 96.3% in cervical intraepithelial neoplasia Grade 2, 98.8% in cervical intraepithelial neoplasia Grade 3 and 88.0% in invasive cervical cancer (97.8% in squamous cell carcinoma and 71.4% in adenocarcinoma). The three most prevalent types were as follows: human papillomavirus 16 (29.3%), human papillomavirus 52 (27.4%) and human papillomavirus 58 (22.0%) in cervical intraepithelial neoplasia Grade 2; human papillomavirus 16 (44.9%), human papillomavirus 52 (26.0%) and human papillomavirus 58 (17.4%) in cervical intraepithelial neoplasia Grade 3; and human papillomavirus 16 (47.7%), human papillomavirus 18 (23.5%) and human papillomavirus 52 (8.7%) in invasive cervical cancer. The prevalence ratio of human papillomavirus 16 was significantly higher in cervical intraepithelial neoplasia Grade 3 compared with cervical intraepithelial neoplasia Grade 2 (prevalence ratio, 1.62; 95% confidence interval, 1.26-2.13) and in squamous cell carcinoma compared with cervical intraepithelial neoplasia Grade 3 (prevalence ratio, 1.55; 95% confidence interval, 1.25-1.87). Multiple infections decreased from cervical intraepithelial neoplasia Grade 2/3 (38.4/29.6%) to invasive cervical cancer (14.1%), whereas co-infections with human papillomavirus 16/52/58 were found in cervical intraepithelial neoplasia Grade 2/3.|The results of this study provide pre-vaccination era baseline data on human papillomavirus type distribution in Japanese women and serve as a reliable basis for monitoring the future impact of human papillomavirus vaccination in Japan.

We have developed a collaborative hospital-based approach to monitoring the impact of a human papillomavirus vaccine on cervical cancer, its precursor lesions and human papillomavirus type-specific prevalence in Japan. The monitoring will be conducted for a total period of 21 years on women aged <40 who are newly diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia or adenocarcinoma in situ at 21 participating institutes. Women are monitored to determine their vaccine history and will be human papillomavirus-genotyped each year. The primary endpoint is the human papillomavirus16/human papillomavirus18-positive rate in women aged 16-25 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ. The major secondary endpoints are the number of women aged <40 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ, the human papillomavirus type-specific prevalence, and the number of deaths from invasive cervical cancer in women aged <40. Long-term surveillance for human papillomavirus-associated cervical diseases in young females is important for the development of future strategies for cervical cancer prevention in Japan.

OBJECTIVE: Human papillomavirus vaccines are being introduced worldwide and are expected to reduce the incidence of cervical cancer. Here we report a cross-sectional study using a validated human papillomavirus genotyping method to reveal the human papillomavirus prevalence and genotype distribution in Japanese women with cervical intraepithelial neoplasia Grade 2/3 and invasive cervical cancer.METHODS: Cervical exfoliated cells were collected from 647 patients with abnormal cervical histology (cervical intraepithelial neoplasia Grade 2, n = 164; cervical intraepithelial neoplasia Grade 3, n = 334; and invasive cervical cancer, n = 149), and subjected to the PGMY-PCR-based genotyping assay. The association between human papillomavirus infection and lesion severity was calculated using a prevalence ratio.RESULTS: Overall, the prevalence of human papillomavirus deoxyribonucleic acid was 96.3% in cervical intraepithelial neoplasia Grade 2, 98.8% in cervical intraepithelial neoplasia Grade 3 and 88.0% in invasive cervical cancer (97.8% in squamous cell carcinoma and 71.4% in adenocarcinoma). The three most prevalent types were as follows: human papillomavirus 16 (29.3%), human papillomavirus 52 (27.4%) and human papillomavirus 58 (22.0%) in cervical intraepithelial neoplasia Grade 2; human papillomavirus 16 (44.9%), human papillomavirus 52 (26.0%) and human papillomavirus 58 (17.4%) in cervical intraepithelial neoplasia Grade 3; and human papillomavirus 16 (47.7%), human papillomavirus 18 (23.5%) and human papillomavirus 52 (8.7%) in invasive cervical cancer. The prevalence ratio of human papillomavirus 16 was significantly higher in cervical intraepithelial neoplasia Grade 3 compared with cervical intraepithelial neoplasia Grade 2 (prevalence ratio, 1.62; 95% confidence interval, 1.26-2.13) and in squamous cell carcinoma compared with cervical intraepithelial neoplasia Grade 3 (prevalence ratio, 1.55; 95% confidence interval, 1.25-1.87). Multiple infections decreased from cervical intraepithelial neoplasia Grade 2/3 (38.4/29.6%) to invasive cervical cancer (14.1%), whereas co-infections with human papillomavirus 16/52/58 were found in cervical intraepithelial neoplasia Grade 2/3.CONCLUSIONS: The results of this study provide pre-vaccination era baseline data on human papillomavirus type distribution in Japanese women and serve as a reliable basis for monitoring the future impact of human papillomavirus vaccination in Japan.

