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Photoacoustic (PA) imaging (PAI) has been shown to be a promising tool for non-invasive blood vessel imaging. A PAI system comprising a hemispherical detector array (HDA) has been reported previously as a method providing high morphological reproducibility. However, further improvements in diagnostic capability will require improving the image quality of PAI and fusing functional and morphological imaging. Our newly developed PAI system prototype not only enhances the PA image resolution but also acquires ultrasonic (US) B-mode images at continuous positions in the same coordinate axes. In addition, the pulse-to-pulse alternating laser irradiation shortens the measurement time difference between two wavelengths. We scanned extremities and breasts in an imaging region 140 mm in diameter and obtained 3D-PA images of fine blood vessels, including arterioles and venules. We could estimate whether a vessel was an artery or a vein by using the S-factor obtained from the PA images at two wavelengths, which corresponds approximately to the haemoglobin oxygen saturation. Furthermore, we observed tumour-related blood vessels around breast tumours with unprecedented resolution. In the future, clinical studies with our new PAI system will help to elucidate various mechanisms of vascular-associated diseases and events. [ABSTRACT FROM AUTHOR]

Aims: Genotype‐guided dosing algorithms can explain about half of the interindividual variability in prothrombin time–international normalized ratio (PT‐INR) under warfarin treatment. This study aimed to refine a published kinetic–pharmacodynamic model and guide warfarin dosage for an optimal PT‐INR based on renal function. Methods: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT‐INR measurements, we refined the kinetic–pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear‐mixed‐effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR50), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT‐INR (2.0–3.0 or 1.6–2.6) based on the significant covariates. Results: A total of 350 patients with 2762 PT‐INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6–199.0] mL/min/1.73 m2). The final kinetic–pharmacodynamic model showed that the EDR50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT‐INR range as eGFR decreased. Conclusions: Model‐informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment. [ABSTRACT FROM AUTHOR]

Aims To assess the tolerability, pharmacokinetics and pharmacodynamics of a novel nonsteroidal and noncompetitive inhibitor of type I and type II 5α-reductases, (–)-(S)-4-[1-[4-[1-(4-isobutylphenyl) butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), after single and multiple oral doses in healthy volunteers. Methods In the single-dose study, six young adult males in each dose group received 25 mg or 50 mg of TF-505, and six older males (≥ 40 years) in each dose group received 75 mg or 100 mg of TF-505. The subjects were given the drug in ascending dose and in the fasting state. Six subjects also received 50 mg of TF-505 after breakfast in a two-period crossover manner. In the multiple-dose study, six older males in each dose group received 12.5 mg or 25 mg TF-505 after breakfast daily for 7 days. Plasma concentrations of TF-505, dihydrotestosterone (DHT) and testosterone were measured. The pharmacokinetics of TF-505 were analysed by a compartment model with first-order absorption, first-order elimination and a lag time. Pharmacokinetic and pharmacodynamic relationships were evaluated by indirect response modelling with inhibition of input. Results Maximum plasma concentration (C max ) and the area under the concentration–time curve (AUC) increased proportionately after the single dose up to 50 mg and with the multiple doses. Linearity was not detected between 75 and 100 mg of TF-505. Dose dependency was also noted for the effect of TF-505 on DHT concentrations following single doses up to 50 mg and multiple doses. Plasma DHT concentrations decreased maximally to 58.2, 49.5, 54.2 and 49.8% of basal values at 8–12 h after single administration of 25, 50, 75 and 100 mg TF-505, respectively, and to 60.5 and 49.4% at the 7th and 5th dose following multiple doses... [ABSTRACT FROM AUTHOR]

