The Efficacy and Safety of a Low Relative Dose Intensity of Cabazitaxel in Patients With Metastatic Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Clinical trials have shown that the efficacy of a reduced dose of cabazitaxel (20 mg/m2 every 3 weeks) was not inferior to that of the standard dose (25 mg/m2 every 3 weeks). However, the efficacy of even lower relative dose intensities, such as 20 mg/m2 every 4 weeks, have not been evaluated conclusively. The aim of this study was to investigate the efficacy and safety of a low relative dose intensity of cabazitaxel in patients with metastatic castration-resistant prostate cancer in the real world. PATIENTS AND METHODS: We retrospectively analyzed 101 consecutive patients treated with cabazitaxel for docetaxel-refractory metastatic castration-resistant prostate cancer. The progression-free and overall survival after introduction of cabazitaxel and prostate-specific antigen response rate were assessed as oncological outcome measures. RESULTS: The patients were divided into two groups (relative dose intensity >60%, n=74 and ≤60%, n=27). Both progression-free and overall survivals were significantly better in the >60% group than in the ≤60% group (median 5 and 2 months, p<0.01, and 15 and 6 months, p<0.01, respectively). In multivariate analyses, visceral metastasis and relative dose intensity ≤60% were prognostic factors for shorter progression-free and overall survivals (p=0.04, p<0.01, respectively). The incidence of adverse events was not significantly different between groups. CONCLUSION: The cabazitaxel relative dose intensity ≤60% group had significantly shorter progression-free and overall survivals than the >60% group, whereas the incidence of adverse events was not significantly different. The results suggested that reducing the relative dose intensity of cabazitaxel to ≤60% may not be recommended.

Treatment Results of High-dose-rate Brachytherapy and External Beam Radiation With Long-term Androgen Deprivation Therapy for Patients With Metastatic Prostate Cancer.

BACKGROUND/AIM: A recent clinical trial indicated the usefulness of local radiation therapy of the prostate in patients with low-volume metastatic prostate cancer. High-dose-rate brachytherapy (HDR-BT) is used mainly for high-risk, localized, and locally advanced cases. However, few studies exist on the efficacy of HDR-BT and external beam radiation therapy (EBRT) for metastatic prostate cancer. PATIENTS AND METHODS: We conducted a retrospective analysis of 39 patients diagnosed with regional lymph node metastasis and/or a limited number of metastases who underwent HDR-BT and EBRT with long-term androgen deprivation therapy. We utilized Cox's proportional hazards models to identify predictors of oncological outcomes. Treatment outcomes, including biochemical recurrence-free survival (BCRFS), clinical progression-free survival (CPFS), and castration-resistant prostate cancer-free survival (CRPCFS), were compared according to the clinical stage. RESULTS: The median follow-up duration was 49 months (range=23-136 months). The 5-year BCRFS, CPFS, CRPCFS, and cancer-specific survival rates were 62.2%, 67.2%, 83.2%, and 93.4%, respectively. Based on Kaplan-Meier analysis, N1M0 and N0-1M1b showed favorable outcomes compared with N1M1a. Multivariate analysis revealed that N1M1a prostate cancer was an independent risk factor for poor BCRFS, CPFS, and CRPCFS. CONCLUSION: HDR-BT and EBRT with androgen deprivation therapy is a feasible approach for patients with newly diagnosed regional and low-metastatic-burden prostate cancer. However, in our cohort M1a prostate cancer had significantly inferior outcomes. A well-controlled prospective study is imperative to confirm our results.

Assessment of facial symmetry by three-dimensional stereophotogrammetry after mandibular reconstruction: A comparison with subjective assessment.

INTRODUCTION: The assessment of facial symmetry, after mandibular reconstruction, currently relies on subjective esthetic assessment by an evaluator. The present study aimed to compare conventional subjective assessment with quantitative evaluation by three-dimensional (3D) stereophotogrammetry of facial cosmetic symmetry. METHODS: This retrospective study enrolled 20 patients who underwent mandibular reconstruction with free fibula flap after segmental resection between 2014 and 2018. Subjective assessments were performed by seven clinicians at 6-12 months after surgery. Simultaneously, lower face symmetry was measured by 3D stereophotogrammetry with the VECTRA H1 system and recorded as the root mean square deviation (RMSD). Data from the subjective and quantitative evaluations were compared using Spearman's rank correlation coefficient. RESULTS: The results showed that subjective assessments were strongly and negatively correlated with RMSD (P=0.00000128). This confirmed that RMSD, obtained by 3D stereophotogrammetry, reflected the subjective assessment of symmetry in our cohort. CONCLUSIONS: Three-dimensional stereophotogrammetry of facial cosmetic symmetry will be an available quantitative method for patients with head and neck cancer after mandibular reconstruction.

