Region-specific regulation of cell proliferation by FGF receptor signaling during the Wolffian duct development.

The Wolffian duct (WD) is a primordium of the male reproductive tract and kidney collecting duct system. Fibroblast growth factor receptors (FGFRs), members of the receptor tyrosine kinase (RTK) family, are essential for kidney development. Although the functions of FGFR signaling in kidney morphogenesis have been analyzed, their function in WD development has not been comprehensively investigated. Here, we demonstrate that Fgfr2 is the major Fgfr gene expressed throughout the WD epithelia and that it is essential for the maintenance of the WD, specifically in the caudal part of the WD. Hoxb7-Cre mediated inactivation of Fgfr2 in the mouse WD epithelia resulted in the regression of the caudal part of the WD and abnormal male reproductive tract development. Cell proliferation and expression of the downstream target genes of RTK signaling (Etv4 and Etv5) were decreased in the caudal part of the WD epithelia in the mutant embryos. Cranial (rostral) WD formation and ureteric budding were not affected. Ret, Etv4, and Etv5 expression were sustained in the ureteric bud of the mutant embryos. Taken together, these data suggest region-specific requirements for FGFR2 signaling in the developing caudal WD epithelia.

Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm.

During organogenesis, Sonic hedgehog (Shh) possesses dual functions: Shh emanating from midline structures regulates the positioning of bilateral structures at early stages, whereas organ-specific Shh locally regulates organ morphogenesis at later stages. The mesonephros is a transient embryonic kidney in amniote, whereas it becomes definitive adult kidney in some anamniotes. Thus, elucidating the regulation of mesonephros formation has important implications for our understanding of kidney development and evolution. In Shh knockout (KO) mutant mice, the mesonephros was displaced towards the midline and ectopic mesonephric tubules (MTs) were present in the caudal mesonephros. Mesonephros-specific ablation of Shh in Hoxb7-Cre;Shh(flox/-) and Sall1(CreERT2/+);Shh(flox/-) mice embryos indicated that Shh expressed in the mesonephros was not required for either the development of the mesonephros or the differentiation of the male reproductive tract. Moreover, stage-specific ablation of Shh in Shh(CreERT2/flox) mice showed that notochord- and/or floor plate-derived Shh were essential for the regulation of the number and position of MTs. Lineage analysis of hedgehog (Hh)-responsive cells, and analysis of gene expression in Shh KO embryos suggested that Shh regulated nephrogenic gene expression indirectly, possibly through effects on the paraxial mesoderm. These data demonstrate the essential role of midline-derived Shh in local tissue morphogenesis and differentiation.

Reirradiation using high-dose-rate interstitial brachytherapy for locally recurrent cervical cancer: a single institutional experience.

OBJECTIVES: This study aimed to evaluate the effectiveness and feasibility of reirradiation using high-dose-rate interstitial brachytherapy (HDR-ISBT) in patients with recurrent cervical cancer. METHODS: The records of 52 consecutive women with central pelvic recurrence who were salvaged with HDR-ISBT-based reirradiation were retrospectively reviewed. Data regarding the primary disease, follow-up findings, recurrence, the treatment outcome, and toxicities were collected. Multivariate analysis was performed using the Cox proportional hazards regression model to identify predictors of the response to HDR-ISBT. Survival rate was calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 52 patients who had been treated with HDR-ISBT-based reirradiation were included in our database. The local control rate was 76.9% (40/52), and the median postrecurrence survival period was 32 months. Grade 3 or 4 late toxicities were observed in 13 patients (25%). Multivariate analysis revealed that tumor size and the treatment-free interval were significant poor prognostic factors of postrecurrence survival. In a comparison between the patients who were salvaged with HDR-ISBT-based reirradiation (ISBT group) and those who were treated with palliative therapy alone (palliative group), we found that among the patients who displayed 0 or 1 poor prognostic factors, the patients in the ISBT group survived significantly longer than those in the palliative group. In contrast, similar survival rates were seen in both groups among the patients with 2 or more poor prognostic factors. CONCLUSIONS: Reirradiation using HDR-ISBT is effective and feasible in patients with recurrent cervical cancer. Our 2-clinical variable prognostic model might enable physicians to identify patients who would not derive clinical benefit from HDR-ISBT and offer them the opportunity to receive other types of treatment.