To clarify the mechanism by which Δ9-tetrahydrocannabinol, a major psychoactive component of marijuana, impairs spatial memory in the 8-arm radial maze in rats via the cholinergic system, we used two acetylcholinesterase inhibitors, physostigmine and tetrahydroaminoacridine. Moreover, we examined the effect of Δ9-tetrahydrocannabinol on acetylcholine release in the frontal cortex and dorsal and ventral hippocampus using in vivo microdialysis. Physostigmine (0.01–0.05 mg/kg, i.p.) and tetrahydroaminoacridine (1–5 mg/kg, p.o.) improved the impairment of spatial memory induced by Δ9-tetrahydrocannabinol (6 mg/kg, i.p.) in the 8-arm radial maze. Δ9-tetrahydrocannabinol (6 mg/kg, i.p.) produced a significant decrease in acetylcholine release in the dorsal hippocampus as assessed by microdialysis. Moreover, tetrahydroaminoacridine at a dose of 1 mg/kg, which improved the impairment of spatial memory, reversed the decrease in acetylcholine release induced by Δ9-tetrahydrocannabinol in the dorsal hippocampus during 60–120 min after the Δ9-tetrahydrocannabinol injection. These findings suggest that inhibition of the cholinergic pathway by reduced acetylcholine release is one of the means by which Δ9-tetrahydrocannabinol impairs spatial memory in the 8-arm radial maze. [Copyright &y& Elsevier]

We developed a method to apply artificial neural networks (ANNs) for predicting time‐series pharmacokinetics (PKs), and an interpretable the ANN‐PK model, which can explain the evidence of prediction by applying Shapley additive explanations (SHAP). A previous population PK (PopPK) model of cyclosporin A was used as the comparison model. The patients' data were used for the ANN‐PK model input, and the output by ANN was the clearance (CL). The estimated CL value from the ANN were substituted into the one‐compartment with one‐order absorption model, the concentrations were calculated, and the parameters of ANN were updated by the back‐propagation method. Kernel SHAP was applied to the trained model and the SHAP value of each input was calculated. The root mean squared error for the PopPK model and the ANN‐PK model were 41.1 and 31.0 ng/ml, respectively. The goodness of fit plots for the ANN‐PK model represented more convergence to y = x compared with that for the PopPK model, with good model performance for the ANN‐PK model. The most influential factors on CL output were age and body weight from the evaluation using Kernel SHAP, and these factors were incorporated into the PopPK model as the significant covariates of CL. The ANN‐PK model could handle time‐series data and showed higher prediction accuracy then the conventional PopPK model, and the scientific validity for the model could be evaluated by applying SHAP. Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?A black‐box property of an artificial neural network (ANN) decreases the scientific confidence of the model, and making it difficult to utilize the ANN in the medical field. Moreover, difficulty in handling the time‐series data is a significant problem for applying the ANN for pharmacometrics study. WHAT QUESTION DID THIS STUDY ADDRESS?How can we apply the ANN for predicting the time‐series pharmacokinetics (PKs) , and confirm the scientific validity of the ANN model? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?Using the ANN in combination with a conventional compartment (ANN‐PK) model enabled to handle the time‐series PK data, and the predicting performance of the model was higher than that of the population PK model. Furthermore, we could evaluate the scientific validity of the ANN model by applying the Shapley additive explanations. HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?We expect that our study will contribute to develop the interpretable ANN model, which can predict the time‐series PKs, drug efficacies, and side effects with high prediction performance. [ABSTRACT FROM AUTHOR]

This paper presented how to establish a clinically relevant specification (CRS) using in silico physiologically based pharmacokinetic (PBPK) modeling. Three different formulations of model drug products were used in the clinical studies in order to distinguish between bioequivalent (BE) batches from non-BE batches. A human PBPK model was constructed by integrating the clinical and non-clinical observations by using GastroPlusTM software. The developed model was verified by the comparison between human PK behavior observed in clinical studies and human PK behavior predicted from the software. The simulation results were obtained by using the dissolution profiles showing clinically relevant discriminatory power as input variables for the developed PBPK model. For three investigated formulations, the simulated PK behavior was comparable to the PK behavior observed in clinical studies. In addition, in silico BE simulation studies confirmed that the verified PBPK model can successfully reproduce the clinical study results. In conclusion, a CRS was established with the BE simulation by using the verified PBPK model, in order to detect and reject non-BE batches of drug products. The establishment of the CRS is useful for a quality control and finding optimal formulation to accomplish target PK behavior, safety, and efficacy. [ABSTRACT FROM AUTHOR]

