Publishing type：Research paper (scientific journal)   Publisher：BMJ  

Objective

The association between sarcopenia and prognosis in patients with platinum-resistant recurrent ovarian cancer remains unclear. This study investigated whether sarcopenia is a prognostic factor in patients with platinum-resistant recurrent ovarian cancer.

Methods

A total of 52 patients diagnosed with platinum-resistant recurrent ovarian cancer who had undergone non-platinum chemotherapy at our institution formed our study population. Body composition and clinicopathological data of these patients were collected retrospectively. Abdominal computed tomography (CT) scans obtained at the time of platinum-resistant recurrent ovarian cancer diagnosis were used to measure the cross-sectional area of skeletal muscles at L3 level. These values were corrected for height to calculate the skeletal muscle index, and accordingly sarcopenia was defined. Overall survival was defined as the primary outcome of the study. The impact of sarcopenia on overall survival was assessed using Cox proportional hazards regression models with inverse probability weighting of treatment based on propensity scores and log-rank tests.

Results

The median patient age was 63 years (IQR: 53–71). The most common International Federation of Gynecology and Obstetrics (FIGO) 2018 stage was stage III (50%) and the most common histology was serous or adenocarcinoma (67.3%). The optimal cut-off value of skeletal muscle index was 35.6 cm²/m², which was calculated using the data of 21 patients with sarcopenia and 31 without sarcopenia. Sarcopenia was significantly associated with shorter overall survival (HR 1.93; 95% CI 1.06–3.49; p=0.03). Subgroup analysis based on patient attributes and prognostic factors suggested a consistent prognostic impact of sarcopenia. Sarcopenia was identified as a significant risk factor, particularly in patients who had higher CA125 levels (HR, 2.47; 95% CI, 1.07 to 5.69; p=0.034) and a higher neutrophil-to-lymphocyte ratio (HR, 2.92; 95% CI, 1.02 to 8.31; p=0.045).

Conclusion

Sarcopenia significantly shortened the overall survival of patients with platinum-resistant recurrent ovarian cancer.

DOI： 10.1136/ijgc-2024-005323

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Primary small bowel carcinoma in pregnant women is extremely rare. Small bowel cancer is difficult to diagnose because of its rarity, lack of specific clinical symptoms, and particular anatomical features. We experienced a case of primary small bowel adenocarcinoma with ovarian metastasis during pregnancy. This is the first reported case of a patient with small bowel adenocarcinoma whose pregnancy continued to term and ended in delivery. CASE PRESENTATION: A 32-year-old pregnant woman developed abdominal pain, and imaging examination revealed an ovarian tumor at 29 weeks of gestation. We performed laparotomy and resected the ovarian tumor, which was initially suspected to be primary ovarian cancer. The patient continued the pregnancy to term. A detailed examination of the abdominal cavity during cesarean delivery at 37 weeks revealed that the primary lesion was located in the small bowel. CONCLUSION: It is important to recognize that the small bowel may be the primary site of metastatic ovarian cancer. Detailed and careful examination is necessary to diagnose small bowel cancer during pregnancy.

DOI： 10.1159/000540524

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy  

DOI： 10.5180/jsgoe.39.2_56

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：神奈川産科婦人科学会  

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Language：Japanese   Publisher：神奈川産科婦人科学会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.nut.2022.111966

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：神奈川産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

症例は55歳、2妊2産、BMI 39.3kg/m2であった。低リスク群の子宮体癌IA期の診断でロボット支援下準広汎子宮全摘術および両側付属器摘出術を完遂した。術中体位は砕石位、頭低位は25度、手術時間は4時間45分であった。麻酔覚醒直後から右下腿の疼痛・腫脹、CK 4419IU/lが出現し、術後14時間でCK 57736IU/lと更なる上昇を認め、右下腿コンパートメント症候群の診断で右下腿の緊急減張切開術を施行した。CKは39619IU/lに低下したが、術後25時間で左下腿にも疼痛・腫脹が出現しCK 43871IU/lと再上昇を認め、左下腿コンパートメント症候群の診断で左下腿の緊急減張切開術を施行した。減張切開術後は合併症を生じることなく経過し、CK値も時間経過とともに改善し、術後16日に一部植皮を用いて閉創した。術後約1年で下腿の創部は完全治癒した。

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Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy  

DOI： 10.5180/jsgoe.39.1_31

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Language：English   Publishing type：Research paper (scientific journal)  

In 2013, the Ministry of Health, Labor, and Welfare (MHLW) in Japan announced a suspension of the governmental recommendation for routine HPV vaccinations. In 2020, MHLW started individual notifications of HPV vaccine to the targeted girls. In April 2022, the governmental recommendation was restarted, and catch-up vaccinations started. We evaluated the benefits and limitations of the MHLW's new vaccination strategies by estimating the lifetime risk for cervical cancer for each birth FY under different scenarios to suggest a measure for the vaccine suspension generation. It was revealed that catch-up immunization coverage among the unvaccinated must reach as high as 90% in FY2022, when the program begins, in order to reduce the risk of the females already over the targeted ages to the same level or lower than that of women born in FY1994-1999 who had high HPV vaccination rates. For women whose vaccination coverage waned because of their birth FYs, strong recommendations for cervical cancer screening should be implemented.

DOI： 10.3390/vaccines10091455

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: This study was conducted to evaluate the status and role of cervical cytology affected by human papillomavirus infection and other infectious diseases screened during routine prenatal checkups. METHODS: We retrospectively examined medical records containing the screening results for infectious diseases and cervical cancer in women who delivered neonates in our hospital from 2014 to 2017. RESULTS: Among 3393 deliveries, 18.8% of women underwent a regular cervical cancer screening within 1 year of becoming pregnant, and 2641 women underwent a cervical cytology screening during this pregnancy. The cytological diagnostic results showed that 2562 women (97.0%) were negative for intraepithelial lesions or malignancy, whereas 79 (3.0%) had abnormal results. Of those with abnormal cytology results, 70 had abnormal cytology that was newly detected in this pregnancy, and 42 had grade ≥1 cervical intraepithelial neoplasia lesions. Spatulas were the most frequently used cytological sampling instruments, followed by cotton swabs. Cervical cytology revealed no major adverse reactions during these pregnancies. CONCLUSIONS: Our results confirm the importance of screening for infectious diseases during pregnancy. Only 20% of the women underwent a regular pre-pregnancy cervical cytology screening. Cervical cytology screening during pregnancy may currently be playing a crucial role in preventing cervical cancer in Japan.

DOI： 10.1177/03000605221097488

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Language：Japanese   Publisher：神奈川産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

症例は40歳(0妊0産)で、子宮筋腫による過多月経と貧血が進行し全腹腔鏡下子宮全摘出術、両側卵管切除術を行った。手術所見でダグラス窩腹膜に約1cmの青黒色の結節を認め周囲に大網が一部癒着しており、子宮内膜症所見はr-ASRM分類2点であった。病理診断で子宮筋層・漿膜、両側卵管は子宮内膜症所見はなく、子宮筋腫であった。術後、周期的な性器出血や腹痛、臍部の疼痛があり、腟断端の生検で腟断端子宮内膜症の診断を得た。臍部はポート孔に生じた子宮内膜症を疑い生検を行ったが診断は得られなかった。術後、腟断端と臍部に子宮内膜症が生じたと考えてジェノゲスト内服を行い、症状は改善している。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J02563&link_issn=&doc_id=20230206480041&doc_link_id=%2Fcj7sanai%2F2022%2F003802%2F041%2F0235-0239%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcj7sanai%2F2022%2F003802%2F041%2F0235-0239%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy  