Nodal cilia-driven flow: Development of a computational model of the nodal cilia axoneme.

Cilia-driven nodal flow is important in the determination of left-right asymmetry in the body. Several theoretical and computational models have been proposed to explain the mechanics of ciliary motion, although the full mechanism remains unknown. Here, we developed a three-dimensional nodal cilia axoneme model using a finite element-boundary element coupling method, and investigated the mechanics of nodal ciliary motion. We found that the rotational orbit was strongly dependent on the dynein activation frequency. We also investigated flow field generated by the ciliary rotation, and the flow strength decayed as r-3 at the far field from the cilium. Our numerical results also suggest that experimentally observed tilt angle θ=2π/9 is sufficiently large to make a leftward flow. These findings are helpful in better understanding ciliary motion and nodal flow.

Serous tubal intraepithelial carcinoma arising from the intrauterine portion of the fallopian tube after bilateral salpingo-oophorectomy.

Serous tubal intraepithelial carcinoma (STIC) is considered the precursor of pelvic serous carcinomas and the earliest malignant alteration in BRCA mutation-positive women. Recently, risk-reducing salpingo-oophorectomy (RRSO) is being performed in BRCA mutation-positive women and STIC is often discovered incidentally in the fallopian tubes. A 62-year-old woman underwent bilateral salpingo-oophorectomy (BSO) for ovarian cysts. Ten months later, cytological screening for the endometrium revealed adenocarcinoma. No atypical tissue was detected by the endometrial curettage. Imaging tests and hysteroscopy found no abnormal findings. She underwent hysterectomy and was diagnosed with STIC originating from the intrauterine portion of the residual fallopian tube. Here, the authors report the first case of STIC being detected during an endometrial cytological examination after BSO. Although STIC associated with the BRCA mutation usually involves the distal fallopian tube, the present case suggests that the intrauterine portion of the fallopian tube should be removed or cauterized during RRSO.

Acute pancreatitis induced by paclitaxel and carboplatin therapy in an ovarian cancer patient.

A 46-year-old female was treated with a regimen of paclitaxel and carboplatin (TC therapy) as adjuvant chemotherapy for Stage IC ovarian adenocarcinoma. There was no severe toxicity except for grade 3 neutropenia during the first four cycles of TC therapy. However, she developed acute pancreatitis at 14 days after fifth cycle. TC therapy is commonly associated with adverse effects such as myelosuppression, hypersensitivity, alopecia, and peripheral neuropathy, but acute pancreatitis has rarely been reported. Ovarian cancer patients often present with nausea and abdominal pain, which are the same symptoms of pancreatitis. It is very important to keep in mind that acute pancreatitis may be concealed in these common symptoms of ovarian cancer during and after TC therapy. Because acute pancreatitis is fatal complication and quitting the drug usually leads to complete cure. The authors report an uncommon case in which TC therapy may have caused acute pancreatitis.

ZFP521 contributes to pre-B-cell lymphomagenesis through modulation of the pre-B-cell receptor signaling pathway.

ZFP521 was previously identified as a putative gene involved in induction of B-cell lymphomagenesis. However, the contribution of ZFP521 to lymphomagenesis has not been confirmed. In this study, we sought to elucidate the role of ZFP521 in B-cell lymphomagenesis. To this end, we used a retroviral insertion method to show that ZFP521 was a target of mutagenesis in pre-B-lymphoblastic lymphoma cells. The pre-B-cell receptor (pre-BCR) signaling molecules BLNK, BTK and BANK1 were positively regulated by the ZFP521 gene, leading to enhancement of the pre-BCR signaling pathway. In addition, c-myc and c-jun were upregulated following activation of ZFP521. Stimulation of pre-BCR signaling using anti-Vpreb antibodies caused aberrant upregulation of c-myc and c-jun and of Ccnd3, which encodes cyclin D3, thereby inducing the growth of pre-B cells. Stimulation with Vpreb affected the growth of pre-B cells, and addition of interleukin (IL)-7 receptor exerted competitive effects on pre-B-cell growth. Knockdown of BTK and BANK1, targets of ZFP521, suppressed the effects of Vpreb stimulation on cell growth. Furthermore, in human lymphoblastic lymphoma, analogous to pre-B-cell lymphoma in mice, the expression of ZNF521, the homolog of ZFP521 in humans, was upregulated. In conclusion, our data showed that the ZFP521 gene comprehensively induced pre-B-cell lymphomagenesis by modulating the pre-B-cell receptor signaling pathway.

