Validation of TNM classification for metastatic prostatic cancer treated using primary androgen deprivation therapy

Purpose

The current tumor–node–metastasis (TNM) classification system has been used for many years. The prognosis of patients with metastatic prostate cancer (mPC) treated using primary androgen deprivation therapy (PADT) was analyzed according to the TNM classification.

Methods

A total of 5618 cases with lymph node metastases only (N1M0), non-regional lymph node metastasis (M1a), bone metastasis (M1b), and distant metastasis (M1c) were selected from the Japanese Study Group of Prostate Cancer database. Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were calculated using Kaplan–Meier analysis. The influence of clinical variables on patient prognosis was evaluated using the Cox proportional hazard regression model.

Results

The 5-year OS, CSS, and PFS were 76.0, 83.2, and 38.8 % in N1M0, 57.5, 69.0, and 23.0 % in M1a, 54.0, 63.1, and 23.0 % in M1b, and 40.0, 51.5, and 16.6 % in M1c, respectively. OS, CSS, and PFS worsened as the stages progressed. OS, CSS, and PFS were all significantly worse in N1M1b compared with N0M1b. Multivariate analysis revealed that OS and CSS were worse in patients with a Gleason score ≥8 and that combined androgen blockade (CAB) treatment provided better OS than non-CAB treatments at any tumor stage. However, OS and CSS were worse in individuals with a prostate-specific antigen >100 ng/ml only in M1b.

Conclusions

Patient prognosis worsened with stage progression; therefore, current TNM classification system of mPC for PADT was shown to be trustworthy. Each PC cell that develops bone or lymphoid metastasis may exhibit different characteristics.

     

Nemaline Myopathy Initially Diagnosed as Right Heart Failure with Type 2 Respiratory Failure

Nemaline myopathy (NM) is a rare muscle disease with various clinical types. In some cases, NM can lead to type 2 respiratory failure and right heart failure. We herein report a patient with congenital NM with nebulin gene mutation who presented with acute right heart failure and type 2 respiratory failure due to respiratory muscle paralysis after upper respiratory tract infection, needing a permanent ventilator for assistance. However, the limb and trunk muscle strengths were within normal limits. This case showed that NM should be considered as a cause of right heart failure and type 2 respiratory failure.     

Effects of acute and long-term treatments with thyrotropin-releasing hormone on locomotor activity and jumping behavior in mice

The acute and chronic effects of thyrotropin-releasing hormone (TRH) on ambulation and, in combination with apomorphine, on jumping behavior were investigated in mice. A single administration of TRH (1-10 mg/kg SC) produced an initial hyperactivity in a dose-dependent manner. Following administration of TRH (1-10 mg/kg SC) for 21 successive days, the stimulatory effect on locomotion progressively increased. Haloperidol exerted a biphasic action on hyperlocomotion induced by acute and repeated TRH, i.e., stimulation at lower doses (0.01-0.02 mg/kg SC) and inhibition at higher doses (0.05-1 mg/kg SC). When TRH was administered in combination with low doses of apomorphine, locomotor activity was inhibited but jumping behavior occurred. The inhibitory effect of low doses of apomorphine on locomotion was shifted from doses of 0.1-0.25 mg/kg SC of apomorphine for acute TRH (10 mg/kg) to 0.25-0.35 mg/kg for repeated TRH (10 mg/kg), whereas the stimulatory effect of higher doses of apomorphine (0.5-1 mg/kg SC) on locomotion tended to decrease with repeated TRH. Jumping behavior induced by the combined treatment of TRH and apomorphine was proportional to the dose of TRH but exhibited an inverted-U response to the dose of apomorphine. Chronic TRH (10 mg/kg) in combination with apomorphine (0.1-1 mg/kg SC) also produced jumping behavior, but the dose-response curve for apomorphine was shifted to the right. The present results suggest that repeated treatment with TRH in mice produces hyperlocomotion, despite attenuation of both pre- and postsynaptic receptor activity, and that the inhibitory effect of repeated TRH on presynaptic receptors may be more potent than that on postsynaptic receptors.     

Mucosal concentration of basic fibroblast growth factor in the healing process in human giant gastric ulcers

OBJECTIVES: Basic fibroblast growth factor (bFGF) is a key factor in the healing of human and experimental peptic ulcers, but the behavior of bFGF in human giant gastric ulcer remains to be determined. We determined the bFGF content in the rim of giant ulcers (bFGF rim) and in non-ulcerated mucosa located opposite the ulcer (bFGF opposite) before and during treatment. METHODS: Biopsy specimens were endoscopically obtained from 31 patients with giant gastric ulcers and 17 patients with small ulcers before and 2, 4 and 8 weeks after treatment. The bFGF concentrations in the specimens were measured using a sandwich enzyme immunoassay. RESULTS: Before treatment, the bFGF rim and bFGF opposite concentrations were not associated with ulcer size. The bFGF rim concentration before treatment in the rapid healing group was higher than that in the slow healing group, but no significant difference in bFGF opposite concentrations were found between the two groups. The bFGF rim concentration in the rapid healing patients decreased during treatment, while the slow healing patients showed an inverse response. The bFGF opposite concentration did not change during treatment and bFGF rim concentrations in Helicobacter pylori-positive stomachs were significantly lower than those in H. pylori-negative stomachs. CONCLUSIONS: The bFGF rim concentration is not involved in the formation of giant gastric ulcers in humans. However, the bFGF rim concentration does appear to promote healing. The bFGF opposite concentration is not related to either the formation or healing of giant gastric ulcers.     