DOI： 10.5180/jsgoe.38.2_235

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The incidence and risk factors of severe anaphylaxis by intravenous anti-cancer drugs are unclear, whereas those of milder reactions have been reported. STUDY DESIGN: Electronic medical charts of cancer patients who have undergone intravenous chemotherapy between January 2013 and October 2020 in a university hospital were retrospectively reviewed. Non-epithelial malignancies were also included in the analysis. "Severe anaphylaxis" was judged using Brown's criteria: typical presentation of anaphylaxis and one or more of hypoxia, shock, and neurologic compromise. (UMIN000042887). RESULTS: Among 5584 patients (2964 males [53.1%], 2620 females [46.9%], median age 66 years), 88,200 person-day anti-cancer drug administrations were performed intravenously, and 27 severe anaphylaxes were observed. The causative drugs included carboplatin (14 cases), paclitaxel (9 cases), and cisplatin, docetaxel, trastuzumab, and cetuximab (1 case each). The person-based lifetime incidence of severe anaphylaxis for patients who received at least one intravenous chemotherapy was 0.48% (27/5584, 95% confidence interval (CI) 0.30%-0.67%) and the administration-based incidence was 0.031% (27/88,200, 95% CI 0.019%-0.043%). Among 124 patients who received at least 10 carboplatin administrations, 10 patients experienced carboplatin-induced severe anaphylaxis (10/124, 8.1%, 95% CI 3.0%-13.1%). Carboplatin caused severe anaphylaxis after at least 9-min interval since the drip started. Thirteen out of 14 patients experienced carboplatin-induced severe anaphylaxis within a 75-day interval from the previous treatment. Paclitaxel infusion caused severe anaphylaxis after a median of 5 min after the first drip of the day at a life-long incidence of 0.93% (9/968, 95% CI 0.27%-1.59%). CONCLUSION: We elucidated the high-risk settings of chemotherapy-induced severe anaphylaxis.

DOI： 10.1002/cam4.4252

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Language：English   Publishing type：Research paper (scientific journal)  

The underlying molecular mechanisms of resistance to cisplatin-based systemic chemotherapy in bladder cancer patients remain to be elucidated, while the link between androgen receptor (AR) activity and chemosensitivity in urothelial cancer has been implicated. Our DNA microarray analysis in control vs. AR knockdown bladder cancer lines identified GULP1 as a potential target of AR signaling. We herein determined the relationship between AR activity and GULP1 expression in bladder cancer cells and then assessed the functional role of GULP1 in cisplatin sensitivity. Androgen treatment in AR-positive cells or AR overexpression in AR-negative cells considerably reduced the levels of GULP1 expression. Chromatin immunoprecipitation further showed direct interaction of AR with the promoter region of GULP1. Meanwhile, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment compared with respective controls. GULP1 knockdown also resulted in a significant decrease in apoptosis, as well as a significant increase in G2/M phases, when treated with cisplatin. In addition, GULP1 was immunoreactive in 74% of muscle-invasive bladder cancers from patients who had subsequently undergone neoadjuvant chemotherapy, including 53% of responders showing moderate (2+)/strong (3+) expression vs. 23% of non-responders showing 2+/3+ expression (P = 0.044). These findings indicate that GULP1 represents a key downstream effector of AR signaling in enhancing sensitivity to cisplatin treatment.

DOI： 10.3390/ijms221810030

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: We aimed to conduct a fixed-point observation questionnaire survey of changes in young women's human papillomavirus (HPV) vaccination status over the course of 10 years. We also investigated the influence of suspension of governmental recommendation for HPV vaccination since June 2013. METHODS: During 2011-2020, we conducted a self-completed questionnaire survey among newly enrolled female medical school students in Yokohama, Japan. The questionnaire featured items regarding HPV vaccination status, age, previous sex education, and knowledge about cervical cancer and HPV vaccination. RESULTS: HPV vaccine uptake rates in 2011 (5.4%) and 2012 (13.5%), when vaccination was self-funded, increased after 2013 (48.7%), when vaccination fees were subsidized. The rate dropped drastically in 2019 (14.3%) and 2020 (5.1%), after suspension of recommendation by the government. Comparisons between new students in 2015/2016, who had high vaccination rates (65.2%), and new students in 2019/2020, who had low vaccination rates (9.8%), showed decreased levels of HPV vaccination awareness, with fewer students having covered cervical cancer prevention in sex education and with respondents having less knowledge about the details of HPV vaccination. CONCLUSIONS: After the suspension of proactive HPV vaccine recommendation, markedly fewer students have been vaccinated against HPV, even those at the vaccination target age. This situation has substantially influenced the lower awareness about cervical cancer prevention, even among medical school students. To protect young women from cervical cancer in Japan, it is crucial for the government to resume proactive recommendation of HPV vaccines as soon as possible.

DOI： 10.1111/jog.14949

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone (p = 0.083) or together with AR negativity (p = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.

DOI： 10.3390/cancers13050975

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: This study aimed to evaluate the outcome of radiation therapy for patients with distant lymph node (LN) metastases, without organ metastases from uterine cervical cancer (UCC). PATIENTS AND METHODS: Twenty-six patients with UCC with distant LN metastases received radiotherapy and were retrospectively analyzed. The sites of distant LN metastasis were as follows; Supraclavicular in 19, inguinal in nine, axillary in four, and others in three. The mean dose prescribed for these was 50 (range=40-60) Gy. RESULTS: The 2-year overall, cause-specific, and progression-free survival, and local control of primary tumor rates were 51.3%, 51.3%, 46.9%, and 67.9%. In multivariate analysis, performance status ≥1 (p=0.007), para-aortic LN metastases (p=0.001), and lack of high-dose-rate intracavitary brachytherapy (p=0.033) were significantly associated with poor overall survival. Performance status ≥1 (p=0.004), and para-aortic LN metastases (p=0.014) were significantly associated with poor cause-specific survival. CONCLUSION: This study demonstrated favorable local control in patients with UCC with distant LN metastases.

DOI： 10.21873/invivo.12365

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Language：English  

We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.

DOI： 10.1111/cas.14557

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Language：English   Publishing type：Research paper (scientific journal)  

Although intravesical BCG immunotherapy has been the gold standard for non-surgical management of non-muscle-invasive bladder cancer (BC), a considerable number of patients exhibit resistance to the adjuvant treatment with unexplained mechanisms. This study aimed to investigate whether and how androgen receptor (AR) signals modulate BCG cytotoxicity in BC. AR knockdown or overexpression in BC lines resulted in induction or reduction, respectively, in intracellular BCG quantity and its cytotoxic activity. Microarray screening identified Rab27b, a small GTPase known to mediate bacterial exocytosis, which was up-regulated in BCG-resistant cells and down-regulated in AR-shRNA cells. Knockdown of Rab27b or its effector SYTL3, or overexpression of Rab27b also induced or reduced, respectively, BCG quantity and cytotoxicity. Additionally, treatment with GW4869, which was previously shown to inhibit Rab27b-dependent secretion, induced them and reduced Rab27b expression in BC cells. Meanwhile, AR expression was up-regulated in BCG-resistant lines, compared with respective controls. In a mouse orthotopic xenograft model, Rab27b/SYTL3 knockdown or GW4869 treatment enhanced the amount of BCG within tumors and its suppressive effect on tumor growth. Moreover, in non-muscle-invasive BC specimens from patients subsequently undergoing BCG therapy, positivity of AR/Rab27b expression was associated with significantly higher risks of tumor recurrence. AR activation thus correlates with resistance to BCG treatment, presumably via up-regulating Rab27b expression. Mechanistically, it is suggested that BCG elimination from urothelial cells is induced by Rab27b/SYTL3-mediated exocytosis. Accordingly, Rab27b inactivation, potentially via anti-androgenic drugs, and/or exocytosis inhibition are anticipated to sensitize the efficacy of BCG therapy, especially in patients with BCG-refractory AR/Rab27b-positive BC.

