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We evaluated the association of prostate volume (PV) with the efficacy and safety of transurethral enucleation with bipolar energy (TUEB) for treatment of benign prostatic hyperplasia (BPH).We retrospectively evaluated data from 180 patients with symptomatic BPH who underwent TUEB between 2008 and 2015. Efficacy was assessed by perioperative changes in international prostate symptom score (IPSS), Quality of Life Score (QOLS), maximum flow rate on uroflowmetry (Qmax), and serum prostate-specific antigen level (PSA), which were recorded at 3 months postoperatively. Safety was assessed by perioperative incidence of adverse events (AEs). AEs were recorded up to 2 years after surgery. Patients were divided into two groups based on PV as the standard group (SG; PV80 mL) and large group (LG; PV ≥ 80 mL).A total of 132 (73%) patients were grouped as the SG, and 48 (27%) were grouped as the LG. No significant differences between the groups were observed in the preoperative variables age, IPSS, and QOLS. However, the LG had a significantly larger PV and higher serum PSA levels. Analysis of surgical outcomes revealed that postoperative changes in IPSS, QOLS, Qmax, serum PSA, serum sodium, and hemoglobin levels did not differ significantly between groups. However, LG had a significantly longer operative time and heavier specimen weight. The rates of early complications, including hyponatremia and blood transfusion, and late complications after surgery did not differ between the groups.The present findings suggest that TUEB is safe and effective for treatment of BPH, regardless of PV.

B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3–targeting antibody–drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species. The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed. DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3–expressing cancer cells, but not that of B7-H3–negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high–B7-H3 tumor xenograft models, including various tumor types of high–B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys. DS-7300a exerted potent antitumor activities against B7-H3–expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3–expressing solid tumors in a clinical setting.

Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKI), which eventually lead to the development of secondary resistance mutations in KIT or PDGFRA and disease progression. Herein, we identified G protein–coupled receptor 20 (GPR20) as a novel non–tyrosine kinase target in GIST, developed new GPR20 IHC, and assessed GPR20 expression in cell lines, patient-derived xenografts, and clinical samples from two institutes (United States and Japan). We studied GPR20 expression stratified by treatment line, KIT expression, GIST molecular subtype, and primary tumor location. We produced DS-6157a, an anti-GPR20 antibody–drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). DS-6157a exhibited GPR20 expression–dependent antitumor activity in GIST xenograft models including a GIST model resistant to imatinib, sunitinib, and regorafenib. Preclinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients who are refractory or have resistance or intolerance to approved TKIs.Significance:GPR20 is selectively expressed in GIST across all treatment lines, regardless of KIT/PDGFRA genotypes. We generated DS-6157a, a DXd-based antibody–drug conjugate that exhibited antitumor activity in GIST models by a different mode of action than currently approved TKIs, showing favorable pharmacokinetics and safety profiles.This article is highlighted in the In This Issue feature, p. 1307

Characteristics for GIST patient samples, GPR20 expression in KIT/PDGFRA wild type GIST, GPR20 expression in normal, malignant and sarcoma tissue microarrays.

Supplementary Data from DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models

B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3–targeting antibody–drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species.The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed.DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3–expressing cancer cells, but not that of B7-H3–negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high–B7-H3 tumor xenograft models, including various tumor types of high–B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys.DS-7300a exerted potent antitumor activities against B7-H3–expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3–expressing solid tumors in a clinical setting.

S1: Expression of GPR20 in clinical GIST specimens from NCCHE S2: Representative images of GPR20 expression in various sarcoma including GIST in University of Basel derived TMA. S3: GPR20 was not expressed in systemic mastocytosis. S4: Protein expression of human, cynomolgus monkey, rat, and mouse GPR20 on CHO-K1 cells. S5: Lack of DS-6157a efficacy in the GPR20-negative KPL-4 xenograft model. S6: Comparison of tumor growth curve of GIST-T1 and GIST-T1/GPR20 xenograft models.

