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Background: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate approved outside Japan for second-line and later metastatic triple-negative breast cancer (mTNBC), based on the ASCENT study (NCT02574455). We report SG safety and efficacy in an open-label, phase 1/2 bridging study in Japanese patients with advanced solid tumors (ASCENT-J02; NCT05101096; jRCT2031210346)., Methods: Phase 1 was a standard 3 + 3 design. Patients received intravenous SG 6 mg/kg, escalating to 10 mg/kg, on Days 1 and 8 per 21-day cycle; primary endpoints were safety, incidence of dose-limiting toxicity/toxicities (DLTs), and determination of the recommended phase 2 dose (RP2D). In the multicohort phase 2 study, patients in the mTNBC cohort with previously treated disease received SG at the RP2D; primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; RECIST v1.1). Safety was a secondary endpoint., Results: In phase 1 (N = 15), one DLT (grade 3 elevated transaminases) occurred with SG 10 mg/kg; RP2D was SG 10 mg/kg regardless of UGT1A1 status. In phase 2, 36 patients with mTNBC received SG 10 mg/kg. At median follow-up of 6.1 months, IRC-assessed ORR was 25.0% (95% CI 12.1-42.2; P = 0.0077). Median progression-free survival was 5.6 months (95% CI 3.9-not reached [NR]); median overall survival was NR. No treatment-emergent adverse events led to discontinuation or death., Conclusions: SG RP2D was established as 10 mg/kg in Japanese patients. SG showed efficacy in Japanese patients with previously treated mTNBC, a manageable safety profile, and no new safety signals, consistent with the previous ASCENT study., (© 2024. The Author(s).)

Background: Gastroesophageal Reflux Disease (GERD) is caused by the reflux of gastric contents into the esophagus and has a 13% global prevalence that is increasing. GERD symptoms negatively impact physical, social, and emotional quality of life. The Frequency Scale for the Symptoms of GERD (FSSG) and the Gastrointestinal Symptom Rating Scale (GSRS) determine the efficacy of treatment but may not correlate with endoscopically estimated esophageal mucosal injury severity. We aimed to probe the correlation between FSSG, GSRS, and esophageal injury severity to evaluate whether these scores can predict GERD severity., Methods: A total of 2962 patients who underwent physical examinations, including upper gastrointestinal endoscopy, at the Kyoto Kuramaguchi Medical Center, Japan, were enrolled in this study. Upper gastrointestinal endoscopy was used to diagnose fundic mucosal atrophy, reflux esophagitis based on the Los Angeles (LA) classification, gastroesophageal flap value function (GEFV) based on Hill's classification, and Barrett's esophagus. Endoscopic diagnoses were examined for correlations with FSSG and GSRS scores., Results: In reflux esophagitis, FSSG and GSRS scores correlated with LA-B and LA-C endoscopic diagnosis but not with LA-M and LA-A endoscopic findings. Multiple regression analysis results were similar. FSSG scores reflected advanced fundic gland mucosal atrophy, while GSRS scores associated with high grade of GEFV., Conclusions: This is the first report to examine the correlation between FSSG and GSRS scores and endoscopic findings in a relatively large patient population. Our findings suggest that these scores can diagnose the severity of reflux esophagitis.

Background: High riding jugular bulb (HRJB) develops after 2 years and is rare at younger ages. High riding jugular bulb sometimes protrudes into the tympanic cavity, which can cause hemorrhagic complications during otologic surgery., Case Presentation: We describe a congenitally deaf child with bilateral inner ear malformations and a right-sided HRJB on CT at 9 months. This child had undergone left cochlear implantation (CI) at 19 months, and right CI was planned at 6 years. However, we decided not to perform the right CI because preoperative CT images revealed that the right jugular bulb (JB) was enlarged and protruded into the tympanic cavity, completely covering the round window (RW)., Conclusion: This is the first pediatric case in which a longitudinal CT scan proves that HRJB develops and protrudes over time. These findings suggest that the earlier the HRJB forms, the larger it may grow. We must keep in mind the possibility of the enlargement and protrusion of HRJB., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acute lung injury caused by Pseudomonas aeruginosa is attributed to the translocation of cytotoxin into pulmonary epithelial cells via the P. aeruginosa type III secretion system. This virulence can be blocked with a specific antibody against PcrV in this secretion system. However, because anti-PcrV antibodies do not have bactericidal activity, the treatment of bacteria depends on the phagocytic system of the host. In this study, we investigated the therapeutic effect of combination therapy with an anti-PcrV antibody and bactericidal bacteriophages on acute lung injury and subsequent death in mice compared with a single treatment. After the mice intratracheally received a lethal dose of the cytotoxic P. aeruginosa strain, a second instillation was performed with saline, anti-PcrV IgG, bacteriophages, or a mixture of anti-PcrV and bacteriophages. The survival rates 24 h after infection were as follows: 7.1% in the saline group, 26.7% in the anti-PcrV group, 41.2% in the phage group, and 66.7% in the anti-PcrV + phage group ( P < 0.001 vs saline-treated group). The activity of surviving mice in the anti-PcrV + phage group was significantly greater than that in the saline group. The lung weight in the anti-PcrV + phage group was significantly lower than that in the anti-PcrV group. In conclusion, combination therapy with an anti-PcrV antibody and a bacteriophage reduces acute lung injury and suggests improved survival compared with each treatment alone. This combination therapy, which does not rely on conventional antibiotics, could constitute a new strategy for treating multidrug-resistant P. aeruginosa infections.IMPORTANCECombination therapy with either bacteriophages alone or in combination with anti-PcrV antibodies in a mouse model of Pseudomonas aeruginosa pneumonia may reduce the acute lung injury and improve survival. This combination therapy, which does not rely on conventional antibiotics, may be a new strategy to treat multidrug-resistant Pseudomonas aeruginosa infections.

This study aimed to investigate the characteristics of resting-state electroencephalography (EEG) activity and brain networks in patients with mild traumatic brain injury (mTBI) and their association with neurocognitive function (NCF). We analyzed 26 patients with subacute mTBI and 21 healthy controls. The subacute mTBI group (9 females, 17 males) had a mean age of 29.9 ± 9.9 years, and the healthy controls (11 females, 10 males) had a mean age of 29.7 ± 11.5 years. Current source density, lagged phase synchronization, and resting-state network activity were analyzed using exact low-resolution electromagnetic tomography (eLORETA) with 60 s resting-state EEG data. In addition, a correlation analysis was performed between these EEG parameters and NCF in patients with mTBI. We used the statistical nonparametric mapping method in eLORETA to correct for multiple comparisons. There were no significant differences in EEG parameters between the patients with mTBI and healthy controls. However, in patients with mTBI, correlation analysis revealed negative correlations between theta activity in the anterior cingulate cortex and verbal short-term memory and between activity in the memory perception network and verbal memory. Our findings suggest that resting-state EEG may be clinically useful in investigating the mechanism of NCF decline in patients with mTBI., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Ulcerative colitis (UC) is a chronic inflammatory disease of unknown cause for which no curative treatments have been developed. Cytokines play an important role in the pathogenesis of UC, and therapies targeting specific cytokines have been successful in treating refractory UC. The purpose of this study was to measure mucosal cytokines in UC and identify those that contribute to non-relapsing mucosal healing diagnosed by endoscopy., Methods: This prospective, observational study included 163 patients with UC. The mucosa was evaluated by Mayo Endoscopic Subscore (MES) and linked color imaging (LCI) at the time of endoscopy, and cytokine mRNA expression in biopsy tissue taken from the same site was quantified by real-time PCR and compared with endoscopic findings. The relationship between cytokine mRNA expression and endoscopic findings was investigated., Results: Cytokines such as IFNγ, IL-1β, IL-8, IL-17A, and IL-23 were significantly elevated in proportion to endoscopic severity of MES and LCI classification.Interestingly, we found differences in the expression of cytokines (e.g., IL-22 and IL-33) between MES and LCI classification according to disease severity. Additionally, pathway analysis based on RNA sequencing compared between LCI-A and LCI-B in the patients diagnosed as MES 0 revealed that IL-5 and IL-6 are involved in the finer differences in endoscopic mucosal redness., Conclusions: This study is the first to report the correlation between mucosal cytokine expression and the pathogenesis of mucosal healing (MH) in UC and supports the contribution of specific cytokines as molecular markers of MH or in the pathogenesis of MH in UC., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The incidence of breast cancer among young Asian women is increasing, yet they remain underrepresented in global data. We analyzed the epidemiology and outcomes of Asian patients with breast cancer <40 years old across different subtypes to identify their clinical unmet needs., Patients and Methods: Female patients aged ≥20 years diagnosed with early breast cancer were analyzed from the prospective cohort of the Asian Breast Cancer Cooperative Group (ABCCG). For comparison, data from the Surveillance, Epidemiology, and End Results Program (SEER) cancer registry were used. Patients were categorized into three age groups: young (<40 years), alleged premenopausal mid-age (40-49 years), and alleged postmenopausal (aged ≥50 years). Multivariable Cox proportional hazards models for survival were adjusted for subtypes, histologic grade, T stage, nodal status, and study centers., Results: A total of 45 021 patients with breast cancer from Asian study centers, 496 332 SEER-White patients, and 18 279 SEER-Asian patients were included in the analysis. The median age at diagnosis was younger in the Asian cohort (51 years) compared with SEER-Whites (62 years) and SEER-Asians (58 years; P < 0.0001). In the young-age group, hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer was more prevalent among Asians and SEER-Asians compared with SEER-Whites (61.2% and 59.8% versus 54.7%). In the Asian population, young patients with HR+/HER2- breast cancer exhibited significantly inferior overall survival than the mid-age group (6-year overall survival 94.4% versus 96.6%; mid-age to young-age group hazard ratio 0.62; P < 0.001). Similarly, young patients in SEER-Whites showed an earlier decline in survival compared with the mid-age group (89.1% versus 94.0%; P < 0.001)., Conclusion: ABCCG-Asian patients with breast cancer <40 years old with HR+/HER2- subtypes were more likely to have worse survival outcomes than their mid-age counterparts. Our study highlights the poorer prognosis of young patients and underscores the need for a tailored therapeutic approach, such as ovarian function suppression, particularly considering ethnic factors., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background/objectives: Circulating bile acid (BA) profiles change with lifestyle and are closely related to intestinal BA metabolisms such as deconjugation and conversion to secondary BAs. The composition of BA in the blood is involved in systemic nutrient metabolism and intestinal health. Herein, we explored the associations of lifestyle and physical fitness with the circulating BA profile of middle-aged men., Methods: Data of 147 male participants (aged 50-64 years; BMI < 26 kg/m 2 ; no medication for diabetes or dyslipidemia) from the Japan Multi-Institutional Collaborative Cohort study were analyzed. Serum concentrations of 15 types of BAs were examined for associations with variables on dietary habits, physical-activity habits, and physical fitness., Results: Green tea intake was positively associated with the deconjugation ratio of total BAs ( p = 0.028) and negatively associated with secondary BA levels (free deoxycholic acid [DCA] ( p = 0.078), glyco-DCA ( p = 0.048), and tauro-DCA ( p = 0.037)). In contrast, physical activity was negatively associated with the deconjugation ratio ( p = 0.029) and secondary BA levels (free DCA ( p = 0.098), and free lithocholic acid ( p = 0.009)). Grip strength was also negatively associated with secondary BA levels (tauro-DCA ( p = 0.041)) but was not associated with the deconjugation ratio. Energy and fat intake and skeletal muscle mass were not associated with the deconjugation ratio or secondary BA levels., Conclusions: The study findings suggest that lifestyle-associated changes in serum deconjugated and secondary BAs indicate improvements in nutrient metabolism and the intestinal environment.