DOI： 10.1158/1535-7163.MCT-20-0050

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Language：English   Publisher：NATURE PUBLISHING GROUP  

Web of Science

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Language：English   Publishing type：Research paper (scientific journal)  

Androgen receptor (AR) and estrogen receptor-β (ERβ) have been implicated in urothelial tumor outgrowth as promoters, while underlying mechanisms remain poorly understood. Our transcription factor profiling previously performed identified FOXO1 as a potential downstream target of AR in bladder cancer cells. We here investigated the functional role of FOXO1 in the development and progression of urothelial cancer in relation to AR and ERβ signals. In non-neoplastic urothelial SVHUC cells or bladder cancer lines, AR/ERβ expression or dihydrotestosterone/estradiol treatment reduced the expression levels of FOXO1 gene and induced those of a phosphorylated inactive form of FOXO1 (p-FOXO1). In chemical carcinogen-induced models, FOXO1 knockdown via shRNA or inhibitor treatment resulted in considerable induction of the neoplastic transformation of urothelial cells or bladder cancer development in mice. Similarly, FOXO1 inhibition considerably induced the viability, migration, and invasion of bladder cancer cells. Importantly, in FOXO1 knockdown sublines, an anti-androgen hydroxyflutamide or an anti-estrogen tamoxifen did not significantly inhibit the neoplastic transformation of urothelial cells, while dihydrotestosterone or estradiol did not significantly promote the proliferation or migration of urothelial cancer cells. In addition, immunohistochemistry in surgical specimens showed that FOXO1 and p-FOXO1 expression was down-regulated and up-regulated, respectively, in bladder tumor tissues, which was further associated with worse patient outcomes. AR or ERβ activation is thus found to correlate with inactivation of FOXO1 which appears to be their key downstream effector. Moreover, FOXO1, as a tumor suppressor, is likely inactivated in bladder cancer, which contributes in turn to inducing urothelial carcinogenesis and cancer growth.

DOI： 10.1530/ERC-20-0004

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Language：English   Publishing type：Research paper (scientific journal)  

Recent preclinical evidence has indicated that both androgen receptor (AR) inactivation and glucocorticoid receptor (GR) transrepression are associated with suppression of urothelial carcinogenesis. We therefore assessed the effect of a unique compound, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride (Compound A; CpdA), which could function as an AR antagonist as well as a GR ligand, on urothelial tumorigenesis. Using the in vitro system with GR-positive non-neoplastic urothelial SVHUC cells stably expressing AR (SVHUC-AR), neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene (MCA) was inhibited similarly by an anti-androgen hydroxyflutamide and a glucocorticoid prednisone, and more strongly by CpdA. CpdA also prevented the neoplastic transformation of AR-negative MCA-SVHUC cells, which was diminished by a GR antagonist RU486, but failed to prevent that of GR knockdown MCA-SVHUC cells. In MCA-SVHUC-AR cells, CpdA significantly reduced the expression levels of oncogenes (c-Fos/c-Jun/c-Myc) and induced those of tumor suppressors (UGT1A/p21/p27/p53/PTEN). Additionally, a potent carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine induced bladder cancer in all of 8 mock-treated mice versus 4 (50%) of flutamide-treated (P = 0.021), 4 (50%) of prednisone-treated (P = 0.021), or 2 (25%) of CpdA-treated (P = 0.002) animals. Finally, CpdA was found to reduce AR transactivation and selectively induce GR transrepression (i.e. suppression of NF-κB transactivation and expression of its regulated genes), but not GR transactivation (i.e. activation of glucocorticoid-response element-mediated transcription and expression of its targets) in SVHUC cells. These findings suggest that CpdA suppresses urothelial tumorigenesis via both the AR and GR pathways, which may consequently provide an effective option of chemoprevention for bladder cancer, especially in patients with superficial disease following transurethral surgery.

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Language：English   Publishing type：Research paper (scientific journal)  

Glucocorticoids, including dexamethasone (DEX) and prednisone (PRED), have been prescribed in patients with neoplastic disease as cytotoxic agents or comedications. Nonetheless, it remains uncertain whether they have an impact on the development of bladder cancer. We, therefore, assessed the functional role of the glucocorticoid-mediated glucocorticoid receptor (GR) signaling in urothelial tumorigenesis. Tumor formation was significantly delayed in xenograft-bearing mice with implantation of control bladder cancer UMUC3 cells or nonneoplastic urothelial SVHUC cells undergoing malignant transformation induced by a chemical carcinogen 3-methylcholanthrene (MCA), compared with respective GR knockdown xenografts. Using the in vitro system with MCA-SVHUC cells, we screened 11 GR ligands, including DEX, and found significant inhibitory effects of PRED on their neoplastic transformation. The effects of PRED were restored by a GR antagonist RU486 in GR-positive MCA-SVHUC cells, while PRED failed to inhibit the neoplastic transformation of GR knockdown cells. Significant decreases in the expression levels of oncogenes (c-Fos/c-Jun) and significant increases in those of a tumor suppressor UGT1A were seen in MCA-SVHUC-control cells (vs GR-short hairpin RNA) or PRED-treated MCA-SVHUC-control cells (vs mock). In addition, N-butyl-N-(4-hydroxybutyl) nitrosamine induced bladder cancer in all of eight mock-treated mice vs seven (87.5%) of DEX-treated (P = .302) or four (50%) of PRED-treated (P = .021) animals. Finally, DEX was found to considerably induce both transactivation (activation of glucocorticoid-response element mediated transcription and expression of its targets) and transrepression (suppression of nuclear factor-kappa B transactivation and expression of its regulated genes) of GR in SVHUC cells, while PRED more selectively induced GR transrepression. These findings suggest that PRED could prevent urothelial tumorigenesis presumably via inducing GR transrepression.

DOI： 10.1002/mc.23118

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Language：English   Publishing type：Research paper (scientific journal)  

We previously reported that aberrant expression of atypical protein kinase C λ/ι (aPKCλ/ι) in low-grade squamous intraepithelial uterine cervix lesions was associated with an increased risk of progression to higher grade. This study aimed to investigate aPKCλ/ι expression patterns in cervical squamous cell carcinoma (SCC) and its association with disease progression. We immunohistochemically assessed aPKCλ/ι expression in 168 SCC samples and 13 normal uterine cervix samples. In 69.0% of SCC cases, aPKCλ/ι was expressed more abundantly than in normal epithelium, but there was no significant association between aPKCλ/ι intensity and disease progression (P=0.087, Cochran-Mantel-Haenszel test). aPKCλ/ι in normal cervical epithelium was confined to the cytoplasm or intercellular junctions. In contrast, aPKCλ/ι was predominantly localized within the nucleus in 36.9% of SCC samples (P<0.001, χ test), and the prevalence was significantly increased relative to advanced tumor stage (P<0.001, Cochran-Mantel-Haenszel test). Moreover, patients with SCC with aPKCλ/ι nuclear localization had worse prognoses than those with cytoplasmic localization (P<0.001, log-rank test). aPKCλ/ι localization differed between the intraepithelial lesion and adjacent invasive cancer in 40% of cases, while the expression pattern was similar between primary and matched metastatic tumors. In conclusion, aPKCλ/ι nuclear localization in cervical cancer is associated with tumor progression and worse prognosis. This is the first report to show aberrant nuclear aPKCλ/ι localization in a subgroup of cervical cancer patients and its association with worse prognosis.

DOI： 10.1097/PGP.0000000000000539

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Language：English   Publishing type：Research paper (scientific journal)  

Emerging evidence has suggested that androgen receptor signaling plays an important role in ovarian cancer outgrowth. Specifically, androgen receptor activation appears to be associated with increased risks of developing ovarian cancer and inducing tumor progression. However, conflicting findings have also been reported. This review summarizes and discusses the available data indicating the involvement of androgens as well as androgen receptor and related signals in ovarian carcinogenesis and cancer growth. Although the underlying molecular mechanisms for androgen receptor functions in ovarian cancer remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches, via modulation of androgen receptor activity, against ovarian cancer. Indeed, several clinical trials have been conducted to determine the efficacy of androgen deprivation therapy in patients with ovarian cancer.

