生水 真紀夫

BACKGROUND: This study sought to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced adenocarcinoma of the uterine cervix in a phase 1/2 clinical trial. METHODS: The treatment consisted of whole-pelvic irradiation of 36.0 gray equivalents (GyE) in 12 fractions and local boost with dose escalation from 26.4 to 38.4 GyE in 8 fractions. The dose escalation was performed with careful observation of acute normal tissue responses. Total dose to the cervical tumor was 62.4 to 74.4 GyE in 20 fractions. RESULTS: Between April 1998 and February 2010, 58 patients were treated with C-ion RT in this clinical trial. The number of patients with stage IIB, IIIB, and IVA disease were 20, 35, and 3, respectively. Median tumor size was 5.5 cm (range, 3.0-11.8 cm). Twenty-seven patients had pelvic lymph node metastases. The median follow-up period was 38 months. All patients completed the treatment schedule. Grade 2 or higher late toxicity was found in 8 patients: 5 with bladder and 2 with small intestine grade 2 toxicities, and 1 patient had grade 4 rectal complication, which was surgically salvaged. The 5-year local control rate, local control rate including salvage surgery, and overall survival rate in all cases were 54.5%, 68.2%, and 38.1%, respectively. CONCLUSIONS: Dose escalation of C-ion RT for adenocarcinoma of the uterine cervix was accomplished without severe toxicities except in 1 case. Although the number of patients in this study was small, the results support continued investigation and analysis to confirm therapeutic efficacy.

Risk-reducing salpingo-oophorectomy for reducing future cancer risk in women with hereditary breast and ovarian cancer syndrome is rarely performed in Japan; therefore, the cancer preventive effect of risk-reducing salpingo-oophorectomy for hereditary breast and ovarian cancer syndrome among the Japanese population remains unclear. Here, we report the first case of serous tubal intraepithelial carcinoma identified through a risk-reducing salpingo-oophorectomy in a Japanese woman with hereditary breast and ovarian cancer syndrome and who had a deleterious germline mutation of E1214X in BRCA1, but not a BRCA2 mutation. A pre-operative examination revealed multiple uterine leiomyomas but no adnexal mass. Robotic-assisted bilateral salpingo-oophorectomy together with hysterectomy was performed. A pathological examination identified serous tubal intraepithelial carcinoma in the right fallopian tube with no dissemination. Serous tubal intraepithelial carcinoma is implicated as an origin of invasive cancer of the fallopian tube with peritoneal dissemination; prophylactic salpingo-oophorectomy is currently the only method to identify this occult cancer. Our case demonstrated that risk-reducing salpingo-oophorectomy can detect occult cancers, including serous tubal intraepithelial carcinoma, thereby preventing future cancer development in the Japanese hereditary breast and ovarian cancer syndrome population.

子宮腺筋症から発生したと推測された子宮体部悪性腫瘍3例を経験したので報告する。患者は何れも閉経後で、主訴は下腹部痛である。症例1、2は内膜細胞診や組織診で悪性細胞が検出されず、MRIで認めた筋層内病変に対し経腟針生検を行った。症例1は類内膜腺癌、症例2は高異型肉腫を認め、手術を施行した。症例1は中分化類内膜腺癌(pT3apN1)、症例2は肉腫成分の過剰増殖を伴う腺肉腫(pT1bpN0)の術後診断であった。症例3は腫瘍による子宮内腔の変形で細胞診や掻爬ができず、抗凝固療法のため針生検を行えなかった。FDG-PET検査で腫瘍に一致した集積を認め、子宮体部悪性腫瘍の術前診断の下に手術を行った。術後診断は混合癌(明細胞腺癌>高分化類内膜腺癌)(pT3bpN0)であった。3例とも腫瘍の主座は子宮筋層で、内膜に腫瘍は認めず、背景の筋層内に腺筋症病変を認めた。症例1、2は腺筋症内膜から腺癌への移行像が確認された。本症の術前診断は内膜細胞診や掻爬では困難な事が多く、症例1、2では経腟針生検が悪性腫瘍の確定に有用であった。症例3は針生検が行えず、FDG-PET検査で臨床的に悪性腫瘍の診断が可能であった。(著者抄録)

