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Drug-induced liver injury (DILI) is a major factor influencing new drug withdrawal; therefore, an appropriate toxicity assessment at the preclinical stage is required. Previous in silico models have been established using compound information listed in large data sources, thereby limiting the DILI risk prediction for new drugs. Herein, we first constructed a model to predict DILI risk based on a molecular initiating event (MIE) predicted by quantitative structure–activity relationships, admetSAR parameters (e.g. cytochrome P450 reactivity, plasma protein binding, and water-solubility), and clinical information (maximum daily dose [MDD] and reactive metabolite [RM]) for 186 compounds. The accuracy of the models using MIE, MDD, RM, and admetSAR alone were 43.2%, 47.3%, 77.0%, and 68.9%, while the “predicted MIE + admetSAR + MDD + RM” model’s accuracy was 75.7%. The contribution of MIE to the overall prediction accuracy was little effect or rather worsening it. However, it was considered that MIE was a valuable parameter and that it contributed to detect high DILI risk compounds in the early development stage. We next examined the effect of stepwise changes in MDD on altering the DILI risk and estimating the maximum safety dose (MSD) for clinical use based on structural information, admetSAR, and MIE parameters because it is important to estimate the dose that could prevent the DILI onset in clinical conditions. Low-MSD compounds might increase the DILI risk, as these compounds were classified as “most-DILI concern” at low doses. In conclusion, MIE parameters were especially useful to check the DILI concern compounds and to prevent the underestimation of DILI risk in the early stage of drug development.

Background: Although few patients with breast cancer experience tumor progression during neoadjuvant systemic therapy (NST), their extremely poor outcomes are similar to patients who fail to achieve pathological complete response (pCR). No reports have compared patients with pCR, non-pCR, and progression during NST to determine the survival outcomes.Methods: This retrospective chart review of patients with stage I–III breast cancer was conducted between January 2001 and December 2018. pCR was defined as no invasive cancer or in situ residuals in the breast and lymph nodes (ypT0 ypN0). Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier methods.Results: Of the 595 patients who received NST, 167 (29.2%) had pCR (pCR group), 404 (70.8%) responded to NST but did not have pCR (non-pCR group), and 24 (4.0%) experienced tumor progression during NST (PD group). The median DFS was 6.0 months, 154.0 months, and not reached in the PD, non-pCR, and pCR groups, respectively. The PD group had significantly shorter DFS than patients without tumor progression in the pCR and non-pCR groups [hazard ratios (HR) 13.0, 95% CI: 8.1–21.0, p < 0.01]. The median OS was 13.6 months (95% CI: 10.4–35.5) in the PD group and was not reached in the pCR and non-pCR (non-PD) groups. The OS was significantly poorer in the PD group than in the non-PD group (HR 15.8, 95% CI: 9.2–27.1, p < 0.01).Conclusion: The PD group had the poorest survival outcomes even after recurrence, thus warranting new treatment targets.

Consumption of green kiwifruit is known to relieve constipation. Previous studies have also reported improvements in gastrointestinal (GI) comfort. We investigated the effect of consuming green kiwifruit on GI function and comfort.Participants included healthy controls (n = 63), patients with functional constipation (FC, n = 60), and patients with constipation-predominant irritable bowel syndrome (IBS-C, n = 61) randomly assigned to consume 2 green kiwifruits or psyllium (7.5 g) per day for 4 weeks, followed by a 4-week washout, and then the other treatment for 4 weeks. The primary outcome was the number of complete spontaneous bowel movements (CSBM) per week. Secondary outcomes included GI comfort which was measured using the GI symptom rating scale, a validated instrument. Data (intent-to-treat) were analyzed as difference from baseline using repeated measures analysis of variance suitable for AB/BA crossover design.Consumption of green kiwifruit was associated with a clinically relevant increase of ≥ 1.5 CSBM per week (FC; 1.53, P0.0001, IBS-C; 1.73, P = 0.0003) and significantly improved measures of GI comfort (GI symptom rating scale total score) in constipated participants (FC, P0.0001; IBS-C, P0.0001). No significant adverse events were observed.This study provides original evidence that the consumption of a fresh whole fruit has demonstrated clinically relevant increases in CSBM and improved measures of GI comfort in constipated populations. Green kiwifruits are a suitable dietary treatment for relief of constipation and associated GI comfort.

Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory compound developed for treating atopic dermatitis and known to inhibit Toll-like receptor 4, in light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once per day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 partially protected against this decrease in retinal thickness and increase in ERG amplitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregulation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and Western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 indirectly protects photoreceptor cells by attenuating light damage progression, by affecting the inflammatory responses.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have been approved for breast cancer (BC) treatment. Several trials suggested that arthralgia was reduced in patients treated with ET plus CDK4/6i compared with that in those with ET-alone. We aimed to compare arthralgia rates in BC patients treated with/without CDK4/6i. We reviewed randomized controlled phase II/III trials investigating CDK4/6i with ET in hormone receptor-positive and epidermal growth factor 2-negative BC. Publications were retrieved from PubMed from January 2014 to April 2021. We compared arthralgia rates between patients who were administered ET plus CDK4/6i (CDK4/6i group) and those treated with ET-alone (control group). We reviewed 12 trials that reported data on adverse effects for arthralgia. These trials included 17,440 patients (9255 in the CDK4/6i group and 8185 in the control group). The arthralgia rate in the CDK4/6i group was significantly lower than that in the control group (27.6% vs. 34.8%, p .001), especially in early BC (28.8% vs. 37.3%, p .001). These suggested that the arthralgia rate in patients treated with ET plus CDK4/6i was lower than that in patients treated with ET-alone and that CDK4/6i may decrease the arthralgia rate in BC patients treated with ET, especially in early BC.

PurposeWomen diagnosed with early breast cancer are faced with a choice of surgical procedures. Although one of the essential factors in surgical shared decision making is the impact on the body image, the breast morphology after breast conserving surgery is particularly difficult to explain in a uniform manner due to large individual differences. MethodsPatients with breast cancer eligible for breast conserving surgery (BCS) were recruited between June 2020 and October 2021. We surveyed the patients’ satisfaction with our explanation method about breast morphology after BCS using 3D breast imaging in the form of a questionnaire.ResultsA total of 162 patients were enrolled and 137 (84.6%) answered the questionnaire. One hundred and sixteen patients (84.6%) answered that they were very satisfied or satisfied with our explanation method and 100 (73.0%) patients were very satisfied or satisfied with the 3D breast imaging. Some patients answered that visually understanding the breast morphology by 3D breast imaging helped them to prepare for BCS, or on the contrary, made them chose mastectomy with breast reconstruction because the postoperative deformation of BCS was found to be unacceptable. Only a few patients who actually underwent BCS felt that their postoperative morphology was more deformed than the preoperatively imagined one.ConclusionOur results suggest that our preoperative explanation method using 3D breast imaging was useful for shared decision making. We think that 3D breast imaging can help the patients to visualize the individual shape of their breast, and the tumor position and size.

