Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Incidence and risk factors for perineal hernia after robotic abdominoperineal resection: a single-center, retrospective cohort study.

BACKGROUND: Perineal hernia (PH) is a late complication of abdominoperineal resection (APR) that may compromise a patient's quality of life. The frequency and risk factors for PH after robotic APR adopting recent rectal cancer treatment strategies remain unclear. METHODS: Patients who underwent robotic APR for rectal cancer between December 2011 and June 2022 were retrospectively examined. From July 2020, pelvic reinforcement procedures, such as robotic closure of the pelvic peritoneum and levator ani muscles, were performed as prophylactic procedures for PH whenever feasible. PH was diagnosed in patients with or without symptoms using computed tomography 1 year after surgery. We examined the frequency of PH, compared characteristics between patients with PH (PH+) and without PH (PH-), and identified risk factors for PH. RESULTS: We evaluated 142 patients, including 53 PH+ (37.3%) and 89 PH- (62.6%). PH+ had a significantly higher rate of preoperative chemoradiotherapy (26.4% versus 10.1%, p = 0.017) and a significantly lower rate of undergoing pelvic reinforcement procedures (1.9% versus 14.0%, p = 0.017). PH+ had a lower rate of lateral lymph node dissection (47.2% versus 61.8%, p = 0.115) and a shorter operative time (340 min versus 394 min, p = 0.110). According to multivariate analysis, the independent risk factors for PH were preoperative chemoradiotherapy, not undergoing lateral lymph node dissection, and not undergoing a pelvic reinforcement procedure. CONCLUSIONS: PH after robotic APR for rectal cancer is not a rare complication under the recent treatment strategies for rectal cancer, and performing prophylactic procedures for PH should be considered.

Effect of baseline urinary glucose levels on the relationship between sodium-glucose cotransporter 2 inhibitors and serum uric acid in Japanese patients with type 2 diabetes mellitus.

In patients with type 2 diabetes mellitus (T2DM), controlling serum uric acid (SUA) and blood glucose levels is important. Moreover, sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease SUA levels by accelerating urinary uric acid excretion. We investigated the effect of baseline urinary glucose levels on the relationship between SGLT2 inhibitors and SUA levels. We conducted a retrospective observational study using the electronic medical records of patients with T2DM of Kindai University Nara Hospital (April 2013 to March 2022). We divided the patients into two groups according to their baseline urinary glucose levels: the N-UG group, which included patients with negative urinary glucose strip test results (-), and the P-UG group, which included patients with positive urinary glucose strip test results (± or more). The changes in SUA levels before and after SGLT2 inhibitor administration were investigated. For comparison, the changes in SUA levels before and after the prescription of antidiabetic agents, excluding SGLT2 inhibitors, were also investigated. Our results revealed that SGLT2 inhibitors significantly decreased the SUA levels in patients in the N-UG group but tended to decrease its levels in those in the P-UG group. Regardless of the urinary glucose status at baseline, the administration of SGLT2 inhibitors may be useful for patients with T2DM to prevent the complications of hyperuricemia.

Production and separation of positron emitters for hadron therapy at FRS-Cave M.

The FRagment Separator FRS at GSI is a versatile spectrometer and separator for experiments with relativistic in-flight separated short-lived exotic beams. One branch of the FRS is connected to the target hall where the bio-medical cave (Cave M) is located. Recently a joint activity between the experimental groups of the FRS and the biophysics at the GSI and Department of physics at LMU was started to perform biomedical experiments relevant for hadron therapy with positron emitting carbon and oxygen beams. This paper presents the new ion-optical mode and commissioning results of the FRS-Cave M branch where positron emitting 15O-ions were provided to the medical cave for the first time. An overall conversion efficiency of 2.9±0.2×10-4 15O fragments per primary 16O ion accelerated in the synchrotron SIS18 was reached.

Clinical characteristics and outcomes of pheochromocytoma crisis: a literature review of 200 cases.