DOI： 10.3390/cells8020176

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To determine factors that impact erythropoietin (EPO) production in leiomyomas. We have previously implicated EPO production in promoting the growth of some leiomyomas. DESIGN: The relationship between EPO messenger RNA (mRNA) expression and MED12 gene mutations or mRNA expression levels of high-mobility group AT-hook (HMGA) 1 and HMGA2 were analyzed. Effects of 10-8 M 17β-E2 on EPO mRNA expression were evaluated using leiomyoma cells grown in primary cultures. SETTING: Graduate school of medicine. PATIENT(S): Patients with leiomyoma. INTERVENTION(S): We used tissue samples and clinical data of 108 patients with leiomyomas to analyze the relation between EPO mRNA expression and MED12 mutation. Tissue samples from another 10 patients with leiomyomas were collected for in vitro experimentation using primary cultures of leiomyoma and myometrial cells. MAIN OUTCOME MEASURE(S): Relations between EPO mRNA expression, MED12 exon 2 mutation, and HMGA1/HMGA2 mRNA expression levels in leiomyoma samplings, in addition to effects of estrogen (E) on EPO mRNA expression in cultures of leiomyoma cells. RESULT(S): The EPO mRNA level was threefold higher in leiomyomas with wild-type (vs. mutated) MED12 genes. There was no correlation between EPO and HMGA1 or HMGA2 mRNA expression levels. In wild-type MED12 leiomyomas only, E2 treatment produced a twofold increase in EPO mRNA expression, whereas mutated MED12 leiomyomas were unaffected. CONCLUSION(S): The EPO mRNA expression increased significantly after E2 treatment only in leiomyomas lacking MED12 mutations. In conjunction with prior evidence linking EPO mRNA expression levels and tumor size, E2-stimulated EPO mRNA expression may explain the marked growth disparities seen in these tumors.

DOI： 10.1016/j.fertnstert.2018.09.014

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The transcription factor forkhead box O1 (FOXO1) can be inactivated via its phosphorylation, resulting in suppression of apoptosis. Using immunohistochemistry, the expression of a phosphorylated form of FOXO1 was assessed in upper urinary tract urothelial carcinoma (UUTUC) specimens. Overall, phospho-FOXO1 (p-FOXO1) was immunoreactive in all 99 UUTUC specimens [12 (12.1%) weak (1+), 46 (46.5%) moderate (2+) and 41 (41.4%) strong (3+)], which was significantly (P=0.018) increased, compared with benign urothelium specimens [77/82 (93.9%): 18 (22.0%) 1+, 41 (50.0%) 2+ and 18 (22.0%) 3+]. Muscle invasion (P=0.031) and lymphovascular invasion (P=0.025) were observed more frequently in p-FOXO1(2+/3+) tumor samples compared with p-FOXO1(1+) tumor samples. No statistically significant associations between p-FOXO1 expression and tumor grade or presence of concurrent carcinoma in situ, hydronephrosis or lymph node metastasis were observed. Furthermore, the levels of p-FOXO1 and estrogen receptor-β expression were significantly (P<0.05) correlated in UUTUC samples [correlation coefficient (CC)=0.244], particularly in tumor samples from male patients (CC=0.330). Additionally, patients with p-FOXO1(3+) tumors had a significantly increased risk of cancer-specific mortality (P=0.043), compared with those with p-FOXO1(1+/2+) tumors. Multivariate analysis further demonstrated a notable, albeit not significant, association between p-FOXO1 expression and cancer-specific survival (hazard ratio=2.204; P=0.053). These findings indicate that FOXO1 is inactivated in UUTUC specimens and p-FOXO1 overexpression may serve as a predictor of poor patient outcomes.

DOI： 10.3892/ol.2018.9510

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We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.

DOI： 10.1530/EC-18-0364

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BACKGROUND: We developed a novel plasma amino acid profile-based index (API) to detect ovarian, uterine, cervical, and endometrial cancers. In this study, we aimed to evaluate whether abnormal API values could be normalized after curative treatment in patients with gynecological malignant tumors. METHODS: Patients with gynecological cancer with abnormal API values were included in this study. Pre-operative absolute API values were compared with those after curative treatment. The normalization rates of API values in patients negative for the expression of three well-known tumor markers (SCC, CA125, and CA19-9) were also evaluated. In addition, related amino acid profiles in healthy controls and patients under pre- and post-treatment conditions were analyzed. RESULTS: Among 94 patients with abnormal pre-operative API values, the median API value was decreased from 9.52 to 2.17 after treatment (normalization rate: 88.3%). The decreased ranges were similar in patients with adenocarcinoma (6.28; 95% confidence interval [CI]: 5.43-6.95) and squamous carcinoma (7.44; 95% CI: 3.04-8.46). In 93.5% (43/46) of patients negative for tumor markers prior to operation, API values were normalized after the successful treatment. In addition, some pre-operative abnormal amino acid profiles, including Ile, Trp, and His, were reversibly normalized after treatment. CONCLUSION: The API is a promising tumor marker in gynecological malignancies for the diagnosis of remission, particularly in patients negative for general tumor markers. Further studies are needed to explore the mechanisms related to the normalization of abnormal amino acid profiles.

DOI： 10.1186/s12885-018-4875-7

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Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, dihydrotestosterone treatment lowered the effects of irradiation. Meanwhile, an antiandrogen hydroxyflutamide enhanced them in AR-positive cells cultured in the presence of androgens. AR knockdown or hydroxyflutamide treatment also resulted in a delay in DNA double-strand break repair 4-24 hours after irradiation. We then established "radiation-resistant" sublines and found considerable elevation of the expression of AR as well as DNA repair genes, such as ATR, CHEK1, and PARP-1, in these sublines, compared with respective controls. Furthermore, dihydrotestosterone induced the expression of these DNA repair genes in irradiated AR-positive cells, and hydroxyflutamide antagonized the androgen effects. Finally, in a mouse xenograft model, low-dose flutamide was found to enhance the inhibitory effects of irradiation, and its tumor size was similar to that of AR knockdown line with radiation alone. These findings suggest that AR activity inversely correlates with radiosensitivity in bladder cancer. Accordingly, antiandrogenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer. Mol Cancer Ther; 17(7); 1566-74. ©2018 AACR.

DOI： 10.1158/1535-7163.MCT-17-1061

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We investigated the role of NF-κB in the development and progression of urothelial cancer as well as cross-talk between NF-κB and androgen receptor (AR) signals in urothelial cells. Immunohistochemistry in surgical specimens showed that the expression levels of NF-κB/p65 (P = 0.015)/phospho-NF-κB/p65 (P < 0.001) were significantly elevated in bladder tumors, compared with those in nonneoplastic urothelial tissues. The rates of phospho-NF-κB/p65 positivity were also significantly higher in high-grade (P = 0.015)/muscle-invasive (P = 0.033) tumors than in lower grade/non-muscle-invasive tumors. Additionally, patients with phospho-NF-κB/p65-positive muscle-invasive bladder cancer had significantly higher risks of disease progression (P < 0.001) and cancer-specific mortality (P = 0.002). In immortalized human normal urothelial SVHUC cells stably expressing AR, NF-κB activators and inhibitors accelerated and prevented, respectively, their neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene. Bladder tumors were identified in 56% (mock), 89% (betulinic acid), and 22% (parthenolide) of N-butyl-N-(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice at 22 weeks of age. NF-κB activators and inhibitors also significantly induced and reduced, respectively, cell proliferation/migration/invasion of AR-positive bladder cancer lines, but not AR-knockdown or AR-negative lines, and their growth in xenograft-bearing mice. In both nonneoplastic and neoplastic urothelial cells, NF-κB activators/inhibitors upregulated/downregulated, respectively, AR expression, whereas AR overexpression was associated with increases in the expression levels of NF-κB/p65 and phospho-NF-κB/p65. Thus, NF-κB appeared to be activated in bladder cancer, which was associated with tumor progression. NF-κB activators/inhibitors were also found to modulate tumorigenesis and tumor outgrowth in AR-activated urothelial cells. Accordingly, NF-κB inhibition, together with AR inactivation, has the potential of being an effective chemopreventive and/or therapeutic approach for urothelial carcinoma. Mol Cancer Ther; 17(6); 1303-14. ©2018 AACR.