We aimed to reanalyze the differences in the pharmacokinetics (PKs) of meloxicam in East Asian populations based on a population approach using previously published data and to investigate the factors found in population PK analysis that affect the pharmacodynamics (PDs) of meloxicam. Population PK analysis was performed in 119 healthy male subjects (30 Japanese, 30 Chinese, 29 Korean, and 30 white) under strictly controlled trial conditions with regulated meals and a single lot of the drug. We found that CYP2C9 genotype and lean body mass were statistically significant predictors of clearance and volume of distribution, respectively. A statistical significant difference in the PK parameters between ethnic groups could not be identified. Simulations using PK/PD models showed that CYP2C9 genotype is the factor that affects the PDs of meloxicam. The genetic polymorphisms highlighted in this study would be beneficial for conducting clinical trials in East Asians with similar genetic backgrounds. [ABSTRACT FROM AUTHOR]

The blood-to-brain transport of amantadine, a weak N-methyl- d-aspartate (NMDA) antagonist, has been shown previously to participate in the cationic drug-sensitive transport system across the mouse blood-brain barrier (BBB). The purpose of the present study was to characterize the influx transport system by means of both an in situ mouse brain perfusion technique and in vitro studies using rat immortalized brain capillary endothelial cells (GPNT). The observed concentration-dependent initial uptake rate of [3H]amantadine suggested the involvement of a carrier-mediated transport mechanism. The normal uptake at physiological pH 7.4 was decreased by 72.9% in acidic perfusate, while it was increased by 35.3% in alkaline perfusate. These results suggest that pH-dependent transport is regulated by utilizing an oppositely directed proton gradient as a driving force. In addition, the [3H]amantadine uptake was moderately inhibited by the adamantane structural analogs (rimantadine and memantine) and other cationic drugs (pyrilamine, clonidine, nicotine, etc.), but not by substrates or inhibitors of the well-characterized organic cation transporters (tetraethylammonium, l-carnitine and choline). A similar inhibition pattern was observed between the in vivo studies and the in vitro experiments. These results indicate that the influx transport for amantadine across the BBB involves a proton-coupled organic cation antiporter. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A single aperture and hollow retroreflector [corner-cube mirror (CCM)] that in principle has no internal optical path difference is a key instrument for achieving lunar laser ranging one order or more accurate than the current level (~2 cm). We are developing CCM whose aperture is 20 cm with optimized dihedral angles. The 20-cm CCM yields two times peak height for returned laser pulse compared with Apollo 15's retroreflector. Two investigations were conducted to confirm the feasibility of the 20-cm aperture CCM. The first is thermo-optical simulation and evaluation of the 20-cm CCM in the lunar thermal environment. Through this simulation, it has turned out for the first time that 20-cm aperture CCM made of single-crystal Si or 'ultra-low expansion glass-ceramics' such as CCZ-EX (OHARA Inc.) can be used for CCM with no thermal control, if the perfectly fixed point of CCM is limited to one. The second is annealing and shear loading experiments of single-crystal silicon (Si) samples. Through these experiments, high-temperature annealing from 100 to 1000 °C is confirmed to be effective for the enhancement of the adhesive strength between optically contacted surfaces with no optical damage in roughness and accuracy, indicating that this annealing process would enhance the rigidity of CCM fabricated by the optically contacted plates. [ABSTRACT FROM AUTHOR]

We report a preclinical study of a pyrrole-imidazole (PI) polyamide that targets the human transforming growth factor (hTGF)-β1 gene as a novel transcriptional gene silencer in a common marmoset primate model. We designed and then synthesized PI polyamides to target the hTGF-β1 promoter. We examined effects of seven PI polyamides (GB1101-1107) on the expression of hTGF-β1 mRNA stimulated with phorbol 12-myristate 13-acetate (PMA) in human vascular smooth muscle cells. GB1101, GB1105 and GB1106 significantly inhibited hTGF-β1 mRNA expression. We examined GB1101 as a PI polyamide to hTGF-β1 for hypertrophic scars in marmosets in vivo. Injection of GB1101 completely inhibited hypertrophic scar formation at 35 days post-incision and inhibited cellular infiltration, TGF-β1 and vimentin staining, and epidermal thickness. Mismatch polyamide did not affect hypertrophic scarring or histological changes. Epidermis was significantly thinner with GB1101 than with water and mismatch PI polyamides. We developed the PI polyamides for practical ointment medicines for the treatment of hypertrophic scars. FITC-labeled GB1101 with solbase most efficiently distributed in the nuclei of epidermal keratinocytes, completely suppressed hypertropic scarring at 42 days after incision, and considerably inhibited epidermal thickness and vimentin-positive fibroblasts. PI polyamides targeting hTGF-β1 promoter with solbase ointment will be practical medicines for treating hypertrophic scars after surgical operations and skin burns. [ABSTRACT FROM AUTHOR]