Increased intratumoral expression of aromatase, the key enzyme for estrogen biosynthesis, is predicted to be of critical importance in the development of breast cancer. Recently, several germline rearrangements at 15q21 have been shown to cause overexpression of the aromatase gene CYP19A1 and resulting aromatase excess syndrome. To determine whether submicroscopic genomic rearrangements at 15q21 are involved in aromatase overexpression in breast cancer tissues, we investigated copy-number alterations in genomic DNA obtained from 44 tumor samples. Comparative genomic hybridization analysis identified no deletion or duplication at 15q21 in the 44 samples. These results, in conjunction with previous data, indicate that aromatase overexpression in breast cancer tissues is likely to result from a promoter switch of CYP19A1 and/or accumulation of CYP19A1-expressing cells, rather than from cryptic transactivation of CYP19A1 because of genomic rearrangements at 15q21.

OBJECTIVE: To establish a novel xenograft model using a severely immunocompromised host that is more convenient for uterine leiomyoma research compared with a pre-existing model using nonobese diabetic/severe combined immunodeficient (NOD/SCID) IL-2Rγ-null mice. DESIGN: Experimental study. SETTING: University and an attached animal facility. ANIMAL(S): NOD/SCID, SCID, BALB/c nude, and NOD/SCID IL-2Rγ-null mice. INTERVENTION(S): Xenografts consisting of primary cultured leiomyoma and myometrial cells in the subrenal and subcutaneous (SC) spaces in ovariectomized mice, followed by sex steroids (estrogen and P) administration. MAIN OUTCOME MEASURE(S): Viability, volume, histology, and sex steroid receptor expression of xenografts in response to sex steroid administration, to evaluate feasibility of the model; and messenger RNA expression levels of 12 genes representative of leiomyoma in the xenografts, to characterize the model. RESULT(S): Leiomyoma xenografts increased in volume at the highest frequency (55.1%) in response to sex steroids in NOD/SCID mice. Xenografts reproduced the histology and maintained expression of sex steroids receptors and representative genes of the original tissues. Subrenal xenografts were significantly larger than the SC xenografts, whereas those consisting of myometrial cells never increased. CONCLUSION(S): The modified NOD/SCID murine subrenal leiomyoma xenograft model reproduced most characteristics of the original leiomyoma tissue. Our model provides a more convenient research tool to investigate the pathogenesis of uterine leiomyoma.

Overexpression of CYP19A1 encoding aromatase results in a rare genetic disorder referred to as aromatase excess syndrome (AEXS). Male patients with AEXS manifest pre- or peri-pubertal onset gynecomastia, gonadotropin deficiency, and advanced bone age, while female patients are mostly asymptomatic. To date, 30 male patients with molecularly confirmed AEXS have been reported. A total of 12 types of submicroscopic rearrangements, i.e., two simple duplications, four simple deletions, two simple inversions, and four complex rearrangements, have been implicated in AEXS. Clinical severity of AEXS primarily depends on the types of the rearrangements. AEXS appears to account for a small number of cases of pre- or peri-pubertal onset gynecomastia, and should be suspected particularly when gynecomastia is associated with an autosomal dominant inheritance pattern, characteristic hormone abnormalities and/or advanced bone age. Treatment with an aromatase inhibitor appears to benefit patients with AEXS, although long-term safety of this class of drugs remains unknown.