DOI： 10.1158/1535-7163.MCT-17-0786

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OBJECTIVE: To determine the expression status of uridine 5'diphospho-glucuronosyltransferase 1A, a major phase II drug metabolism enzyme, in upper urinary tract urothelial carcinoma, as well as to assess its prognostic significance. METHODS: We immunohistochemically stained for uridine 5'diphospho-glucuronosyltransferase 1A in tissue microarray consisting of 99 upper urinary tract urothelial carcinoma samples and paired non-neoplastic urothelial tissues. We also assessed the effect of uridine 5'diphospho-glucuronosyltransferase 1A knockdown on urothelial cancer cell growth. RESULTS: Uridine 5'diphospho-glucuronosyltransferase 1A was positive in 92.9% (27.3% weak [1+], 37.4% moderate [2+], 28.3% strong [3+]) of tumors, which was significantly (P < 0.001) lower than in benign urothelial tissues (98.8%; 3.5% 1+, 18.8% 2+, 76.4% 3+). All 37 (100%) non-muscle-invasive versus 55 (88.7%) of 62 muscle-invasive tumors (P = 0.043) were immunoreactive for uridine 5'diphospho-glucuronosyltransferase 1A. The rates of moderate-to-strong uridine 5'diphospho-glucuronosyltransferase 1A expression and its positivity were also strongly associated with the absence of concomitant carcinoma in situ (P = 0.034) and lymphovascular invasion (P = 0.016), respectively. However, there were no statistically significant associations between uridine 5'diphospho-glucuronosyltransferase 1A expression and tumor grade or pN/M status. Uridine 5'diphospho-glucuronosyltransferase 1A loss in M0 tumors was strongly associated with lower progression-free survival (P < 0.001) and cancer-specific survival (P < 0.001) rates. Multivariate analysis further identified a strong correlation of uridine 5'diphospho-glucuronosyltransferase 1A positivity with reduced cancer-specific mortality (hazard ratio 0.28, P = 0.018). Meanwhile, uridine 5'diphospho-glucuronosyltransferase 1A knockdown in urothelial cancer cells resulted in significant increases in their viability and migration. CONCLUSIONS: These results suggest a preventive role of uridine 5'diphospho-glucuronosyltransferase 1A signals in the development and progression of upper urinary tract urothelial carcinoma. Loss of uridine 5'diphospho-glucuronosyltransferase 1A expression might serve as an independent predictor of poor prognosis in patients with upper urinary tract urothelial carcinoma.

DOI： 10.1111/iju.13528

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Men have had a substantially higher risk of developing bladder cancer than women. This has prompted research on androgen-mediated androgen receptor (AR) signaling in urothelial cancer. Indeed, increasing preclinical evidence indicates that AR activation correlates with the promotion of urothelial carcinogenesis and tumor outgrowth. In this article, we summarize and discuss available data suggesting the involvement of androgens and the AR pathway in the development and progression of urothelial cancer. Although precise mechanisms for the functions of AR and related signals in urothelial cells remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches for urothelial cancer. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to urothelial cancer patients is thus anticipated.

DOI： 10.1016/j.mce.2017.06.021

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Using preclinical models, we have recently found that ELK1, a transcriptional factor that activates downstream targets, including c-fos proto-oncogene, induces bladder cancer outgrowth. Here, we immunohistochemically determined the expression status of phospho-ELK1, an activated form of ELK1, in upper urinary tract urothelial carcinoma (UUTUC). Overall, phospho-ELK1 was positive in 47 (47.5%; 37 weak (1+) and 10 moderate (2+)) of 99 UUTUCs, which was significantly (P = 0.002) higher than in benign urothelium (21 (25.3%) of 83; 17 1+ and 4 2+) and was also associated with androgen receptor expression (P = 0.001). Thirteen (35.1%) of 37 non-muscle-invasive versus 34 (54.8%) of 62 muscle-invasive UUTUCs (P = 0.065) were immunoreactive for phospho-ELK1. Lymphovascular invasion was significantly (P = 0.014) more often seen in phospho-ELK1(2+) tumors (80.0%) than in phospho-ELK1(0/1+) tumors (36.0%). There were no statistically significant associations between phospho-ELK1 expression and tumor grade, presence of concurrent carcinoma in situ or hydronephrosis, or pN status. Kaplan-Meier and log-rank tests revealed that patients with phospho-ELK1(2+) tumor had marginally and significantly higher risks of disease progression (P = 0.055) and cancer-specific mortality (P = 0.008), respectively, compared to those with phospho-ELK1(0/1+) tumor. The current results thus support our previous observations in bladder cancer and further suggest that phospho-ELK1 overexpression serves as a predictor of poor prognosis in patients with UUTUC.

DOI： 10.3390/ijms19030777

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BACKGROUND: We previously demonstrated that a seminal plasma protein, semenogelin I (SgI), functioned as an androgen receptor (AR) coactivator. Meanwhile, several short sequence motifs in AR coregulators, such as LxxLL (L=leucine), have been shown to mediate specific interactions with AR. METHODS: We investigated the role of the LxxLL motif within SgI in the interactions with AR and cell growth in prostate cancer lines in vitro. RESULTS: A full-length SgI with mutations in the motif (i.e., LxxAA; A=alanine) failed to significantly increase cell proliferation/migration as well as androgen-mediated AR transcription. Co-immunoprecipitation showed no physical interactions between AR and the mutant SgI. In addition, transfection of an 18-amino acid peptide of SgI containing LxxLL, but not LxxAA, resulted in considerable reduction in cell growth and prostate-specific antigen expression in LNCaP and C4-2 lines. CONCLUSIONS: The LxxLL motif of SgI could be a novel therapeutic target for both androgen-sensitive and castration-resistant prostate cancers.

DOI： 10.1038/bjc.2017.404

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BACKGROUND: We investigated the role of prostaglandin receptors (e.g. prostaglandin E2 receptor 2 (EP2), EP4) and the efficacy of celecoxib in urothelial tumourigenesis and cancer progression. METHODS: We performed immunohistochemistry in bladder cancer (BC) tissue microarrays, in vitro transformation assay in a normal urothelial SVHUC line, and western blot/reverse transcription-polymerase chain reaction/cell growth assays in BC lines. RESULTS: EP2/EP4 expression was elevated in BCs compared with non-neoplastic urothelial tissues and in BCs from those who were resistant to cisplatin-based neoadjuvant chemotherapy. Strong positivity of EP2/EP4 in non-muscle-invasive tumours or positivity of EP2/EP4 in muscle-invasive tumours strongly correlated with disease progression or disease-specific mortality, respectively. In SVHUC cells, exposure to a chemical carcinogen 3-methylcholanthrene considerably increased and decreased the expression of EP2/EP4 and phosphatase and tensin homologue (PTEN), respectively. Treatment with selective EP2/EP4 antagonist or celecoxib also resulted in prevention in 3-methylcholanthrene-induced neoplastic transformation of SVHUC cells. In BC lines, EP2/EP4 antagonists and celecoxib effectively inhibited cell viability and migration, as well as augmented PTEN expression. Furthermore, these drugs enhanced the cytotoxic activity of cisplatin in BC cells. EP2/EP4 and PTEN were also elevated and reduced, respectively, in cisplatin-resistant BC sublines. CONCLUSIONS: EP2/EP4 activation correlates with induction of urothelial cancer initiation and outgrowth, as well as chemoresistance, presumably via downregulating PTEN expression.

