Published papers

遺伝性乳癌卵巣癌(hereditary breast cancer ovarian cancer syndrome、HBOC)は、BRCA1またはBRCA2(BRCA1/2)の生殖細胞系列病的変異(バクアント)が原因であり、家系内に乳癌・卵巣癌・卵管癌・腹膜癌などが好発し、BRCA1/2遺伝子変異保持者では70歳までに卵巣癌発症例が40%以上であると報告されている。BRCA1/2遺伝子変異保持者に対するマネージメントとして、リスク低減卵管卵巣摘出術(risk reduction salpingo-oophorectomy、RRSO)は卵巣癌や卵管癌の発症リスクを減少させ、全死亡率を低下することも報告されているが、閉経前の両側卵巣摘出術は医原性の卵巣欠落症状を惹起するため、その管理が重要である。本検討では、当院でRRSOを施行した8症例を対象に、RRSO後の諸症状より女性QOLについて後方視的に検討した。8例のうち6例で乳癌の既往があった。術後に薬物治療を必要とする卵巣欠落症状を呈した症例は3例で漢方治療を行っていた。またRRSO後早期に脂質異常症を発症した例もあった。BRCA1/2遺伝子変異保持者に対するRRSOは本邦の実臨床に導入されてきているが、RRSO実施例では短期的には卵巣欠落症状、長期的には脂質異常症や骨粗鬆症などを発症してQOL低下をもたらす可能性が高い。海外の各種ガイドラインでは術後卵巣欠落症状に対するホルモン補充療法(HRT)が提唱されているものの、乳癌既往例などではHRTが禁忌な例が存在し、症例には漢方療法が有効である。RRSO後はがんサーベイランスとともに、女性医学の観点から将来的なQOLに関係する項目を経時的に追跡することが重要である。(著者抄録)

遺伝性乳癌卵巣癌症候群(hereditary breast and ovarian cancer syndrome:HBOC)は、BRCA1またはBRCA2(BRCA1/2)の生殖細胞系列変異(病的バリアント)が原因であり、家系内に乳癌や卵巣癌(卵管癌・腹膜癌含む)などが好発する。BRCA1/2遺伝子変異保持者では70歳までに卵巣癌発症例が40%以上であり、現時点ではリスク低減卵管卵巣摘出術(risk-reducing salpingo-oophorectomy:RRSO)が卵巣癌発症リスクを減少させ全死亡率の低下を可能とすることから、最も確実な癌予防法とされている。しかしながら閉経前のRRSOは医原性の卵巣欠落症状を惹起するため、その術後の管理が重要である。本検討では当院でRRSOを施行した症例における術後の女性QOL管理について検討した。2008年から2016年までに当院にてRRSOを施行した8例を調査対象として、RRSO後の卵巣欠落症状の有無・血清脂質・骨密度検査について検討した。特に卵巣欠落症状に対する漢方薬を含めた介入につき後方視的に検討した。8例のうち7例が継続的に当院女性健康維持外来に受診をしており、7例全例(100%)で介入を施行されていた。術後に薬物治療を必要とする卵巣欠落症状を呈したのは5例(71%)で、いずれも術後に漢方治療を行っていた。なお6例で乳癌の既往があった。BRCA1/2遺伝子変異保持者に対するRRSOはわが国の実臨床に導入されてきているが、RRSO実施例では短期的には卵巣欠落症状、長期的には脂質異常症や骨粗鬆症などを発症してQOL低下をもたらす可能性が高い。海外の各種ガイドラインでは術後卵巣欠落症状に対するホルモン補充療法(HRT)が提唱されているものの、乳癌既往例などET療法が困難な例が存在し、症例によっては漢方療法が有効であると考えられた。(著者抄録)