Background Neoplastic seeding (NS) can occur after tissue biopsy, which is a clinical issue especially in mastectomy with immediate reconstruction. This is because postoperative radiation is not usually given and local recurrence of preserved skin flap may increase. The purpose of this study is to investigate the importance of preoperative evaluation of NS and the validity of biopsy scar excision. Patients and methods We retrospectively analysed 174 cases of mastectomy with immediate breast reconstruction. The primary endpoint is the frequency of clinical and pathological NS and the secondary endpoint is the problem of excision of needle biopsy site. Results Three cases (1.7%) had preoperative clinical findings of NS. Pathological examination revealed NS in all three cases. Biopsy scars could be excised in 115 cases among 171 cases without clinical NS. Pathological NS was found in 1 of 66 (1.5%) cases of which pathological examination was performed. Biopsy scars could not be excised in the remaining 56 cases: the biopsy scar could not be identified in 41 cases, and there was concern about a decrease in flap blood flow after excision in 15 cases. In 12 of these 15 cases, the scars were close to the skin incision; excision of these scars might have triggered skin necrosis between the incision and the biopsy scar excision site. No postoperative complications were observed. Conclusions It is important to preoperatively evaluate clinical NS, and biopsy scars should be excised in clinical NS cases. Even in cases without clinical NS, biopsy scar excision should be considered. It is also important to perform a biopsy in consideration of the incision design for reconstructive surgery., It is important to evaluate clinical neoplastic seeding (NS) due to biopsy. Biopsy scars should be excised in clinical NS cases. Excision should be considered even without clinical NS.

Channelrhodopsins have been utilized in gene therapy to restore vision in patients with retinitis pigmentosa and their channel kinetics are an important factor to consider in such applications. We investigated the channel kinetics of ComV1 variants with different amino acid residues at the 172nd position. Patch clamp methods were used to record the photocurrents induced by stimuli from diodes in HEK293 cells transfected with plasmid vectors. The channel kinetics (τon and τoff) were considerably altered by the replacement of the 172nd amino acid and was dependent on the amino acid characteristics. The size of amino acids at this position correlated with τon and decay, whereas the solubility correlated with τon and τoff. Molecular dynamic simulation indicated that the ion tunnel constructed by H172, E121, and R306 widened due to H172A variant, whereas the interaction between A172 and the surrounding amino acids weakened compared with H172. The bottleneck radius of the ion gate constructed with the 172nd amino acid affected the photocurrent and channel kinetics. The 172nd amino acid in ComV1 is a key residue for determining channel kinetics as its properties alter the radius of the ion gate. Our findings can be used to improve the channel kinetics of channelrhodopsins.

Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress, decreased phagocytic activity, and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory drug developed for treating atopic dermatitis and known to inhibit toll-like receptor 4, on light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once a day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 protected against this decrease in retinal thickness and increase in ERG am-plitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregu-lation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 protects photoreceptor cells by attenuating light damage progression through inhibiting inflammatory responses.

Purpose: Breast cancer-related lymphedema (LE) significantly impairs the patients’ quality of life. Axillary lymph node dissection (ALND) is a strong risk factor for LE in breast cancer surgery. In addition, postoperative administration of docetaxel (DTX) has been reported to be a risk factor for LE in patients who undergo ALND. Herein, we performed a secondary analysis of the risk of objective LE after ALND using data from our previous study.Methods: Patients who visited the medical follow-up clinic between 12 November 2018 and 11 January 2019 and at least one year postoperatively were eligible for this study. Objective LE was defined as a difference of at least 2 cm between the affected and unaffected arms or when therapeutic intervention had already been performed for LE. The risk factors for objective LE according to taxane-containing regimen, radiation therapy, and body mass index and the effects of a taxane-containing regimen followed by supraclavicular irradiation on LE were examined.Results: Objective LE was observed in 52 patients (24%). Univariate and multivariate analyses showed that supraclavicular field irradiation was a statistically significant risk factor for objective LE. The sequential use of taxane-containing regimen and supraclavicular RT was more likely to be a risk factor for LE than ALND alone.Conclusion: The risk for LE was more likely to be higher with the sequential use of taxane-containing chemotherapy and supraclavicular field irradiation. Therefore, management of LE is important these cases.