DOI： 10.1038/bjc.2017.393

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We have recently demonstrated that ELK1, a transcription factor that triggers downstream targets including c-Fos proto-oncogene, promotes the growth of bladder cancer cells possessing a functional androgen receptor (AR). We here assessed the function of ELK1, as well as the efficacy of a selective α1A-adrenergic blocker silodosin that has been shown to inhibit ELK1 activity in bladder cancer cells, in urothelial tumorigenesis. The level of ELK1 expression in an immortalized normal urothelial cell line SVHUC stably expressing wild-type AR (SVHUC-AR) was considerably higher than that in AR-negative SVHUC-vector cells, which was induced further or reduced by dihydrotestosterone or silodosin treatment, respectively. In SVHUC-AR cells exposed to a chemical carcinogen 3-methylcholanthrene, silodosin significantly reduced the expression levels of oncogenes (e.g. c-Fos, Jun, Myc), as well as phospho-p38 MAPK and phospho-ERK proteins, and increased those of tumor suppressor genes (e.g. p53, PTEN, UGT1A). ELK1 suppression via ELK1-short hairpin RNA virus infection or silodosin treatment also resulted in significant inhibition in 3-methylcholanthrene-induced neoplastic transformation of SVHUC-AR cells, but not that of SVHUC-vector cells. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice, the incidence rate of bladder tumors was significantly (P = 0.007) lower in the silodosin group than in the control group. ELK1 thus appears to play a critical role in urothelial tumorigenesis, and silodosin prevents it presumably via down-regulation of ELK1. Moreover, ELK1 may require an activated AR for inducing neoplastic transformation of urothelial cells. Our findings may therefore offer a novel chemopreventive approach, via ELK1 inactivation using silodosin treatment, for bladder cancer.

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We recently found that NFATc1, a member of the NFAT family and a key regulator of the immune response, could induce bladder carcinogenesis and cancer progression. In this study, we immunohistochemically stained for NFATc1 in upper urinary tract urothelial carcinoma (UUTUC) specimens and paired nonneoplastic urothelial tissues. NFATc1 was positive in 51 [52%; 40 (40%) weak (1+), 9 (9%) moderate (2+), and 2 (2%) strong (3+)] of 99 UUTUCs, which was significantly higher than in benign urothelium [30 (36%) of 83; 28 (34%) weak and 2 (2%) moderate] (0 vs 1+/2+/3+, P=.038; 0/1+ vs 2+/3+, P=.023). There were no significant associations between NFATc1 expression pattern and tumor grade or pT stage. However, the positive rates of NFATc1 expression tended to be higher in renal pelvic tumors (60%) than in ureteral tumors (42%; P=.080) as well as in pN+ tumors (75%) than in pN0 tumors (49%; P=.089). Kaplan-Meier and log-rank tests revealed that moderate (2+) to strong (3+) NFATc1 expression correlated with lower progression-free survival (P=.032) and cancer-specific survival (P=.005) rates in the 99 cases. Patients with high (2+/3+) NFATc1 muscle-invasive tumor (n=9) also had a significantly higher risk of cancer-specific mortality (P=.021) compared to those with low (0/1+) NFATc1 muscle-invasive tumor (n=53). Thus, compared with nonneoplastic urothelium, a significant increase in the expression of NFATc1 in UUTUC was seen, implying the involvement of NFATc1 signals in the development of UUTUC. The current results further suggest that NFATc1 overexpression serves as a predictor of poor prognosis in patients with UUTUC.

DOI： 10.1016/j.tranon.2017.01.012

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Immunohistochemistry of a transcription factor, GATA3, has been widely used as a promising urothelial marker in diagnostic surgical pathology practice. However, the expression status of GATA3 in upper urinary tract urothelial carcinomas (UUTUCs) and its prognostic significance have not been fully investigated. We immunohistochemically stained for GATA3 in 99 UUTUC samples and paired nonneoplastic urothelial tissues. GATA3 was positive in 51 (51.5%; 32 [32.3%] weak, 11 [11.1%] moderate, 8 [8.1%] strong) of 99 UUTUCs, which was significantly lower than in benign urothelium (79 [96.3%] of 82; 33 [40.2%] weak, 35 [42.7%] moderate, 11 [13.4%] strong; P<.001). However, there were no statistically significant associations between GATA3 expression and tumor grade, pT stage, lymph node involvement, or distant metastasis. Meanwhile, the rate of GATA3 positivity was significantly higher (P=.004) in ureteral tumors (66.0%) than in renal pelvic tumors (35.6%). Kaplan-Meier and log-rank tests revealed that GATA3 negativity was significantly associated with lower recurrence-free survival (P=.037 for all cases, P=.026 for muscle-invasive tumors) and cancer-specific survival (P=.007 for all cases, P=.012 for muscle-invasive tumors, P=.035 for cases with adjuvant chemotherapy) rates. Multivariate analysis further identified strong correlations of GATA3 expression with tumor progression (all cases: hazard ratio [HR], 0.479 [95% confidence interval {CI},0.229-1.003; P=.051]; muscle-invasive tumors: HR, 0.387 [95% CI, 0.166-0.903; P=.028) or cancer-specific mortality (all cases: HR, 0.354 [95% CI, 0.135-0.925; P=.034]; muscle-invasive tumors: HR, 0.402 [95% CI, 0.149-1.086; P=.072]). Thus, compared with nonneoplastic urothelium, a significant decrease in the expression of GATA3 in UUTUC was seen. Moreover, loss of GATA3 expression was found to be an independent predictor of poor patient outcomes. Of note was that only roughly half of high-grade and/or muscle-invasive UUTUCs were immunoreactive for GATA3.

DOI： 10.1016/j.humpath.2017.04.003

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DOI： 10.1016/j.juro.2017.02.2264

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INTRODUCTION: Patients with non-muscle-invasive or muscle-invasive bladder cancer undergoing surgery and currently available conventional therapy remain having a high risk of tumor recurrence or progression, respectively. Novel targeted molecular therapy is therefore expected to improve patient outcomes. Meanwhile, substantially higher incidence of bladder cancer in men has prompted research on androgen-mediated androgen receptor (AR) signaling in this malignancy. Indeed, preclinical evidence has suggested that AR signaling plays an important role in urothelial carcinogenesis and tumor outgrowth as well as resistance to some of the currently available conventional non-surgical therapies. Areas covered: We summarize and discuss available data suggesting the involvement of AR and its potential downstream targets in the development and progression of bladder cancer. Associations between AR signaling and sensitivity to cisplatin/doxorubicin or bacillus Calmette-Guérin treatment are also reviewed. Expert opinion: AR activation is likely to correlate with the promotion of urothelial carcinogenesis and cancer outgrowth as well as resistance to conventional therapies. Molecular therapy targeting the AR may thus provide effective chemopreventive and therapeutic approaches for urothelial cancer. Accordingly, bladder cancer can now be considered as an endocrine-related neoplasm. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to bladder cancer patients is anticipated.

DOI： 10.1080/14728222.2017.1280468

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Emerging preclinical evidence suggests the critical role of androgen-mediated androgen receptor (AR) signals in the development of bladder cancer. However, little is known about the efficacy of enzalutamide, an AR signaling inhibitor, in androgen-induced urothelial tumorigenesis. We therefore aimed to assess the effects of enzalutamide on neoplastic transformation of urothelial cells. An immortalized normal urothelial cell line SVHUC stably expressing wild-type AR (SVHUC-AR) was exposed to a chemical carcinogen 3-methylcholanthrene (MCA) to induce neoplastic transformation, and subsequently cultured for 6 weeks in the presence of anti-androgens, including enzalutamide, hydroxyflutamide, and bicalutamide. Tumorigenesis was then monitored, using plate and soft agar colony formation assays as well as mouse xenograft models. In SVHUC-AR cells exposed to MCA, each anti-androgen inhibited AR-mediated transcriptional activity, but only enzalutamide prevented AR nuclear translocation. In vitro transformation showed that treatment with each anti-androgen during the process of neoplastic transformation reduced the efficiency of colony formation in vitro. Compared with mock treatment, culture with enzalutamide (P = 0.028), hydroxyflutamide (P = 0.033), or bicalutamide (P = 0.038) also resulted in prevention/retardation of tumor formation in male NOD-SCID mice. In addition, anti-androgens up-regulated the expression of several molecules that play a protective role in bladder tumorigenesis, including p53, p21, and PTEN, and down-regulated that of several oncogenic genes, such as c-myc, cyclin D1, and cyclin E, in MCA-exposed SVHUC-AR cells. Thus, enzalutamide, flutamide, and bicalutamide were found to similarly prevent neoplastic transformation of urothelial cells. These findings offer a potential chemopreventive approach for urothelial tumors using AR antagonists.

