野村 弘行

Purpose: At present, it remains unclear whether the third-line chemotherapy has clinical benefit. In this study, we retrospectively evaluated the effect of third-line chemotherapy. Methods: We reviewed the medical records of 40 women with recurrent epithelial ovarian cancer (EOC) who received third-line chemotherapy after platinum/taxan regimens as first line chemotherapy. Results: In the first recurrence. 23 cases were platinum-sensitive and 17 cases were platinum-resistant. The cases for which the treatment-free interval from second-line chemotherapy (TFI) was >= 3 months had a higher non-PD rate than those with TFI < 3 months (86% vs 33%, p = 0.002). In addition, the median overall survival (OS) was longer for TFI >= 3 months than for TFI < 3 months (1195 days vs 235 days, p = 0.004). Finally, TFI was an independent significant prognostic factor by univariate (HR 3.28, p = 0.006) and multivariate (HR 3.21, p = 0.018) proportional hazard tests. Conclusion: TFI from second-line chemotherapy may predict a survival benefit of third-line chemotherapy.

Microsatellite instability (MSI) is an indicator of DNA instability and is caused by abnormalities in DNA mismatch repair (MMR) genes such as hMLH1, hMSH2 and hMSH6. MSI occurs frequently in endometrial cancer (in approximately 30% of cases), and accumulation of gene mutations due to MSI may therefore have a major role in the mechanism of malignant transformation. However, a responsible target gene has not been identified in endometrial cancer. In this study, we analyzed mutations in 11 cancer-related genes with mononucleotide repeats susceptible to MST in a coding region [hMSH3 (A8), hMSH6 (C8), TGF-beta RII (A10), MBD4 (A10), BAX (G8), PTEN (A6 in exon 7), HDAC2 (A9), EPHB2 (A9), Caspase-5 (A10), TCF-4 (A9) and Axin2 (G7)] in 22 patients with MSI-H sporadic endometrial cancer. Mutations in hMSH6 (C8) and TGF-beta RII (A10) were found most frequently, at rates of 36.3% (8/22) each. Mutations of BAX (G8) and TCF-4 (A9), which are common in MSI-positive colorectal cancer, occurred at rates of 22.7 and 0%, respectively, which suggests that the MSI target gene may differ between endometrial and colorectal cancers. Mutations in hMSH6 (C8) were correlated with reduced protein expression (p=0.042) and patients with these mutations had significantly more mutations in mononucleotide repeats in other cancer-related genes compared to patients without hMSH6 (C8) mutations (p=0.042). This suggests the possibility of a novel cascade in carcinogenesis of endometrial cancer in which MST mutates hMSH6 (C8), increases gene instability, and leads to accumulation of mutations in other cancer-related genes. To our knowledge, this is the first report to show that hMSH6 (C8) has an important role as an MSI target gene in sporadic endometrial cancer.

Improvements in epigenetics have resulted in identification of a number of genes with aberrant hypermethylation associated with systematic occurrence of cancer. It is now evident that aberrant hypermethylation inactivates cancer-related genes including those associated with cell cycle control, apoptosis, and DNA repair. An epigenetic analysis of DNA hypermethylation in type I endometrial cancer has led to a proposed mechanism for endometrial carcinogenesis. Reduced DNA mismatch repair due to loss of hMLH1expression is thought to have a major role in carcinogenesis and these findings open up approaches to prevention, diagnosis, risk assessment, and treatment of type I endometrial cancer. Aberrant DNA hypermethylation can be detected with high sensitivity for identification of cancer cells in sputum, blood and other biopsy materials, including in endometrial cancer specimens. There have been many attempts to use methylation inhibitors as anticancer agents, and epigenetic abnormalities may be useful as biomarkers of anticancer drug sensitivity and to identify biological characteristics of tumor cells for determination of treatment options based on hypermethylation. For example, aberrant hypermethylation of the CHFR gene is correlated with cellular sensitivity to microtubule inhibitors, and this may be useful in treatment of type I endometrial cancer. An ultimate objective of epigenetics is to identify the type of hereditary methylation responsible for cancer, with the goal of improved diagnosis and treatment based on control of methylation.