Background Bevacizumab is an antiangiogenic agent, and that synergizes with chemotherapeutic drugs. When used in combination therapies, Bevacizumab is associated with adverse events such as hemorrhage, gastrointestinal perforation, delayed wound healing, and pneumothorax. However, the molecular mechanisms underlying these adverse events are not fully understood. Case summary A 45-year-old female with multiple lung metastases that were derived from primary breast cancer, was placed on Bevacizumab + paclitaxel therapy, since this combination has a potent antitumor effect. She reported dyspnea before cycle 3, day 1 and we therefore ran a chest X-ray, which detected a right pneumothorax. The coronal plane computed tomography revealed that one solid mass rapidly necrosed and was replaced by a cavity that passed through the bronchus in the right lower lobe. The cavity eventually ruptured the pleura and made the bronchopleural fistula that led to this pneumothorax. Thoracic cavity drainage using an intercostal catheter was performed. On the 7th day of drainage, the patient was discharged from our hospital on recovery. Recurrence of pneumothorax was not reported, and continuation of chemotherapy was made possible by changing the regimen. Conclusion Patients with lung metastases surrounding the bronchi and on the pleura should be monitored for pneumothorax by Bevacizumab-containing chemotherapies.

The utility of regional nodal irradiation (RNI) is being considered in cases of 1-3 axillary node metastases after breast-conserving surgery (BCS) with axillary lymph-node dissection (ALND). Therefore, we examined the necessity of RNI by examining the sites of recurrences in cases at our institution. We retrospectively analyzed 5,164 cases of primary breast cancer between January 2000 and December 2014 at the Aichi Cancer Centre, identifying local and distant recurrences in 152 patients with primary breast cancer treated with BCS and ALND and who had 1-3 positive axillary nodes. All patients received whole-breast irradiation (WBI) and adjuvant systemic therapy with either chemotherapy or anti-endocrine therapy with or without anti-human epidermal growth factor receptor 2 therapy. The present study excluded patients with ipsilateral breast tumor recurrence, contralateral breast cancer, neoadjuvant chemotherapy, T4 tumors or N2-3 nodes and distant metastasis. From the database of our institution, we identified 152 cases that met the defined criteria. The median follow-up period was 71 months (1-176). Isolated locoregional recurrences were found in three patients (2.0%) and were recurrent only in the breast. Only one patient had local lymph node recurrence with distant recurrence. The 10-year rates of isolated regional disease-free survival (DFS), DFS, and overall survival were 95.41, 89.50 and 96.75%, respectively, which was better compared with previous studies. We conclude that the addition of RNI to WBI is not necessary for Japanese patients who have 1-3 positive axillary nodes and ALND.

Background The effectiveness of psychotherapeutic interventions for eating disorders (EDs) is widely studied in Europe, North America, and Australia/New Zealand. However, few controlled studies and no randomized controlled trials (RCTs) have been conducted in Japan despite the relatively high prevalence of EDs in the Japanese population. The aim of this study is to evaluate the effect of enhanced cognitive behavior therapy (CBT-E), an evidence-supported ED-focused form of cognitive behavior therapy (CBT), for the treatment of bulimia nervosa (BN) in Japan. Methods/design This multicenter RCT will compare CBT-E with treatment as usual (TAU), which is widely used in Japan. A group of 140 adult outpatients with a Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) diagnosis of BN, ≥18 years of age, a body mass index (BMI) > 17.5 and 2 will be randomly assigned to CBT-E or TAU. Participants will be stratified by intervention site and BN severity. CBT-E participants will receive 20 sessions of focused form CBT-E for 20 weeks. Those in the TAU group will receive routine treatment provided by specialists. Assessment will be performed in a blinded manner prior to the start of treatment, after 6 weeks of treatment, at the end of treatment (20 weeks), and at follow-up at 40 and 80 weeks after the start of treatment. The primary outcome is the remission of BN, defined by the absence, in the previous 4 weeks, of symptoms required to meet the DSM-5 criteria for a diagnosis of BN. Secondary outcomes include the levels of ED psychopathology and impairment due to the ED, anxiety, depression, family function, and satisfaction with treatment. Discussion This will be the first RCT conducted in Japan to compare CBT-E and TAU for the treatment of BN. If CBT-E is found to be more effective than TAU, then the evidence would support its wider use for patients with BN in Japan. Because it is possible to train therapists who do not possess extensive specialist experience, wider use is also likely to be practically feasible. In addition, demonstrating the effectiveness of CBT-E in Japan would demonstrate that it could be successfully extended to additional world cultures and regions. Trial registration UMIN, UMIN000031625. Registered 7 Mar 2018.