ベバシズマブは婦人科がんにおいて日常的に用いられる分子標的薬となっているが、特有の有害事象により投与継続が困難となるケースを経験する。そこで本研究ではベバシズマブ投与中止の原因となった重篤な有害事象と臨床的背景を明らかにすることを目的とした。ベバシズマブ併用化学療法を2013年12月から開始した上皮性卵巣癌、卵管癌、腹膜癌(以下卵巣癌)48例および2017年1月から開始した子宮頸癌12例の計60例について後方視的に有害事象とその発現時期を検討した。卵巣癌は初発投与19例、再発投与29例の計48例、子宮頸癌は初発投与1例、再発投与11例の計12例を組み入れた。卵巣癌の年齢中央値は54歳(37〜76歳)、ベバシズマブ投与サイクル数中央値は15回(1〜68回)であった。子宮頸癌の年齢中央値は50歳(33〜68歳)、ベバシズマブ投与サイクル数中央値は5.5回(1〜10回)であった。卵巣癌48例中有害事象による投与中止例は4例あり、内訳は高度蛋白尿・ネフローゼ2例(4.2%)、腸炎1例(2.08%)、血栓塞栓症1例(2.08%)であった。子宮頸癌12例中有害事象による投与中止例は3例あり、全例血栓塞栓症(25%)であった。血液毒性、高血圧による投与中止例は認めず、出血および消化管穿孔、瘻孔は認めなかった。有害事象の発現時期について高度蛋白尿・ネフローゼは17、23サイクル終了時、血栓塞栓症はそれぞれ1、1、2、8サイクル終了時に認めた。高度蛋白尿・ネフローゼは投与数を重ねてから出現し、血栓塞栓症は投与開始後早期に認めた。検討した症例数は少ないものの、子宮頸癌では卵巣癌に比較して血栓塞栓症を多く認める可能性が示唆され、今後症例の蓄積が必要である。(著者抄録)

緒言:卵巣癌合併妊娠は1万から5万例に1例と頻度が低く、対応に一定の見解はない。今回我々は妊娠中期に卵巣癌を診断され、手術療法と化学療法を行い生児を得られた症例を経験した。症例:44歳、1妊0産。妊娠16週時に卵巣癌を疑われ、妊娠18週時に右付属器摘出術、左卵巣腫瘍摘出術、大網生検を施行した。右卵巣原発の高異型度漿液性癌IIIC期の診断にて術後パクリタキセルとカルボプラチン(TC)併用療法を4サイクル施行し、妊娠35週5日時に選択的帝王切開術とinterval debulking surgeryを同時に施行した。2118gの女児を娩出し、術後TC療法を2サイクル施行した。術後母体は再発を認めず、児の発育も良好である。結論:卵巣癌合併妊娠に対して、予め分娩時期を想定した管理・治療を行ったことで母児ともに合併症なく手術療法と化学療法を行うことができた。(著者抄録)

更年期障害を疑われ受診したが、甲状腺疾患を認めた2症例につき報告する。症例1:52歳、0妊0産。子宮頸部腺癌IB1期に対し広汎子宮全摘出術および両側付属器摘出術後である。冷え、関節痛を主訴に受診し、採血でTSH高値を認め精査にて潜在性甲状腺機能低下症の診断となった。症例2:65歳。1妊1産。ほてり、動悸を主訴に受診した。変動するTSHを認め、精査の結果、橋本病に合併した無痛性甲状腺炎の診断となった。甲状腺機能異常は亢進症/低下症ともに症状が更年期障害と類似していることから鑑別疾患の一つとして念頭に置くことが重要である。(著者抄録)

Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life.|This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated.|No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations.|These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.

Objective Microsatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer. Methods The data of 123 patients with endometrial cancer were analyzed. The numbers of tumor-infiltrating CD8+ T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses. Results The MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2-high group showed significantly fewer TILs than did the COX-2-low group. Multivariate analysis identified a low number of TILs (<10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression. Conclusions The number of TILs, which was increased by MSI and decreased by COX-2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment.

未固定遺体のマルチスライスCTで得た0.3125mmスライス幅の連続断層画像を、三次元構築ソフトにて3D再構築を行うことで、系統解剖では理解が難しかった解剖構造を示すことができた。3Dモデルでは基靱帯、膀胱側腔、直腸側腔が確認でき、実際の手術風景と近似していた。第2仙椎の高さでは、直腸側腔が後腹膜と骨盤側壁の間に見られ、第2仙骨神経前枝が直腸側腔の深部にあり、直腸側腔深部の扱いに注意が必要と考えられた。第3仙椎の高さでは、基靱帯が内腸骨血管と子宮との間にあり、基靱帯の腹側に膀胱側腔、背側に直腸側腔を認めた。第4仙椎の高さでは、膀胱側腔は豊富な脂肪組織を含み、内閉鎖筋と基靱帯の間に示され、直腸側腔は内腸骨血管と仙骨子宮靱帯との間に示された。骨盤神経叢は直腸側腔の底部と仙骨子宮靱帯のすぐ外側に認めた。恥骨の高さでは、膀胱側腔の外側、背側に内閉鎖筋と肛門挙筋が存在し、膀胱側腔は尿道近くまで展開していた。