Point mutations of KRAS and BRAF genes are thought to be important in carcinogenesis of colon cancer. In particular, gene instability caused by decreased expression of the hMLH1 gene, a DNA mismatch repair (MMR) gene, may be linked to the activating BRAF V600E point mutation in sporadic colon cancer. However, a consensus has not been established regarding the correlation between point mutations of KRAS or BRAF and carcinogenesis in patients with endometrial cancer, which is closely related to colon cancer. Therefore, we analyzed aberrant hypermethylation of the hMLH1 gene, microsatellite instability (MSI), and point mutations of KRAS and BRAF in 44 samples of sporadic endometrial cancer, with the aim of examining the mechanism of carcinogenesis in patients with endometrial cancer. Aberrant hMLH1 hypermethylation was found in 17 of the 44 cases (38.6%) and showed a significant positive correlation with MSI (p=0.02). This suggests that an abnormal MMR mechanism plays an important role in carcinogenesis of sporadic endometrial cancer. Point mutation of KRAS was found in 6 of the 44 cases (13.6%), but no BRAF V600E mutation was detected. These data suggest that the BRAF V600E mutation is not the target gene for abnormal MMR in carcinogenesis in patients with sporadic endometrial cancer, unlike in colon cancer. This is supported by the relatively few previous reports indicating a correlation between endometrial cancer and the BRAF V600E mutation. Identification of new candidates for the target gene for abnormal MMR in endometrial cancer requires further work.

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Such tumors are thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene, but many aspects of the pathology of familial endometrial cancer are unclear and no effective screening method has been established. However, the pathology of endometrial cancer with familial tumor has been progressively clarified in recent studies. At present, about 0.5% of all cases of endometrial cancers meet the clinical diagnostic criteria for HNPCC. A recent analysis of the three MMR genes (hMLH1, hMSH2 and hMSH6) revealed germline mutations in 18 of 120 cases (15.0%) of endometrial cancer with familial accumulation of cancer or double cancer, with a frameshift mutation of the hMSH6 gene being the most common. Many cases with mutation did not meet the current clinical diagnostic criteria for HNPCC, indicating that familial endometrial cancer is often not diagnosed as HNPCC. The results suggest that the hMSH6 gene mutation may be important in carcinogenesis in endometrial cancer and germline mutations of the MMR gene may be more prevalent in cases associated with familial accumulation of cancer. An international large-scale muticenter study is required to obtain further information about the pathology of endometrial cancer as a familial tumor.

成熟嚢胞性奇形腫はしばしば充実部分を有し、画像診断で悪性腫瘍との鑑別に苦慮する症例が多い。今回我々は成熟嚢胞性奇形腫と腺癌または境界悪性腫瘍の共存する2例を経験したので報告する。1例はMRIで腫瘍内に造影される充実部分を認め、悪性の可能性を否定できなかった。術後に成熟嚢胞性奇形腫の悪性転化腺癌と診断され、進行期分類はIV期で、術後化学療法を施行したが術後16ヵ月で死亡した。もう1例はMRIでは充実部分を認めず良性の診断で手術を施行したが、術後に成熟嚢胞性奇形腫と粘液性境界悪性腫瘍との合併と診断された。進行期分類はI a期であり、術後20ヵ月間無病生存している。成熟嚢胞性奇形腫は稀であるが悪性転化する可能性があること、または(境界)悪性腫瘍と合併することもあるため、十分なインフォームドコンセントのもと積極的に組織学的検索を行う必要もあると考えられた。(著者抄録)

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

産婦人科で初回治療として両側卵巣摘出術を伴う手術療法を施行した子宮体癌(体癌群)132例、健康維持外来を受診した非担癌自然閉経症例(対照群)224例、計356例を対象に、子宮体癌術後患者における骨代謝の特徴について自然閉経例と比較検討した。体癌群においては骨粗鬆症/骨量減少と診断できた症例は132例中35例(27%)で、対照群では224例中90例(40%)で、体癌群では骨量正常例が有意に多かった。また卵巣摘出時の閉経の有無によって骨粗鬆症/骨量減少の発生頻度に有意差を認めなかった。検討結果から、子宮体癌例は卵巣摘出を施行しているにも拘わらず、骨粗鬆症/骨量減少の高危険群とはいいがたいことが判明した。しかし、近年、若年発症例が増加していることから長期的フォローアップが必要と思われた。

子宮内膜組織検査(EMB)施行後の子宮内感染はしばしば経験される。検査施行後に感染が重症化し、緊急子宮全摘出術を余儀なくされた3症例を報告する。症例1:50歳、子宮腺筋症。EMB後2日目より39度発熱、WBC13100/μlにて入院。第3病日目に低酸素血症、胸部X線上透過性低下認め、敗血症に伴う肺水腫と診断され緊急手術を施行した。症例2:50歳、子宮腺筋症。ネフローゼ症候群にてステロイド内服中。EMB後下腹部痛持続、38.4度発熱、WBC19800/μlにて入院。低酸素血症、胸部X線上透過性低下認め、敗血症と診断し緊急手術を施行した。症例3:49歳、経腟的子宮筋腫分娩術後、EMB施行第4日目に下腹部出現、WBC15900/μl、39度発熱にて入院、敗血症と診断し、緊急手術を施行した。子宮腺筋症など、子宮内病変共存時のEMBは子宮内感染が遷延・重症化する可能性も念頭に置き診療にあたるべきと考えられた。(著者抄録)