PURPOSE: Pheochromocytoma crisis is a life-threatening endocrine emergency that requires prompt diagnosis and treatment. Because of its rarity, sudden onset, and lack of internationally uniform and validated diagnostic criteria, pheochromocytoma crisis remains to be fully clarified. Therefore, we aimed to describe the clinical characteristics and outcomes of pheochromocytoma crisis through a literature review. METHODS: We performed a systematic literature search of PubMed/MEDLINE database, Igaku-Chuo-Zasshi (Japanese database), and Google Scholar to identify case reports of pheochromocytoma crisis published until February 5, 2021. Information was extracted and analyzed from the literature that reported adequate individual patient data of pheochromocytoma crisis in English or Japanese. Cases were also termed as pheochromocytoma multisystem crisis (PMC) if patients had signs of hyperthermia, multiple organ failure, encephalopathy, and labile blood pressure. RESULTS: In the 200 cases of pheochromocytoma crisis identified from 187 articles, the mean patient age was 43.8 ± 15.5 years. The most common symptom was headache (39.5%). The heart was the most commonly damaged organ resulting from a complication of a pheochromocytoma crisis (99.0%), followed by the lungs (44.0%) and the kidney (21.5%). PMC accounted for 19.0% of all pheochromocytoma crisis cases. After excluding 12 cases with unknown survival statuses, the mortality rate was 13.8% (26/188 cases). Multivariable logistic regression analysis revealed that nausea and vomiting were significantly associated with a higher mortality rate. CONCLUSION: Pheochromocytoma can present with different symptomatology, affecting different organ systems. Clinicians should be aware that patients with nausea or vomiting are at a higher risk of death because of pheochromocytoma crisis.

Cutaneous ischemia-reperfusion injury is exacerbated by IL-36 receptor antagonist deficiency.

BACKGROUND: Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), has been implicated in the pathogenesis of skin disorders. However, the pathogenic role of IL-36Ra in cutaneous ischemia-reperfusion (I/R) injury remains unclear. OBJECTIVES: We investigated the role of IL36Ra in cutaneous I/R injury. METHODS: We examined I/R injury in Il36rn-/- mice. The area of wounds, numbers of infiltrated cells, apoptotic cells and neutrophil extracellular trap (NET) formation were assessed. The expression levels of various genes were analysed using real-time RT-PCR. The expression of high mobility group box 1 (HMGB1), an endogenous toll-like receptor (TLR) 4 ligand, was confirmed using immunohistology, and serum HMGB1 levels were measured by ELISA. Cytokine production by stimulated cultured J774A.1 and HaCaT cells was examined. RESULTS: IL-36Ra deficiency resulted in significantly delayed wound healing and increased neutrophil and macrophage infiltration into the wound tissues. Il36rn-/- mice had increased mRNA expression levels of CXCL1, CXCL2, CCL4, TNF-α, TGF-ß, IL-1ß, IL-6 and IL-36γ relative to wild-type mice. Apoptosis was identified in keratinocytes by TUNEL assay. HMGB1 expression in the I/R site was decreased in both keratinocytes and adnexal cells, while serum HMGB1 levels were significantly elevated after reperfusion. The mRNA levels of various cytokines, including IL-1ß, were elevated in J774A.1 cells through TLR4 signalling by HMGB1 stimulation. In addition, HaCaT cells stimulated with IL-1ß showed significantly increased CXCL1, TNF-α, IL-6, IL-36ß and IL-36γ mRNA expression. Furthermore, NET formation was increased by IL-36Ra deficiency. Finally, either the blockade of TLR4 signalling by TAK-242 or inhibition of NET formation by Cl-amidine normalized exacerbated I/R injury in Il36rn-/- mice. CONCLUSIONS: This study indicated that IL-36Ra deficiency exacerbates cutaneous I/R injury due to excessive inflammatory cell recruitment, NET formation, and excessive cytokine and chemokine production via the TLR4 pathway by HMGB1 released from epidermal apoptotic cells.

Osteoporosis case ascertainment strategies in European and Asian countries: a comparative review.