Pyrrole-imidazole (PI) polyamides are nuclease-resistant novel compounds that inhibit transcription factors by binding to the minor groove of DNA. A PI polyamide that targets mouse ABCA1 and increases ABCA1 gene expression was designed and evaluated as an agent to increase plasma HDL concentration. A PI polyamide was designed to bind the activator protein-2 binding site of the mouse ABCA1 promoter. The effect of this PI polyamide on ABCA1 expression was evaluated by real-time RT-PCR and Western blotting using RAW264 cells. In vivo effects of this polyamide on ABCA1 gene expression and plasma HDL level were examined in C57B6 mice. One milligram per kilogram of body weight of PI polyamide was injected via the tail veins every 2 days for 1 week, and plasma lipid profiles were evaluated. PI polyamide showed a specific binding to the target DNA in gel mobility shift assay. Treatment of RAW264 cells with 1.0 μM PI polyamide significantly increased ABCA1 mRNA expression. PI polyamide also significantly increased apolipoprotein AI-mediated HDL biogenesis in RAW264 cells. Cellular cholesterol efflux mediated by apolipoprotein AI was significantly increased by the PI polyamide treatment. PI polyamide significantly increased expression of ABCA1 mRNA in the liver of C57B6 mice. Plasma HDL concentration was increased by PI polyamide administration. All of the HDL sub-fractions showed a tendency to increase after PI polyamide administration. The designed PI polyamide that targeted ABCA1 successfully increased ABCA1 expression and HDL biogenesis. This novel gene-regulating agent is promising as a useful compound to increase plasma HDL concentration. Key messages: [ABSTRACT FROM AUTHOR]

Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. We examined the effects of a transforming growth factor (TGF)-β1-targeted PI polyamide (Polyamide) on hypertrophic skin scars in rats. Hypertrophic scars were created dorsally in rats by incisions. FITC-labeled Polyamide was injected to investigate its distribution in the skin. Expression of TGF-β1, connective tissue growth factor (CTGF), collagen type1, and fibronectin mRNAs was evaluated by reverse transcription PCR analysis. The extent of fibrosis and the expression of TGF-β1 were evaluated histologically and immunohistochemically. Polyamide was distributed in almost all nuclei of skin cells. Expression of TGF-β1 mRNA reached a peak at 3 days after skin incision. Expression of CTGF and extracellular matrix mRNAs was increased continuously even after the peak induction of TGF-β1 mRNA. Injection of Polyamide completely inhibited both the development of scars and the induction of growth factors and extracellular matrix mRNAs. The treatment also markedly inhibited fibrotic changes and reduced the numbers of vimentin-positive spindle-shaped fibroblasts. Injection of Polyamide also reduced established hypertrophic scars in rats. Thus, TGF-β1-targeted PI polyamide should be a feasible gene silencer for hypertrophic scars and keloids. [ABSTRACT FROM AUTHOR]

Pyrrole-imidazole (PI) polyamides are small synthetic molecules that recognize and attach to the minor groove of DNA, thereby inhibiting gene transcription by blocking transcription factor binding. These derivatives can act as gene silencers inhibiting target gene expression under stimulatory conditions such as disease. To evaluate PI polyamides as treatments for the progression of renal diseases, we examined morphological effects, pharmacological properties, and the specificity of PI polyamides targeted to the transforming growth factor (TGF)-β1 promoter during salt-induced hypertensive nephrosclerosis in Dahl salt-sensitive rats. The targeted PI polyamide markedly reduced glomerulosclerosis and interstitial fibrosis without side effects. PI polyamide significantly decreased expression of TGF-β1 and extracellular matrix in the renal cortex. Microarray analysis found that only 3% of the transcripts were affected by PI polyamide, but this included decreased expression of extracellular matrix, TGF-β1-related cytokines, angiogenic, and cell stabilizing factors, proteinases, and renal injury-related factors. Thus, targeted PI polyamides are potential gene silencers for diseases not treatable by current remedies. [ABSTRACT FROM AUTHOR]

