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Treatment options for patients who progressed to castration-resistant prostate cancer (CRPC) are very limited. The purpose of this study was to assess the efficacy of estramustine phosphate (EMP) in patients with CRPC, grouped according to the risk classification advocated by Armstrong et al. and to identify candidates for EMP treatment. Between March 2003 and July 2010, 82 patients with CRPC were treated with 280 or 560 mg EMP per os daily until disease progression or occurrence of unacceptable adverse events. Prostate-specific antigen (PSA) response and overall survival were evaluated according to risk classification. 52 (67%) patients achieved PSA decline. Rates of PSA decline in the good-, intermediate-, and poor-risk groups were 77, 71, and 25%, respectively, significantly higher in the good- and intermediate-risk groups than the poor-risk group ( p  = 0.03). The median overall survival times in good-, intermediate-, and poor-risk groups were 21, 19, and 9 months, respectively ( p  = 0.005 for good vs intermediate, p  = 0.001 for intermediate vs poor). When the intermediate-risk group was divided into two subgroups by PSA doubling time (PSADT), men with PSADT ≥ 2 months achieved higher PSA response rate (88%) and longer survival (22 months) than those with PSADT < 2 months (53%, 15 months). Patients with good-risk or intermediate-risk with PSA doubling time ≥2 months achieved favourable PSA response and survival and may benefit from chemotherapy with EMP.

We aimed to clarify the association between body mass index (BMI) and clinical outcomes of pembrolizumab treatment for advanced urothelial cancer (UC). We retrospectively reviewed the records of patients with advanced UC who received pembrolizumab after chemotherapy between March 2018 and December 2021. Patients were divided according to BMI into the non-overweight group (BMI <25 kg/m ) and the overweight group (BMI ≥25 kg/m ). We compared the two groups' tumour response, survival rates, and incidence of immune-related adverse events (irAEs) and investigated the factors predicting survival. Of 84 eligible patients, 63 (75%) and 21 (25%) were in the non-overweight and overweight groups, respectively. Although the objective response rate was higher in the overweight group (55%) than that in the non-overweight group (29%), the difference was not significant. Progression-free survival (PFS) was significantly longer in the overweight group (median 15.2 months) than that in the non-overweight group (median 4.8 months; p=0.01). Overall survival was also longer in the overweight group (median 36.1 months) compared to that in the non-overweight group (13.4 months), but the difference was not significant (p=0.11). Multivariable analysis showed that overweight was significantly associated with favourable PFS. Any and severe (grade 3) irAEs were observed in 15 (24%) and 5 (7.9%) patients in the non-overweight group, respectively, and in 8 (38%) and 2 (9.5%) patients in the overweight group, respectively, but the differences were not significant. BMI was associated with oncological outcomes in patients with advanced UC who received pembrolizumab but not with the development of irAEs.

Data on the C-reactive protein (CRP) flare response in patients with metastatic and unresectable urothelial carcinoma (mUC) are limited. The present study aimed to clarify the clinical significance of the CRP flare response in patients with mUC who received pembrolizumab. Between March 2018 and December 2022, patients with mUC who received pembrolizumab following chemotherapy were retrospectively reviewed. Patients were categorized into three groups based on the early kinetics of CRP: i) Flare-responders, in which CRP levels increased >2-fold from baseline (BL) within 1 month after pembrolizumab administration (CRP flare) and decreased to below-BL levels within 3 months; ii) responders, in which CRP levels decreased ≥30% from baseline within 3 months without CRP flare; and iii) non-responders, which included the remaining patients. Tumor response, survival and incidence of immune-related adverse events (AEs) were compared between the groups. Of the 108 eligible patients, 17 (16%), 27 (25%) and 64 (59%) were classified as CRP flare-responders, CRP responders and CRP non-responders, respectively. Objective response rate was higher in CRP flare-responders and CRP responders than in CRP non-responders. Progression-free survival and overall survival were longer in CRP flare-responders and CRP responders than in CRP non-responders. Among CRP flare-responders, patients with low BL CRP levels had a better tumor response and survival than patients with high BL CRP levels. Notably, there was no difference in the incidence of immune-related AEs. In patients with mUC who received pembrolizumab, CRP flare-responders showed favorable oncological outcomes; therefore, BL CRP levels could predict oncological outcomes in CRP flare-responders.

