生水 真紀夫

Cervical cancer is one of the most common cancers in women. More than 275,100 women die from cervical cancer each year. Cervical squamous cell carcinoma (cervical SCC), one of the most frequent types of cervical cancers, is associated with high-risk human papilloma virus (HPV), although HPV infection alone may not be enough to induce malignant transformation. MicroRNAs (miRNAs), a class of small non-coding RNAs, regulate protein-coding gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. A growing body of evidence suggests that miRNAs contribute to cervical SCC progression, development and metastasis. miRNA expression signatures in SCC (hypopharyngeal SCC and esophageal SCC) revealed that miR-218 expression was significantly reduced in cancer tissues compared with adjacent non-cancerous epithelium, suggesting that miR-218 is a candidate tumor suppressor. The aim of this study was to investigate the functional significance of miR-218 in cervical SCC and to identify novel miR‑218-mediated cancer pathways in cervical SCC. Restoration of miR-218 significantly inhibited cancer cell migration and invasion in both HPV-positive and HPV-negative cervical SCC cell lines. These data indicated that miR-218 acts as a tumor suppressor in cervical SCC. Our in silico analysis showed that miR-218 appeared to be an important modulator of tumor cell processes through suppression of many targets, particularly those involved in focal adhesion signaling pathways. Gene expression data indicated that LAMB3, a laminin protein known to influence cell differentiation, migration, adhesion, proliferation and survival, was upregulated in cervical SCC clinical specimens, and silencing studies demonstrated that LAMB3 functioned as an oncogene in cervical SCC. The identification of novel tumor-suppressive miR-218-mediated molecular pathways has provided new insights into cervical SCC oncogenesis and metastasis.

OBJECTIVE: Bladder dysfunction caused by autonomic nerve injury is a well-recognized complication of pelvic surgery. Modified posterior exenteration with or without nerve preservation was performed in patients with primary ovarian, tubal, peritoneal, and endometrial cancer. The aim of this retrospective study was to evaluate the impact of this surgical technique on bladder function. METHODS: Among the 60 consecutive patients in whom modified posterior exenteration was performed, bilateral and unilateral nerve-sparing surgeries were performed in 43 (72%) and 15 (25%) patients, respectively. In the remaining 2 patients (3%), the pelvic autonomic nerves on both sides were sacrificed. Symptoms and bladder function after bilateral or unilateral nerve-sparing surgery were analyzed using standardized questionnaires before and 3 and 6 months after surgery. RESULTS: All patients with bilateral nerve-sparing surgery had sufficient micturition from the early postoperative period. Though 40% of the patients with unilateral nerve-sparing surgery had difficulty in spontaneous voiding and needed intermittent catheterization, voiding ability of them improved and no self-catheterization was required 3 months after surgery. The assessment of patient questionnaires suggested that bladder function was acceptable in both groups at 6 months. Patients with bilateral nerve-sacrificing surgery complained of neurogenic bladder requiring self-catheterization even 6 months after surgery. CONCLUSIONS: This preliminary study showed that preservation of bladder function after modified posterior exenteration was feasible with a nerve sparing approach and that standardized outcome measures could be used to monitor this. However, careful follow-up is required. Future larger studies are needed to investigate pelvic autonomic nerve function.

2000年から2011年の進行卵巣がん手術94例を標準術式中心の前期47例と拡大術式を積極的に採用した後期47例に分けて治療成績を比較した。progression free survival(PFS)は前期14.6ヵ月、後期21.2ヵ月と有意に改善した。治療内容は、前期でprimary debulking surgery(PDS)を6例、intervaldebulking surgery(IDS)を41例に行い、PFSはそれぞれ11ヵ月、15ヵ月と有意差はなかった。後期はPDSが15例、IDSが32例で、PFSはPDSでは中央値に達しておらず、IDSは21ヵ月であった。optimal rateは前期57.5%、後期89.4%で、PDSでは33.3%から93.3%に、IDSでは61%から87.5%に上昇した。術式は、前期で子宮全摘・両側付属器・大網切除(基本術式)が22例、基本術式+結腸切除が12例、基本術式+結腸・横隔膜全層分層切除(+膵尾部合併脾臓摘出)が1例、no debulking surgeryが12例、後期はそれぞれ3例、12例、28例、4例であった。