Quantitative evaluation of the antibacterial activity of conventional antibacterial agents in situ is difficult. In this study, we demonstrated that antibacterial activity can be quantitatively estimated from the photoluminescence intensity of pyrene fluorophores incorporated into tannic acid, a naturally occurring antibacterial agent., Bulletin of the Chemical Society of Japan. 95 [5] (2022)

We investigated the efficacy and safety of twice-daily bilayer sustained-release tramadol hydrochloride tablets (35% immediate-release; 65% sustained-release) in patients with postherpetic neuralgia.This was a Phase III treatment-withdrawal study with 1-4-week dose-escalation, 1-week fixed-dose, and 4-week randomized, double-blind, placebo-controlled withdrawal periods performed at 43 medical institutions in Japan. Patients aged ≥20 years, ≥3 months after the onset of herpes zoster with localized, persistent pain despite fixed-dose analgesics for ≥2 weeks before enrollment were eligible. Patients started tramadol at 100 mg/day and its dose escalated to a maximum of 400 mg/day to achieve a reduction in their Numeric Rating Scale (NRS) for pain of ≥2 points. Eligible patients were randomized to continue tramadol or switched to placebo for 4 weeks (double-blind period). Patients were withdrawn due to inadequate analgesia (NRS deteriorated on ≥2 consecutive days) or their request.Overall, 252 patients started tramadol and 173 were randomized (tramadol: 85; placebo: 88). Tramadol was superior to placebo for the primary endpoint (time from randomization to an inadequate analgesic effect) with log-rank test p = 0.0005. The hazard ratio was 0.353 (95% confidence interval 0.190-0.657) in favor of tramadol and fewer patients in the tramadol group experienced inadequate analgesic effects (16.9% vs. 39.8%). Adverse events in ≥10% of patients in the open-label period were constipation (43.8%), nausea (34.9%), somnolence (18.5%), and dizziness (11.6%). The frequencies of adverse events in the double-blind period were similar in both groups.Sustained-release tramadol tablets with an immediate-release component are effective and well tolerated for managing postherpetic neuralgia.

Ceramic matrix composites (CMCs), especially SiC/SiC, have garnered significant attention owing to their remarkable mechanical properties at higher temperatures. For the protection of the substrate from oxidation, the SiC/SiC CMCs inherently require environmental barrier coating (EBC). Because aeroengines must function under a wide range of conditions and environments, the coated CMC must be sufficiently resistant to various damage modes. Among these, the effect of microparticles is one of the limiting factors for the durability and performance of components, particularly when the engine is operated in dusty areas. The main goal of this experimental research is to investigate and determine the surface damage behavior of the coated CMC caused by micro-sand particles. The data were surveyed across a fairly broad range of exposed temperatures and velocities, and covered conditions relevant to advanced hot section designs. In the experiments, silica or alumina sand entrained in the gas stream was jet-blasted from the nozzle and then impinged on the target CMC + EBC coupon. Owing to the broad testing range, the damage mode and extent of damage varied considerably by condition. The obtained data were then reorganized and compared with several previously proposed particle impact models. This is to first understand and obtain a complete picture of all the probable consequences in the expected design and off-design conditions and, second, to determine the validity of, and deviations from the conventional modeling with the present CMC + EBC material, which will be useful in the next component design phase.

Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKI), which eventually lead to the development of secondary resistance mutations in KIT or PDGFRA and disease progression. Herein, we identified G protein–coupled receptor 20 (GPR20) as a novel non–tyrosine kinase target in GIST, developed new GPR20 IHC, and assessed GPR20 expression in cell lines, patient-derived xenografts, and clinical samples from two institutes (United States and Japan). We studied GPR20 expression stratified by treatment line, KIT expression, GIST molecular subtype, and primary tumor location. We produced DS-6157a, an anti-GPR20 antibody–drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). DS-6157a exhibited GPR20 expression–dependent antitumor activity in GIST xenograft models including a GIST model resistant to imatinib, sunitinib, and regorafenib. Preclinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients who are refractory or have resistance or intolerance to approved TKIs. Significance: GPR20 is selectively expressed in GIST across all treatment lines, regardless of KIT/PDGFRA genotypes. We generated DS-6157a, a DXd-based antibody–drug conjugate that exhibited antitumor activity in GIST models by a different mode of action than currently approved TKIs, showing favorable pharmacokinetics and safety profiles. This article is highlighted in the In This Issue feature, p. 1307

A linear inertial electrostatic confinement fusion neutron source equipped with a cooling system for high power operation was developed and its discharge characteristics and neutron produc...

A compact inertial electrostatic confinement (IEC) fusion neutron source was developed. Imaging tests using the cylindrical IEC neutron source were conducted with the indirect imaging plate (IP) method using dysprosium foil and an imaging plate. An array of B 4 C powder contained in a stainless-steel blade and Cd pins was successfully imaged. To calculate thermal neutron flux of the device, we tested multiple types of IP and IP scanners with the indirect IP method to create a calibration curve, and it was confirmed that dental IP scanners, which are more widely used than industrial ones, can be applied to the indirect IP method.