While many clinical guidelines recommend screening for osteoporosis for early detection and treatment, there is great diversity in the case-finding strategies globally. We sought to compare case-finding strategies, focusing on the approaches used in European and Asian countries. This article provides an overview of the current case-finding strategies in the UK, Germany (including Austria and German-speaking regions of Switzerland), China, Japan, and Korea. We conducted a review of current treatment guidelines in each country and included expert opinions from key opinion leaders. Most countries define osteoporosis among patients with a radiographically identified fracture of the hip or the vertebrae. However, for other types of fractures, or in the absence of a fracture, varying combinations of risk-factor assessment and areal bone mineral density (aBMD) assessed by dual X-ray absorptiometry are used to define osteoporosis cases. A T-score ≤ - 2.5 is accepted to identify osteoporosis in the absence of a fracture; however, not all countries accept DXA alone as the sole criteria. Additionally, the critera for requiring clinical risk factors in addition to aBMD differ across countries. In most Asian countries, aBMD scanning is only provided beyond a particular age threshold. However, all guidelines recommend fracture risk assessment in younger ages if risk factors are present. Our review identified that strategies for case-finding differ regionally, particularly among patients without a fracture. More homogenized ways of identifying osteoporosis cases are needed, in both the Eastern and the Western countries, to improve osteoporosis case-finding before a fracture occurs.Case-finding in osteoporosis is essential to initiate treatment and minimize fracture risk. We identified differences in case-finding strategies between Eastern and Western countries. In the absence of a diagnosed fracture, varying combinations of risk factors and bone density measurements are used. Standardized case-finding strategies may help improve treatment rates.

Swelling of Doubly Magic

Interaction cross sections for ^{42-51}Ca on a carbon target at 280 MeV/nucleon have been measured for the first time. The neutron number dependence of derived root-mean-square matter radii shows a significant increase beyond the neutron magic number N=28. Furthermore, this enhancement of matter radii is much larger than that of the previously measured charge radii, indicating a novel growth in neutron skin thickness. A simple examination based on the Fermi-type distribution, and mean field calculations point out that this anomalous enhancement of the nuclear size beyond N=28 results from an enlargement of the core by a sudden increase in the surface diffuseness of the neutron density distribution, which implies the swelling of the bare ^{48}Ca core in Ca isotopes beyond N=28.

Two-Neutron Halo is Unveiled in

We report the measurement of reaction cross sections (σ_{R}^{ex}) of ^{27,29}F with a carbon target at RIKEN. The unexpectedly large σ_{R}^{ex} and derived matter radius identify ^{29}F as the heaviest two-neutron Borromean halo to date. The halo is attributed to neutrons occupying the 2p_{3/2} orbital, thereby vanishing the shell closure associated with the neutron number N=20. The results are explained by state-of-the-art shell model calculations. Coupled-cluster computations based on effective field theories of the strong nuclear force describe the matter radius of ^{27}F but are challenged for ^{29}F.

Smectic Liquid-Crystalline Structure of Skyrmions in Chiral Magnet Co_{8.5}Zn_{7.5}Mn_{4}(110) Thin Film.

The organizing of magnetic skyrmions shows several forms similar to atomic arrays of solid states. Using Lorentz transmission electron microscopy, we report the first direct observation of a stable liquid-crystalline structure of skyrmions in chiral magnet Co_{8.5}Zn_{7.5}Mn_{4}(110) thin film, caused by magnetic anisotropy and chiral surface twist. Elongated skyrmions are oriented and periodically arranged only in the ⟨110⟩ directions, whereas they exhibit short-range order along the ⟨001⟩ directions, indicating a smectic skyrmion state. In addition, skyrmions possess anisotropic interaction with an opposite sign depending on the crystal orientation, in contrast to existing isotropic interaction.

First Spectroscopy of the Near Drip-line Nucleus

One of the most exotic light neutron-rich nuclei currently accessible for experimental study is ^{40}Mg, which lies at the intersection of the nucleon magic number N=28 and the neutron drip line. Low-lying excited states of ^{40}Mg have been studied for the first time following a one-proton removal reaction from ^{41}Al, performed at the Radioactive Isotope Beam Factory of RIKEN Nishina Center with the DALI2 γ-ray array and the ZeroDegree spectrometer. Two γ-ray transitions were observed, suggesting an excitation spectrum that shows unexpected properties as compared to both the systematics along the Z=12, N≥20 Mg isotopes and available state-of-the-art theoretical model predictions. A possible explanation for the observed structure involves weak-binding effects in the low-lying excitation spectrum.

Towards the Limits of Existence of Nuclear Structure: Observation and First Spectroscopy of the Isotope

The most remote isotope from the proton dripline (by 4 atomic mass units) has been observed: ^{31}K. It is unbound with respect to three-proton (3p) emission, and its decays have been detected in flight by measuring the trajectories of all decay products using microstrip detectors. The 3p emission processes have been studied by the means of angular correlations of ^{28}S+3p and the respective decay vertices. The energies of the previously unknown ground and excited states of ^{31}K have been determined. This provides its 3p separation energy value S_{3p} of -4.6(2) MeV. Upper half-life limits of 10 ps of the observed ^{31}K states have been derived from distributions of the measured decay vertices.