Impact of the addition of concurrent chemotherapy to pelvic radiotherapy in surgically treated stage IB1-IIB cervical cancer patients with intermediate-risk or high-risk factors: a 13-year experience.

OBJECTIVES: To identify groups of patients who derive clinical benefit from postoperative adjuvant concurrent chemoradiotherapy (CCRT), we retrospectively investigated the survival outcomes of surgically treated early-stage cervical cancer patients. METHODS: We reviewed the medical records of 316 patients with FIGO stage IB1-IIB cervical cancer who had been treated with adjuvant radiotherapy (RT) (n = 124, RT group) or adjuvant CCRT (n = 192, CCRT group) after radical hysterectomy between January 1996 and December 2009. Of these, 187 patients displayed high-risk prognostic factors (high-risk group), and 129 displayed intermediate-risk prognostic factors (intermediate-risk group). Sixty patients with 1 intermediate-risk prognostic factor who received no adjuvant therapy were also identified and used as controls (NFT group). Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: In the high-risk group, adjuvant CCRT was significantly superior to RT alone with regard to recurrence rate, progression-free survival (PFS), and overall survival. In the intermediate-risk group, CCRT was superior to RT with regard to recurrence rate and PFS in patents with 2 or more risk factors. Among the patients with only 1 intermediate-risk factor, although no survival benefit of CCRT over RT was observed, addition of adjuvant treatment resulted in significantly improved PFS compared with the NFT group in patients with deep stromal invasion (log-rank, P = 0.012). CONCLUSIONS: Postoperative CCRT improved the prognosis of FIGO stage IB1-IIB cervical cancer patients in the high-risk group and patients who displayed 2 or more intermediate-risk factors. Patients who displayed deep stromal invasion alone also derived clinical benefit from adjuvant treatment.

Impact of histological subtype on survival of patients with surgically-treated stage IA2-IIB cervical cancer: adenocarcinoma versus squamous cell carcinoma.

OBJECTIVES: To evaluate the significance of adenocarcinoma (AC) compared with squamous cell carcinoma (SCC) with regard to the survival of surgically-treated early stage cervical cancer patients. METHODS: We retrospectively reviewed the medical records of 520 patients with FIGO stage IA2-IIB cervical cancer who were treated with radical hysterectomy with or without adjuvant radiotherapy between January 1998 and December 2008. The patients were classified according to (i) pathological risk factors (low-, intermediate-, or high-risk group) and (ii) adjuvant radiotherapy (concurrent chemoradiotherapy [CCRT group] or radiotherapy alone [RT group]). Survival outcomes were examined by Kaplan-Meier method and compared with Log-rank test. Multivariate analysis for disease-specific survival (DSS) was performed using Cox proportional hazards regression model to investigate the prognostic significance of histological subtype. RESULTS: AC histology was associated with significantly decreased DSS compared with SCC histology in the intermediate- and high-risk groups (hazard ratio: 3.06 and 2.88, respectively, both P<0.05) while there was no survival difference in the low-risk group (P=0.1). Among patients who received any types of adjuvant radiotherapy, DSS of AC histology patients were significantly poorer than SCC histology. Multivariate analysis demonstrated AC histology to be an independent predictor of decreased DSS in both CCRT and RT groups. Moreover, pelvic nodal metastasis significantly predicted the poor survival of patients with AC histology who received CCRT in multivariate analysis CONCLUSIONS: Adenocarcinoma is an independent prognostic indicator of poor survival in early stage cervical cancer patients with intermediate- and high-risk factors, regardless of the type of adjuvant radiotherapy after radical hysterectomy.