A 54-year-old woman with persistent fatigue and a high fever presented with central pontine myelinolysis (CPM) on brain imaging, despite the absence of neurological symptoms. The patient had a slightly low serum sodium concentration. Further investigation led to a diagnosis of primary splenic diffuse large B-cell lymphoma (PS-DLBCL). Brainstem auditory-evoked potentials (BAEP) indicated minor abnormalities. CPM was successfully resolved after splenectomy and immunochemotherapy. This is the first reported case of CPM in a patient with PS-DLBCL confirmed by a pathological diagnosis following splenectomy and BAEP-detected abnormalities that improved with immunochemotherapy.

Objective: This study aimed to elucidate the long-term impact of prelingual deafness and elderly age at cochlear implantation on cochlear implant (CI) programming parameters and CI thresholds METHODS: We retrospectively reviewed patients who underwent cochlear implantation less than 5 years (Prelingual group) and equal and more than 18 years in our institute. The latter group was further divided into Adult and Elderly groups according to whether the patient was younger or older than 65 at implantation. From 152, 69, and 55 patients in the Prelingual, Adult, and Elderly groups, 242, 92, and 58 ears were included. We compared CI thresholds and CI programming parameters, including impedances, T/C levels, and dynamic ranges for 8 years after implantation between the Prelingual, Adult, and Elderly groups., Results: The Prelingual group showed consistently lower CI thresholds than the Adult and Elderly groups during the postoperative 2-8 years, but no difference was detected between the Elderly and Adult groups, except at the postoperative 4 years. The elderly group's CI thresholds did not deteriorate until postoperative 8 years. The Prelingual group showed consistently larger T/C levels (minimum/maximum current strength from CI), especially C levels, than the other two groups. At the same time, there was no significant difference between the Elderly and Adult groups except for smaller dynamic ranges in the Elderly group until postoperative 2 years. These results in the CI programming parameters might explain the lower CI thresholds in the Prelingual group than in the other groups. Focusing on CI maps 1 and 3 years after implantation, the strength of the T/C levels was similar for all channels in the Prelingual group, but the Adult and Elderly groups showed larger electrical stimuli in channels responsible for the middle frequencies than those for the lower or higher frequencies., Conclusions: Our results suggest a significant influence of prelingual deafness but less impact of elderly age at implantation on long-term CI programming parameters and CI thresholds. The larger C levels and lower CI thresholds in the Prelingual group than in the Adult and Elderly groups implied that CI children with prelingual deafness tolerate and prefer larger CI stimuli, which may reflect the CI-dependent development of their auditory system before the critical period. No age-related reduction in hearing thresholds was observed in the Elderly group, probably because the CI compensates for age-related dysfunction of the peripheral auditory system., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Conventional conditioning regimens for children with lymphoid malignancy undergoing allogeneic hematopoietic cell transplantation (HCT) are myeloablative and involve high-dose total body irradiation (TBI). Such regimens are associated with significant late complications., Observations: Here, we used a reduced-toxicity conditioning regimen comprising fludarabine, cytarabine, melphalan, and low-dose TBI (FLAMEL) to treat 5 patients with lymphoid malignancy before HCT. Four patients maintained complete remission (range, 18 to 63 mo), whereas the remaining patient who had positive minimal residual disease (MRD) before HCT relapsed., Conclusions: FLAMEL might be a suitable conditioning regimen for children with lymphoid malignancy if pre-HCT MRD is negative., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To assess the importance of appropriate opioid administration methods according to nociceptive monitoring., Methods: We conducted a randomized controlled trial involving 54 patients who underwent robot-assisted laparoscopic radical prostatectomy at our hospital. Patients were randomly allocated to either receive nociception level (NOL)-directed intraoperative opioid management with a minimum flow of remifentanil (NOL group) or conventional intraoperative analgesic management (control group). The primary outcome was the mean intraoperative remifentanil infusion flow rate (intraoperative remifentanil usage [μg]/ideal body weight [kg]/operation time [min]). The main secondary outcomes were plasma concentrations of three perioperative inflammatory biomarkers (interleukin-6, C-reactive protein [CRP], and cortisol levels) and postoperative pain (Numeric Rating Scale [NRS]) scores 2 h postoperatively and on postoperative days 1, 2, 3, and 7., Results: Compared with standard analgesia management, NOL-directed analgesic management reduced remifentanil consumption by 20% ( - 0.038; 95% confidence interval, - 0.059 to - 0.017; p = 0.0007). NOL-directed management did not lead to an increase in IL-6, CRP, or cortisol levels compared with conventional analgesic management. Furthermore, this protocol led to improvements in the NRS scores at rest 2 h postoperatively and upon movement up to postoperative day 3., Conclusion: NOL-directed analgesic management reduced remifentanil consumption by 20% and the NRS scores at rest 2 h postoperatively and upon movement up to postoperative day 3 without an increase in inflammatory marker levels., Registry Number: Japan Registry of Clinical Trials, JRCTs052220034., (© 2024. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

The precise organization of pre- and postsynaptic terminals is crucial for normal synaptic function in the brain. In addition to its canonical role as a neurotrophin-3 receptor tyrosine kinase, postsynaptic TrkC promotes excitatory synapse organization through interaction with presynaptic receptor-type tyrosine phosphatase PTPσ. To isolate the synaptic organizer function of TrkC from its role as a neurotrophin-3 receptor, we generated mice carrying TrkC point mutations that selectively abolish PTPσ binding. The excitatory synapses in mutant mice had abnormal synaptic vesicle clustering and postsynaptic density elongation, more silent synapses, and fewer active synapses, which additionally exhibited enhanced basal transmission with impaired release probability. Alongside these phenotypes, we observed aberrant synaptic protein phosphorylation, but no differences in the neurotrophin signaling pathway. Consistent with reports linking these aberrantly phosphorylated proteins to neuropsychiatric disorders, mutant TrkC knock-in mice displayed impaired social responses and increased avoidance behavior. Thus, through its regulation of synaptic protein phosphorylation, the TrkC-PTPσ complex is crucial for the maturation, but not formation, of excitatory synapses in vivo., (© 2024. The Author(s).)

Whereas severe COVID-19 is often associated with elevated autoantibody titers, the underlying mechanism behind their generation has remained unclear. Here we report clonal composition and diversity of autoantibodies in humoral response to SARS-CoV-2. Immunoglobulin repertoire analysis and characterization of plasmablast-derived monoclonal antibodies uncovered clonal expansion of plasmablasts producing cardiolipin (CL)-reactive autoantibodies. Half of the expanded CL-reactive clones exhibited strong binding to SARS-CoV-2 antigens. One such clone, CoV1804, was reactive to both CL and viral nucleocapsid (N), and further showed anti-nucleolar activity in human cells. Notably, antibodies sharing genetic features with CoV1804 were identified in COVID-19 patient-derived immunoglobulins, thereby constituting a novel public antibody. These public autoantibodies had numerous mutations that unambiguously enhanced anti-N reactivity, when causing fluctuations in anti-CL reactivity along with the acquisition of additional self-reactivities, such as anti-nucleolar activity, in the progeny. Thus, potentially CL-reactive precursors may have developed multiple self-reactivities through clonal selection, expansion, and somatic hypermutation driven by viral antigens. Our results revealed the nature of autoantibody production during COVID-19 and provided novel insights into the origin of virus-induced autoantibodies., (© 2024 Sakakibara et al.)