Predictive factors of the efficacy of chemotherapy for Japanese patients with recurrent cervical cancer who have been previously treated with concurrent chemoradiotherapy (CCRT) are currently unknown, and hence we aimed to investigate this. We retrospectively studied the prognostic outcomes of patients with recurrent cervical cancer treated with CCRT between 2002 and 2010 at four medical facilities. A total of 64 patients were included in this study. Forty-two patients received definitive CCRT and 22 patients received postoperative adjuvant CCRT, with 55 receiving platinum-based combination chemotherapy and nine receiving single-agent chemotherapy. The overall response rate (ORR) was 12.5 %, with one complete response. The median survival period was 12 months. The ORR and overall survival rate did not differ significantly according to recurrence site, post-CCRT interval, or chemotherapy regimen. None of the factors analyzed in this study were identified as positive predictive factors for the efficacy of chemotherapy in patients with recurrent cervical cancer after CCRT. Based on the results of previous studies, in order to improve long-term prognosis in recurrent cases, adjuvant chemotherapy should be considered as a potential treatment option for selected patients, especially as postoperative adjuvant therapy.

Lymph node metastasis is the major clinicopathologic feature associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Here, web-based bioinformatics meta-analysis was performed to elucidate the molecular mechanism of lymph node metastasis of human HNSCC. Preferential upregulation of Myosin 1b (MYO1B) transcript in HNSCC datasets was identified. Myo1b mRNA was highly expressed in human HNSCC cells and patient tissue specimens compared with their normal counterparts as shown by quantitative PCR (qPCR) analyses. Immunohistochemistry (IHC)-detected Myo1b expression was significantly correlated with lymph node metastases in patients with oral cancer of the tongue. HNSCC with high expression of Myo1b and chemokine receptor 4 (CCR4), another metastasis-associated molecule, was strongly associated with lymph node metastasis. RNA interference (RNAi) of Myo1b in HNSCC cells, SAS and HSC4, significantly inhibited migratory and invasive abilities through decreased large protrusion formation of cell membranes. Finally, Myo1b knockdown in SAS cells significantly inhibited in vivo cervical lymph nodemetastases in a cervical lymph node metastatic mouse model system. Implications: Myo1b is functionally involved in lymph node metastasis of human HNSCC through enhanced cancer cell motility and is an attractive target for new diagnostic and therapeutic strategies for patients with HNSCC. Mol Cancer Res; 13(4); 721-31.

p16(INK4a) immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16(INK4a) immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16(INK4a) and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16(INK4a)/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system.|From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16(INK4a)/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared.|p16(INK4a)/Ki-67 immunocytochemistry was positive in 33.5 % (63/188) of ASCUS, and 36.8 % (88/239) of LSIL specimens. The sensitivity and specificity of p16(INK4a)/Ki-67 immunocytochemistry was 87.3 % (95 % confidence interval 78.0-93.8 %) and 76.4 % (71.6-80.8 %), respectively. The positive and negative predictive values were 45.7 % (37.6-54.0 %) and 96.4 % (93.4-98.3 %), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16(INK4a)/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test|Compared with high-risk HPV genotyping, p16(INK4a)/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.

BACKGROUND: Immune responses in the uterine cervix are considered to play an important role in persistent human papillomavirus (HPV) infection and carcinogenesis, but many aspects of the mechanism are still unclear. The goal of this study was to measure cytokines to analyze immune responses in patients with cervical intraepithelial neoplasia (CIN).MATERIALS AND METHODS: The levels of 17 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, INF-γ, MCP-1, MIP-1β, and TNFα) in cervical mucus were simultaneously measured using a multiplex immunoassay in 52 high-grade squamous intraepithelial lesion (HSIL) cases and overproduction of IL-1β, IL-8, and MIP-1β was identified. The levels of these 3 cytokines were measured in 130 patients with or without CIN lesions using enzyme-linked immunosorbent assay. The associations of the cytokine levels with the cytology, infecting HPV type, and status of cigarette smoking were investigated.RESULTS: IL-1β and IL-8 levels were associated with the cytology, and these levels were higher in HSIL cases than in NILM (negative for intraepithelial lesion and malignancy) and LSIL (low-grade squamous intraepithelial lesion) cases (P = 0.005, P = 0.001, respectively). The MIP-1β level was significantly lower in smokers (P = 0.018) and high-risk (HR)-HPV-infected patients (P = 0.021).CONCLUSIONS: Enhanced expression of IL-1β and IL-8 indicates that Th2 inflammatory responses become stronger in the local uterine cervical region with the progression of CIN lesions, and a decrease in the MIP-1β level may be advantageous for immunoescape of HPV. Cigarette smoking may further facilitate persistent HPV infection.