Abstract: Pyrrole (Py)–imidazole (Im) polyamides synthesized by combining N-methylpyrrole and N-methylimidazole amino acids have been identified as novel candidates for gene therapy. In this study, a sensitive method using liquid chromatography–tandem mass spectrometry (LC–MS/MS) with an electrospray ionization (ESI) source was developed and validated for the determination and quantification of Py–Im polyamide in rat plasma. Py–Im polyamide was extracted from rat plasma by solid-phase extraction (SPE) using a Waters Oasis® HLB cartridge. Separation was achieved on an ACQUITY UPLC HSS T3 (1.8μm, 2.1×50mm) column by gradient elution using acetonitrile:distilled water:acetic acid (5:95:0.1, v/v/v) and acetonitrile:distilled water:acetic acid (95:5:0.1, v/v/v). The method was validated over the range of 10–1000ng/mL and the lower limit of quantification (LLOQ) was 10ng/mL. This method was successfully applied to the investigation of the pharmacokinetics of Py–Im polyamide after intravenous administration. [Copyright &y& Elsevier]

Summary: Pyrrole-imidazole polyamide (PIP) is a nuclease-resistant novel compound that inhibits gene expression through binding to the minor groove of DNA. Human aurora kinase-A (AURKA) and -B (AURKB) are important regulators in mitosis during the cell cycle. In this study, two specific PIPs (PIP-A and PIP-B) targeting AURKA and AURKB promoter regions were designed and synthesized, and their biological effects were investigated by several in vitro assays. PIP-A and PIP-B significantly inhibited the promoter activities, mRNA expression, and protein levels of AURKA and AURKB, respectively, in a concentration-dependent manner. Moreover, 1:1 combination treatment with both PIPs demonstrated prominent antiproliferative synergy (CI value [ED50] = 0.256) to HeLa cells as a result of inducing apoptosis-mediated severe catastrophe of cell-cycle progression. The novel synthesized PIP-A and PIP-B are potent and specific gene-silencing agents for AURKA and AURKB. [Copyright &y& Elsevier]

The present study investigated the involvement of the serotonin (5-hydroxytryptamine, 5-HT) neuronal system in the Δ9-tetrahydrocannabinol-induced impairment of spatial memory in the eight-arm radial maze in rats. Δ9-Tetrahydrocannabinol (6 mg/kg, i.p.), which impairs spatial memory, significantly increased the 5-HT content in the ventral hippocampus. A microdialysis study showed that Δ9-tetrahydrocannabinol (6 mg/kg, i.p.) decreased 5-HT release in the ventral hippocampus. The 5-HT precursor, 5-hydroxy-l-tryptophan (5-HTP; 50 mg/kg, i.p.), the 5-HT re-uptake inhibitor, clomipramine (0.01 and 0.1 mg/kg, i.p.), the 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 0.01 and 0.03 mg/kg, i.p.), and the 5-HT2 receptor agonist, 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI; 10 μg/kg, i.p.), significantly attenuated the Δ9-tetrahydrocannabinol-induced impairment of spatial memory. These results suggest that the 5-HT neuronal system may be involved in the Δ9-tetrahydrocannabinol-induced impairment of spatial memory. [Copyright &y& Elsevier]