Low-intensity pulsed ultrasound enhances bone morphogenetic protein expression of human mandibular fracture haematoma-derived cells.

We previously demonstrated that human mandibular fracture haematoma-derived cells (MHCs) play an important role in mandibular fracture healing and that low-intensity pulsed ultrasound (LIPUS) accelerates this effect by stimulating various osteogenic cytokines. In the present study, we investigated how LIPUS affects the expression of bone morphogenetic proteins (BMPs), which are also known to have the ability to induce bone formation. MHCs were isolated from human mandibular fracture haematomas and the cells were divided into two groups: a LIPUS (+) group and a LIPUS (-) group, both of which were cultured in osteogenic medium. LIPUS was applied to the LIPUS (+) group 20 min a day for 4, 8, 14, and 20 days (1.5 MHz, 30 mW/cm(2)). Real-time PCR and immunofluorescence studies were carried out to determine the expression of BMP-2, 4, and 7. Compared to the LIPUS (-) group, gene expression levels were significantly increased in the LIPUS (+) group for BMP-2 on day 20 (67.38 ± 26.59 vs. 11.52 ± 3.42, P < 0.001), for BMP-4 on days 14 (45.12 ± 11.06 vs. 9.20 ± 2.88, P = 0.045) and 20 (40.96 ± 24.81 vs. 3.22 ± 1.53, P = 0.035), and for BMP-7 on day 8 (48.11 ± 35.36 vs. 7.03 ± 3.96, P = 0.034). These findings suggest that BMP-2, 4, and 7 may be mediated by LIPUS therapy during the bone repair process.

The real impact of telaprevir dosage on the antiviral and side effects of telaprevir, pegylated interferon and ribavirin therapy for chronic hepatitis C patients with HCV genotype 1.

Triple therapy with telaprevir, pegylated interferon and ribavirin has been reported to improve antiviral efficacy but have potentially severe adverse effects in patients with chronic hepatitis C. To avoid the severe effects of telaprevir, lowering the dose has been suggested. However, impact of dosage changes on antiviral and adverse effects remains unclear. One hundred and sixty-six Japanese patients with HCV genotype 1 were treated with triple therapy. The drug exposure of each medication was calculated by averaging the dose actually taken. The overall SVR rate was 82%. The telaprevir discontinuation rate was 26%. The factors associated with discontinuation were an older age (≥65 y.o.) and a higher average dose during treatment. The telaprevir discontinuation rates were 42%, 25% and 14% in patients at ≥35, 25-35 and <25 mg/kg/day of telaprevir and 58% in older patients at ≥35 mg/kg/day of TVR. The factors associated with SVR were treatment-naïve, relapse to previous treatment, higher average telaprevir dose during treatment and completion of treatment. The SVR rate was higher, at 91%, in patients at 25-35 mg/kg/day of telaprevir than the 71% and 78% observed in those at <25 and ≥35 mg/kg/day of drug. In Japanese patients, a mean telaprevir dose of 25-35 mg/kg/day during treatment can augment its efficacy in triple therapy for patients with HCV genotype 1.

Retrospective study of changes in the sensitivity of the oral mucosa: sagittal split ramus osteotomy (SSRO) versus intraoral vertical ramus osteotomy (IVRO).

We investigated changes in the sensitivity of cutaneous points and the oral mucosa after sagittal split ramus osteotomy (SSRO) and assessed the differences between SSRO and intraoral vertical ramus osteotomy (IVRO). The subjects included in this study were 46 patients with mandibular prognathism who underwent IVRO (88 rami) and 30 patients who underwent SSRO (59 rami). An objective evaluation of the neurosensory status of each patient was completed preoperatively and at 1, 4, 8, 12, and 24 weeks postoperatively. Other variables studied for each patient included sex, age, magnitude of mandibular setback, and amount of blood loss during surgery. We found that a neurosensory recovery occurred earlier in the oral mucosa than at cutaneous points. The number of oral mucosa points showing reduced neurosensory function and neurosensory disturbance after SSRO was significantly higher than after IVRO at 1, 4, and 8 weeks (P<0.05). The nerve recovery observed after SSRO was delayed for a longer period than that noted in our previous study of IVRO. In conclusion, we found changes in sensitivity at cutaneous points and the oral mucosa after SSRO and assessed the differences between SSRO and IVRO.