Equol inhibits growth and spore formation of Clostridioides difficile.

AIMS: Equol is a nonsteroidal oestrogen of the isoflavone class. We investigated the antibacterial ability of equol with respect to the growth rate, toxin production and spore-forming abilities of Clostridioides difficile BI/027/NAP1. METHODS AND RESULTS: Isoflavones, or female hormones, were added to bacterial culture, which was grown at 35°C. The absorbance of the culture was measured at various time points for evaluating the growth inhibition. The toxin levels in the media and morphological changes were also assessed. To evaluate the influence of equol on the sporulation of C. difficile, cells were collected at various time points from the equol-supplemented culture and the number of spores was counted. Our results show that equol inhibits bacterial growth in a concentration-dependent manner. However, it does not inhibit the production of toxin by C. difficile. Other isoflavones and female hormones did not inhibit the C. difficile growth. At the 14th day, approximately 600 spores were present in the control medium and only six were seen in the equol-containing medium. CONCLUSION: Our results suggest that equol may directly inhibit the C. difficile growth in a concentration-dependent manner and spore formation. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on the antimicrobial ability of equol.

Correlation of histological and microbiological findings in septic and aseptic knee implant failure.

INTRODUCTION: The Musculoskeletal Infection Society (MSIS) has defined specific clinical and laboratory criteria for the diagnosis of periprosthetic joint infection (PJI). In this study we assessed the diagnostic utility of MSIS microbiological and histological criteria for PJI in 138 cases of septic and aseptic knee implant failure. MATERIALS AND METHODS: Intra-operative samples from 60 cases of knee septic implant failure (SIF) and 78 cases of aseptic implant failure (AIF), defined on the basis of clinical, laboratory and operative findings/surgical management, were analysed microbiologically and histologically. Findings were correlated with the final clinical diagnosis and the specificity, sensitivity, accuracy, positive and negative predictive value of MSIS microbiological and histological criteria for knee PJI were assessed. RESULTS: 80% of SIF cases showed culture of the same organism from two or more samples (ie MSIS microbiological criteria for definite PJI); 8.3% grew an organism from one sample, and 11.7% showed no growth from any sample. 23.1% of AIF cases grew an organism from one sample and 76.9% showed no growth from any sample. MSIS histological criteria for PJI identified 96.7% of SIF cases. The sensitivity, specificity, accuracy and positive and negative predictive value of MSIS histological criteria for PJI were 96.7%, 100%, 98.6%, 100% and 97.5%, respectively. MSIS microbiological and histological criteria identified all AIF cases. CONCLUSIONS: Knee PJI is more often identified by current MSIS histological than microbiological criteria. A significant proportion of SIF cases show either no growth or growth of an organism from only one sample. AIF is identified by both MSIS microbiological and histological criteria. Correlation of clinical, radiological and laboratory findings is required for the diagnosis of knee PJI.

The influence of viscosity-enhancing agents on oral absorption of drugs.

The objective of this study was to evaluate the influence of viscosity-enhancing agents on oral absorption of metoprolol (MPL) and bisoprolol (BPL). Although the viscosity values were similar for MPL and BPL in hydroxypropyl methylcellulose (HPMC, 1.2 % (w/w)) and polyvinyl alcohol (PVA, 8.8 % (w/w)) solutions, the order of diffusion rate constants of the drugs in media were phosphate buffer solution (reference) > HPMC solution > PVA solution. In in vivo rat intestinal absorption experiments showed that the Cmax and AUC values of the drugs were lowest when they were administered into the rat jejunum in a PVA solution. In vitro binding studies showed that this may have been due to adsorption of the drugs to PVA molecules, resulting in decreased free fractions of the drugs. Our results indicated that intestinal absorption of the drugs in PVA solution was influenced both by decreased diffusion of the drugs and by interaction with PVA. Since various viscosity-enhancing agents are widely used as pharmaceutical and food additives, these findings may be of significance for understanding therapeutic efficacy and safety of oral drug products.

Transfer of epinastine to infants through human breast milk.