Figure Scheme of the human PBPK model with the ACAT model for edoxaban. [Display omitted] The purpose of this study was to evaluate the impact of P-glycoprotein (P-gp) efflux on edoxaban absorption in gastrointestinal tracts quantitatively by a physiologically based pharmacokinetic (PBPK) model constructed with clinical and non-clinical observations (using GastroPlus™ software). An absorption process was described by the advanced compartmental absorption and transit model with the P-gp function. A human PBPK model was constructed by integrating the clinical and non-clinical observations. The constructed model was demonstrated to reproduce the data observed in the mass-balance study. Thus, elimination pathways can be quantitatively incorporated into the model. A constructed model successfully described the difference in slopes of plasma concentration (Cp)-time curve at around 8 – 24 hr post-dose between intravenous infusion and oral administration. Furthermore, the model without P-gp efflux activity can reproduce the Cp-time profile in the absence of P-gp activity observed from the clinical DDI study results. Since the difference of slopes between intravenous infusion and oral administration also disappeared by the absence of P-gp efflux activity, P-gp must be a key molecule to govern edoxaban's PK behavior. The constructed PBPK model will help us to understand the significant contribution of P-gp in edoxaban's disposition in gastrointestinal tracts quantitatively. [ABSTRACT FROM AUTHOR]

Earthquake occurrence in the stress shadow provides a unique opportunity for extracting information about the physical processes behind earthquakes because it highlights processes other than the ambient stress change in earthquake generation. In this study, we examined the fault structure and the spatiotemporal distribution of the aftershocks of the 2019 M6.7 Yamagata-Oki earthquake, which occurred in the stress shadow of the 2011 M9.0 Tohoku-Oki earthquake, to better understand the earthquake generation mechanism. The detection and hypocenter relocation of the aftershocks led to the delineation of three planar earthquake structures consitent with their focal mechanisms. The results suggest that individual aftershocks were caused by a slip on these macroscopic planar structures. Aftershock hypocenters rapidly migrated upward from the deeper part of the major plane (fault), similar to the recent earthquake swarm sequences following the Tohoku-Oki earthquake in the upper plate. Moreover, we investigated the temporal evolution of the surface strain rate distribution in the source region using GNSS data. The east–west contraction strain rate in the source region of the Yamagata-Oki earthquake, with an E–W compressional reverse fault mechanism, changed to an E–W extension as a result of the Tohoku-Oki earthquake, and it continued until the occurrence of the Yamagata-Oki earthquake. The upward hypocenter migrations, together with the earthquake occurrence in the stress shadow and in the E–W extension strain rate field, suggest that a reduction in the fault strength due to uprising fluids contributed to the occurrence of this earthquake sequence. Localized aseismic deformations, such as aseismic creeps, beneath the fault zone may also have contributed to the earthquake occurrence. The results support the hypothesis that aseismic processes in the deeper part of the fault play crucial roles in the occurrence of shallow intraplate earthquakes. • 2019 Yamagata-Oki earthquake occurred in stress shadow of 2011 Tohoku-Oki earthquake. • Aftershocks formed three planar structures and showed upward migration. • The mainshock is caused by the reduction in fault strength due to uprising fluids. [ABSTRACT FROM AUTHOR]