In strategies to extend a healthy lifespan, early detection and prevention of frailty are critical. The purpose of this study was to analyze the current state and clinical risk factors of frailty among community-dwelling older to conduct a cross-sectional analysis of the individuals, correlation between frailty and nutrient intake, dietary diversity, and dietary patterns, and to elucidate the correlation between frailty-related dietary factors and the gut microbiota. The study included 786 participants aged ≥65 years from the Kyotango Multipurpose Cohort Study who had available data on their gut microbiota. Frailty was quantitatively assessed by selecting 32 items from the previously reported frailty index, with those scoring ≥0.21 classified as frailty ( n  = 119) and those with scores <0.21 as non-frailty ( n  = 667), followed by group comparisons. The frailty group had significantly higher values and rates than the non-frailty group for the following items: age, obesity (in females only), diabetes, hypertension, history of cancer treatment, polypharmacy, disturbed sleep quality, low physical activity, serum insulin levels, and high-sensitivity C-reactive protein. The frailty group had significantly lower levels of nutrients, including plant proteins, potassium (K), magnesium (Mg), iron (Fe), copper (Cu), vitamins B and C, folic acid, and total, soluble, and insoluble dietary fiber. When analyzed by food groups of dietary fiber, the frailty group had significantly lower intakes of soy products and non-green-yellow vegetables, specifically. The Japanese Diet Index score (rJDI12) was significantly lower in the frailty group, with significant deficiencies in soy products and mushrooms included in the rJDI12. Cluster analysis of the Spearman correlation values between nutrient intake related to frailty and the gut microbiota abundance revealed a positive correlation between the cluster containing dietary fiber and the abundance of the phylum Bacillota, including the [ Eubacterium ]&#95; eligens &#95;group. In conclusion, our findings clarify the current state of frailty among older community residents and suggest the importance of a diverse range of plant-based foods, including soy products and non-green yellow vegetables, through correlation analysis with nutrients and food groups, and partially reveal the involvement of the gut microbiota., Competing Interests: YN received scholarship funds from Taiyo Kagaku Co. Ltd., Morinaga Co. Ltd., Miyarisan Pharma Co. Ltd., Morishita-Jintan Co. Ltd., Fujikko Co. Ltd., Mizkan Co. Ltd., a collaboration research fund from Taiyo Kagaku Co., Ltd.; and received lecture fees by Takeda Pharma. Co. Ltd., Mochida Pharma. Co. Ltd., Biofermin. Co. Ltd., Otsuka Pharma. Co. Ltd., and Miyarisan Pharma. Co. Ltd. TT and RI received a collaboration research fund from PreMedica Inc. The present research was partly supported by these funds. Neither the funding agency nor any outside organization has participated in the study design or have any competing interests. These companies have approved the final version of the manuscript., (Copyright © 2024 JCBN.)

CD22 (also known as Siglec-2) is an inhibitory receptor expressed in B cells. CD22 specifically recognizes α2,6 sialic acid and interacts with α2,6 sialylated membrane proteins expressed on the same cell (cis-ligands) and those derived from outside of the cell (trans-ligands). Previously, CD22 cis-ligands were shown to regulate the activity of CD22, thereby regulating both BCR ligation-induced signaling and low-level "tonic" signaling in the absence of BCR ligation that regulates the survival and differentiation of B cells. Mouse CD22 prefers Neu5Gc to Neu5Ac thereby binding to α2,6-linked Neu5Gc with high affinity. Although human CD22 binds to a distinct α2,6 sialylated glycan with high affinity, expression of high-affinity ligands is regulated in a conserved and stringent manner. However, how high- versus low-affinity CD22 ligands regulate B cells is poorly understood. Here we demonstrate that the interaction of CD22 with the endogenous ligands enhances BCR ligation-induced signaling but reduces tonic signaling in Cmah -/- mouse B cells deficient in Neu5Gc as well as wild-type B cells. Moreover, Cmah -/- B cells do not show alterations in the phenotypes correlated to tonic signaling. These results indicate that low-affinity interaction of the CD22 cis-ligands with CD22 is sufficient for the regulation of B cell signaling, and suggest that expression of high-affinity CD22 ligands might be involved in the regulation of B cells by competing for the binding of CD22 with exogenous trans-ligands of CD22., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Factors associated with severe COVID-19 infection have been identified; however, the impact of infection on longer-term outcomes is unclear. The objective of this study was to examine the impact of COVID-19 infection on the trajectory of lung function and nutritional status in people with cystic fibrosis (pwCF)., Methods: This is a retrospective global cohort study of pwCF who had confirmed COVID-19 infection diagnosed between January 1, 2020 and December 31, 2021. Forced expiratory volume in one second percent predicted (ppFEV 1 ) and body mass index (BMI) twelve months prior to and following a diagnosis of COVID-19 were recorded. Change in mean ppFEV 1 and BMI were compared using a t-test. A linear mixed-effects model was used to estimate change over time and to compare the rate of change before and after infection., Results: A total of 6,500 cases of COVID-19 in pwCF from 33 countries were included for analysis. The mean difference in ppFEV 1 pre- and post-infection was 1.4 %, (95 % CI 1.1, 1.7). In those not on modulators, the difference in rate of change pre- and post-infection was 1.34 %, (95 % CI -0.88, 3.56) per year (p = 0.24) and -0.74 % (-1.89, 0.41) per year (p = 0.21) for those on elexacaftor/tezacaftor/ivacaftor. No clinically significant change was noted in BMI or BMI percentile before and after COVID-19 infection., Conclusions: No clinically meaningful impact on lung function and BMI trajectory in the year following infection with COVID-19 was identified. This work highlights the ability of the global CF community to unify and address critical issues facing pwCF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors of this manuscript receive funding in the form of consulting fees or honoraria from Vertex Pharmaceuticals, Chiesi Pharmaceuticals, Enterprise Therapeutics, Gilead Sciences, GSK, Astra-Zeneca, Insmed, MSD, Sanofi, Viartis, Zambon, Limbic, Effrx Pharmaceuticals and Omron. Additionally, there is an author who serves on the Novartis Data and Safety Monitoring Board. There are several authors who are employed by the Cystic Fibrosis Foundation (CFF). The CFF, to advance drug development and search for a cure, have contracts with several companies to help fund the development of potential treatments and/or cures for cystic fibrosis. Pursuant to these contracts, CFF may receive milestone-based payments, equity interests, royalties on the net sales of therapies, and/or other forms of consideration. Resulting revenue received by CFF is used in support of our mission. See “How Drugs Get on the Pipeline” on the CFF website for more information. Additionally, CFF may license CFF Patient Registry data to some companies to monitor drug safety as part of the U.S. Food and Drug Administration's required Phase 4 clinical trials process and to encourage research aimed at improving the care of people with CF, while maintaining our obligation and commitment to protect the privacy of Registry participants. In connection with these licenses, and upon request, CFF may also assist company researchers in interpreting CFF Patient Registry data to aid in designing, analyzing, and interpreting real world studies in CF., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Hemi-resurfacing arthroplasty (Hemi) and metal-on-metal hip resurfacing arthroplasty (HR) were proposed as alternatives to conventional total hip arthroplasty (THA) for patients with osteonecrosis of the femoral head (ONFH). Long-term results were evaluated., Methods: Twenty-three hips with ONFH were treated, using Hemi in 12 and HR in 11. Mean follow-up was 15 years in the Hemi group and 10 years in the HR group. Long-term outcomes were reviewed retrospectively., Results: In the Hemi group, 8 hips showed acetabular protrusion and were revised to THA. One of the 8 hips showed femoral loosening. In the HR group, pseudotumor was detected in 4 hips (36%), and 1 hip was revised due to symptomatic pseudotumor. No evidence of any femoral or acetabular loosening was seen in the HR group. Ten-year survival rates were 64.2% and 90.9% in the Hemi and HR groups, respectively. Survival rate in the Hemi group dropped to 22.9% at 15 years., Conclusions: Long-term results of Hemi for patients with ONFH were very poor, and Hemi should not continue to be used. Although HR had a concern of pseudotumor, it could offer attractive indications for 10 years., (© 2023. The Japanese Society for Artificial Organs.)