The prognostic significance of multiple pelvic node metastases in cervical cancer patients treated with radical hysterectomy plus adjuvant chemoradiotherapy.

OBJECTIVE: We investigated the prognostic significance of multiple pelvic node metastases in cervical cancer patients who were treated with radical hysterectomy plus adjuvant chemoradiotherapy. METHODS: We retrospectively reviewed the medical records of 311 patients with International Federation of Gynecology and Obstetrics stage IB1-IIB cervical cancer who had been treated with radical hysterectomy plus adjuvant radiotherapy (RT) between January 1998 and December 2008. Of these, 119 received adjuvant RT and 192 received adjuvant concurrent chemoradiotherapy (CCRT) postoperatively. Multivariate analysis for progression-free survival (PFS) was performed using the Cox proportional hazards regression model to investigate the prognostic significance of pelvic node metastases in the 2 treatment groups. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Multivariate analysis demonstrated pelvic node metastasis to be an independent prognostic factor for shorter PFS in both treatment groups. When the node-positive patients were analyzed according to the number of positive pelvic nodes, we found that the patients with multiple pelvic node metastases (≥3) displayed significantly shorter PFS than those with 1 or 2 pelvic node metastases in the RT group. In contrast, in the CCRT group, the PFS of the patients with multiple pelvic node metastases (≥3) was similar to that observed of the patients with 1 or 2 pelvic node metastases. CONCLUSIONS: The presence of multiple pelvic node metastases was not an independent predictor of shorter PFS in the CCRT group.

Comparison of the prognoses of FIGO stage I to stage II adenosquamous carcinoma and adenocarcinoma of the uterine cervix treated with radical hysterectomy.

OBJECTIVES: To evaluate the significance of adenosquamous carcinoma (ASC) compared with adenocarcinoma (AC) in the survival of surgically treated early-stage cervical cancer. METHODS: We retrospectively reviewed the medical records of 163 patients with International Federation of Gynecology and Obstetrics stage IA2 to stage IIB cervical cancer who had been treated with radical hysterectomy with or without adjuvant radiotherapy between January 1998 and December 2008. The patients were classified according to the following: (1) histological subtype (ASC group or AC group) and (2) pathological risk factors (low-risk or intermediate/high-risk group). Survival was evaluated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis of progression-free survival (PFS) was performed using the Cox proportional hazards regression model to investigate the prognostic significance of histological subtype. RESULTS: Clinicopathological characteristics were similar between the ASC and AC histology groups. Patients with the ASC histology displayed a PFS rate similar to that of the patients with the AC histology in both the low-risk and intermediate/high-risk groups. Neither the recurrence rate nor the pattern of recurrence differed between the ASC group and the AC group. Univariate analysis revealed that patients with pelvic lymph node metastasis and parametrial invasion achieved significantly shorter PFS than those without these risk factors. CONCLUSIONS: Characteristics of the patients and the tumors as well as survival outcomes of ASC were comparable to adenocarcinoma of early-stage uterine cervix treated with radical hysterectomy. Our results in part support that the management of ASC could be the same as the one of AC of the uterine cervix.

Postoperative whole pelvic radiotherapy plus concurrent chemotherapy versus extended-field irradiation for early-stage cervical cancer patients with multiple pelvic lymph node metastases.