1999〜2012年に当院で経験した子宮内反症9症例について,出血管理を中心に後方視的に検討した.全て産褥搬送例であり,搬送時の診断名は子宮内反症が4例,内反整復後の弛緩性出血が4例,弛緩性出血が1例であった.いずれも当院に到着後の診察で子宮内反症と診断された.胎盤娩出時に臍帯牽引が行われた症例が8例,胎盤用手剥離が行われた症例が2例あった.全例で全麻下の用手整復に成功した.この際,3例でIABO,1例で内腸骨動脈結紮,1例でUAEによる出血抑制が行われた.総出血量は,6,600g±3,500gで,全例にMAP(22±4.8単位)とFFP(21±4.2単位)輸血が実施されていた.全例にDICを認めたが,内反発症後すみやかに搬送された症例では,DICからの回復が早く総出血量が少ない傾向にあった.逆に,搬送が遅れ輸血開始までの時間が長かった2症例では,DICが遷延し予後が不良であった(出血性脳梗塞を来して神経症状を後遺した1例と母体死亡1例).当院到着直後のHb・shock index・産科DIC scoreは,搬送時に前医から伝達された推定総出血量とは全く相関を示さなかった.以上より,内反症整復後は内反の再発を念頭に管理にあたる必要がある,輸血の必要性の判断には前医より報告された推定総出血量よりshock indexなどを優先すべきであろうと考えられた.(著者抄録)

婦人科悪性腫瘍手術後の合併症として,感染性リンパ嚢胞が発症することがある.感染性リンパ嚢胞は,リンパ節郭清後にリンパ液がうっ滞して生じるリンパ嚢胞に対する感染である.術後治療の遅延・患者のQOL低下をきたす可能性があるため,その管理は重要である.治療方法には,保存的治療・経皮的ドレナージ・手術などがある.近年,当科では,感染性リンパ嚢胞の管理に,マレコット型ネフロストミーキット(ウロステント)を用いた持続的ドレナージによる治療を行っている.2004年から2010年までの間に,感染性リンパ嚢胞と診断し,治療を行った19症例を後方視的に検討した.単回および反復穿刺のみで治療した群,始めからウロステントによる持続ドレナージを施行した群,穿刺治療で改善せずにウロステントでの管理に移行した群に分類し比較した.ウロステントによる管理を行った症例では,穿刺によりドレナージを行った症例に比べて,臨床所見・検査値の改善が良好であった.また,ウロステント留置にともなう合併症の発生は少なく,ウロステントによる感染性リンパ嚢胞の管理は有用と考えられた.(著者抄録)

BACKGROUND: Although early diagnosis is important for selecting an effective surgical treatment for secondary lymphedema, an efficient screening test for detecting early-stage lymphedema has not yet been established. Serial changes of lymphatic function before and after lymph node dissection and risk factors for secondary lymphedema are important indicators. METHODS: A prospective cohort observational study was conducted with 100 consecutive gynecologic cancer patients who underwent pelvic lymph node dissection. Lymphatic function was assessed by noninvasive lymphography using indocyanine green fluorescence imaging on a routine schedule. Earliest findings after lymphadenectomy and risk factors for lower leg lymphedema were investigated. RESULTS: Atypical transient dermal backflow patterns were observed in an early postoperative period in 50 cases, all of which disappeared within 3 months. Of these patterns, the splash pattern was observed in 31 patients, of which five improved to normal following a natural course. In contrast, the stardust pattern was observed in 27 patients, and none had improved with conservative therapy. Postoperative radiotherapy was a significant risk factor for the stardust pattern. CONCLUSIONS: All patients who undergo lymphadenectomy for gynecologic malignancies should be examined for secondary lower extremity lymphedema by qualitative evaluation methods on a routine schedule to determine the earliest possible diagnosis. Because the splash pattern on indocyanine green lymphography is a reversible lymphatic disorder following a natural course, surgical treatments are not recommended. The decision regarding surgical treatment can be made after observing the stardust pattern. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV.