Endometriosis is a chronic inflammatory disease frequently observed in the ovary, pelvic peritoneum, and rectovaginal septum. The growth and progression of an endometriotic lesion depends on a sex steroid, estrogen. Aromatase, a key enzyme in estrogen biosynthesis, is highly expressed in the endometriotic tissue, resulting in in situ production of estrogen that, in addition to endocrine estrogen from the ovary, may contribute to the etiology and progression of endometriosis. The aberrant expression of aromatase together with the elevated expression of 17β-hydroxysteroid dehydrogenase type 1 and the absence of 17β-hydroxysteroid dehydrogenase type 2 observed in the endometriotic tissue would contribute to an increase in the tissue concentration of estrogen. Aromatase expression is regulated at multiple levels, from the transcription of CYP19A1 and epigenetic codes to posttranslational modification and degradation of the protein. Among the multiple promoters of CYP19A1, the most proximal promoter PII is the most active in endometriosis and is regulated by cAMP, prostaglandin E2, steroidogenic factor-1, and possibly the end product estrogen. Hypomethylation of CpG islands on CYP19A1 observed in the endometriotic tissue may contribute to the upregulation of aromatase expression. Similar to spontaneous menopause, inhibition of in situ estrogen biosynthesis may regress endometriosis. The use of aromatase inhibitors (AIs), which selectively inhibit aromatase activity in human tissues, is a possible treatment for inhibiting local estrogen biosynthesis in endometriosis. AIs have been used as monotherapy or in combination therapies with progestins, oral contraceptive pills, and gonadotropin-releasing hormone agonists to reduce endometriosis-related pain in premenopausal women.

OBJECTIVE: The authors performed phase I/II clinical trial to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced squamous cell carcinoma of the uterine cervix. METHODS: Between April 2000 and January 2006, 22 patients for Protocol 9902 were treated with C-ion RT. The number of patients with stage IIB, IIIB, and IVA diseases was 1, 18, and 3, respectively. All patients had bulky tumors measuring 4.0-12.0 cm (median 6.2 cm). The whole pelvic dose was fixed at 39.0 GyE for 13 fractions, and additional 15.0 GyE for 5 fractions was given to the gross tumor volume (GTV) and surrounding tissues. With regard to local boost, a dose-escalation study was planned for 2 fractions to GTV. Total dose to the cervical tumor was 64.0-72.0 GyE for 20 fractions. RESULTS: All patients completed the scheduled therapy and no patient developed Grade 2 or higher acute toxicity. There was no Grade 3 or higher late complications at each dose. The 5-year overall survival rate and local control rate were 50.0% and 68.2%, respectively. Seven out of the 16 patients who received 64.0-68.0 GyE developed local recurrences, but all patients who received 72.0 GyE maintained local control. CONCLUSIONS: There were no severe acute or late complications in this trial. C-ion RT has the potential to improve the treatment for locally advanced bulky cervical cancer by applying a total dose of 72.0 GyE, with the results lending incentive to further investigations to confirm the therapeutic efficacy.

OBJECTIVE: Compression of the left common iliac vein between the right common iliac artery and the vertebrae is known to be associated with the occurrence of left iliofemoral deep vein thrombosis (DVT). In this study, we described the variability in vascular anatomy of the common iliac veins and evaluated the relationship between the degree of iliac vein compression and the presence of DVT using the data from surgeries for gynecologic cancer. METHODS: The anatomical variations and the degrees of iliac vein compression were determined in 119 patients who underwent systematic para-aortic and pelvic lymphadenectomy during surgery for primary gynecologic cancer. Their medical records were reviewed with respect to patient-, disease-, and surgery-related data. RESULTS: THE DEGREES OF COMMON ILIAC VEIN COMPRESSION WERE CLASSIFIED INTO THREE GRADES: grade A (n=28, 23.5%), with a calculated percentage of 0%-25% compression; grade B (n=47, 39.5%), with a calculated percentage of 26%-50% compression; and grade C (n=44, 37%), with a calculated percentage of more than 50% compression. Seven patients (5.9%) had common iliac veins with anomalous anatomies; three were divided into small caliber vessels, two with a flattened structure, and two had double inferior vena cavae. The presence of DVT was associated with the elevated D-dimer levels but not with the degree of iliac vein compression in this series. CONCLUSION: Although severe compression of the common iliac veins was frequently observed, the degree of compression might not be associated with DVT in surgical patients with gynecologic cancer. Anomalous anatomies of common iliac veins should be considered during systematic para-aortic and pelvic lymphadenectomy in the gynecologic cancer patients.