The osteogenic activity of human mandibular fracture haematoma-derived progenitor cells is affected by bisphosphonate in vitro.

It is known that bisphosphonates (BPs) suppress the activity of osteoclasts; however, it has not been reported whether BPs affect the potential of human mandibular fracture haematoma-derived cells (MHCs) for bone differentiation. In this study, we examined whether the degree of bone differentiation changes following the administration of BP in vitro. The effects of alendronate and risedronate (10(-8) to 10(-7)M (mol/l)) on cell proliferation were evaluated at 4 and 8 days, after which BP treatment was applied for 4, 8, 14, and 20 days prior to assessing the alkaline phosphatase (ALP) activity and performing the mineralization assay. Alendronate 10(-8) and 10(-7)M and risedronate 10(-7)M decreased the degree of cell proliferation on day 8 (P<0.05). Using an ELISA, the ALP activity of the control, alendronate 10(-8)M, risedronate 10(-8)M, and risedronate 10(-7)M groups were 112.1±10.2%, 156.1±24.3%, 138.8±16.5%, and 133.3±10.3%, respectively, at 14 days after treatment (day 0 in each group was considered to be 100%). ALP activity was significantly higher in the alendronate 10(-8)M and risedronate 10(-8) and 10(-7)M groups than in the control group (P=0.010, 0.014, and 0.009, respectively). It is possible that BPs increase the potential of MHCs for osteogenic differentiation depending on the concentration of the drug.

Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin.

Pegylated interferon (Peg-IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase levels (NALT). However, it remains unclear whether the risk of hepatocellular carcinoma (HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT (ALT ≤ 40 IU/mL) treated with Peg-IFN alpha-2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan-Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response (SVR) or relapse compared with those showing nonresponse (NR) (SVR vs NR, hazard ratio (HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs <60 years, HR: 6.0, P = 0.032, 60-64 vs <60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT (ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT (ALT ≤ 30 IU/mL) patients should be carefully determined.

Ambulatory blood pressure monitoring for risk stratification in obese and non-obese subjects from 10 populations.

Overweight clusters with high blood pressure (BP), but the independent contribution of both risk factors remains insufficiently documented. In a prospective population study involving 8467 participants (mean age 54.6 years; 47.0% women) randomly recruited from 10 populations, we studied the contribution of body mass index (BMI) to risk over and beyond BP, taking advantage of the superiority of ambulatory over conventional BP. Over 10.6 years (median), 1271 participants (15.0%) died and 1092 (12.9%), 637 (7.5%) and 443 (5.2%) experienced a fatal or nonfatal cardiovascular, cardiac or cerebrovascular event. Adjusted for sex and age, low BMI (<20.7 kg m(-2)) predicted death (hazard ratio (HR) vs average risk, 1.52; P<0.0001) and high BMI (> or = 30.9 kg m(-2)) predicted the cardiovascular end point (HR, 1.27; P=0.006). With adjustments including 24-h systolic BP, these HRs were 1.50 (P<0.001) and 0.98 (P=0.91), respectively. Across quartiles of the BMI distribution, 24-h and nighttime systolic BP predicted every end point (1.13 < or = standardized HR < or = 1.67; 0.046 < or = P<0.0001). The interaction between systolic BP and BMI was nonsignificant (P > or = .22). Excluding smokers removed the contribution of BMI categories to the prediction of mortality. In conclusion, BMI only adds to BP in risk stratification for mortality but not for cardiovascular outcomes. Smoking probably explains the association between increased mortality and low BMI.

The osteogenic activity of human mandibular fracture haematoma-derived cells is stimulated by low-intensity pulsed ultrasound in vitro.