OBJECTIVES: The aim of this study was to compare the efficacy of postoperative pelvic radiotherapy plus concurrent chemotherapy with that of extended-field irradiation (EFRT) in patients with FIGO Stage IA2-IIb cervical cancer with multiple pelvic lymph node metastases. METHODS: We retrospectively reviewed the medical records of patients with FIGO Stage IA2-IIb cervical cancer who had undergone radical surgery between April 1997 and March 2008. Of these, 55 patients who demonstrated multiple pelvic lymph node metastases were treated postoperatively with pelvic radiotherapy plus concurrent chemotherapy (n=29) or EFRT (n=26). Thirty-six patients with single pelvic node metastasis were also treated postoperatively with pelvic radiotherapy plus concurrent chemotherapy. The recurrence rate, progression free survival (PFS), and overall survival (OS) were compared between the treatment groups. RESULTS: Pelvic radiotherapy plus concurrent chemotherapy was significantly superior to EFRT with regard to recurrence rate (37.9% vs 69.2%, p=0.0306), PFS (log-rank, p=0.0236), and OS (log-rank, p=0.0279). When the patients were treated with pelvic radiotherapy plus concurrent chemotherapy, there was no significant difference in PFS or OS between the patients with multiple lymph node metastases and those with single node metastases. With regards to grade 3-4 acute or late toxicities, no statistically significant difference was observed between the two treatment groups. CONCLUSIONS: Postoperative pelvic radiotherapy plus concurrent chemotherapy is superior to EFRT for treating patients with FIGO Stage IA2-IIb cervical cancer displaying multiple pelvic lymph node metastases.

Radical hysterectomy with adjuvant radiotherapy versus definitive radiotherapy alone for FIGO stage IIB cervical cancer.

OBJECTIVES: The aim of this study was to compare the treatment outcomes and adverse effects of radical hysterectomy followed by adjuvant radiotherapy with definitive radiotherapy alone in patients with FIGO stage IIB cervical cancer. METHODS: We retrospectively reviewed the medical records of FIGO stage IIB cervical cancer patients who were treated between April 1996 and December 2009. During the study period, 95 patients were treated with radical hysterectomy, all of which received adjuvant radiotherapy (surgery-based group). In addition, 94 patients received definitive radiotherapy alone (RT-based group). The recurrence rate, progression-free survival (PFS), overall survival (OS), and treatment-related complications were compared between the two groups. RESULTS: Radical hysterectomy followed by adjuvant radiotherapy resulted in comparable recurrence (44.2% versus 41.5%, p=0.77), PFS (log-rank, p=0.57), and OS rates (log-rank, p=0.41) to definitive radiotherapy alone. The frequencies of acute grade 3-4 toxicities were similar between the two groups (24.2% versus 24.5%, p=1.0), whereas the frequencies of grade 3-4 late toxicities were significantly higher in the surgery-based group than in the RT-based group (24.1% versus 10.6%, p=0.048). Cox multivariate analyses demonstrated that treatment with surgery followed by adjuvant radiotherapy was associated with an increased risk of grade 3-4 late toxicities, although the statistical significance of the difference was marginal (odds ratio 2.41, 95%CI 0.97-5.99, p=0.059). CONCLUSIONS: Definitive radiotherapy was found to be a safer approach than radical hysterectomy followed by postoperative radiotherapy with less treatment-related complications and comparable survival outcomes in patients with FIGO stage IIB cervical cancer.

Clonality and HPV infection analysis of concurrent glandular and squamous lesions and adenosquamous carcinomas of the uterine cervix.

We analyzed the clonality and human papillomavirus (HPV) infection status of concurrent glandular and squamous lesions and adenosquamous carcinomas of the uterine cervix to clarify their histogenesis. The glandular and squamous components were clonally different from each other in 7 informative concurrent lesions. HPV was episomal in 2 polyclonal glandular dysplasias (GDs). HPV was in a mixed integrated-episomal form in a monoclonal GD, an adenocarcinoma in situ, and an adenocarcinoma. Both tumor components were monoclonal in origin in 6 adenosquamous carcinomas, with identical patterns of X-chromosomal inactivation and types and physical status of HPV. These results imply that the concurrent glandular and squamous lesions are formed separately, whereas adenosquamous carcinoma is more likely to be a combination tumor of monoclonal origin, and that integration of HPV has an important role in the progression from polyclonal GD through monoclonal expansion to adenocarcinoma in situ and adenocarcinoma.

[Efficacy of 5-FU hepatic arterial infusion with l-leucovorin for patients with unresectable colorectal liver metastasis].