Keishibukuryogan (KBG; Guizhi-Fuling-Wan in Chinese) is one of the Kampo (Japanese traditional) medicines used to treat patients with climacteric syndrome. KBG can be used by patients who cannot undergo hormone replacement therapy due to a history of breast cancer. We evaluated whether cytosine-adenine (CA) repeat polymorphism of the estrogen receptor β gene can be a predictor of the beneficial effect of KBG on climacteric syndrome. We also investigated the relationship between CA repeat polymorphism, the patients' profiles, and the therapeutic effect. We found that CA was an SS, SL, or LL genotype according to the number of repeats. We studied 39 consecutive patients with climacteric disorders who took KBG for 12 weeks. The diagnosis of climacteric disorders was made on the basis of the Kupperman index. KBG significantly improved the patients' climacteric symptoms (i.e., vasomotor symptoms in the patients with the LL genotype and melancholia in the patients with the SL genotype). No relationship between the patients' profiles and CA repeat polymorphism was recognized. CA repeat polymorphism could thus be a potential biomarker to predict the efficacy of KBG in climacteric syndrome, and its use will help to reduce the cost of treating this syndrome by focusing the administration of KBG on those most likely to benefit from it.

Context: Genomic rearrangements at 15q21 have been shown to cause overexpression of CYP19A1 and resultant aromatase excess syndrome (AEXS). However, mutation spectrum, clinical consequences, and underlying mechanisms of these rearrangements remain to be elucidated. Objective: The aim of the study was to clarify such unsolved matters. Design, Setting, and Methods: We characterized six new rearrangements and investigated clinical outcome and local genomic environments of these rearrangements and of three previously reported duplications/deletions. Results: Novel rearrangements included simple duplication involving exons 1-10 of CYP19A1 and simple and complex rearrangements that presumably generated chimeric genes consisting of the coding region of CYP19A1 and promoter-associated exons of neighboring genes. Clinical severities were primarily determined by the copy number of CYP19A1 and the property of the fused promoters. Sequences at the fusion junctions suggested nonallelic homologous recombination, non-homologous end-joining, and replication-based errors as the underlying mechanisms. The breakpoint-flanking regions were not enriched with GC content, palindromes, noncanonical DNA structures, or known rearrangement-associated motifs. The rearrangements resided in early-replicating segments. Conclusions: These results indicate that AEXS is caused by duplications involving CYP19A1 and simple and complex rearrangements that presumably lead to the usage of cryptic promoters of several neighboring genes. Our data support the notion that phenotypes depend on the dosage of CYP19A1 and the characteristics of the fused promoters. Furthermore, we show that the rearrangements in AEXS are generated by both recombination- and replication-mediated mechanisms, independent of the known rearrangement-inducing DNA features or late-replication timing. Thus, AEXS represents a unique model for human genomic disorders.

胎児骨系統疾患には様々な病態があり,出生前の鑑別は容易でない.最近,ヘリカルCT検査のデータを再構築することで骨格の三次元(3D)像の把握が可能になっている.この方法を用いて,Antley-Bixler症候群を出生前に診断した症例を報告する.妊娠23週時の超音波断層法でクローバー状頭蓋を指摘され,妊娠28週時に当院に紹介された.超音波断層法で胎児前頭部の狭小化,眼球突出,眼間距離の拡大を認めたが,胎児発育やそのほかの胎児異常は認めず,初診時には頭蓋縫合早期癒合症とその症候群という診断にとどまった.妊娠31週時に胎児ヘリカルCT検査を実施し,短頭・顔面骨低形成・上腕骨頭癒合を認めたことからAntley-Bixler症候群と診断し,本疾患は骨折等を伴う疾患ではないことから,計画的経腟分娩の方針とした.妊娠39週2日,自然破水・陣痛発来し,2,484g,アプガースコア8/9点の女児を経腟分娩した.児はCTでの評価の通り,頭蓋骨早期癒合・顔面骨低形成・上腕骨橈骨癒合を認めAntley Bixler症候群の特徴を有していた.児の遺伝子検査は実施していない.胎児ヘリカルCT検査を用いた骨3D構造の把握は,正確な胎児診断を可能にし,分娩管理の方針決定に有用と考えられた.(著者抄録)