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The expression status of ZKSCAN3, a zinc-finger transcription factor containing KRAB and SCAN domains, as well as its biological significance, in human bladder cancer remains largely unknown. In the current study, we aimed to determine the functional role of ZKSCAN3 in bladder cancer progression. Immunohistochemistry in tissue specimens detected ZKSCAN3 signals in 138 (93.2%) of 148 urothelial neoplasms, which was significantly higher than in non-neoplastic urothelial tissues [76 (84.4%) of 90; P=0.044]. Correspondingly, the levels of ZKSCAN3 gene were significantly elevated in bladder tumors, compared with those in adjacent normal-appearing bladder mucosae (P=0.008). In a validation set of tissue microarray, significantly higher ZKSCAN3 expression was observed in high-grade and/or muscle-invasive urothelial carcinomas than in low-grade and/or non-muscle-invasive tumors. Two bladder cancer cell lines, UMUC3 and 647V, were found to strongly express ZKSCAN3 protein/mRNA, whereas its expression in 5637 bladder cancer and SVHUC normal urothelium cell lines was very weak. ZKSCAN3 silencing via its short hairpin RNA (shRNA) in UMUC3 and 647V resulted in significant decreases in cell viability/colony formation, cell migration/invasion, and the expression of matrix metalloproteinase (MMP)-2/MMP-9 and oncogenes c-myc/FGFR3, as well as significant increases in apoptosis and the expression of tumor suppressor genes p53/PTEN. ZKSCAN3 overexpression in 5637 also induced cell growth and migration. In addition, ZKSCAN3-shRNA expression considerably retarded tumor formation as well as its subsequent growth in xenograft-bearing mice. These results suggest that ZKSCAN3 plays an important role in bladder cancer outgrowth. Thus, ZKSCAN3 inhibition has the potential of being a therapeutic approach for bladder cancer.

DOI： 10.18632/oncotarget.10679

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Atypical protein kinase C lambda/iota (aPKC lambda/iota) is a regulator of epithelial cellular polarity. It is also overexpressed in several cancers and functions in cell proliferation and invasion. Therefore, we hypothesized that aPKC lambda/iota may be involved in development and progression of cervical intraepithelial neoplasia (CIN), the precancerous disease of cervical cancer induced by human papillomavirus. To do this, we investigated the relationship between aPKC lambda/iota expression and CIN. aPKC lambda/iota expression level and subcellular localization were assessed in 192 CIN biopsy samples and 13 normal epithelial samples using immunohistochemistry. aPKC lambda/iota overexpression (normal epithelium, 7.7%; CIN1, 41.7%; CIN2/3, 76.4%) and aPKC lambda/iota nuclear localization (normal epithelium, 0.0%; CIN1, 36.9%; CIN2/3, 78.7%) were higher in CIN samples than normal samples (P &lt; 0.05), suggesting that CIN grade is related to aPKC lambda/iota overexpression and nuclear localization. Then, 140 CIN cases were retrospectively analyzed for 4-yr cumulative disease progression and regression rates using the Cox proportional hazards model. CIN1 cases with aPKC lambda/iota overexpression or aPKC lambda/iota nuclear localization had a higher progression rate than CIN1 cases with normal aPKC lambda/iota expression levels or cytoplasmic localization (62.5% vs. 9.7% and 63.1% vs. 9.4%, respectively; P &lt; 0.001). Multivariate analysis indicated that human papillomavirus types 16 and 18, aPKC lambda/iota overexpression (hazard ratio=4.26; 95% confidence interval, 1.50-12.1; P=0.007), and aPKC lambda/iota nuclear localization (hazard ratio=3.59; 95% confidence interval, 1.24-10.4; P=0.019) were independent risk factors for CIN1 progression. In conclusion, aPKC lambda/iota could be useful for the therapeutic management of patients with CIN, particularly those with non-human papillomavirus 16/18 types.

DOI： 10.1097/PGP.0000000000000228

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

To assess the expression status of steroid hormone receptors in upper urinary tract urothelial carcinoma (UUTUC), we immunohistochemically stained for androgen receptor (AR), estrogen receptor-alpha (ER alpha), ER beta, glucocorticoid receptor (GR), and progesterone receptor (PR) in 99 UUTUC specimens and paired nonneoplastic urothelial tissues. AR/ER alpha/ER beta/GR/PR was positive in 20%/18%/62%/63%/16% of tumors, which was significantly lower (except PR) than in benign urothelial tissues [57% (P &lt; 0.001)/40% (P = 0.001)/85% (P = 0.001)/84% (P = 0.002)/13% (P = 0.489)]. There were no significant associations between each receptor expression pattern and histopathological characteristic of the tumors including tumor grade/stage. Kaplan-Meier and log-rank tests revealed no significant prognostic value of each receptor expression in these 99 patients. However, patients with UUTUC positive for either ER alpha or PR had a significantly higher risk of disease-specific mortality (P = 0.025), compared with those with UUTUC negative for both. PR positivity alone in pT3 or pT4 tumors was also strongly associated with the risk of disease-specific mortality (P = 0.040). Multivariate analysis further identified the expression of ER alpha and/or PR as a strong predictor for disease-specific mortality in the entire cohort of the patients (hazard ratio, 2.434; P = 0.037). Thus, in accordance with previous observations in bladder specimens, significant decreases in the expression of AR/ER alpha/ER beta/GR in UUTUC, compared with that in non-neoplastic urothelium, were observed. Meanwhile, the negativity of both ERa and PR in UUTUC as well as the negativity of PR alone in deeply invasive tumor was suggested to serve as a prognosticator.

DOI： 10.1080/15384047.2016.1235667

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

OBJECTIVE: Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth.
STUDY DESIGN: Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry.
RESULTS: EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 +/- 4122 vs 1455 +/- 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (rho = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test).
CONCLUSION: This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which some uterine leiomyomas reach a large size, and the understanding of EPO expression patterns in these tumors may be useful for management of the patients with leiomyomas.