Hydrogen atoms dissolve in Pd at densities up to one H atom per Pd, which provides higher atomic H density than in solid H 2 . They are known to have large diffusion coefficient due to quantum tunneling. Torsional oscillator (TO) technique is employed to investigate the phases of H in Pd, which is known to show phase boundaries at the lowest T among metal-hydrogen (MH) systems. Specific heat measurements have been performed for PdH x with x up to high H concentration specimens as well as studies of the resistivity study to establish the unique x − T phase diagram. We have, in addition, been performing TO experiments, in order to study the effect of atomic H intrusion and the dynamics in the PdH(D) x system. The TO is a well-established, powerful instrument method to investigate superfluidity and quantum vortices of liquid He, especially in thin films, as well as dislocation dynamics in solids. In our TO experiments on PdH x specimens have shown a resonance frequency shift for PdH x , with 0.16≤ x ≤0.75 at the lowest T ’s, which can be largely explained by the lattice deformation by H intrusion. This x dependent contribution has a smaller, additional change depending on x and T above ∼50 K. We will show the details of experimental data and discuss the correspondence to the phonon modes change and further possibility of studying occurrence of quantum phenomena for the hydrogen system.

It is important to understand the mechanisms that regulate macrophage activation to establish novel therapies for inflammatory diseases, such as sepsis; a systemic inflammatory response syndrome generally caused by bacterial lipopolysaccharide (LPS). In this study, we investigated the involvement of extracellular ATP-mediated autocrine signaling in LPS-induced macrophage activation. We show here that ATP release via exocytosis, followed by activation of P2Y11 receptor, is a major pathway of the macrophage activation, leading to release of cytokines. Treatment of human monocyte THP-1 cells with LPS induced rapid ATP release from cells, and this release was blocked by knockdown of SLC17A9 (vesicular nucleotide transporter, VNUT), which is responsible for exocytosis of ATP. ATP-enriched vesicles were found in cytosol of THP-1 cells. These data suggest the involvement of vesicular exocytosis in the release of ATP. Knockdown of SLC17A9, the P2Y11 antagonist NF157 or knockdown of P2Y11 receptor significantly suppressed both M1-type polarization and IL-6 production in THP-1 cells, indicating an important role of activation of P2Y11 receptor by released ATP in macrophage activation. Next, the effect of NF157 on LPS-induced immune activation was examined in vivo. Administration of LPS to mice caused increase of serum IL-1ß, IL-6, IL-12 and TNF-alpha levels at 3-24 h after the administration. Pre-treatment of LPS-treated mice with NF157 suppressed both elevation of proinflammatory cytokines in serum and M1 polarization of peritoneal/spleen macrophages. Moreover, post-treatment with NF157 at 30 min after administration of LPS also suppressed the elevation of serum cytokines levels. We conclude that vesicular exocytosis of ATP and autocrine, positive feedback through P2Y11 receptors is required for the effective activation of macrophages. Consequently, P2Y11 receptor antagonists may be drug candidates for treatment of inflammatory diseases such as sepsis.

Wetwood of living trees is a habitat of methanogenic archaea, but the ubiquity of methanogenic archaea in the trunk of various trees has not been revealed. The present study analysed methanogenic archaeal communities inside coniferous and broadleaved trees in a cold temperate mountain forest by culture-dependent or independent techniques. Heartwood and sapwood segments were obtained from the trunk of seven tree species, Cryptomeria japonica , Quercus crispula , Fraxinus mandshurica , Acer pictum , Aesculus turbinata , Magnolia obovata , and Populus tremula . Amplicon sequencing analysis of 16S rRNA genes showed that Methanobacteriaceae predominated the archaeal communities and Methanomassiliicoccaceae also inhabited some trees. Real-time PCR analysis detected methanogenic archaeal mcrA genes from all the tree species, with a maximum of 10 7  copies g −1 dry wood. Digital PCR analysis also detected mcrA genes derived from Methanobacterium spp. and Methanobrevibacter spp. from several samples, with a maximum of 10 5 and 10 4  copies g −1 dry wood. The enumeration by the most probable number method demonstrated the inhabitation of viable methanogenic archaea inside the trees; 10 6  cells g −1 dry wood was enumerated from a heartwood sample of C. japonica . Methanogenic archaea related to Methanobacterium beijingense were cultivated from a heartwood sample of Q. crispula and F. mandshurica . The present study demonstrated that the inside of various trees is a common habitat for methanogenic archaeal communities and a potential source of methane in forest ecosystems.