We investigated the efficacy of 5-FU hepatic artery infusion (HAI)for patients with unresectable colorectal liver metastasis. Fifteen patients who received HAI between June 2004 and December 2006 were studied. HAI was attempted as first-line chemotherapy in seven patients(Group A)and as second-line or more in eight(Group B). The response rate, time to progression, survival and toxicity were compared with those of 39 patients treated with systemic chemotherapy(18 as first-line: Group C, 21 as second-line or more: Group D). Response rate was 85.7%, 35.7%, 50.0%, and 4.8% in Groups A, B, C, and D, respectively. Time to progression was 12.5 months, 4.7 months, 5.8 months, and 2.3 months, in Groups A, B, C, and D, respectively, and significantly longer in Group A compared with Group C, as well as in Group B compared with Group D. Median survival was 15.4 months, 9.1 months, 11.3 months, and 8.0 months in Groups A, B, C, and D, respectively, and significantly longer in Group B compared with Group D. Grade 3 or 4 non-hematological toxicity was not observed in Group A and B. HAI was effective for the control of unresectable colorectal liver metastasis and improved survival as second-line chemotherapy or more.

Chemoradiotherapy followed by consolidation chemotherapy involving paclitaxel and carboplatin and in FIGO stage IIIB/IVA cervical cancer patients.

OBJECTIVE: To evaluate the efficacy and toxicity of paclitaxel plus carboplatin (TC)-based concurrent chemoradiotherapy (CCRT) followed by consolidation chemotherapy in the International Federation of Gynecology and Obstetrics (FIGO) stage IIIB/IVA cervical cancer patients. METHODS: We reviewed the medical records of FIGO stage IIIB/IVA cervical cancer patients (n=30) who had been intended to be treated with TC-based CCRT followed by consolidation chemotherapy (TC-CCRT-group) from April 2012-May 2016. Patients who had been treated with CCRT involving a single platinum agent (CCRT-group; n=52) or definitive radiotherapy alone (RT-group; n=74) from January 1997-September 2012 were also identified and used as historical controls. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Of the 30 patients included in the TC-CCRT-group, 22 patients (73.3%) completed the planned TC-based CCRT. The most frequently observed acute grade 3/4 hematological toxicities were leukopenia and neutropenia, and diarrhea was the most common acute grade 3/4 non-hematological toxicity. After a median follow-up of 35 months, 9 patients (30.0%) had developed recurrent disease. The patients' estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 67.9% and 90.8%, respectively. In comparisons with historical control groups, the survival outcomes of TC-CCRT-group was significantly superior to CCRT-group in terms of OS (p=0.011) and significantly superior to RT-group in terms of both PFS (p=0.009) and OS (p<0.001). CONCLUSION: TC-based CCRT followed by consolidation chemotherapy is safe and effective. A randomized controlled study needs to be conducted to further evaluate the efficacy of this multimodal approach in this patient population.

Clinical implication of surgically treated early-stage cervical cancer with multiple high-risk factors.

OBJECTIVE: Presence of high-risk factor in cervical cancer is known to be associated with decreased survival outcomes. However, the significance of multiple high-risk factors in early-stage cervical cancer related to survival outcomes, recurrence patterns, and treatment implications is not well elucidated. METHODS: A retrospective study was conducted for surgically treated cervical cancer patients (stage IA2-IIB, n=540). Surgical-pathological risk factors were examined and tumors expressing ≥1 high-risk factors (nodal metastasis, parametrial involvement, or positive surgical margin) were eligible for analysis (n=177, 32.8%). Survival analysis was performed based on the number of high-risk factors and the type of adjuvant therapy. RESULTS: There were 68 cases (38.4%) expressed multiple high-risk factors (2 high-risk factors: n=58, 32.8%; 3 high-risk factors: n=10, 5.6%). Multiple high-risk factors remained an independent prognosticator for decreased survival outcomes after controlling for age, histology, stage, and treatment type (disease-free survival: hazard ratio [HR], 2.34; p=0.002; overall survival: HR, 2.32; p=0.007). Postoperatively, 101 cases (57.1%) received concurrent chemoradiotherapy (CCRT) and 76 cases (42.9%) received radiotherapy (RT) alone. CCRT was beneficial in single high-risk factor cases: HRs for CCRT over RT alone for cumulative risk of locoregional and distant recurrence, 0.27 (p=0.022) and 0.27 (p=0.005), respectively. However, tumor expressing multiple high-risk factors completely offset the benefit of CCRT over RT alone for the risk of distant recurrence: HR for locoregional and distant recurrence, 0.31 (p=0.071) and 0.99 (p=0.980), respectively. CONCLUSION: Special consideration for the significance of multiple high-risk factors merits further investigation in the management of surgically treated early-stage cervical cancer.