The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies. Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed. The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876-16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2- subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group. The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ST reports honoraria from Ono, Chugai, Yakult Honsha, Taiho, Asahi Kasei Pharma, Eisai, Bristol-Myers Squibb and Eli Lilly; Prof. NM reports grants from Chugai, Eli Lilly, Astra Zeneca, Pfizer, Daiichi-Sankyo, MSD, Eisai, Novartis, Sanofi, Kyowa-Kirin, Nippon-Kayaku, Ono and Gilead Science, and honoraria from Chugai, Pfizer, Astra Zeneca, Eli Lilly and Daiichi-Sankyo, and Representative of a board of directors of JBCRG and Board of Directors of JBCS; MK reports honoraria from Pfizer, Daiichi-Sankyo, Astra Zeneca, Eli Lilly, Taiho, Kyowa-Kirin and Chugai; HI reports grants from Chugai, Daiichi-Sankyo and Astra Zeneca, and consulting fee from Daiichi-Sankyo, Chugai, Astra Zeneca, Eli Lilly, MSD, Pfizer and Gilead Science, and honoraria from Daiichi-Sankyo, Chugai, Astra Zeneca, Eli Lilly, MSD, Pfizer, Taiho and Kyowa-Kirin; TI reports honoraria from Pfizer, Kyowa-Kirin, Chugai, Daiichi-Sankyo, Astra Zeneca and Eli Lilly; TU reports grant from Eli Lilly, and honoraria from Chugai, Eisai, Astra Zeneca and Novartis; SO reports honoraria from Chugai, MSD, Nippon-Kayaku and Eli Lilly; HY reports grants from Eli Lilly and Eiken Kagaku; ET reports honoraria from Daiichi-Sankyo, Eli Lilly and Astra Zeneca; KA reports grants from Chugai, Eisai and Takeda, and consulting fee from Taiho, and honoraria from Chugai, Eisai, Astra Zeneca, Taiho, Novartis, Daiichi-Sankyo, Mochida, Ono, Pfizer, Eli Lilly, Terumo and Becton Dickinson; TT reports grants from Eli Lilly, Chugai, Eisai, Takeda, Kyowa-Kirin, Daiichi-Sankyo and Nippon-Kayaku, and honoraria from Daiichi-Sankyo, Pfizer, Novartis, Astra Zeneca, Chugai and Takeda; YY reports grants from Chugai, Kyowa-Kirin, Eisai, Daiichi-Sankyo, Nippon-Kayaku, Taiho, Takeda, Eli Lilly, Pfizer and Novartis, and honoraria from Astra Zeneca, Chugai, Kyowa-Kirin, Novartis, Eli Lilly, Pfizer, Daiichi-Sankyo, Nippon-Kayaku, Taiho, Eisai, Takeda, MSD, Sysmex and Exact Science, and participation on Advisory Board of Astra Zeneca, Chugai, Novartis, MSD, Eli Lilly, Pfizer and Daiichi-Sankyo, and member of the Board of Directors of JBCS and JBCRG; TY reports grants from Chugai, Taiho, Nippon-Kayaku and Kyowa-Kirin, and honoraria from Chugai, Eisai, Novartis, Taiho, Nippon-Kayaku, Astra Zeneca, Kyowa-Kirin, Pfizer, Eli Lilly and Daiichi-Sankyo; TY reports honoraria from Pfizer, Eli Lilly and Eisai; MT reports grants from Chugai, Takeda, Pfizer, JBCRG assoc., KBCRN assoc., Eisai, Eli Lilly, Daiichi-Sankyo, Astra Zeneca, Astellas, Shimadzu, Yakult, Nippon-Kayaku, AFI technology, Luxonus, Shionogi, GL Science and Sanwa Shurui, and honoraria from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, Astra Zeneca, Eli Lilly, MSD, Exact Science, Novartis, Shimadzu, Yakult, Nippon-Kayaku, Devicore Medical Japan and Sysmex, and advisory board of Daiichi-Sankyo, Eli Lilly, BMS, Athenex Oncology, Bertis Terumo and Kansai Medical Net, and a member of the board of directors of JBCRG, KBCRN and OOTR, and chairman of the board of directors of JBCS, and associate editor of British Journal of Cancer, Scientific Reports, Breast Cancer Research and Treatment, Cancer Science, Frontiers in Women's Cancer, Asian Journal of Surgery and Asian Journal of Breast Surgery; TY reports grants from AC Medical, A2 Healthcare, ClinChoice, Japan Tabacco, Japan Media, Medidata Solutions, Ono, Kyowa-Kirin, Tsumura, Daiichi-Sankyo, Otsuka, Eisai, Solasia Pharma, Asahi Intecc, 3H Clinical Trial, Medrio, Nipro, Intellim, Welby, 3H Medi Solution, Baseconnect, Nobori, Puravida Technologies and Hemp Kitchen, and consulting fee from Public Health Research Foundation, EPS, Japan Tabacco, Medidata Solutions, Ono, Kowa, Chugai, Daiichi-Sankyo, Eisai, 3H Clinical Trial, Intellim, Astra Zeneca, Sonire Therapeutics, Seikagaku, Merck, Mebix