The purpose of this study was to develop an analytical method for analyzing epinastine in breast milk and maternal plasma samples to determine the safety of epinastine in breastfed infants. Six nursing mothers took epinastine hydrochloride (20 mg) once a day for 7 days, while a nursing mother took it for 30 days. Breast milk and blood samples were collected 2, 4, and 10 h after administration from the volunteers. A liquid chromatography-mass spectrometry system was used to analyze samples pretreated by liquid-liquid extractions. The concentration of epinastine in human milk was 10.3-33.5 ng/mL after 2 h, 9.1-63.8 ng/mL after 4 h, and 8.3-28.9 ng/mL after 10 h. The increase achieved 4 h after administration indicates that epinastine was transferred into human breast milk. However, the milk-to-plasma ratio had a wide range (0.82-3.39), while the relative infant dose at 4 h was 0.36-2.49%, which is lower than the safety level of transferability (10%). Moreover, the plasma levels of epinastine in two infants were slightly below the quantification limit. Overall, our results suggested that epinastine can safely be used by nursing mothers without affecting their infants.

Correction: Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells.

The authors report that there is a mistake in the representative picture of Fig. 4D (top row: PC3-miR1260b inh-0h) in the original version. The correct version of Fig. 4 with the original pictures for both PC3 miR-NC inh-0h and PC3-miR1260b inh-0h are provided below.

Clinical and functional significance of STEAP4-splice variant in CD14+ monocytes in patients with rheumatoid arthritis.

Tumour necrosis factor alpha (TNF)-α-induced adipose-related protein (TIARP) is a negative regulator of inflammation in arthritis model mice. In humans, six-transmembrane epithelial antigen of prostate 4 (STEAP4) (human counterpart of TIARP) is also expressed in CD14+ monocytes from patients with rheumatoid arthritis (RA). Recently, highly levels of exon 3-spliced variant STEAP4 (v-STEAP4) expression have been observed in porcine lung. The aim of this study is to elucidate the expression and functional role of v-STEAP4, comparing it with that of STEAP4, in the pathogenesis of arthritis. We identified v-STEAP4 in CD14+ cells. The expression of STEAP4 and v-STEAP4 was higher in patients with RA than in healthy participants. We also found that STEAP4 and v-STEAP4 were correlated positively with C-reactive protein and that their expression was decreased after treatment with an interleukin (IL)-6 antagonist in patients with RA. To investigate further the role of STEAP4 and v-STEAP4, we produced STEAP4 and v-STEAP4 over-expressing human monocytic cell lines (THP-1) for functional analysis. In the v-STEAP4 over-expressing cells, the production of IL-6 was suppressed significantly, but TNF-α was increased significantly through lipopolysaccharide (LPS) stimulation. Immunoblot analysis revealed that phosphorylated (p-)nuclear factor kappa B (NF-κB) was increased after LPS stimulation and degradation of nuclear factor kappa B inhibitor alpha (IκBα) was sustained, whereas p-signal transducer and activator of transcription 3 (STAT-3) was decreased with v-STEAP4. We identified specific up-regulation of v-STEAP4 in RA monocytes. V-STEAP4 might play a crucial role in the production of TNF-α and IL-6 through NF-κB and STAT-3 pathways, resulting in the generation of RA.

Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia.

6-Mercaptopurine (6-MP) is a main component of childhood acute lymphoblastic leukemia (ALL) treatment. Some candidate gene variants are associated with its toxicities, but the major variants and effects of combined variants remain unclear. We used Cox regression analysis to evaluate the time-dependent association between candidate variants and the cumulative incidence of 6-MP intolerability in 95 Japanese patients. The major risk factors for severe leukopenia were ABCC4 rs3765534, NUDT15 rs116855232 and rs186364861 in multi-covariate analysis (P<0.05). NUDT15 intermediate activity variant, that is, heterozygous rs116855232 or rs186364861 variant, and the ABCC4 rs3765534 variant showed leukopenia more frequently than either variant alone. All patients with both the intermediate activity NUDT15 variant and the ABCC4 rs3765534 variant suffered from leukopenia, and 57.1% patients required 50% protocol dose by day 168. These data indicate that NUDT15 and ABCC4 are major factors for 6-MP intolerability and that the interaction between these variants enhances intolerability to 6-MP.