BackgroundVonoprazan is a potassium competitive acid blocker used to treat erosive gastroesophageal reflux disease (GERD) with stronger, more stable acid-suppressing effects than proton pump inhibitors (PPIs). This study clarified the usefulness and superiority of vonoprazan administered every second day over PPIs in the maintenance therapy of erosive GERD.MethodsThis is a prospective, multicenter, open-label, two-period randomized cross-over study. Patients were randomized to either the vonoprazan-lansoprazole (VP-LZ) group, who were given vonoprazan 10 mg for the first 4 weeks and then lansoprazole 15 mg for the next 4 weeks both administered once every second day, or the lansoprazole-vonoprazan (LZ-VP) group, who were treated in reverse. GERD symptoms were compared using symptom diaries, the frequency scale for symptoms of GERD (FSSG), and the gastrointestinal symptom rating scale (GSRS).ResultsWe enrolled 122 patients between December 2017 and May 2019. Symptoms were well controlled in vonoprazan administration and lansoprazole administration were 93.6% and 82.1%, respectively, with a significant difference on McNemar’s test (P = 0.003). During the second 4 weeks, 94.4% and 76.7% of patients in the VP-LZ and LZ-VP groups, respectively, were well controlled following for ≥ 6 consecutive days a week (P = 0.009). During the first 4 weeks, 96.7% and 80.0% of patients were well controlled with < 1 weekly in the VP-LZ and LZ-VP groups, respectively, during the first 4 weeks (P = 0.007). GERD symptoms, assessed via FSSG and GSRS, significantly decreased with vonoprazan administration once every second day.ConclusionsVonoprazan administered once every second day could be an effective alternative to PPIs in the maintenance treatment of erosive GERD (UMIN000030393).

BackgroundIntraductal papillary mucinous neoplasm (IPMN) involves adenoma (IPMA), a precancerous lesion, cancer (IPMC) including high-grade dysplasia (HGD), and invasive carcinoma (IC). DNA markers of IPMN are required for detection of invasive disease, and cysteine dioxygenase 1 (CDO1) gene promoter hypermethylation is a potential candidate. However, it has never been investigated in the context of IPMN.Patients and MethodsA total of 107 IPMN tumor tissues, including 41 IPMC and 66 IPMA, were studied. CDO1 promoter methylation was quantified using TaqMan quantitative methylation-specific polymerase chain reaction (qMSP) in patients with IPMN and other pancreatic cystic disorders after pancreatectomy.ResultsThe methylation values (TaqMeth Vs) of CDO1 increased when noncancerous pancreas tissues were compared with IPMA and HGD (p < 0.0001). Among IPMC, the TaqMeth Vs in IC were not significantly higher than in HGD. The TaqMeth Vs of the solid tumors were higher than those of the cystic tumors (p = 0.0016), which were in turn higher than the corresponding noncancerous tissues (p < 0.0001). Prognostic analysis revealed that high TaqMeth Vs (≥ 14.1) resulted in a poorer prognosis than low TaqMeth Vs (< 14.1) (p < 0.0001). In other pancreatic cystic diseases, only malignant mucinous cystic neoplasm showed DNA hypermethylation of its promoter. A pilot study in pancreatic juice confirmed methylation in all IPMN samples but not in benign pancreatic diseases (p = 0.0277).ConclusionsCDO1 promoter hypermethylation is extremely specific to IPMN and may accumulate with IPMN tumor progression during the adenoma–carcinoma sequence. It might be a promising candidate as a diagnostic marker of pancreatic cystic diseases.