目的:子宮頸がん集団検診における、細胞診・HPV-DNA検査(以下、HPVテストとする)併用検診の有効性を明らかにすることを目的とした。方法:併用検診を行った2,733人(A町B村)を対象としてSure Path法にてLBC標本を作製し、残りの細胞懸濁液を用いHPVテストを行った。要精検率とCIN2以上の発見率を従来法およびLBCのみ(C市)のそれらと比較検討した。成績:LBC法により不適正標本はなくなった。要精検者数はA町で21例(1.8%)、B村で36例(2.3%)、C市は81例(2.5%)であった。CIN2以上の病変は、A町で6例(0.5%)、B村で9例(0.6%)でありC市では22例(0.7%)であった。要精検率およびCIN2以上の発見率は従来法と比較して上昇した。細胞診NILMでHPVテスト陽性例95例を鏡検し直すと、5例がASC-USとなり要精検率が2.1%から2.3%と上昇したが有意差はなかった。結論:併用検診において要精検率およびCIN2以上の検出率が上昇したのは、LBCによる細胞診の精度向上が考えられ、HPVテストの効果については今後の検討が必要であることが示唆された。(著者抄録)

OBJECTIVE: The present study assessed the use of an intraoperative tube thoracostomy for patients with primary advanced-stage ovarian, fallopian tube, or peritoneal cancer who underwent a diaphragmatic resection as part of debulking surgery and to define which patients are more likely to benefit from an intraoperative tube thoracostomy. METHODS: All consecutive patients with stage IIIC-IV Müllerian cancer who underwent diaphragmatic resection at our institution between April 2008 and March 2013 were retrospectively reviewed. When a full-thickness resection of the diaphragm was performed and the thoracic cavity was opened, a chest tube was routinely placed during surgery. Patient-, disease-, and surgery-related data were collected from the patients' medical records. The data were evaluated with particular attention directed at pleural effusion after diaphragmatic resection. RESULTS: A total of 37 patients were included in this study. No complications associated with the intraoperative tube thoracostomy procedures occurred. An infection of the thoracic cavity occurred in one patient, following the presence of intra-abdominal abscess. The total volume of pleural drainage ranged from 88 to 2826 mL (median, 965 mL). The estimated blood loss, intraoperative blood transfusion, and area of the diaphragmatic opening were significantly associated with the total volume of pleural drainage in univariate analyses. In a multivariate analysis, the estimated blood loss was the only factor to be significantly associated with the total volume of pleural drainage. CONCLUSIONS: A prophylactic tube thoracostomy might be considered if the volume of the estimated blood loss is higher than usual.

OBJECTIVE: This study evaluated the incidence of postoperative morbidities, focusing specifically on pancreatic fistulas, after a splenectomy performed as part of cytoreductive surgery for the treatment of ovarian cancer. METHODS: A retrospective chart review was performed for all the patients with ovarian, tubal, or peritoneal cancer who underwent splenectomy during a 5-year period. Patient-, disease-, and surgery-related data were collected. Pancreatic fistulas were identified when the drainage fluid obtained via a surgically placed drain had an amylase content greater than 3 times the normal serum value after postoperative day 3. RESULTS: A splenectomy was performed in 21 patients. Postoperative pancreatic fistulas developed in 6 patients (29%). Of these 6 patients, 2 had no symptoms and did not require specific treatment for their pancreatic fistulas. Therapeutic intervention was required in the remaining 4 patients. The durations of oral feeding prohibition and the use of a peripancreatic drain were longer in the patients with a pancreatic fistula than in those without a pancreatic fistula. Overall, the pancreatic fistulas were managed conservatively or using minimally invasive procedures. Staple-line reinforcement seemed to be an effective means of closing the transected stump during the splenectomy, compared with the standard stapling technique. CONCLUSIONS: Elevated amylase levels in the drainage fluid reflect the patient's actual condition better than serum amylase levels. We recommend the intraoperative placement of a peripancreatic drain and postoperative measurement of amylase concentrations in the drainage fluid to identify the development of pancreatic fistulas and to facilitate the management of this complication.

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。