Development of the external genitalia and their sexual dimorphic regulation in mice.

The study of the external genitalia is divided into 2 developmental stages: the formation and growth of a bipotential genital tubercle (GT) and the sexual differentiation of the male and female GT. The sexually dimorphic processes, which occur during the second part of GT differentiation, are suggested to be governed by androgen signaling and more recently crosstalk with other signaling factors. The process of elucidating the regulatory mechanisms of hormone signaling towards other signaling networks in the GT is still in its early stages. Nevertheless, it is becoming a productive area of research. This review summarizes various studies on the development of the murine GT and the defining characteristics of a masculinized GT and presents the different signaling pathways possibly involved during masculinization.

Dissection of unsuspicious para-aortic lymph nodes does not improve prognosis of advanced endometrial carcinoma with intra- or extra-abdominal metastasis.

BACKGROUND: The aim of this study was to analyze the significance of dissection of unsuspicious para-aortic lymph nodes (PAN) in patients with advanced endometrial carcinomas with intra- or extra-abdominal metastasis. PATIENTS AND METHODS: We conducted a retrospective comparison of the results of PAN dissection versus non-dissection for endometrial carcinomas with macroscopic metastatic lesions beyond the uterus (without significant swelling of the regional lymph nodes, including PAN), whose lesions were completely resected. RESULTS: Disease-free survival and overall survival did not exhibit a significant difference between the two groups. Multivariate Cox proportional hazards analysis demonstrated that PAN dissection was not an independent prognostic factor for survival. The frequency of PAN involvement at the first recurrence did not differ between the two groups. CONCLUSION: For advanced endometrial carcinomas with macroscopic metastatic lesions beyond the uterus, without significant swelling of regional lymph nodes, PAN dissection may be omitted without a significant adverse effect on prognosis and survival.

Chemotherapy for endometrial carcinoma (GOGO-EM1 study): TEC (paclitaxel, epirubicin, and carboplatin) is an effective remission-induction and adjuvant therapy.

BACKGROUND: TAP chemotherapy (paclitaxel, doxorubicin, and cisplatin) is effective for advanced and recurrent endometrial carcinoma, but has occasional severe toxicity. TEC chemotherapy (paclitaxel, epirubicin, and carboplatin) has been suggested to have less toxicity; however, the optimal dosage has yet to be determined. PATIENTS AND METHODS: Phase I/II prospective study for TEC therapy was performed. A retrospective comparison of the prognosis between adjuvant TEC therapy and radiation for completely resected cases with risk factors was also performed. RESULTS: The recommended dose of TEC therapy was determined to be paclitaxel 150 mg/m(2), epirubicin 50 mg/m(2), and carboplatin AUC 4. A TEC regimen at this dose level was shown to be tolerable. The response rate and median overall survival were 74% and 37 months for those with advanced primary disease (Group B) and 50% and 26 months for recurrent tumors (Group C), respectively. A retrospective comparison showed that adjuvant TEC therapy for completely resected stage III cases improved their prognosis when compared to an adjuvant radiation therapy. CONCLUSION: TEC therapy was demonstrated to be a tolerable and effective treatment, not only as a remission-induction therapy for advanced and recurrent endometrial carcinomas but also as the adjuvant therapy.