Background: Thoracic epidural analgesia (TEA) and intravenous patient-controlled analgesia (IV-PCA) are widely used to mitigate immediate postoperative pain; however, their effects on long-term disability-free survival are poorly documented. This study aimed to compare the effects of postoperative TEA and IV-PCA on disability-free survival in patients who underwent thoracic or abdominal surgery., Methods: This post hoc analysis of a prospective observational study included 845 inpatients aged ≥55 years that underwent elective thoracic and abdominal surgery between 1 April 2016 and 28 December 2018 in a tertiary care hospital. Inverse probability of treatment weighted (IPTW) using stabilized inverse propensity scores was adopted to minimize bias. The primary outcome in this study was disability-free survival, defined as survival with a 12-item World Health Organization Disability Assessment Schedule 2.0 score of <16%, assessed at 3 months and 1 year after surgery., Results: The final analysis included 601 patients who received TEA and 244 who received IV-PCA. After IPTW, the weighted incidence of disability-free survival at 3 months and 1 year was 60.5% and 61.4% in the TEA group and 78.3% and 66.2% in the IV-PCA group, respectively. The adjusted OR for disability-free survival at 3 months and 1 year was 0.84 (95% confidence interval [CI]: 0.50-1.39) and 1.21 (95% CI: 0.72-2.05), respectively, for the TEA group., Conclusion: No significant differences were observed in the disability-free survival at 3 months and 1 year after elective thoracic and abdominal surgery in patients aged ≥55 years who received TEA or IV-PCA., Significance Statement: This study is the first in our setting to document the long-term effects of patient-controlled analgesia. In a post hoc analysis of our prospective cohort study, we show that although differences in chronic postsurgical pain exist at 3 months post-surgery, disability-free survival rates at 1 year do not differ irrespective of the choice of patient-controlled analgesia. The findings of this study highlight the need for shared decision-making between clinicians and patients., (© 2024 European Pain Federation ‐ EFIC ®.)

Immunoglobulin A (IgA)-mediated mucosal immunity is important for the host because it contributes to reducing infection risk and to establishing host-microbe symbiosis. BTB and CNC homology 1 (Bach1) is a transcriptional repressor with physiological and pathophysiological functions that are of particular interest for their relation to gastrointestinal diseases. However, Bach1 effects on IgA-mediated mucosal immunity remain unknown. For this study using Bach1-deficient ( Bach1 -/- ) mice, we investigated the function of Bach1 in IgA-mediated mucosal immunity. Intestinal mucosa, feces, and plasma IgA were examined using immunosorbent assay. After cell suspensions were prepared from Peyer's patches and colonic lamina propria, they were examined using flow cytometry. The expression level of polymeric immunoglobulin receptor (pIgR), which plays an important role in the transepithelial transport of IgA, was evaluated using Western blotting, quantitative real-time PCR, and immunohistochemistry. Although no changes in the proportions of IgA-producing cells were observed, the amounts of IgA in the intestinal mucosa were increased in Bach1 -/- mice. Furthermore, plasma IgA was increased in Bach1 -/- mice, but fecal IgA was decreased, indicating that Bach1 -/- mice have abnormal secretion of IgA into the intestinal lumen. In fact, Bach1 deficiency reduced pIgR expression in colonic mucosa at both the protein and mRNA levels. In the human intestinal epithelial cell line LS174T, suppression of Bach1 reduced pIgR mRNA stability. In contrast, the overexpression of Bach1 increased pIgR mRNA stability. These results demonstrate that Bach1 deficiency causes abnormal secretion of IgA into the intestinal lumen via suppression of pIgR expression. NEW & NOTEWORTHY The transcriptional repressor Bach1 has been implicated in diverse intestinal functions, but the effects of Bach1 on IgA-mediated mucosal immunity remain unclear. We demonstrate here that Bach1 deficiency causes abnormal secretion of IgA into the intestinal lumen, although the proportions of IgA-producing cells were not altered. Furthermore, Bach1 regulates the expression of pIgR, which plays an important role in the transepithelial transport of IgA, at the posttranscriptional level.

Three thienopyrrole-fused thiadiazole (TPT) fluorescent dyes featuring a common amide linker and different alkoxy substituents on peripheral trialkoxybenzene moieties were synthesized, and their self-assembly behavior in solution was investigated. The obtained results revealed a substantial steric effect of the alkoxy substituents on the supramolecular polymerization mechanism, which results from a combination of π-stacking and hydrogen (H)-bonding interactions. Detailed spectroscopic measurements revealed that with increasing steric demand of the substituents, the supramolecular polymerization processes in pure methylcyclohexane (MCH) or a mixture of MCH and toluene become temperature-sensitive and enthalpically favorable, resulting in a change from the isodesmic assembly mechanism to the cooperative mechanism. Theoretical calculations suggested that in TPTs with bulky substituents, steric hindrance causes the H-bonding array of the amide moieties to be aligned along the stacking axis of the π-systems; thus, the H-bonding interactions are strengthened compared to those in TPTs with less bulky substituents, compensating for the weakened π-stacking interactions. A chiral TPT derivative with (S) stereogenic centers was found to form homochiral helical supramolecular assemblies that generate discernible circularly polarized luminescence. Achiral TPTs also generate helical assemblies to which preferential helicity can be imparted through the external chiral bias of the solvents (R)- and (S)-limonene., (© 2024 Wiley-VCH GmbH.)