Flux waveforms of aluminum cluster beams supplied from a laser-ablation cluster source were precisely investigated under various source conditions such as background pressure, ablation laser intensity, and nozzle structure. A time-of-flight mass spectroscopy revealed that aluminum clusters with sizes up to 200 were generated and the amount of the clusters could be maximized by choosing a proper background pressure (~2 MPa) and an ablation laser fluence (~40 mJ/cm2). Flux waveforms of clusters having specific sizes were carefully reconstructed from the observed mass spectra. It is found that the pulse widths of the aluminum cluster beams were typically about 100 µs and much smaller than that of the monoatomic aluminum beam, indicating that the cluster formation was limited in a relatively small volume in the laser-ablated vapor. Introducing a conical nozzle having a large open angle was also found to enhance the cluster beam velocity and reduce its pulse width. A velocity measurement of particles in the cluster beam was conducted to examine the velocity spread of the supplied clusters. We found that the aluminum clusters were continuously released from the source for about 100 µs and this release time mainly determined the pulse width of the cluster beam, suggesting that controlling the behavior of an ablated vapor plume in the waiting room of the cluster source holds the key to drastically improving the cluster beam flux.

Introduction: B7-H3 (encoded by the CD276 gene) is suggested to act as an immune checkpoint molecule and is highly expressed in some pediatric solid tumors. Monoclonal antibodies targeting B7-H3 (8H9 and MGA271) are well-tolerated but have demonstrated limited success in clinical trials. DS-7300a is a B7-H3 targeting ADC with a payload of DXd (an exatecan derivative that inhibits DNA topoisomerase I). DS-7300a has a drug-to-antibody ratio of 4 and it has shown promising early clinical activity in adults with advanced solid cancers (Johnson, Annals of Oncology 2021; 32:S583-S585). Methods: Xenograft models for several pediatric cancer types were selected for preclinical testing of DS-7300a based on the high rates of B7-H3 expression in these cancers. Models were dosed at 10 mg/kg administered intravenously every other week for two doses (Q2wk x 2). Different experimental designs were used for efficacy testing. For rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, and other pediatric solid tumors a single mouse trial (SMT) design with 40 models was used. A cohort design (N=10) was used for efficacy testing in 6 osteosarcoma models, 3 patient-derived orthotopic xenograft glioblastoma (PDOX) models, and 3 PDOX ependymoma models. For neuroblastoma models, 10 models (2 mice per model) were tested. To evaluate treatment efficacy, objective response measures based on changes in relative tumor volume were used (Houghton, Pediatr Blood Cancer 2007;49:928-940). Results: As a single agent, DS-7300a induced a statistically significant prolongation of survival in 2 of 3 orthotopic glioblastoma and 1 of 3 ependymal tumor models. DS-7300a demonstrated high efficacy (maintained complete response, complete response, and partial response) in most non-CNS models tested: 17 of 21 rhabdomyosarcomas, 5 of 7 osteosarcomas, 7 of 10 neuroblastomas and 2 of 2 Wilms tumors. For Ewing sarcoma, most models were classified as progressive disease (9 of 15). For osteosarcoma models, the log cell kill per dose values ranged from 0.95 to 2.76 indicating high activity of the agent in these models. The activity for DS-7300a followed the general pattern of protein and RNA expression levels for B7-H3/CD276 in the models, with Ewing sarcoma models showing lower expression compared to the other models. Conclusions: DS-7300a shows tumor-regressing anticancer activity across a wide range of pediatric solid tumor models. The maintained complete remissions observed for osteosarcoma models are noteworthy, as this level of response is uncommon for these models and as osteosarcoma shows the highest B7-H3 expression among pediatric cancers. The high level of preclinical activity observed for DS-7300a combined with the promising early clinical activity observed for adult patients provide strong rationale for studying DS-7300a in children with B7-H3 expressing solid tumors. Citation Format: Richard Gorlick, E. Anders Kolb, Yifei Wang, Peter Houghton, Raushan Kurmasheva, Yael Mosse, John Maris, Matthew Tsang, David Groff, Kateryna Krytska, Xiao-Nan Li, Yuchen Du, Jun Hasegawa, Nanae Izumi, Steven Neuhauser, Anuj Srivastava, Tim Stearns, Vivek Philip, Emily L. Jocoy, Jeff Chuang, Carol J. Bult, Beverly Teicher, Malcolm Smith. Evaluation of the in vivo efficacy of the B7-H3 targeting antibody-drug conjugate (ADC) DS7300a: A report fro the Pediatric Preclinical In Vivo Resting (PIVOT) program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB061.