現在、上皮性卵巣癌患者の標準的化学療法としてTJ療法などのタキサン製剤とプラチナ製剤の併用療法が広く行われている。今回われわれは、これに関連してパクリタキセルおよびカルボプラチンによる過敏症反応を呈した3症例を経験したので報告する。症例1は29歳女性、卵巣癌III c期、TJ療法1コース目を施行時、パクリタキセルによるアナフィラキシー様反応が出現した。症例2は53歳女性、卵巣癌I a期、TJ療法2コース目でパクリタキセルによるアナフィラキシー反応が出現した。症例3は69歳女性、卵巣癌再発のためプラチナ製剤を含む複数回の化学療法後にDJ療法を行い、2コース目でカルボプラチンによるアナフィラキシー反応が出現した。TJ療法などの施行にあたってパクリタキセルの初回導入時だけでなく、とくにカルボプラチン投与時には、複数回投与後の過敏症反応にさらなる注意が必要である。(著者抄録)

The purposes of this study were to compare the relationships between para-aortic lymph node metastasis and various clinicopathologic factors to evaluate whether para-aortic lymph node dissection is necessary when treating endometrial cancer. A retrospective study was performed on 841 patients with endometrial cancer, who underwent the initial surgery at the Keio University Hospital. Clinicopathologic factors related to para-aortic lymph node metastasis significant on a univariate analysis were analyzed in a multivariate fashion using a logistic model. According to the multivariate analysis, the clinicopathologic factor most strongly related to the existence of para-aortic lymph node metastasis was positive pelvic lymph node metastasis (P < 0.01). Among the 155 patients who underwent pelvic and para-aortic lymph node dissection, the difference of 5-year overall survival by the presence of retroperitoneal lymph node metastasis was examined by Kaplan-Meier method. The prognosis was poor even if para-aortic lymph node dissection was performed in cases of positive para-aortic lymph node metastasis. In conclusion, when deciding whether to perform para-aortic lymph node dissection in patients with endometrial cancer, it is necessary to consider the pelvic lymph nodal status. If there is no pelvic lymph node metastasis, it could not be necessary to perform para-aortic lymph node dissection.

胎児小脳低形成は,菲薄な小脳半球幅および大槽の拡大などの超音波所見により出生前診断が可能である.今回,我々は妊娠初期より継続する重症妊娠悪阻の治療に難渋し,同時にその胎児には,小脳低形成を呈するDandy-Walker variant(以下DWv)を合併した1例を経験したので報告する.症例は25歳,0経妊0経産.妊娠7週時より悪阻症状を認め,入院管理となった.治療開始後も症状の改善を認めなかったため,原因の検索を施行したが,明らかな異常を認めなかった.妊娠20週時の胎児超音波検査で,頭部の巨大化を呈する非対称な発育所見となった.さらに頭蓋内において大槽および脳室の拡大を認める一方,小脳は描出されなかった.再検査を重ね,小脳低形成および胎児水頭症であり,Dandy-Walker奇形(以下DW)の異型であるDWvであると出生前診断した.夫婦への十分なインフォームド・コンセントを行ったが,患者の強い希望があり,妊娠21週時にゲメプロスト腟坐剤による人工妊娠中絶術を施行した(著者抄録)

Cell surface carbohydrate expression strongly influences the biological characteristics of cancer cells. Especially, it is known that the change of sialic acid expression could be related to the invasive and metastatic potentials of tumors. This study aimed to investigate sialidase expression of ovarian cancer cells and to evaluate the relationship between plasma membrane-associated sialidase (NEU3) expression and various clinicopathological factors in ovarian clear cell adenocarcinoma patients. In 18 cell lines derived from human ovarian cancers (including clear cell, mucinous, and serous adenocarcinoma), sialidase mRNA expression was evaluated by RT-PCR. NEU1 and NEU3 expression levels were found to be elevated in most cell lines while NEU2 and NEU4 expression was rarely elevated. Interestingly, NEU3 expression was detected in all clear cell adenocarcinoma cell lines. In 71 patients with ovarian clear cell adenocarcinoma, treated at Keio University Hospital from February 1983 to February 2002, NEU3 expression was examined by immunohistochemical staining of surgical specimens and clinocopathological factors were reviewed. NEU3 expression was found to be positive in 77.5% of all cases. Furthermore, a high level of NEU3 expression was significantly correlated with T3 factor of pTNM classification on univariate and multivariate analysis. This is the first report to show that NEU3 is expressed in most of ovarian clear cell adenocarcinoma. And our results show that NEU3 expression is correlated with T factor (pTNM classification) in ovarian clear cell adenocarcinoma.