Fungal Secondary Metabolite Exophillic Acid Selectively Inhibits the Entry of Hepatitis B and D Viruses

Current anti-hepatitis B virus (HBV) drugs are suppressive but not curative for HBV infection, so there is considerable demand for the development of new anti-HBV agents. In this study, we found that fungus-derived exophillic acid inhibits HBV infection with a 50% maximal inhibitory concentration (IC₅₀) of 1.1 µM and a 50% cytotoxic concentration (CC₅₀) of >30 µM in primary human hepatocytes. Exophillic acid inhibited preS1-mediated viral attachment to cells but did not affect intracellular HBV replication. Exophillic acid appears to target the host cells to reduce their susceptibility to viral attachment rather than acting on the viral particles. We found that exophillic acid interacted with the HBV receptor, sodium taurocholate cotransporting polypeptide (NTCP). Exophillic acid impaired the uptake of bile acid, the original function of NTCP. Consistent with our hypothesis that it affects NTCP, exophillic acid inhibited infection with HBV and hepatitis D virus (HDV), but not that of hepatitis C virus. Moreover, exophillic acid showed a pan-genotypic anti-HBV effect. We thus identified the anti-HBV/HDV activity of exophillic acid and revealed its mode of action. Exophillic acid is expected to be a potential new lead compound for the development of antiviral agents.     

Epigenetic regulator UHRF1 orchestrates proinflammatory gene expression in rheumatoid arthritis in a suppressive manner

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, eventually leading to joint destruction. However, the epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here, we showed that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is a central epigenetic regulator that orchestrates multiple pathogeneses in RA in a suppressive manner. UHRF1 expression was remarkably upregulated in synovial fibroblasts (SFs) from arthritis model mice and patients with RA. Mice with SF-specific Uhrf1 conditional knockout showed more severe arthritic phenotypes than littermate controls. Uhrf1-deficient SFs also exhibited enhanced apoptosis resistance and upregulated expression of several cytokines, including Ccl20. In patients with RA, DAS28, CRP, and Th17 accumulation and apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, Ryuvidine administration stabilized UHRF1 ameliorated arthritis pathogeneses in a mouse model of RA. This study demonstrated that UHRF1 expressed in RA SFs can contribute to negative feedback mechanisms that suppress multiple pathogenic events in arthritis, suggesting that targeting UHRF1 could be one of the therapeutic strategies for RA.     

Ultrasound biomicroscopic measurement of anterior chamber biometry between before and after pupil dilation in children

PURPOSE: To evaluate anterior chamber biometry of the eyes of normal children using ultrasound biomicroscopy (UBM) and to evaluate the differences in biometry between children and adults, and before and after pupil dilation in children. METHODS: Anterior chamber depth (ACD) and trabecular-iris angle (TIA) were measured in 94 normal children and 15 normal adults using UBM. Before and after pupil dilation were measured in 42 children with emmetropic and hyperopic eyes. RESULTS: In 66 emmetropic children, ACD and TIA were 2.93+/-0.18 mm and 34.42+/-4.02 degrees, respectively. In 28 hyperopic children, ACD and TIA were 2.92+/-0.21 mm and 35.05+/-4.42 degrees, respectively. There was no significant difference in anterior chamber biometry associated with the refraction. ACD did not differ between children and adults, but TIA in children was wider than in adults. There was no significant difference in ACD or TIA before versus after pupil dilation in any case. CONCLUSIONS: Anterior chamber biometry in children showed no differences before and after pupil dilation. Also, there was no difference in ACD of children as compared to adults; however, TIA in children was significantly wider than in adults.     

Key points in dermoscopic differentiation between lentigo maligna and solar lentigo

A clinical diagnosis of lentigo maligna at an early stage is often difficult even for experienced dermatologists. Differential diagnoses would include solar lentigo, early lesions of seborrheic keratosis, lichen planus-like keratosis, pigmented actinic keratosis and melanocytic nevus. Dermoscopy has been shown to have higher diagnostic accuracy, especially in the diagnosis of pigmented skin lesions, in the past two decades. To aim of the present study was to review the diagnostic key points on dermoscopy in the published work to differentiate lentigo maligna from other differential diagnoses and reassess these important features on dermoscopy for specificity by describing the findings in detail. Diagnostic key points for lentigo maligna/lentigo maligna melanoma on dermoscopy are asymmetrical pigmented follicular openings, rhomboidal structures, annular-granular structures and gray pseudo-network. Lentigo maligna, at first, seems to occur as asymmetrical pigmented follicular openings and/or annular-granular structures, then expand and develop into the rhomboidal structures. Annular-granular structures and gray pseudo-network seem to be observed also in regressive areas of solar lentigo/initial seborrheic keratosis, lichen planus-like keratosis and pigmented actinic keratosis. The four important criteria on dermoscopy for the diagnosis of lentigo maligna have been reviewed, and the former two criteria seem to be more specific, but it might be difficult to recognize these findings without misinterpretation. The latter two seem to be not so specific as they would also be demonstrated in other pigmented epidermal lesions, although the distribution of the structures in these disorders would be inclined to be more homogeneous than that of lentigo maligna.