Cervical cancer ranks high among the causes of female cancer mortalities and is an important disease in developing and developed countries. Current diagnosis of cervical cancer depends on colposcopy, pathological diagnosis and preoperative diagnosis using methods, including magnetic resonance imaging and computed tomography. Advanced cervical cancer has a poor prognosis. The tumor marker squamous cell carcinoma is conventionally used for screening, but recent studies have revealed the mechanisms of carcinogenesis and the factors associated with a poor prognosis in cervical cancer. These include epigenetic biomarkers, with the methylation level of the checkpoint with forkhead and ring finger gene being potentially useful for predicting the malignancy of cervical cancer and sensitivity to treatment with paclitaxel. The extent of methylation of the Werner DNA helicase gene is also useful for determining sensitivity to an anticancer agent, CPT-11. In addition to epigenetic changes, the expression levels of hypoxia-inducible factor 1α subunit, epidermal growth factor receptor and cyclooxygenase-2 have been reported as possible biomarkers in cervical cancer. Novel prognostic factors, including angiogenic factors, fragile histidine triad, thymidylate synthase, glucose-related protein 58 and mucin antigens, have also been described, and hemoglobin and platelets may also be significant prognostic biomarkers. Utilization of these biomarkers may facilitate personalized treatment and improved outcomes in cervical cancer.

子宮頸部円錐切除術は主に診断の確定のために行われ、異形成・上皮内癌の場合は治療法ともなりうる侵襲の少ない術式であるが、術後出血を認める例が少なくない。そこで今回、円錐切除術後の出血に関する検討を後方視的に行った。2012年1月から12月に当科での施行症例は228例であり、年齢・手術時間の中央値は39歳、22分であった。手術後に止血処置を要した症例(止血群)は21例(9.2%)、術後日数(中央値)は13日であった。このうち、4例で縫合止血を要し、17例では止血剤散布とガーゼ圧迫での止血が可能であった。年齢・手術時間は、止血群と非止血群で有意差を認めなかったが、止血群で年齢が高い傾向を認めた。使用器具や出産経験による出血の頻度に違いは認めなかった。子宮頸部円錐切除術は、術後1〜2週間を中心に約1割の症例で止血処置を要するため、出血に関する情報提供を行う必要がある。(著者抄録)

Although T-cell immunity is thought to be involved in the prognosis of epithelial ovarian cancer (EOC) patients, immunosuppressive conditions hamper antitumour immune responses. Thus, their mechanisms and overcoming strategies need to be investigated.|The role of NF-κB in human EOC cells and macrophages was evaluated by in vitro production of immunosuppressive IL-6 and IL-8 by EOC cells and in vivo analysis of immune responses in nude mice implanted with human EOC cells using an NF-κB inhibitor DHMEQ.|In EOC patients, increased plasma IL-6, IL-8, and arginase were observed. The NF-κB inhibitor DHMEQ inhibited the production of IL-6 and IL-8 by EOC cell lines. Immunosuppression of human DCs and macrophages by culture supernatant of EOC cells was reversed with the pretreatment of DHMEQ. Administration of DHMEQ to nude mice implanted with human EOC resulted in the restoration of T-cell stimulatory activity of murine DCs along with the reduction of tumour accumulation and arginase expression of MDSCs. Nuclear factor-κB inhibition in tumour-bearing mice also enhanced antitumour effects of transferred murine naive T cells.|NF-κB is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF-κB is an attractive target for EOC treatment.

Background:Although T-cell immunity is thought to be involved in the prognosis of epithelial ovarian cancer (EOC) patients, immunosuppressive conditions hamper antitumour immune responses. Thus, their mechanisms and overcoming strategies need to be investigated.Methods:The role of NF-κB in human EOC cells and macrophages was evaluated by in vitro production of immunosuppressive IL-6 and IL-8 by EOC cells and in vivo analysis of immune responses in nude mice implanted with human EOC cells using an NF-κB inhibitor DHMEQ.Results:In EOC patients, increased plasma IL-6, IL-8, and arginase were observed. The NF-κB inhibitor DHMEQ inhibited the production of IL-6 and IL-8 by EOC cell lines. Immunosuppression of human DCs and macrophages by culture supernatant of EOC cells was reversed with the pretreatment of DHMEQ. Administration of DHMEQ to nude mice implanted with human EOC resulted in the restoration of T-cell stimulatory activity of murine DCs along with the reduction of tumour accumulation and arginase expression of MDSCs. Nuclear factor-κB inhibition in tumour-bearing mice also enhanced antitumour effects of transferred murine naive T cells.Conclusions:NF-κB is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF-κB is an attractive target for EOC treatment. © 2014 Cancer Research UK.