BACKGROUND: Human papillomavirus genotypes 52 and 58 (HPV52/58) are frequently detected in patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) in East Asian countries including Japan. As with other HPV genotypes, HPV52/58 consist of multiple lineages of genetic variants harboring less than 10% differences between complete genome sequences of the same HPV genotype. However, site variations of nucleotide and amino acid sequences across the viral whole-genome have not been fully examined for HPV52/58. The aim of this study was to investigate genetic variations of HPV52/58 prevalent among Japanese women by analyzing the viral whole-genome sequences. METHODS: The entire genomic region of HPV52/58 was amplified by long-range PCR with total cellular DNA extracted from cervical exfoliated cells isolated from Japanese patients with CIN or ICC. The amplified DNA was subjected to next generation sequencing to determine the complete viral genome sequences. Phylogenetic analyses were performed with the whole-genome sequences to assign variant lineages/sublineages to the HPV52/58 isolates. The variability in amino acid sequences of viral proteins was assessed by calculating the Shannon entropy scores at individual amino acid positions of HPV proteins. RESULTS: Among 52 isolates of HPV52 (CIN1, n = 20; CIN2/3, n = 21; ICC, n = 11), 50 isolates belonged to lineage B (sublineage B2) and two isolates belonged to lineage A (sublineage A1). Among 48 isolates of HPV58 (CIN1, n = 21; CIN2/3, n = 19; ICC, n = 8), 47 isolates belonged to lineage A (sublineages A1/A2/A3) and one isolate belonged to lineage C. Single nucleotide polymorphisms specific for individual variant lineages were determined throughout the viral genome based on multiple sequence alignments of the Japanese HPV52/58 isolates and reference HPV52/58 genomes. Entropy analyses revealed that the E1 protein was relatively variable among the HPV52 isolates, whereas the E7, E4, and L2 proteins showed some variations among the HPV58 isolates. CONCLUSIONS: Among the HPV52/58-positive specimens from Japanese women with CIN/ICC, the variant distributions were strongly biased toward lineage B for HPV52 and lineage A for HPV58 across histological categories. Different patterns of amino acid variations were observed in HPV52 and HPV58 across the viral whole-genome.

Immune checkpoint blockade (ICB) and adoptive cell therapies (ACT) with antigen-receptor gene-engineered T cells have been shown to be successful for a limited number of patients with solid tumors. Responders to ICB therapy typically have T cell-inflamed tumors. Thus, it is important to develop strategies that convert non-T cell-inflamed tumors to T cell-inflamed tumors. Although chimeric antigen receptor transduced T (CAR-T) cell therapy targeting hematological malignancies demonstrated durable clinical responses, the success of gene-engineered T cell therapies in solid tumors is hampered by a lack of unique antigens, antigen loss in cancer cells, and the immune-suppressive tumor microenvironment (TME) of solid tumors. However, gene-engineered T cells possess strong killing activity and cytokine production capacity, which can induce antigen spreading and modulate the TME of non-T cell-inflamed tumors seen in non-responders to ICB therapy. Immune responses against cancer are highly heterogeneous, not only between tumor types, but also within a patient or between different patients with the same type of cancer, indicating that personalized immunotherapy should be employed, based on the immune status of the individual patient. Here, we offer our perspective for personalized combination immunotherapy for solid tumors based on ACT and ICB therapies.

BACKGROUND: To assess the efficacy of screening with concurrent liquid-based cytology and human papillomavirus (HPV) testing for primary cervical cancer screening, we initiated a randomized trial entitled CervIcal cancer screening Trial by Randomization of HPV testing intervention for Upcoming Screening (CITRUS). METHODS: Between June 2013 and March 2015, women aged 30-64 years of age who participated in a regular cervical cancer screening program (every 2 years) were invited to enrollment of our study. After giving their informed consent, 18,402 women were randomly assigned to liquid-based cytology as the control group (n=9145) or to HPV DNA testing with liquid-based cytology as the intervention group (n=9257). We subsequently compared the incidence rate of cervical intraepithelial neoplasia (CIN), the rate of false positive tests and the rate of overdiagnosis, as well as assessing the risks and benefits of receiving screening for women in both groups. The primary outcome of our study was the incidence of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) during the study period of around 6 years. RESULTS: In the control group, 97.9% of women were NILM, and 2.06% ASC-US or worse (ASC-US+). In the intervention group, 87.13% of women were NILM/HPV negative, 0.72% ASC-US/HPV negative, 10.34% NILM/HPV positive, 0.69% ASC-US/HPV positive, 0.90% worse than ASC-US/either HPV. Positive HPV testing was not linearly related to age in our study. CONCLUSIONS: Insights from CITRUS will provide future prospects for cervical cancer screening focused on the use of HPV testing in Japan. CLINICAL TRIAL REGISTRATION NUMBER: NCT01895517, UMIN000010843, TRIUC1312.