Low intensity pulsed ultrasound (LIPUS) stimulation is a clinically established treatment method used to accelerate long bone fracture healing; however, this method is currently not applied to mandibular fractures. In this study, we investigated the effects of LIPUS on human mandibular fracture haematoma-derived cells (MHCs) in order to explore the possibility of applying LIPUS treatment to mandibular fractures. MHCs were isolated from five patients. The cells were divided into two groups: (1) LIPUS (+) group: MHCs cultured in osteogenic medium with LIPUS treatment; and (2) LIPUS (-) group: MHCs cultured in osteogenic medium without LIPUS treatment. The osteogenic differentiation potential and proliferation of the MHCs were compared between the two groups. The waveform used was equal to the wave conditions of a clinical fracture healing system. The gene expression levels of ALP, OC, Runx2, OSX, OPN, and PTH-R1 and mineralization were increased in the LIPUS (+) group compared to the LIPUS (-) group. There were no significant differences in cell proliferation between the two groups. These findings demonstrate the significant effects of LIPUS on the osteogenic differentiation of MHCs. This study provides significant evidence for the potential usefulness of the clinical application of LIPUS to accelerate mandibular fracture healing.

Donor cell-derived leukemia after cord blood transplantation and a review of the literature: differences between cord blood and BM as the transplant source.

Donor cell-derived leukemia (DCL) is a rare complication of SCT. Here, we present a case of DCL following cord blood transplantation (CBT) and review the clinical features of previously reported DCL. To our knowledge, this is the first report comparing clinical characteristics of DCL from the standpoint of the transplant source, with umbilical cord blood and BM. AML and myelodysplastic syndrome (MDS) were recognized more frequently in DCL after CBT, whereas the incidence of AML and ALL was similar after BMT. The median duration between the occurrence of DCL following CBT and BMT was 14.5 and 36 months, respectively. DCL occurred in a significantly shorter period after CBT than after BMT. Abnormal karyotypes involving chromosome 7 were observed in 52.4% of CBT recipients and 17.3% of BMT recipients; this was a statistically significant difference. Particularly, the frequency of monosomy 7 was significantly higher in DCL after CBT than after BMT. The types of abnormal karyotypes in DCL following BMT were similar to those characteristically observed in adult de novo AML and MDS. DCL patients generally have a poor prognosis in both groups. SCT is the best treatment for curing DCL. DCL appears to have different clinical features according to the transplant source.

Gap-junction-mediated communication in human periodontal ligament cells.

Periodontal tissue homeostasis depends on a complex cellular network that conveys cell-cell communication. Gap junctions (GJs), one of the intercellular communication systems, are found between adjacent human periodontal ligament (hPDL) cells; however, the functional GJ coupling between hPDL cells has not yet been elucidated. In this study, we investigated functional gap-junction-mediated intercellular communication in isolated primary hPDL cells. SEM images indicated that the cells were in contact with each other via dendritic processes, and also showed high anti-connexin43 (Cx43) immunoreactivity on these processes. Gap-junctional intercellular communication (GJIC) among hPDL cells was assessed by fluorescence recovery after a photobleaching (FRAP) analysis, which exhibited dye coupling between hPDL cells, and was remarkably down-regulated when the cells were treated with a GJ blocker. Additionally, we examined GJs under hypoxic stress. The fluorescence recovery and expression levels of Cx43 decreased time-dependently under the hypoxic condition. Exposure to GJ inhibitor or hypoxia increased RANKL expression, and decreased OPG expression. This study shows that GJIC is responsible for hPDL cells and that its activity is reduced under hypoxia. This is consistent with the possible role of hPDL cells in regulating the biochemical reactions in response to changes in the hypoxic environment.

Risk factors associated with inferior alveolar nerve injury after extraction of the mandibular third molar--a comparative study of preoperative images by panoramic radiography and computed tomography.

In this study we investigated the relationships among the risk factors for inferior alveolar nerve injury (IANI), and the difference between preoperative imaging findings on panoramic radiographs and computed tomography (CT), by univariate and multivariate analyses. We determined the following to be significant variables by multivariate analysis: panoramic radiographic signs, such as the loss of the white line of the inferior alveolar canal or the diversion of the canal; excessive haemorrhage during extraction; and a close relationship of the roots to the IAN (type 1 cases) on CT examination. CT findings of type 1 were associated with a significantly higher risk (odds ratio 43.77) of IANI. In addition, many panoramic findings were not consistent with CT findings (275 of 440 teeth; 62.5%). These results suggest that CT findings may be able to predict the development of IANI more accurately than panoramic findings. Panoramic radiography alone did not provide sufficiently reliable images required for predicting IANI. Therefore, when the panoramic image is suggestive of a close relationship between the impacted tooth and the IAN, CT should be recommended as a means of conducting further investigations.