Somatic mutations accumulate in senescent cells. Bcl6, which functions as a transcriptional repressor, has been identified as a potent inhibitor of cell senescence, but a role of Bcl6 in the accumulation of somatic mutations has remained unclear. Ig class-switch recombination simultaneously induces somatic mutations in an IgM class-switch (Ig-Sμ) region of IgG B cells. Surprisingly, mutations were detected in the Ig-Sμ region of Bcl6-deficient IgM B cells without class-switch recombination, and these mutations were mainly generated by conversion of adenosine to guanosine, suggesting a novel DNA mutator in the B cells. The ADAR1 (adenosine deaminase acting on RNA1) gene was overexpressed in Bcl6-deficient cells, and its promoter analysis revealed that ADAR1 is a molecular target of Bcl6. Exogenous ADAR1 induced adenosine-targeted DNA mutations in IgM B cells from ADAR1-transgenic mice and in wild-type mouse embryonic fibroblasts (MEFs). These mutations accumulated in senescent MEFs accompanied with endogenous ADAR1 expression, and the frequency in senescent Bcl6-deficient MEFs was higher than senescent wild-type MEFs. Thus, Bcl6 protects senescent cells from accumulation of adenosine-targeted DNA mutations induced by ADAR1.

Osteoporosis causes an enormous health and economic impact in Japan. We investigated the relation between lifestyle and bone fracture in middle-aged and elderly women. This was a population-based, multicenter, cross-sectional survey for postmenopausal osteoporosis in Chiba City, Japan (Chiba bone survey). This survey included 64,809 Japanese women aged > 40 years. All participants underwent anthropometric measurements including bone mineral density (BMD) and completed a structured, nurse-assisted, self-administered questionnaire also including patient lifestyle. Bone fracture during the recent 5 years was observed in 5.3%, and the fracture group had significantly higher age, BMI, and prevalence of delivery, family histories of kyphosis and hip fracture, diabetes mellitus (DM), dyslipidemia, kidney disease, exercise, fall, and osteoporosis, and had significantly lower BMD and proportion of menstruating participants. Logistic regression analysis revealed that bone fracture was closely associated with not only low bone mass but also age, fall, family histories of kyphosis and hip fracture, DM, kidney disease, menopause, and lifestyle factors of dieting, exercise, and alcohol. Women's health care focusing on lifestyle-related fracture risks such as dieting, exercise, and alcohol appears necessary to prevent bone fracture in postmenopausal osteoporosis.

Acute liver failure (ALF) during pregnancy remains difficult to treat, and despite advances in treatment, liver transplantation must be selected as treatment option in certain cases. We report a 30-year-old woman with ALF of unknown etiology, occurring during the first trimester of pregnancy. Her condition was complicated by consciousness disturbance and coagulopathy due to ALF, but she was successfully treated with living donor liver transplantation 7 days after dilatation and curettage. At 9-month followup, she was in good medical condition. Liver transplantation has been reported as one of the treatment options for ALF during pregnancy with the prognosis varying depending on the trimester, from living donor or deceased donor liver transplantation. Of importance is that clinicians always think of emergent liver transplantation as a therapeutic option in ALF even in the first trimester of pregnancy.

Innate immune responses play a central role in neuroprotection and neurotoxicity during inflammatory processes that are triggered by pathogen-associated molecular pattern-exhibiting agents such as bacterial lipopolysaccharide (LPS) and that are modulated by inflammatory cytokines such as interferon γ (IFNγ). Recent findings describing the unexpected complexity of mammalian genomes and transcriptomes have stimulated further identification of novel transcripts involved in specific physiological and pathological processes, such as the neural innate immune response that alters the expression of many genes. We developed a system for efficient subtractive cloning that employs both sense and antisense cRNA drivers, and coupled it with in-house cDNA microarray analysis. This system enabled effective direct cloning of differentially expressed transcripts, from a small amount (0.5 µg) of total RNA. We applied this system to isolation of genes activated by LPS and IFNγ in primary-cultured cortical cells that were derived from newborn mice, to investigate the mechanisms involved in neuroprotection and neurotoxicity in maternal/perinatal infections that cause various brain injuries including periventricular leukomalacia. A number of genes involved in the immune and inflammatory response were identified, showing that neonatal neuronal/glial cells are highly responsive to LPS and IFNγ. Subsequent RNA blot analysis revealed that the identified genes were activated by LPS and IFNγ in a cooperative or distinctive manner, thereby supporting the notion that these bacterial and cellular inflammatory mediators can affect the brain through direct but complicated pathways. We also identified several novel clones of apparently non-coding RNAs that potentially harbor various regulatory functions. Characterization of the presently identified genes will give insights into mechanisms and interventions not only for perinatal infection-induced brain damage, but also for many other innate immunity-related brain disorders.

