Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. PATIENTS AND METHODS: Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. RESULTS: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. CONCLUSIONS: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

Relationships among maxillofacial morphologies, bone properties, and bone metabolic markers in patients with jaw deformities.

The aim of this study was to determine the relationships among bone properties, bone metabolic markers, and types of jaw deformity. The subjects were 55 female patients with jaw deformities. Skeletal morphology was examined using lateral cephalograms, and the patients were divided into three groups according to the type of anteroposterior skeletal pattern. Serum osteocalcin, bone alkaline phosphatase, and tartrate-resistant acid phosphatase isoform 5b, as well as deoxypyridinoline in urine, were measured as bone metabolic markers. Quantitative ultrasound (QUS) measurements were used to assess bone properties at the calcaneal bone. The bone volume and bone density of the condylar process were measured in 43 patients by computed tomography. There were no significant differences in bone metabolic markers and QUS parameters between the groups, although bone formation and resorption markers tended to be higher in patients with a protrusive mandible. On the other hand, patients with mandibular retrusion had a higher tendency to have small and dense condylar processes. In conclusion, the results suggest that growth depression or a degenerative change in the mandibular condyle is involved in the pathogenesis of mandibular retrusion, although risk factors for progressive condylar resorption were not determined.

Downregulation of Ral GTPase-activating protein promotes tumor invasion and metastasis of bladder cancer.

The small GTPase Ral is known to be highly activated in several human cancers, such as bladder, colon and pancreas cancers. It is reported that activated Ral is involved in cell proliferation, migration and metastasis of bladder cancer. This protein is activated by Ral guanine nucleotide exchange factors (RalGEFs) and inactivated by Ral GTPase-activating proteins (RalGAPs), the latter of which consist of heterodimers containing a catalytic α1 or α2 subunit and a common ß subunit. In Ras-driven cancers, such as pancreas and colon cancers, constitutively active Ras mutant activates Ral through interaction with RalGEFs, which contain the Ras association domain. However, little is known with regard to the mechanism that governs aberrant activation of Ral in bladder cancer, in which Ras mutations are relatively infrequent. Here, we show that Ral was highly activated in invasive bladder cancer cells due to reduced expression of RalGAPα2, the dominant catalytic subunit in bladder, rather than increased expression of RalGEFs. Exogenous expression of wild-type RalGAPα2 in KU7 bladder cancer cells with invasive phenotype, but not mutant RalGAPα2-N1742K lacking RalGAP activity, resulted in attenuated cell migration in vitro and lung metastasis in vivo. Furthermore, genetic ablation of Ralgapa2 promoted tumor invasion in a chemically-induced murine bladder cancer model. Importantly, immunohistochemical analysis of human bladder cancer specimens revealed that lower expression of RalGAPα2 was associated with advanced clinical stage and poor survival of patients. Collectively, these results are highly indicative that attenuated expression of RalGAPα2 leads to disease progression of bladder cancer through enhancement of Ral activity.

Inflammatory histopathogenesis of nasopalatine duct cyst: a clinicopathological study of 41 cases.

OBJECTIVE: The aim of this study is to characterize immunohistochemical profiles of lining epithelia of nasopalatine duct cyst (NPC) as well as to correlate those findings with their clinicopathological features to understand the histopathogenesis of NPC. MATERIALS AND METHODS: Forty-one surgical specimens from NPC were examined for clinical profiles and expression of keratin-7, 13, MUC-1, and P63 by immunohistochemistry, compared to radicular cyst (RC) and maxillary sinusitis. RESULTS: Nasopalatine duct cyst was clinically characterized by male predominant occurrence: 44% of the cases involved tooth roots, and 70% with inflammatory backgrounds. Lining epithelia of NPCs without daughter cysts were immunohistochemically distinguished into three layers: a keratin 7-positive (+) ciliated cell layer in the surface, a keratin-13+ middle layer, and a MUC-1+/P63+ lower half, indicating that they were not respiratory epithelia, and the same layering pattern was observed in RC. However, those immunolocalization patterns of the main cyst lining with daughter cyst were exactly the same as those of daughter cyst linings as well as duct epithelia of mucous glands. CONCLUSIONS: Two possible histopathogenesis of NPC were clarified: one was inflammatory cyst like RC and the other was salivary duct cyst-like mucocele.

Efficacy of neoadjuvant chemotherapy followed by radical hysterectomy in locally advanced non-squamous carcinoma of the uterine cervix: a retrospective multicenter study of Tohoku Gynecologic Cancer Unit.