Objective: Platinum-free interval (PFI) is the period from the end of platinum-based chemotherapy to the date of recurrence. If the PFI is > 6 months, a platinum-based chemotherapy rechallenge is considered; however, its efficacy after poly adenosine 5'-diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy is unknown. This study aimed to examine the efficacy of a platinum-based chemotherapy rechallenge after PARP inhibitor therapy., Methods: We retrospectively evaluated patients with ovarian cancer with a PFI≥6 months with PARP inhibitor maintenance therapy, receiving platinum-based chemotherapy. Duration of PARP inhibitor therapy, best response to subsequent platinum chemotherapy rechallenge, and clinical characteristics were collected from medical records. Tumor response was assessed according to RECIST 1.1. Correlations were calculated using Spearman's correlation coefficients., Results: Among the 10 included patients, seven (70 %) received PARP inhibitors after primary chemotherapy, and three (30 %) received chemotherapy for platinum-sensitive relapse. One and five patients harbored a germline BRCA1 and BRCA wild-type mutations, respectively, and two had homologous recombination proficiency. The median PFI was 303.5 (182-602) days, and PARP inhibitor therapy duration was 249 (147-570) days. Platinum chemotherapy rechallenge efficacy was complete and partial response and stable disease in one (10 %), six (60 %), and three (30 %) patients, respectively. The longer the duration of PARP inhibitor treatment, better the response to platinum agents (Spearman correlation coefficient 0.284, p = 0.0288)., Conclusion: Platinum-based chemotherapy rechallenge is reasonable for patients with platinum-sensitive disease, using the traditional PFI cutoff of 6 months, even when the PFI is obtained with a maintenance PARP inhibitor., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis., Methods: CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing., Findings: From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6-35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7-6·5) in the MGT group versus 4·4 months (4·1-5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56-0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy., Interpretation: In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests All authors received research funding in the form of third-party medical writing assistance from F Hoffmann-La Roche. AK reports research funding for a clinical trial in CUP from Bristol Myers Squibb; research funding for a clinical trial in CUP from Molecular Health; and consulting fees, support for attending meetings or travel, or both, participation in a data safety monitoring board or advisory board from F Hoffmann-La Roche. TB was study oncologist for the CUPISCO trial for F Hoffman-La Roche and received remuneration for this work for the benefit of employer, and support for attending meetings or travel, or both. CP reports travel, accommodation, or expenses and additional costs linked to the study (paid to institution), and investigator fees from F Hoffmann-La Roche. K-KS reports grants or contracts (paid to institution for running trials) from Merck Sharp & Dohme, Roche, AstraZeneca, and Merck; consulting fees (personal) from Nouscom; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (personal) from Merck Sharp & Dohme, Bristol Myers Squibb, Merck, Servier, Seagen, and Nouscom; support for attending meetings or travel (personal), or both, from Merck Sharp & Dohme, Bristol Myers Squibb, Roche, and Merck; and an advisory board (personal) for Mirati Therapeutics. NCo reports honoraria, advisory board membership, support for attending meetings or travel, or both, from F Hoffman-La Roche; a patent pending, application number GB2317261.2; an advisory or leadership role for CUP Foundation (Jo's Friends; unpaid); and research support to team from AstraZeneca, Orion, F Hoffmann-La Roche, Taiho, GSK, Novartis, Starpharma, Bayer, Eisai, UCB, Redx Pharmaceuticals, Stemline Therapeutics, Boehringer Ingelheim, Merck, AstraZeneca, Cancer Research UK, Orion, and LOXO-Oncology. JJdM reports support for attending meetings or travel, or both, from Bristol Myers Squibb. RAP-C reports medical writing and processing fees from Astellas, Ipsen, Roche, BeiGene, and Bristol Myers Squibb; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Eisai, Bristol Myers Squibb, Astellas, Roche, Amgen, and Eli Lilly; payment for expert testimony from AstraZeneca, Eli Lilly, and Bristol Myers Squibb; support for attending meetings or travel, or both, from Roche, Lilly, Astellas, and Bristol Myers Squibb; and participation on a data safety monitoring board or advisory board for AstraZeneca, Roche, and Ipsen. FL reports grants or contracts from Lilly and Merck Sharp & Dohme; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lilly, Merck, Sanofi, and Roche; and support for attending meetings or travel, or both from Lilly, Merck, and Merck Sharp & Dohme. DGJR reports consulting fees from Merck, Pfizer, and Astellas; payment for honoraria, lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Merck Sharp & Dohme; and participation on a data safety monitoring board or advisory board for Janssen and AstraZeneca. JT reports consulting fees from Servier and Bristol Myers Squibb; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Merck Sharp & Dohme, Servier, Bayer, and Ipsen; and reports support for attending meetings or travel, or both (American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2022), from Zentiva and Roche. CA reports research grants from Roche, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Nektar, Johnson & Johnson, Lilly, Amgen, Incyte, and Bayer; advisory boards for Novartis, Merck, AstraZeneca, Johnson & Johnson, Lilly, Teva, Astellas, and Bristol Myers Squibb; and peakers bureaus for Bristol Myers Squibb, Johnson & Johnson, Lilly, Teva, Amgen, and Bayer. MÖ reports an advisory board, honoraria, and travel support from Janssen; additional costs linked to the study (paid to institution), investigator fees, and honoraria from F Hoffmann-La Roche; an advisory board and honoraria from Sanofi; an advisory board and honoraria for Astellas; honoraria from Novartis; travel support from Bristol Myers Squibb; and travel support and speaker support from AstraZeneca. MS reports honoraria for lectures F Hoffmann-La Roche. FB reports additional costs linked to the study and investigator fees from F Hoffmann-La Roche; an advisory board for AstraZeneca, Merck Sharp & Dohme, and Bristol Myers Squibb; speakers bureaus for AstraZeneca and Bristol Myers Squibb; and travel support or accommodation from Takeda, Merck Sharp & Dohme. SYK reports research funding (paid to institution; principal investigator since 2019) from F Hoffmann-La Roche; honorarium for lecture (May, 2023) from LG Chem; honorarium for lecture (August, 2023) from Merck Sharp & Dohme Korea; an advisory board (December, 2021) for Ono Korea; and an advisory board (December, 2022) for Guardant Health. YN reports research funding (paid to institution) from AbbVie, Ono, Daiichi Sankyo, Taiho, Pfizer, Boehringer Ingelheim, Eli Lilly, Eisai, AstraZeneca, Chugai, and Bayer; payment for honoraria, lectures, presentations, speakers’ bureaus, manuscript writing, or educational events (personal) from AstraZeneca, Eisai, Ono, Gardant, Takeda, Eli Lilly, Novartis, Pfizer, Chugai, PDR pharma, Nihon Kayaku, Taiho, Bristol Myers Squibb, Bayer, Daiichi Sankyo, and Merck Sharp & Dohme. AI reports additional costs linked to the study, investigator fees, advisory role, honoraria, and research funding from F Hoffmann-La Roche; an advisory role and honoraria from Daiichi Sankyo; an advisory role for Immune Design; an advisory role and honoraria from Epizyme; an advisory role and honoraria from Bayer and Lilly; patents, royalties, or intellectual property from Bristol Myers Squibb; honoraria from Novartis and Ipsen; and research funding from AstraZeneca–MedImmune, PharmaMar, Merck Sharp & Dohme Oncology, and Merck Serono. NCh reports being an employee and holding stocks or shares at F Hoffmann-La Roche. GD-P reports being an employee and holding stocks or shares at F Hoffmann-La Roche. CM reports being an employee of F Hoffmann-La Roche. JS reports being an employee and holding stocks or shares at F Hoffmann-La Roche. MT reports being an employee and holding stocks or shares at F Hoffmann-La Roche, and patents planned, issued, or pending (antibodies against human CSF-1R and uses thereof; modulators for HER2 signalling in HER2 expressing patients with gastric cancer) from F Hoffmann-La Roche. JSR reports being an employee of Foundation Medicine; and holding stocks or shares at Roche Holdings. HM reports research funding (paid to institution), consulting fees, and participation on a data safety monitoring board or advisory board for F Hoffmann-La Roche; and an advisory role and honoraria for lectures from Amgen, Astellas, Bayer, AstraZeneca, Merck, Stemline Therapeutics. LM reports additional costs linked to the CUPISCO trial (paid to institution), support for the presentation of the CUPISCO trial results and associated publication; and travel and accommodation expenses to attend the 2023 European Society for Medical Oncology meeting and present the CUPISCO trial results from F Hoffmann-La Roche., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Interactions between cells in the tumor microenvironment (TME) shape cancer progression and patient prognosis. To gain insights into how the TME influences cancer outcomes, we derive gene expression signatures indicative of signaling between stromal fibroblasts and cancer cells, and demonstrate their prognostic significance in multiple and independent squamous cell carcinoma cohorts. By leveraging information within the signatures, we discover that the HB-EGF/EGFR/MAPK axis represents a hub of tumor-stroma crosstalk, promoting the expression of CSF2 and LIF and favoring the recruitment of macrophages. Together, these analyses demonstrate the utility of our approach for interrogating the extent and consequences of TME crosstalk., Competing Interests: We confirm that all affiliations are listed on the title page of the manuscript, in the "declaration of interests" form and section of the manuscript. The funding sources for this study are listed in the “Acknowledgments” section of the manuscript. We, the authors, have noted any financial interest in this section below and in the “declaration of interests” form and we have noted the interests of our immediate family members. The authors and/or their immediate family members have management/advisory or consulting relationships noted in this section below and in the “declaration of interests” form. We, the authors, have a patent related to this work, which is noted in this section below and in the “declaration of interests” form, and we have noted the patents of immediate family members. G.G., A.R., Y.N., YH.L., S.H., P.N., S.B., MCU.C., P.C., and E.H. declares no conflict of Interest. K.H. and A.M. disclosures: Honoraria: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Codiak Biosciences (Inst), F-Star Therapeutics (Inst), Inzen Therapeutics (Inst), Merck Serono (Inst), MSD (Inst), Oncolys Biopharma (Inst), Pfizer (Inst), Replimune (Inst), VacV Biotherapeutics (Inst); Consulting or Advisory Role: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Inzen Therapeutics (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Replimune (Inst); Speakers’ Bureau: BMS (Inst), Merck Serono (Inst), MSD (Inst); Research Funding: AstraZeneca (Inst), Boehringer Ingelheim (Inst), Merck Sharp & Dohme (Inst), Replimune (Inst). D.B. reports personal fees from NanoString and AstraZeneca, and has a patent PCT/GB2020/050221 issued on methods for cancer prognostication. C.S. is an AstraZeneca Advisory Board member and Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board. He receives consultant fees from Achilles Therapeutics (also an SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, Roche Innovation Center – Shanghai, Metabomed (until July 2022), and the Sarah Cannon Research Institute. C.S has received honoraria from Amgen, AstraZeneca, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Illumina, and Roche-Ventana. C.S. had stock options in Apogen Biotechnologies and GRAIL until June 2021, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and has stock options and is a co-founder of Achilles Therapeutics. C.S. holds patents relating to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), US patent relating to detecting tumor mutations (PCT/US2017/28013), methods for lung cancer detection (US20190106751A1) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). C.S. is a Royal Society Napier Research Professor (RSRP\R\210001). E.S. declares research funding from Merck Sharp & Dohme and Astrazeneca and consultancy work for Phenomic AI and Theolytics., (© 2024 The Authors.)

Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future., (© 2024. The Author(s).)

In occupational therapy, crafts and groups are used as therapeutic tools, but their electrophysiological effects have not been well described. This study aimed to investigate the effects of group crafting on the physiological synchrony (PS) of dyadic heartbeats and on the autonomic activity and electroencephalogram (EEG) of individuals. In this cross-sectional study, individuals' EEG and dyadic electrocardiogram (ECG) were measured during the task in a variety of conditions. The three conditions were alone, parallel, nonparallel. Autonomic activity from the subjects' ECG, PS from the dyadic ECG, and current source density from exact Low Resolution Brain Electromagnetic Tomography (eLORETA) from subjects' EEG were analyzed. Measurements from 30 healthy young adults showed that the parallel condition significantly increased subjects' parasympathetic activity and dyadic PS. Parallel condition and frontal midline theta influenced parasympathetic activity, whereas parasympathetic activity was not associated with PS. Dyadic lag value were correlated with frontal delta, beta, and gamma activity. The results suggest that crafting in parallel groups increases parasympathetic activity and PS through different mechanisms, despite the absence of direct interaction. They also explain the electrophysiological evidence for the use of crafts and groups in psychiatric occupational therapy, such as increased relaxation and PS., (© 2024. The Author(s).)

Deep dissecting hematoma (DDH) is a disease in which minor trauma leads to the formation of an extensive hematoma. If left untreated, this can result in significant skin necrosis. Therefore, early treatment following a precise diagnosis is essential. However, the complexity of the disease may require differentiating it from soft tissue infections. A 58-year-old man with severe coronavirus disease 2019 (COVID-19) pneumonia developed skin complications such as purpura and blisters on his right upper extremity while undergoing veno-venous extracorporeal membrane oxygenation (VV-ECMO). We initially suspected a soft tissue infection or venous perfusion defect caused by the VV-ECMO cannula; however, these conditions were not observed. After making an exploratory incision, we diagnosed the patient with DDH and performed hematoma removal and skin grafting. The initial symptoms of DDH include erythema, swelling, and pain. It is important to differentiate DDH from soft tissue infections, especially necrotizing fasciitis, which is a more urgent condition. Because a surgical incision is necessary for the diagnosis and treatment of DDH, we do not hesitate to perform an exploratory incision to prevent skin necrosis, thereby contributing to early healing., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kotani et al.)