42歳(1経妊0経産婦)。右下腹部痛を主訴に前医を受診、超音波検査およびMRIにて卵巣腫瘍を指摘され、著者らの施設へ紹介となった。MRIでは下腹部のほぼ正中にT1で低信号、T2で高信号の多房性嚢胞性腫瘍が認められた。そこで、腹腔鏡下にて子宮付属器腫瘍摘出術を施行されたが、術後2日目に第3トロカール刺入部にあたる左側腹部に腹壁血腫を発症、血腫除去および止血術を行ったところ、トロカール挿入口のうちの1ヶ所から非拍動性の持続性出血が確認された。腹膜側からの縫合止血を行なった結果、術後経過は良好で、患者は再手術から7日目に退院となった。尚、摘出物病理検査にて右卵巣腫瘍は境界悪性粘液性嚢胞腺腫であったため、術後の追加治療は行わず、目下は3ヵ月毎に外来通院にて経過観察中である。

Background: There are few large studies of fetal congenital bradyarrhythmia. The aim of the present study was to investigate the effects and risks of transplacental treatment for this condition. Methods and Results: Using questionnaires, 128 cases of fetal bradyarrhythmia were identified at 52 Japanese institutions from 2002 to 2008. Of the 128 fetuses, 90 had structurally normal hearts. Among these 90 fetuses, 61 had complete atrioventricular block (CAVB), 16 had second-degree AVB, 8 had sinus bradycardia, and 5 had other conditions. The 61 CAVB fetuses were divided into those who did (n=38) and those who did not (n=23) receive transplacental medication. Monotherapy with β-sympathomimetics, steroid monotherapy, and combination therapy with these agents was given in 11, 5 and 22 cases, respectively. Beta-sympathomimetics improved bradycardia (P&lt 0.001), but no medication could significantly improve the survival rate. Fetal hydrops was associated with a 14-fold increased risk of perinatal death (P=0.001), and myocardial dysfunction was a significant risk factor for poor prognosis (P=0.034). Many adverse effects were observed with steroid treatment, with fetal growth restriction increasing significantly after &gt 10 weeks on steroids (P=0.043). Conclusions: Treatment with β-sympathomimetics improved bradycardia, but survival rate did not differ significantly in fetuses with and without transplacental medication. It is recommended that steroid use should be limited to &lt 10 weeks to avoid maternal and fetal adverse effects, especially fetal growth restriction and oligohydramnios.

We report a case of sex cord tumor with annular tubules featuring a giant multilocular cyst, grossly similar to cystadenoma, in the ovary of an 8.5 year old girl. Estrogen-related symptoms, including precocious puberty and irregular uterine bleeding, immediately improved after tumor resection.

33歳女。29歳時に過多月経があり、開腹による粘膜下筋腫核出術・腺筋症腫核出術・内膜ポリープ切除術・右卵巣チョコレート嚢胞核出術を受けた。子宮手術から3年後(32歳)に、妊娠を希望して受診した。超音波検査では、子宮体部は小さく、子宮筋層の菲薄化も疑われた。右卵巣には、チョコレート嚢胞を認めた。子宮体部筋層の部分欠損を伴う子宮の狭小化および右卵巣チョコレート嚢胞と診断した。33歳時、体外受精により妊娠が成立した。子宮破裂のリスクを考慮し、妊娠15週より入院管理とした。妊娠後の超音波検査およびMRI検査で、体部筋層の一部に限局性で高度の菲薄化部位が存在し、妊娠経過に伴い外方に膨隆するようになり切迫子宮破裂と判断した。子宮破裂のリスクと早産による胎児リスクとを勘案して妊娠28週という早期の娩出を決定した。