Background: To investigate the incidence of pulmonary embolism and risk factors for this condition after obstetric and gynecologic surgery, as well as the efficacy of intermittent pneumatic compression. Methods: A total of 6,218 patients operated at Keio University Hospital excluding obstetric or infertility-related surgery and uterine cervical conization were evaluated retrospectively to determine the preventive effect of intermittent pneumatic compression on postoperative pulmonary embolism. Results: Pulmonary embolism occurred in 42 patients (0.68%). Multivariate analysis showed that malignancy, blood transfusion, and a body mass index ≥25 kg/m2 or ≥28 kg/m2 were independent risk factors for postoperative pulmonary embolism. A significantly lower incidence of pulmonary embolism occurred in patients receiving pneumatic compression postoperatively versus those without it. Among gynecologic malignancies, endometrial cancer was a significant risk factor for pulmonary embolism. Conclusion: Preventive measures, including intermittent pneumatic compression, should be taken to avoid postoperative pulmonary thromboembolism in the gynecology field. © 2005 Suzuki et al., licensee BioMed Central Ltd.

婦人科疾患手術後肺血栓塞栓症(PTE)症例40例を対象に,PTE発症の危険因子について検討した.その結果,妊娠関連手術,円錐切除術を除く婦人科関連手術後のPTE発症率は,0.58%で,PTE症例40例中悪性疾患は31例77.5%であった.自覚症状は27例で認め,胸痛,呼吸困難が約半数であった.単変量解析,多変量解析の結果,悪性腫瘍,後腹膜リンパ節郭清,術中輸血,高血圧,耐糖能異常で有意に合併率が高く,年齢40歳以上,BMI25kg/m2,術中出血量1000cc以上,所要手術時間4時間以上で有意差を認めた.以上より,これらの危険因子を有する例や高齢者に対しては,術中より間欠的下肢空気圧迫法および弾性ストッキングでPTEを予防し,静脈血栓塞栓症を早期に発見することが重要であると考えられた

日本麻酔科学会が2003年に周術期肺血栓塞栓症(Pulmonary Thromboembolism:PTE)の調査を行った結果,産婦人科は整形外科,消化器外科に次いで3番目に発症件数が多かったという.妊娠時に静脈血栓塞栓症(Venous Thromboembolism:VTE)の発症が高頻度に生じることは周知の事実であるが,婦人科領域において術後VTE発症に関する報告は多くなく,特に悪性腫瘍の拡大手術患者では術後PTE発症の頻度が増加するという報告などからも悪性疾患を含む婦人科疾患手術後のPTEを中心としたVTEに関する詳細なデータの構築が必要となっている.そこで,本研究では慶應義塾大学病院における婦人科疾患手術後のPTE発症の頻度および危険因子を後方視的に解析した結果,多変量解析にて悪性疾患,輸血,BMIが25kg/m2以上,28kg/m2以上でそれぞれ有意差が得られた.本稿では,これら結果を中心に文献的考察も加えて報告する(著者抄録)

卵管留膿症によって尿路閉塞をきたした高齢女性の一例を経験した

51歳女.過多月経のため受診した.経膣超音波にて5cm大の子宮筋腫を認めた.子宮頸部,体部細胞診に異常はなく,貧血も認めなかったため,3ヵ月ごとの経過観察とした.約1年後に再度月経過多と不正出血を訴えた.腫瘤の増大は見られず,酢酸ブセレリンの投与を開始した.その後も少量持続出血があり,2回目の酢酸ブセレリン投与後に腫瘤の急速な増大を認め,約2ヵ月間には小児頭大にまで増大した.血清LDHは4209IU/Lと高値を示した.MRI T2強調画像では骨盤腔に通常の筋腫とは異なり,高信号と低信号が混在する不均一な信号を示す腫瘤を認めた.内膜組織診では多形性に富み,異型の強い腫瘍細胞が充実性に増殖し,核分裂像も散見され,未分化癌もしくは子宮肉腫が推定された.急速な臨床経過,画像所見およびLDH値と合わせて臨床的に子宮平滑筋肉腫と診断し,開腹手術を行った.子宮は小児頭大で,病理組織検査で子宮平滑筋肉腫と確定診断した