Introduction: We aimed to compare periprosthetic femoral bone remodeling after cementless total hip arthroplasty (THA) using a short-tapered wedge stem and a fully hydroxyapatite (HA)-coated stem., Materials and Methods: In this retrospective study, 24 primary cementless THA procedures with short-tapered wedge stem and 24 using a fully HA-coated stem were performed. The follow-up duration was 2 years for both groups. Clinical evaluation was performed using the Merle d'Aubigné and Postel scoring systems. Standardized anteroposterior radiographs of the pelvis and femur were obtained. Dual-energy X-ray absorptiometry was performed, and the bone mineral density (BMD) around the stem was assessed in each Gruen zone at the first postoperative week as a baseline value and at 6 weeks, 3 and 6 months, and 1 and 2 years postoperatively., Results: The mean Merle d'Aubigné and Postel scores improved significantly postoperatively in both groups. None of the hips showed loosening in either group. Spot welds occurred in zones 1, 2, 6, and 7 in the short-tapered wedge group, and in all zones in the fully HA-coated group. Significant BMD loss occurred only in zone 4 in the short-tapered wedge group, and no significant bone loss occurred in any zone in the fully HA-coated stem group; a significant difference between the two groups was observed only in zone 4 at 2 years after THA., Conclusions: Clinical and radiographical outcomes in both groups were good, and both stems suppressed postoperative BMD loss at 2 years., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST.

Background/aim: This study aimed to characterize intraductal papillary neoplasm of the bile duct (IPNB) in patients undergoing initial and recurrent surgical resection and to evaluate the appropriateness of surgical treatment strategies., Patients and Methods: This study included 14 patients who underwent liver resection for intrahepatic IPNB. We assessed intraoperative and postoperative clinicopathological factors in patients undergoing both initial and recurrent surgeries., Results: Four patients experienced recurrence after initial surgery; all underwent pancreaticoduodenectomy. Postoperative complications were classified as Clavien-Dindo Grade 1-2 in three patients and Grade IIIb in one patient. There were no in-hospital deaths., Conclusion: Pancreaticoduodenectomy for recurrent cases following hepatectomy for IPNB is considered safe within an acceptable range and contributes to a favorable long-term prognosis., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Concurrent KRAS LKB1 (STK11, KL) mutant Non-Small Cell Lung Cancers (NSCLC) is particularly difficult to treat and does not respond well to current immune checkpoint blockade (ICB) therapies. This is due to numerous mechanisms including low antigen presentation limiting T cell mediated killing. To activate anti-tumor immunity, we targeted tumor cell - natural killer (NK) cell interactions. We tested whether a novel antibody based therapeutic strategy that predominantly activates natural killer (NK) cells demonstrates efficacy in pre-clinical mouse models of KL NSCLC. NK cells rely on binding of ligands, such as Major Histocompatibility Complex (MHC) class I-related chain A or B (MICA/B), to the activating receptor NKG2D. Importantly MICA and MICB are widely expressed in elevated levels across NSCLC subtypes including KL lung cancers. Proteases with the tumor microenvironment (TME) can cleave these proteins rendering tumor cells less visible to NK cells. We therefore developed a MICA monoclonal antibody, AHA-1031, which utilizes two NK cell activating receptors. AHA1031 prevents ligand shedding without interfering with binding to NKG2D while targeting cancer cells to antibody mediated cell dependent cytotoxicity (ADCC). Our therapeutic novel antibody has significant monotherapy activity in KL cancer models including xenografts of human cell lines and patient derived xenografts. Activating NK cells through MICA/B stabilization and inducing ADCC offers an alternative and potent therapy option in KL tumors. MICA/B are shed across different tumors making this therapeutic strategy universally applicable.

Background: Hand washing instructions for children have been implemented in school education to establish good lifestyle habits. However, repeated hand washing through education from early childhood was common for both teachers and children. If this continues, children might assume they already know how to wash their hands, stop taking handwashing instructions seriously, and become increasingly lax about washing their hands., Purpose: This study aimed to develop a new handwashing education method for children., Methods: We applied the adenosine triphosphate (ATP) test to health education on hand washing in elementary schools. This study was conducted as part of a class for elementary school students in October 2023, in Hokkaido, Japan. The subjects were 157 third-grade (9-10 years old) elementary school students. After excluding absent pupils, 147 were included in the analysis., Results: Both pre- and post-education, ATP values after handwashing were lower than those before handwashing. Following the education, children's handwashing behavior improved, with an increase in the number of point washed and appropriate timing of handwashing., Conclusion: The new handwashing education program utilizing the ATP-test succeeded in promoting handwashing behavior among many children. Visualizing handwashing using ATP values was effective in motivating children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Oura, Naito, Yako-Suketomo, Nakata, Koyama and Ohnishi.)

Hedgehog (Hh) signaling pathway dysregulation is involved in the pathogenesis of metabolic dysfunction-associated steatohepatitis, and the sonic Hh (SHh) protein, a pivotal molecule in the Hh pathway, is expressed in ballooned hepatocytes. The present study aimed to investigate the clinicopathological significance of SHh expression in steatohepatitic hepatocellular carcinoma (SH-HCC). Reverse transcription-quantitative polymerase chain reaction and immunohistochemistry were performed to examine SHh gene and SHh protein expression in SH-HCC. Additionally, patients with conventional HCC (C-HCC) were included in the control group. Comparisons of patient and tumor characteristics were also performed. The prevalence of SH-HCC was 3% in the whole cohort, and it was significantly associated with a high prevalence of diabetes mellitus. SHh mRNA was detected in all patients with SH-HCC, but not in 23% of patients with C-HCC. Notably, SHh mRNA expression was not significantly different between patients with SH-HCC and those with C-HCC; however, high SHh protein expression was significantly more frequent in SH-HCC patients than in those with C-HCC. Although the prognosis was not significantly different between the SH-HCC and C-HCC groups, high SHh protein expression was an independent poor prognostic factor for HCC. In conclusion, SHh could potentially serve as a therapeutic target for patients with HCC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Kusano et al.)

The development of high-throughput anticancer drug screening methods using patient-derived cancer cell (PDC) lines that maintain their original characteristics in an in vitro three-dimensional (3D) culture system poses a significant challenge to achieving personalized cancer medicine. Because stromal tissue plays a critical role in the composition and maintenance of the cancer microenvironment, in vitro 3D-culture using reconstructed stromal tissues has attracted considerable attention. Here, a simple and unique in vitro 3D-culture method using heparin and collagen together with fibroblasts and endothelial cells to fabricate vascularized 3D-stromal tissues for in vitro culture of PDCs is reported. Whereas co-treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, and 5-fluorouracil significantly reduced the survival rate of 3D-cultured PDCs to 30%, separate addition of each drug did not induce comparable strong cytotoxicity, suggesting the possibility of evaluating the combined effect of anticancer drugs and angiogenesis inhibitors. Surprisingly, drug evaluation using eight PDC lines with the 3D-culture method resulted in a drug efficacy concordance rate of 75% with clinical outcomes. The model is expected to be applicable to in vitro throughput drug screening for the development of personalized cancer medicine. STATEMENT OF SIGNIFICANCE: To replicate the cancer microenvironment, we constructed a cancer-stromal tissue model in which cancer cells are placed above and inside stromal tissue with vascular network structures derived from vascular endothelial cells in fibroblast tissue using CAViTs method. Using this method, we were able to reproduce the invasion and metastasis processes of cancer cells observed in vivo. Using patient-derived cancer cells, we assessed the possibility of evaluating the combined effect with an angiogenesis inhibitor. Further, primary cancer cells also grew on the stromal tissues with the normal medium. These data suggest that the model may be useful for new in vitro drug screening and personalized cancer medicine., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michiya Matsusaki, Ryohei Katayama and Eiji Shinozaki report that financial support was provided by TOPPAN Holdings Inc. Michiya Matsusaki, Ryohei Katayama, Shinji Irie, Satoshi Nagayama and TOPPAN Holdings Inc are inventors of several patents related to the CAViTs method. Yuki Takahashi, Rii Morimura, Kei Tsukamoto, Sayaka Gomi, Asuka Yamada, Miki Mizukami, Yasuyuki Naito and Shiro Kitano are employees of TOPPAN Holdings Inc., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Maintaining the mucus layer is crucial for the innate immune system. Urolithin A (Uro A) is a gut microbiota-derived metabolite; however, its effect on mucin production as a physical barrier remains unclear. This study aimed to elucidate the protective effects of Uro A on mucin production in the colon. In vivo experiments employing wild-type mice, NF-E2-related factor 2 (Nrf2)-deficient mice, and wild-type mice treated with an aryl hydrocarbon receptor (AhR) antagonist were conducted to investigate the physiological role of Uro A. Additionally, in vitro assays using mucin-producing cells (LS174T) were conducted to assess mucus production following Uro A treatment. We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function., (© 2024. The Author(s).)

Background: Cancer patients are often complicated by weight loss and malnutrition, thus it is important to provide nutritional therapy in parallel with disease treatment. This study examined the significance of early intervention by NST for cancer patients., Methods: Seventy-five cancer patients out of 281 patients who underwent NST intervention between July 2021 and June 2022 were included. Intervention outcomes, such as energy and protein sufficiency(=intake/target), and final evaluation by a NST nutritionist at the end of the intervention("improvement"/"unchanged"/"disease progression"/ "death"), were compared between patients who received NST intervention within 7 days from admission(Group A)and after 7 days from admission(Group B)., Results: Nutritional sufficiency at the end of NST intervention was higher in Group A for both energy and protein, and the proportion of"improvement"was higher in Group A for the final evaluation by a NST nutritionist. Patients' situation(pre-initial treatment/post-chemotherapy/post-surgery/worsening nutritional status during follow-up)was biased between 2 groups, however Group A showed better results for nutritional sufficiency rate and final evaluation in each subgroup of patients' situation., Conclusion: Early intervention may improve the effectiveness of NST for cancer patients. It is important to extract subjects and start NST intervention at early timing.