DOI： 10.1016/j.ajog.2015.02.016

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Language：Japanese   Publisher：神奈川産科婦人科学会  

57歳(0経妊0経産婦)。下腹部膨満感と体重減少を主訴とした。経腟超音波、MRI、血液腫瘍マーカーより子宮体癌と診断され、単純子宮全摘出術+両側付属器摘出術+大網切除術を施行、病理組織学的にstage IIbの同所性癌肉腫であった。しかし術後、化学療法としてTC療法を3コース施行したが縦隔・肺門部にリンパ節転移が認められ、PDと判断し、IA療法を6コース施行することでCRが得られた。目下、治療終了後31ヵ月経過で再発や転移は認められていない。尚、2009年〜2011年までに著者らが経験した子宮癌肉腫4例の検討では、うち2例は初回TC療法後に再発・転移を来したが、いずれも化学療法や放射線療法にて担癌生存中であった。

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Language：Japanese   Publisher：(株)診断と治療社  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J00525&link_issn=&doc_id=20130524170014&doc_link_id=%2Fae4sanke%2F2013%2F008006%2F015%2F0777-0783%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2013%2F008006%2F015%2F0777-0783%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

Aim: The aim of this study was to identify factors that can predict the resistance to parenteral therapy in patients with tubo-ovarian abscesses (TOA). Material and Methods: We conducted a case-control study involving 55 admitted patients with TOA. The subjects eligible for this study included 28 patients who failed antibiotic therapy and required surgery (surgical cases) and 27 patients who were conservatively cured (control cases). The clinical characteristics of the patients on admission were reviewed. Logistic regression analysis was performed after univariate analysis to identify potentially important variables and to calculate odds ratios with 95% confidence intervals. Results: As per the univariate analysis, compared to the control cases, the surgical cases were older (40.4 vs 31.5 years), had higher white blood cell counts (14000 vs 11828 cells/mm3), higher C-reactive protein levels (16.1 vs 7.6 mg/dL), and a larger abscess diameter (6.6 vs 3.9 cm). There were no significant differences in gravidity, parity, body temperature, rate of endometrial cyst formation, and Chlamydia trachomatis infection rates between the groups. Multiple logistic regression analysis indicated that the only statistically significant risk factor predicting parenteral antibiotic therapy failure was the abscess diameter &gt
5 cm (odds ratio = 69.6
95% confidence interval = 9.3-527, P &lt
0.0001). Conclusion: An abscess diameter &gt
5 cm is an important factor for predicting the failure of antibiotic therapy in patients with TOA. Moreover, it is useful for determining whether patients with TOA should be surgically treated. © 2013 The Authors.

DOI： 10.1111/jog.12018

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Overexpression of atypical protein kinase C/ (aPKC/), a regulator of cell polarity, is frequently associated with the poor prognoses of several cancers, including gastric cancer. Recent studies revealed a molecular link between aPKC and KIBRA, an upstream regulator of tumor suppressor Hippo pathway that regulates cell proliferation and apoptosis. Further, KIBRA directly inhibits the kinase activity of aPKC to regulate epithelial cell polarity. These observations suggest that the KIBRA-aPKC connection plays a role in cancer progression; however, clinical significance of the correlation between these factors remains unclear. Here we examined the correlation between KIBRA/aPKC/ expression, as detected by immunohistochemistry, and clinicopathological outcomes in 164 gastric cancer patients using Fisher's exact test and KaplanMeier log-rank test. We found an intimate correlation between the expression level of KIBRA and aPKC/ (P=0.012). Furthermore, high expression of KIBRA is correlated with lymphatic (P=0.046) and venous invasion (P=0.039). The expression level of KIBRA by itself did not correlate with the prognosis; however, high expression of KIBRA in low aPKC/-expressing gastric cancer correlated with disease-specific (P=0.037) and relapse-free survival (P=0.041) by KaplanMeier with log-rank test and higher lymphatic invasion cases by Fisher's exact test (P=0.042). Furthermore, overexpression of the aPKC-binding region of KIBRA disrupted tight junctions in epithelial cells. These results suggest that high expression of KIBRA in low aPKC-expressing cells causes massive loss of aPKC activity, leading to loss of polarity and invasiveness of gastric cancer cells.

DOI： 10.1111/cas.12066

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Language：Japanese   Publisher：神奈川産科婦人科学会  

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Language：Japanese   Publisher：神奈川産科婦人科学会  

卵巣腫瘍における術中迅速病理組織検査(以下迅速診断)は、良悪性や組織型を術中に鑑別することで適切な術式選択を可能とし、不要な二期的手術や拡大手術を防ぐために重要である。2014年7月から2019年6月までに当院で迅速診断を施行した卵巣腫瘍118例を対象とし、最終病理診断との乖離、手術術式に与えた影響、合併症、予後等について診療録をもとに後方視的に検討した。最終病理診断は良性31例、境界悪性25例、悪性62例であった。迅速診断と最終病理診断との乖離は18例で認められ、迅速診断の正診率は84.7%であった。2016年7月に卵巣腫瘍・卵管癌・腹膜癌取扱い規約が改訂され良悪性の診断基準が一部変更されたが、規約改定前後での乖離はそれぞれ3例、15例であった。正診率はそれぞれ94.1%、77.6%と有意な差を認めた(p=0.019)。迅速診断の正診率低下には、規約改訂による境界悪性の微小浸潤の定義の変更が関与している可能性が示唆された。間質浸潤の所見をもとに迅速診断で悪性と過大評価した境界悪性の2例では、骨盤及び傍大動脈リンパ節の系統的郭清による術後合併症として乳び漏、下肢浮腫をそれぞれ1例ずつ認めた。迅速診断で間質浸潤の有無を評価するには限界があり、最終病理診断との乖離が生じる可能性を考える必要がある。その場合には術前と術中の臨床的所見も含めた総合的な視野で、合併症のリスクを伴う拡大手術を避けるため、二期的手術も念頭においた術式選択を考慮すべきである。(著者抄録)

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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J-GLOBAL

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Language：Japanese   Publisher：金原出版(株)  

＜文献概要＞子宮頸がんは,1次予防としてのHPVワクチン接種と2次予防としての高度前がん病変を検出可能な検診の組み合わせで,将来的に排除されうる疾患となった.しかし,日本では,機能性身体症状とされる副反応問題による2013年からの積極的接種勧奨の差し控えにより,接種率はほぼゼロに近い状況であることに加え,検診受診率も約40%と低迷している.本邦で若い女性に罹患リスクが高い本疾患の罹患率・死亡率を減らすために,早期の積極的接種勧奨再開は必須であるが,高い接種率を回復することは容易ではないと考えられる.一方で2020年以降に,4価HPVワクチンの男性への適応拡大,9価HPVワクチンの発売があり,適切な情報の国民への周知が喫緊の課題である.

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00639&link_issn=&doc_id=20210622130004&doc_link_id=10.18888%2Fsh.0000001744&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fsh.0000001744&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：神奈川産科婦人科学会  

今回我々はベバシズマブ投与中に血栓症の初発症状として皮膚症状が出現したが、その原因を臨床的抗リン脂質抗体症候群と診断し抗血小板薬を投与しながらベバシズマブ併用化学療法を継続できた症例を経験したので報告する。症例は73歳。3妊3産。食思不振と腹部膨満感で紹介、画像検査で12cm大の左卵巣腫瘍、多発腹膜播種、大量腹水貯留、肝臓には最大径6cmの腫瘍を認めた。腹式単純子宮全摘術、両側付属器切除術、大網部分切除術及び腹膜生検を施行し、卵巣癌IVB期と診断した。残存する肝転移に対してパクリタキセル、カルボプラチン、ベバシズマブの併用療法を開始したところ、4サイクル投与日に右第2指及び第3指に爪の黒色変化を生じた。パクリタキセルの有害事象と考え継続したが、投与3日後に指の皮膚末端の黒色壊死への増悪を認めた。5サイクル目の治療を延期とし、臨床所見及び血液検査で抗リン脂質抗体が陽性であったことから臨床的抗リン脂質抗体症候群と診断した。外用薬や抗血小板薬を使用して8週間程で皮膚症状は改善したため、抗血小板薬を投与しながらベバシズマブ併用化学療法を再開することができた。化学療法による重篤な有害事象を疑った場合にすぐにベバシズマブを中止するのではなく血栓の原因を精査することで、ベバシズマブ投与が継続できる可能性がある。(著者抄録)

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Language：Japanese   Publisher：神奈川産科婦人科学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2020-2071

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：神奈川産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(株)メジカルビュー社  

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.juro.2017.02.2733

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.juro.2017.02.1494

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：日本産科婦人科学会  

CiNii Books

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=456337

Language：Japanese  

J-GLOBAL

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Language：Japanese  

CiNii Books

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：日本産科婦人科学会  

CiNii Books

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=453169

Language：Japanese   Publisher：日本産科婦人科学会  

CiNii Books

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=450446