OBJECTIVE: Radical hysterectomy (RH) is a standard treatment for locally advanced non-squamous cell carcinoma (N-SCC) of the uterine cervix, but there have been no reports on whether neoadjuvant chemotherapy (NAC) followed by radical hysterectomy could improve the outcome of patients with this disease. MATERIALS AND METHODS: This multicenter retrospective study enrolled 77 patients with Stage IB2 to IIB N-SCC of the uterine cervix. Of these, 27 patients were treated with NAC prior to radical hysterectomy (NAC group) and 50 with RH alone (RH group). The two-year recurrence-free survival (RFS) rate, progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Clinical parameters such as clinical stage, histological type, and postoperative treatment were also examined between the groups. RESULTS: While the two-year RFS rates were 81.5% and 70.0% in NAC and RH groups, respectively (p = 0.27) and the median PFS was 51 months and 35 months in NAC and RH groups, respectively (p = 0.35), the median OS was 58 months and 48 months in NAC and RH groups, respectively, which was significant (p = 0.0014). The median OS of patients with mucinous adenocarcinoma in NAC group was significantly higher than that in RH group: 58 months versus 37 months (p = 0.03). CONCLUSION: NAC prior to RH may offer the prognostic advantage of patients with locally advanced N-SCC of the uterine cervix, especially mucinous adenocarcinoma.

Malignant mixed Müllerian tumor of the fallopian tube: a case report.

Malignant mixed Müllerian tumor (MMMT) of the female genital tract is uncommon and extremely rare in the Fallopian tube. We describe a case of primary MMMT of the Fallopian tube with carcinomatous and heterologous mesenchymal components in a 60-year-old woman. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, pelvic and paraaortic lymph node dissection, and resection of intrapelvic metastases. The tumor formed a large polypoid mass within the right Fallopian tube and had penetrated the wall to the paraovarian space. Microscopic examination revealed two components of poorly differentiated adenocarcinoma and high-grade sarcoma with chondromatous differentiation. The patient received six courses of adjuvant chemotherapy with ifomide and cisplatin and is currently in remission. Although MMMT in the Fallopian tube shows poor prognosis, primary cytoreductive surgery with platinum-based combination chemotherapy may improve survival.

Evaluation of bone volume changes after sinus floor augmentation with autogenous bone grafts.

The aim of this study was to establish an objective method for quantitative evaluation of bone volume change after sinus augmentation. 11 sinuses in 9 patients were evaluated by computed tomography images taken before treatment (T0), and 3 months (T1) and at least 1 year (T2) after sinus augmentation. Based on the 3D digital subtraction technique, augmented bone images were extracted and bone volumes were calculated from voxel numbers of the extracted images. The mean augmented bone volumes at T1 and T2 were 2.46 cm3 and 1.85 cm3, respectively. These bone volume changes were statistically significant and the mean bone volume change ± SE was -24.8% ± 6.1%. Loss of augmented bone was observed in all except one of the patients. The correlation coefficient between bone volume change and elapsed time was -0.64, which was statistically significant and indicated that bone resorption progressed with elapse of time after sinus augmentation. The authors' method of analysis enabled visualization of augmented bone and objective assessment of bone volume change. Within the limited number of cases, the present investigation demonstrated a significant decrease in augmented bone volume between 3 and 23 months after surgery.

JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma.

Inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene causes both hereditary and sporadic clear-cell renal-cell carcinoma (ccRCC). Although the best-characterized function of the VHL protein (pVHL) is regulation of hypoxia-inducible factor-α (HIFα), pVHL also controls the development of pheochromocytoma through HIF-independent pathways by regulating JunB. However, it is largely unknown how these pathways contribute to the development and progression of ccRCC. In the present study, we confirmed that JunB was upregulated in VHL-defective ccRCC specimens by immunostaining. Short-hairpin RNA (shRNA)-mediated knockdown of JunB in 786-O and A498 VHL null ccRCC cells suppressed their invasiveness. In addition, JunB knockdown significantly repressed tumor growth and microvessel density in xenograft tumor assays. Conversely, forced expression of wild-type, but not dimerization-defective, JunB in a VHL-restored 786-O subclone promoted invasion in vitro and tumor growth and vessel formation in vivo. Quantitative PCR array analysis revealed that JunB regulated multiple genes relating to tumor invasion and angiogenesis such as matrix metalloproteinase-2 (MMP-2), MMP-9 and chemokine (C-C motif) ligand-2 (CCL2) in 786-O cells. JunB knockdown in these cells reduced the proteolytic activity of both MMPs in gelatin zymography and the amount of CCL2 in the culture supernatant. Moreover, shRNA-mediated knockdown of MMP-2 or inhibition of CCL2 activity with a neutralizing antibody repressed xenograft tumor growth and angiogenesis. Collectively, these results suggest that JunB promotes tumor invasiveness and enhances angiogenesis in VHL-defective ccRCCs.

The lingual lymph node identified as a sentinel node on CT lymphography in a patient with cN0 squamous cell carcinoma of the tongue.