Fibromyalgia (FM) presents a diagnostic challenge due to its complex symptoms and lack of definitive tests. This study discusses a 54-year-old female initially diagnosed with FM, characterized by widespread pain, fatigue, and tender points. Despite treatment, she developed elevated C-reactive protein (CRP) and anemia after two years, leading to further investigations. These tests revealed non-secretory multiple myeloma, underscoring the importance of vigilant monitoring in FM patients. This case highlights the need for regular CRP measurements and thorough follow-up to detect underlying conditions. Early detection and appropriate intervention are crucial in managing FM and improving patient outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ohta et al.)

Insertion of a nasogastric tube is one of the most common methods of administering nutrition, but can cause vocal cord paralysis., Competing Interests: The authors have no conflicts of interest to report., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Maca ( Lepidium meyenii ), mainly grown in Peru, is a traditional herbal medicine that is mostly used to improve sperm motility and serum hormone levels. Maca phenotypes are represented by purple, black, yellow, white, and mixed colors. Recently, a method for Maca cultivation has been established in Japan. Therefore, we determined the effects of different phenotypes and portions on the antioxidant activities and total polyphenols, anthocyanins, and benzyl-glucosinolate contents in Japanese Maca. Purple Maca skin possessed the highest contents of both total polyphenols, antioxidant activity and anthocyanin content in all Macas. Regarding the benzyl-glucosinolate content, white maca had the highest content and was not correlated with antioxidant activity. In the present study, we revealed that purple Maca skin is recommended for high polyphenol content, antioxidant activity, and anthocyanin content. The results of this study will be useful for selecting phenotypes for the improvement of antioxidant activity or hormone balance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways. Among them, pulmonary surfactant-associated protein B (SFTPB) in serum EVs could predict ILD progression better than the known biomarkers, serum KL-6 and SP-D, and it was identified as an independent prognostic factor from ILD-gender-age-physiology index. Subsequently, the utility of SFTPB for predicting ILD progression was evaluated further in 2 cohorts using serum EVs and serum, respectively, suggesting that SFTPB in serum EVs but not in serum was helpful. Among SFTPB forms, pro-SFTPB levels were increased in both serum EVs and lungs of patients with PPF compared with those of the control. Consistently, in a mouse model, the levels of pro-SFTPB, primarily originating from alveolar epithelial type 2 cells, were increased similarly in serum EVs and lungs, reflecting pro-fibrotic changes in the lungs, as supported by single-cell RNA sequencing. SFTPB, especially its pro-form, in serum EVs could serve as a biomarker for predicting ILD progression.

Purpose: To investigate the molecular mechanism of pathological keratinization in the chronic phase of ocular surface (OS) diseases., Methods: In this study, a comprehensive gene expression analysis was performed using oligonucleotide microarrays on OS epithelial cells obtained from three patients with pathological keratinization (Stevens-Johnson syndrome [n = 1 patient], ocular cicatricial pemphigoid [n = 1 patient], and anterior staphyloma [n = 1 patient]). The controls were three patients with conjunctivochalasis. The expression in some transcripts was confirmed using quantitative real-time PCR., Results: Compared to the controls, 3118 genes were significantly upregulated by a factor of 2 or more than one-half in the pathological keratinized epithelial cells (analysis of variance P < 0.05). Genes involved in keratinization, lipid metabolism, and oxidoreductase were upregulated, while genes involved in cellular response, as well as known transcription factors (TFs), were downregulated. Those genes were further analyzed with respect to TFs and retinoic acid (RA) through gene ontology analysis and known reports. The expression of TFs MYBL2, FOXM1, and SREBF2, was upregulated, and the TF ELF3 was significantly downregulated. The expression of AKR1B15, RDH12, and CRABP2 (i.e., genes related to RA, which is known to suppress keratinization) was increased more than twentyfold, whereas the expression of genes RARB and RARRES3 was decreased by 1/50. CRABP2, RARB, and RARRES3 expression changes were also confirmed by qRT-PCR., Conclusions: In pathological keratinized ocular surfaces, common transcript changes, including abnormalities in vitamin A metabolism, are involved in the mechanism of pathological keratinization.

Background and Aims: Free D-amino acids, which have different functions from L-amino acids, have recently been discovered in various tissues. However, studies on the potential interactions between intestinal inflammation and D-amino acids are limited. We examined the inhibitory effects of D-alanine on the pathogenesis of intestinal inflammation., Methods: We investigated serum D-amino acid levels in 40 patients with ulcerative colitis and 34 healthy volunteers. For 7 days [d], acute colitis was induced using dextran sulphate sodium in C57BL/6J mice. Plasma D-amino acid levels were quantified in mice with dextran sulphate sodium-induced colitis, and these animals were administered D-alanine via intraperitoneal injection. IFN-γ, IL-12p35, IL-17A, and IL-23p19 mRNA expression in the colonic mucosa was measured using real-time polymerase chain reaction [PCR]. In vitro proliferation assays were performed to assess naïve CD4+ T cell activation under Th-skewing conditions. Bone marrow cells were stimulated with mouse macrophage-colony stimulating factor to generate mouse bone marrow-derived macrophages., Results: Serum D-alanine levels were significantly lower in patients with ulcerative colitis than in healthy volunteers. Dextran sulphate sodium-treated mice had significantly lower plasma D-alanine levels than control mice. D-alanine-treated mice had significantly lower disease activity index than control mice. IFN-γ, IL-12p35, IL-17A, and IL-23p19 mRNA expression levels were significantly lower in D-alanine-administered mice than in control mice. D-alanine suppressed naïve T cell differentiation into Th1 cells in vitro, and inhibited the production of IL-12p35 and IL-23p19 in bone marrow-derived macrophages., Conclusions: Our results suggest that D-alanine prevents dextran sulphate sodium-induced colitis in mice and suppresses IL-12p35 and IL-23p19 production in macrophages., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients' wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries., (© 2024. The Author(s).)