and Nippon Boehringer Ingelheim, and advisory board of Incyte Bioscience; CI reports grants from Chugai, Asahi Kasei Pharma, Ono, Eli Lilly, Shionogi, Yakult, Otsuka, Sanofi, Merck, Astra Zeneca, Nippon Boehringer Ingelheim, Yansen, MSD, Sonia-Therapy, Taiho, Takeda, Daiichi-Sankyo, Bayer, Nippon-Kayaku, Tsumura, Kyowa-Kirin, Hitachi, Incyte, Ascent, Eisai, PRA Health Science, Novartis and Riken Genesis, and honoraria from Taiho, Merck, Eli Lilly, Bristol-Myers Squibb, Daiichi-Sankyo, Nippon-Kayaku, Nihon-Servier, M3, MSD, Novartis, Astra Zeneca, Ono, Sanofi, Chugai, Terumo, Asahi Kasei Pharma, Pfizer, Bayer, Incyte, Takeda and Kyowa-Kirin. All remaining authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Dermatomyositis (DM) is an autoimmune disease that causes proximal muscle weakness in the extremities leading to severe immobility and dysphagia. Approximately 20% of patients with DM are positive for anti-TIF-1γ antibody and frequently accompanied by malignant tumors. Although DM remission after tumor resection has been reported, the indications for surgery in patients with severe DM are unknown. Herein, we report a case of a 79-year-old Japanese woman who presented with breast cancer and anti-TIF-1γ antibody-positive DM. She became bedridden shortly after DM onset. Although pulsed steroid therapy, intravenous immunoglobulin, tacrolimus, and endocrine therapy with fulvestrant did not improve her symptoms, tumor resection with axillary lymph node dissection resulted in complete remission of the DM after 8 months. Immunohistochemistry revealed high expression of TIF-1γ in cancer cells, both in the primary tumor and axillary lymph nodes. Since the serum levels of anti-TIF-1γ antibody decreased after the surgery, the existence of breast cancer with TIF-1γ expression may have contributed to the worsening of DM. The present case suggests that curative surgery should be considered as a treatment option even if the patient has severe symptoms, such as immobility and dysphagia. Careful discussions with patients and multidisciplinary collaboration are essential to make surgery feasible, particularly for those with severe symptomatic DM., Competing Interests: Conflict of interestMasahiro Kawashima received lecture fees from Pfizer Japan Inc., Daiichi Sankyo, Guardant Health AMEA, Eisai Co., Ltd., and Chugai Pharmaceutical Co., Ltd.. Masahiro Kawashima received research fundings from Nippon Kayaku Co., Ltd., and Kyowa Kirin Co., Ltd.. Nobuko Kawaguchi-Sakita has an endowed chair at Fujitsu, Meiji Seika Pharma, Yakult, NTT, PRiME-R, CANNON Medical, HUG, NTT-DATA, and IHC. Masahiro Takada received lecture fees from Chugai Pharmaceutical Co., Ltd., Astra Zeneca K.K., and Daiichi Sankyo. Masahiro Takada received research fundings from Astra Zeneca K.K., Daiichi Sankyo, Eisai Co.,Ltd., KBCRN, JBCRG, ABCSG, Yakult Honsha Co., Ltd., MedBis co., Ltd., and IQVIA Japan. Masakazu Toi has a leadership position of JBCRG, KBCRN, OOTR, and JBCS. Masakazu Toi has an advisory role of Daiichi-Sankyo, Eli Lilly and companies, Bristol Myers Squibb, Athenex Oncology, Bertis Inc., Terumo Corporation, and Kansai Medical Net. Masakazu Toi received lecture fees from Chugai Pharmaceutical Co.,Ltd., Takeda Pharmaceuticals, Pfizer Japan Inc., Kyowa Kirin Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eisai Co., Ltd., Daiichi-Sankyo, Astra Zeneca K.K., Eli Lilly and companies, MSD K.K., EXACT Sciences, Novartis Pharmaceuticals, Shimadzu Corporation, Yakult, Nippon Kayaku Co., Ltd., Devicor Medical Japan K.K., and Sysmex Corporation. Masakazu Toi received research funding from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceuticals, Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., JBCRG, KBCRN, Eisai Co., Ltd., Eli Lilly and companies, Daiichi Sankyo, Astra Zeneca K.K., Astellas Pharma Inc., Shimadzu Corporation, Yakult Honsha Co., Ltd., Nippon Kayaku Co., Ltd., AFI Corporation, Luxonus Inc., Shionogi Pharma Co., Ltd., and GL Sciences Inc.. The other authors declare that they have no conflict of interest., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)