We performed CT lymphography on an 81-year-old female patient with a histologically confirmed squamous cell carcinoma of the tongue with no clinical or radiological evidence of cervical lymph node involvement. The lateral lingual lymph node was identified as a sentinel node, which is the first lymph node to receive drainage from a primary tumour. CT lymphography also showed draining lymphatics passing through the sublingual space, the medial side of the submandibular gland and near the hyoid bone and connected with the middle internal jugular node. Although metastasis to the lateral lingual lymph node is known as one of the crucial events in determining survival outcome in cancer of the tongue and floor of the mouth, very few reports are available on the imaging of the lateral lingual lymph node metastasis. This is the first report regarding the lateral lingual lymph node identified as a sentinel node demonstrated on CT lymphography.

Clinicopathological factors associated with clinical outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) permits removal of colorectal epithelial neoplasms en bloc, but a substantial risk of procedure-related perforation has been reported. We sought to unravel the clinicopathological factors associated with the clinical outcomes of ESD for colorectal epithelial neoplasms in a large series. PATIENTS AND METHODS: ESD was done in 278 patients with 292 colorectal tumors that fulfilled the inclusion criteria. The criteria for ESD were: lesion greater than 20 mm in size, lesion with fibrotic scarring, locally residual colorectal lesion, or invasive carcinoma with slight submucosal penetration. Resection was assessed as en bloc or piecemeal, complete (en bloc with tumor-free lateral and basal margins) or incomplete. Complications including perforation and bleeding were assessed, and factors related to each were analyzed using logistic regression. Patients underwent multiple follow-up endoscopic examinations (mean 4.6; median 4; range 2 - 9; total number 1010). RESULTS: En bloc resection was achieved in 90.1 % of lesions (263/292) and resection was deemed to be complete in 233 (79.8 %). Right-side colonic location and the finding of fibrosis were the significant contributors to incomplete resection. Perforation was seen in 24 cases (8.2 %), and was associated with large tumor size and the presence of fibrosis. When the contributive factors for each were combined, the risks of incomplete resection and perforation were substantially increased. CONCLUSION: The present study provides useful information for predicting risks for incomplete resection and complication in colorectal ESD.

Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study.

OBJECTIVE: Endoscopic submucosal dissection (ESD) has the advantage over conventional endoscopic mucosa resection, permitting removal of early gastric cancer (EGC) en bloc, but long-term clinical outcomes remain unknown. A follow-up study on tumour recurrence and survival after ESD was conducted. METHOD: ESD was performed for patients with EGC that fulfilled the expanded criteria: mucosal cancer without ulcer findings irrespective of tumour size; mucosal cancer with ulcer findings

Adenoid cystic carcinoma of sublingual gland involving the submandibular duct.

We report an unusual case of adenoid cystic carcinoma (ACC) arising in the sublingual gland and extending into the submandibular duct. Our article mainly describes the MR findings. The margin of the mass was well-defined and the mass was divided into two parts - anterior and posterior. The anterior part of the mass showed isointense to surrounding muscle on T(1) weighted images and hyperintense on fat-saturated T(2) weighted images. The posterior part of the mass showed hyperintense both on T(1) weighted and fat-saturated T(2) weighted images. The findings indicated that the cystic space of the posterior part was filled with tumour mass which extended from the anterior part. ACC of the sublingual gland extending into the submandibular duct is rare and the MR findings have not been previously described in the literature.

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3beta with p53.

To improve conventional chemotherapeutic efficacy, a combination use of traditional medicines is effective but detailed mechanisms have been rarely elucidated. In the this study, we attempted to clarify how triptolide (PG490), an oxygenated diterpene derived from a Chinese herb, enhances the cisplatin (CDDP)-induced cytotoxicity in urothelial cancer cells. Our results showed that a combined CDDP/triptolide therapy induced apoptosis in urothelial cancer cell lines with wild-type p53, but not in those with mutant-type p53 or normal human urothelium. As the mechanism, triptolide suppressed CDDP-induced p53 transcriptional activity, leading to p21 attenuation, which promoted apoptosis via the activation of c-Jun N-terminal kinase (JNK) and Bax. We further demonstrated that the functional regulation of p53 by triptolide was mediated by an intranuclear association of p53 with glycogen synthase kinase-3beta (GSK3beta), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3beta axis by triptolide was observed in a cancer-specific manner. A mouse xenograft model also showed that a combined CDDP/triptolide therapy completely suppressed tumor growth without any side effects. We expect that cancer-specific enhancement of CDDP-induced cytotoxicity with triptolide may effectively overcome the resistance to a CDDP-based conventional chemotherapy as a treatment for urothelial cancer.

Follow-up study of condylar bony changes using helical computed tomography in patients with temporomandibular disorder.