Purpose: This study aimed to compare the hemodynamic effects of remimazolam- and propofol-based total intravenous anesthesia in patients who underwent transcatheter aortic valve replacement., Methods: This was a single-center, single-blind, randomized controlled trial set at Nara Medical University, Kashihara, Japan. We included 36 patients aged ≥ 20 years scheduled to undergo elective transfemoral transcatheter aortic valve replacement (TAVR) under general anesthesia. The participants were randomly assigned to the remimazolam and propofol groups (n = 18 each). Remimazolam- or propofol-based total intravenous anesthesia was initiated at 12 mg/kg/min or 2.5 mcg/mL via target-controlled infusion, respectively, along with remifentanil. After confirming the loss of consciousness, the administration rate was adjusted using electroencephalographic monitoring. The primary outcome was the rate of arterial hypotension, defined as a mean arterial pressure < 60 mmHg, from anesthesia induction until the beginning of the surgical incision. The total doses of ephedrine and phenylephrine were also assessed., Results: During anesthesia induction, the arterial hypotension rates were 11.9% and 21.6% in the remimazolam and propofol groups, respectively (P = 0.01). The total dose of ephedrine was higher in the propofol group (14.4 mg) than in the remimazolam group (1.6 mg) (P < 0.001); however, the total dose of phenylephrine was not significantly different between the two groups (propofol 0.31 mg vs. remimazolam: 0.17 mg, P = 0.10)., Conclusion: Remimazolam-based total intravenous anesthesia resulted in a lower hypotension rate than propofol-based total intravenous anesthesia during induction in patients undergoing TAVR. Remimazolam-based total intravenous anesthesia can be used safely during anesthetic induction in patients with severe aortic stenosis., (© 2024. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Background: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations., Methods: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting., Findings: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis., Interpretation: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting., Funding: AstraZeneca and Daiichi Sankyo., Competing Interests: Declaration of interests BTL has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Jiangsu Hengrui Pharmaceuticals, and Lilly. He has received academic travel support from Amgen. He is an inventor on two institutional patents at MSK (US62/685,057 and US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. He is supported by the Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748 and Research Project Grant R01CA249666 from the National Institutes of Health. FM-B reports institutional grants or contracts from Aileron, AstraZeneca, Bayer, Calithera, Curis, CytomX, Daiichi Sankyo, Debiopharm, eFFECTOR, Genentech, Guardant, KLUS, Novartis, Puma Biotechnology, Taiho, and Takeda; personal consulting fees from AbbVie, Aduro, Alkermes, AstraZeneca, Calibr (a division of Scripps Research), Daiichi Sankyo, Debiopharm, EcoR1 Capital, eFFECTOR, F Hoffmann-La Roche, GT Apeiron, Genentech, Harbinger Health, IBM Watson, Infinity, Jackson Laboratory, Kolon Life Science, LegoChem Biosciences, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer, Protai, Samsung Bioepis, Seattle Genetics, Tallac, Tyra Biosciences, Xencor, and Zymeworks; personal meeting or travel support from the Cholangiocarcinoma Foundation, the European Organisation for Research and Treatment of Cancer, and the European Society for Medical Oncology; and personal participation on a data safety monitoring board or advisory board for Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm, Loxo Oncology, Mersana, OnCusp, Puma Biotechnology, Seattle Genetics, Sanofi, Silverback, Spectrum, Theratechnologies, and Zentalis. AB reports grants or contracts from AstraZeneca/Daiichi Sankyo, Eli Lilly, Genentech/Roche, Immunomedics/Gilead, Merck, Novartis, Pfizer, Radius/Menarini, and Sanofi; consulting fees from BioTheranostics, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Genentech/Roche, Immunomedics/Gilead, Innocrin Pharma, Merck, Novartis, Pfizer, Philips, Puma Biotechnology, Radius Health, Radius/Menarini, Sanofi, and Spectrum Pharmaceuticals; institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo/AstraZeneca, Genentech, Eli Lilly, Immunomedics/Gilead, Merck, Novartis, Pfizer, Radius Health, and Sanofi; personal participation on a data safety monitoring board or advisory board for AstraZeneca, Daiichi Sankyo, Eisai, Genentech, Gilead, Lilly, Menarini, Merck, Mersana, Novartis, Pfizer, and Sanofi; other personal financial or non-financial interests for AstraZeneca, Daiichi Sankyo, Genentech, Gilead, Lilly, Merck, Mersana, Novartis, Pfizer, and Sanofi. YN reports institutional grants or contracts from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, Eisai, Ono, Pfizer, and Taiho; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Guardant, MSD, Nihon Kayaku, Novartis, Ono, PDR Pharma, Pfizer, Taiho, and Takeda. SS reports personal participation on a data safety monitoring board or advisory board for Agenus, AstraZeneca, Bristol Myers Squibb, CheckmAb, Daiichi Sankyo, GlaxoSmithKline, MSD, Novartis, Seagen, and T-One Therapeutics. PA reports institutional grants or contracts from Roche; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events for Amgen and Synthon; support for attending meetings and/or travel from Amgen, Daiichi Sankyo, MSD, Pfizer, and Roche; personal participation on a data safety monitoring board or advisory board for Amcure, Boehringer Ingelheim, Deloitte, Eisai, G1 Therapeutics, Gilead, Lilly, MacroGenics, Menarini, Novartis, Radius, Roche, and Servier. GC reports grants or contracts from Merck; consulting fees from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Ellipsis, Gilead, Lilly, Menarini, Merck, Novartis, Pfizer, Roche, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Gilead, Lilly, Novartis, Pfizer, and Relay; support for attending meetings or travel from Daiichi Sankyo. MdM reports institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and MSD; and other personal financial or non-financial interests for AbbVie, Achilles, Amunix, Arcus, BioNTech, Catalym, Dizal, Furmo, Genentech, Janssen, Loxo, MSD, Novartis, Numab, PharmaMar, Replimune, Roche, and Seagen. MK reports stock or stock options from Athenex, CRISPR, Eli Lilly, Natera, and Pfizer. D-YO reports personal grants or contracts from Array, AstraZeneca, Basilea, BeiGene, Eli Lilly, Handok, MSD, Novartis, and Servier; and participation on a data safety monitoring board or advisory board for Arcus, ASLAN, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb/Celgene, Genentech/Roche, Halozyme, IQVIA, Merck Serono, MSD, Novartis, Taiho, Turning Point, Yuhan, and Zymeworks. MK's current affiliation is Breast Medical Oncology, LifeBridge Health, Baltimore, MD, USA. JOP reports personal grants or contracts from ABL Bio, Bristol Myers Squibb (Celgene), Eutilex, MedPacto, and Servier; personal support for attending meetings and/or travel from Minneamrita; personal participation on a data safety monitoring board or advisory board for Adicet Bio, AstraZeneca, Bristol Myers Squibb (Celgene), ImmuneOncia, MediRama, MedPacto Merck, Merck Sereno, MedPacto, and Servier. SP-V reports institutional grants or contracts from AstraZeneca and IMCore Hoffman LaRoche; institutional participation on data safety monitoring board or advisory board for Amgen and Daiichi Sankyo; and other personal financial or non-financial interests for Amgen, AstraZeneca, Bristol Myers Squibb, Clovis, GlaxoSmithKline, Novartis, Oxford Biotherapeutics, PEP Therapy, and Roche. SYR reports institutional grants or contracts from ABL Bio, ALX Oncology, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, BeiGene, Bold Therapeutics, Daiichi Sankyo, Eisai, Ipsen, Leap Therapeutics, MacroGenics, MedPacto, Merck KGaA, MSD, Ono Pharmaceutical, Pfizer, Seagen, Taiho Pharmaceutical, and Zymeworks; consulting fees from Individumed and LG Biochem; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Daiichi Sankyo, Eisai, Lilly, and MSD; and participation on a data safety monitoring board or advisory board for Amgen. TS reports personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events for Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Biopharm, Ono Pharmaceutical, Taiho, Takara Bio, Takeda, and Yakult Honsha; institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events for Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Gilead, HUTCHMED, Merck Biopharm, Ono Pharmaceutical, Parexel, Taiho, and Yakult Honsha; and personal participation on a data safety monitoring board or advisory board for Takara Bio. IS reports institutional grants or contracts from AstraZeneca, Genentech, Incyte, MSD, Orion, Pfizer, Puma Biotechnology, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; support for attending meetings or travel from AstraZeneca, Incyte, and Merck/Pfizer; and other financial or non-financial interests for AstraZeneca, Genentech, Incyte, MSD, Orion, Pfizer, Puma Biotechnology, and Roche. FM reports other personal financial or non-financial interests for AstraZeneca. AS reports personal stock or stock options for AstraZeneca and other financial or non-financial interests for AstraZeneca. KKM reports other personal financial or non-financial interests for AstraZeneca. CS reports personal participation in advisory boards or travel grants from AstraZeneca, Ax's Consulting, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F Hoffmann-La Roche Ltd, Gilead, Lilly, MediTech, MSD, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma Biotechnology, SeaGen, Synthon Biopharmaceutical, and Zymeworks. IA declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties., Methods: Individual patient-level data from 6 centers on stage I-III hormone receptor-positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC., Results: Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43-0.80), RFS (HR, 0.70; 95% CI, 0.56-0.89), and OS (HR, 0.71; 95% CI, 0.53-0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non-breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08-5.40), radiotherapy (HR, 0.44; 95% CI, 0.23-0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09-0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups., Conclusions: Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.

Background and Aims: Precise diagnostic biomarkers are urgently required for pancreatic ductal adenocarcinoma (PDAC). Therefore, the aim of this study was to identify PDAC-specific exosomal microRNAs (Ex-miRs) from pancreatic juice (PJ) and evaluate their diagnostic potential., Methods: Exosomes in PJ and serum were extracted using ultracentrifugation and confirmed morphologically and biochemically. PDAC-specific Ex-miRs were identified using our original miR arrays, in which "Ex-miRs derived from the PJ of patients with chronic pancreatitis (CP)" were subtracted from Ex-miRs commonly expressed in both "human PDAC cell lines" and "the PJ of patients with PDAC." We verified the expression of these miRs using quantitative real-time reverse transcription polymerase chain reaction. Changes in serum Ex-miR levels were assessed in 2 patients with PDAC who underwent curative resection. In situ hybridization was performed to directly visualize PDAC-specific miR expression in cancer cells., Results: We identified novel Ex-miR-4516 and Ex-miR-4674 from the PJ of patients with PDAC, and they showed 80.0% and 81.8% sensitivity, 80.8% and 73.3% specificity, and 90.9% and 80.8% accuracy, respectively. The sensitivity, specificity, and accuracy of a triple assay of Ex-miR-4516/4674/PJ cytology increased to 93.3%, 81.8%, and 88.5%, respectively. In serum samples (n = 88), the sensitivity, specificity, and accuracy of Ex-miR-4516 were 97.5%, 34.3%, and 68%, respectively. Presurgical levels of serum-derived Ex-miR-4516 in 2 patients with relatively early disease stages declined after curative resection. In situ hybridization demonstrated that Ex-miR-4516 expression exclusively occurred in cancer cells., Conclusion: Liquid assays using the in situ-proven Ex-miR-4516 may have a high potential for detecting relatively early-stage PDAC and monitoring its clinical course., (© 2024 The Authors.)

Androgen receptor signaling inhibitors combined with androgen deprivation therapy have become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC), regardless of tumor volume or risk. However, survival of approximately one-third of these patients has not improved, necessitating further treatment escalation. On the other hand, for patients with oligometastatic mCSPC, there is an emerging role for local radiation therapy. Although data remain scarce, it is expected that treatment of both primary tumor as well as metastasis-directed therapy may improve survival outcomes. In these patients, systemic therapy may be de-escalated to intermittent therapy. However, precise risk stratification is necessary for risk-based treatment escalation or de-escalation. In addition to risk stratification based on clinical parameters, research has been conducted to incorporate genomic and/or transcriptomic data into risk stratification. In future, an integrated risk model is expected to precisely stratify patients and guide treatment strategies. Here, we first review the transition of the standard treatment for mCSPC over the last decade and further discuss the newest concept of escalating or de-escalating treatment using a multi-modal approach based on the currently available literature., Competing Interests: The authors declare no conflict of interest regarding the contents of the manuscript.

Background: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes., Objective: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs)., Methods: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps., Results: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo., Conclusion: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)