OBJECTIVES: We investigated condylar bone changes in 1032 joints from 516 subjects in order to clarify the incidence and type of bone changes in the temporomandibular joint (TMJ), and alteration of the change during follow-up, in patients with temporomandibular disorders (TMD). METHODS: We classified condylar bone change into five types on multiplanar reformatted (MPR) images of helical CT: N, no bone change; F, flattening; E, erosion with or without roughening; D, deformity; S, deformity accompanied by erosion with or without roughening. In 51 of 516 subjects, follow-up CT examination was performed and transition of condylar bone change was observed. RESULTS: Condylar bone change was seen in 617 (63.7%) of 1032 joints and in 70 (68.6%) of 102 follow-up joints. The number of joints of Types D and S increased at follow-up, but those of Types N, F and E decreased. CONCLUSION: In this study, the main direction of transition of condylar bone change in joints with TMD was absorptive bone change to absorptive with sclerotic (proliferative) bone change and further to sclerotic (proliferative) bone change. Our classification of condylar bone change was thought to be convenient for the evaluation of bone change in TMD.

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation.

The purpose of this study was to investigate the accumulation of genetic alterations during metachronous and/or synchronous development of multifocal low-grade superficial urothelial tumours in the same patient, by using array-based comparative genomic hybridisation (array-CGH) and FGFR mutation analysis. We analysed 24 tumours (pTa-1 G1-2) from five patients. We had previously identified a clonal relationship among the tumours of each patient by microsatellite analysis. This time, unsupervised hierarchical cluster analysis revealed that the tumours from each patient were clustered together independently of the tumours from the other patients. All of the tumours from a single patient showed a set of 2-7 identical regional or whole-arm chromosomal changes. In addition, several individual alterations were also found. Cladistic diagrams revealed that the accumulation of genetic alterations could not be explained by a linear model, and the existence of a hypothetical precursor cell was assumed in four patients. In some cases, FGFR mutation seemed to occur later during multifocal tumour development. Taken together, these findings suggest that low-grade superficial urothelial tumours accumulate minor genetic alterations during multifocal development, although these tumours are genetically stable.

Health-related quality-of-life after external beam radiation therapy for localized prostate cancer: intensity-modulated radiation therapy versus conformal radiation therapy.

We compared health-related quality-of-life (HRQL) after intensity-modulated radiotherapy (IMRT) with statuses obtained after old and new protocols of three-dimensional conformal radiation therapy (3DCRT) for localized prostate cancer. We measured the general and disease specific HRQL using the MOS 36-Item Health Survey (SF-36), and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI), respectively. IMRT resulted in similar profiles of general and disease-specific HRQL to two other methods within the first year after treatment. Moreover, IMRT gave rise to comparable urinary, intestinal and sexual side effects despite the high dose of radiation applied.

Genotyping of congenital adrenal hyperplasia due to 21-hydroxylase deficiency presenting as male infertility: case report and literature review.

We describe here two infertile male patients who were referred to our hospital with azoospermia at the ages of 33 and 30 years, respectively. Hormonal examinations led to a diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in both patients. Genotyping revealed that the patients had a homozygous I172N and a heterozygous compound I172N/IVS2-13A/C>G mutation, respectively. Glucocorticoid replacement therapy succeeded in improving the seminal status of one patient, but not the other. For the latter patient and his wife, a pregnancy was achieved by testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) following genetic counseling. It is important to investigate genotyping and to classify patients on the basis of genotypic information in order to arrive at better treatment strategies for male infertility; especially in counseling of TESE-ICSI.

Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines.

3-3'-Methylene-bis [4-hydroxycoumarin] (dicoumarol), an inhibitor of NADPH:quinone oxidoreductase 1, has been reported to possess potential antineoplastic effects and the ability to abrogate p53 protein. In the present study, we investigated the cytotoxic effects of dicoumarol in combination with cisplatin (CDDP), using four bladder (RT112, 253J, J82 and UMUC3) and two prostate (LNCap and PC3) cancer cell lines. Single treatment with 100 microM dicoumarol suppressed cell proliferation but did not induce apoptosis at 24 h in all cell lines examined. On the other hand, pretreatment with dicoumarol enhanced cytotoxicity of CDDP in three cell lines with wild type of p53 (RT112, 253J and LNCap), but not in three other cell lines with mutant p53 or in RT112 stable transfectants with a dominant-negative mutant of p53. In RT112 and LNCap, CDDP induced p53 and p21 expression, while pretreatment of dicoumarol suppressed induction of p53/p21 and resulted in sequential activation of c-Jun N-terminal kinase (JNK) in a time-dependent manner. Furthermore, inhibition of JNK, using SP600125, completely suppressed activity of caspases and poly-(ADP-ribose) polymerase cleavage, leading to suppression of enhancement of CDDP-mediated apoptosis by dicoumarol. These results suggested that dicoumarol could enhance cytotoxicity of CDDP in urogenital cancer cells with wild-type p53 through the p53/p21/JNK pathways.