This study aimed to determine interstitial lung disease (ILD) incidences in patients receiving cancer drug therapies with or without bevacizumab treatment.Systematic searches of PubMed, Embase, and Cochrane Library were conducted in January 2021. The main inclusion criteria were randomized clinical trials that compared bevacizumab with standard treatment in patients with solid tumors. Cochrane Collaboration's Tool was used for assessing risk-of-bias.Thirteen records involving 7201 patients were included in the meta-analysis. There were 42 ILD events in bevacizumab groups and 72 in control groups. In bevacizumab groups, the odds ratio for ILD was 0.62 (95% CI 0.42-0.92; p = 0.02), which was a significantly lower incidence than the control. This tendency was shown in targeted therapy groups but not in the cytotoxic agent groups.Our data suggest that bevacizumab may reduce the incidence of ILD.

Salt is an important seasoning that adds a salty taste to enhance or suppress other tastes in cooking. Porridge is treated with salt, even with the addition of a small amount of salt to tighten its taste. This salty taste intensity is also influenced by the amount of bittern component contained in the salt because not only the bittern component but also the change of pH affects the degree of swelling and penetration into rice. However, excessive salt intake causes lifestyle-related diseases. For that reason, salt intake reduction is recommended. When salt and citric acid are added to the porridge simultaneously, the contrasting effects of acidity and saltiness enhance the salty flavor, allowing for the reduction of salt intake.

PurposeThe DESTINY-Breast04 clinical trial is currently investigating whether trastuzumab deruxtecan (T-DXd) is effective in HER2-low as well as HER2-positive breast cancer. This highlights the interest in treatment strategies for patients with HER2-low breast cancer. The current study was therefore designed to determine the frequency of HER2-low among all breast cancers, and to compare the prognosis of HER2-low patients with that of HER2-negative patients. MethodsWe retrospectively reviewed the biological data from 4,918 of 4,977 primary breast cancer patients who attended our institute. We quantified the overall frequency of breast cancer patients with a new HER2-low subtype that was defined by an immunohistochemistry score of IHC1+ or IHC2+/ISH-. We then compared the clinical characteristics and prognosis of HER2-low patients with that of patients who did not have HER2 amplification (HER2-0). ResultsLow HER2 expression was found in 3169 (64.4%) patients; 2860 (58.1%) were HR-positive and 309(6.3%) were HR-negative. Among HER2-0 patients, 681(13.9%) were HR-positive and 157(3.2%) were HR-negative. The HER2-0 group tended to have more poor prognostic factors than the HER2-low group, irrespective of HR status. There were no statistically significant differences between the prognosis of HER2-low and HER2-0 patients, regardless of HR status. However, patients in the HER2-low group tended to have better prognosis than those in the HER2-0 group.ConclusionHER2-low patients did not have a significantly different prognosis than HER2-0 patients, regardless of HR status. However, we should consider tailoring therapies for patients with HRE2-low early breast cancer according to their HR status.

IntroductionAnorexia nervosa is a refractory psychiatric disorder with a mortality rate of 5.9% and standardised mortality ratio of 5.35, which is much higher than other psychiatric disorders. The standardised mortality ratio of bulimia nervosa is 1.49; however, it is characterised by suicidality resulting in a shorter time to death. While there is no current validated drug treatment for eating disorders in Japan, cognitive–behavioural therapy (CBT) is a well-established and commonly used treatment. CBT is also recommended in the Japanese Guidelines for the Treatment of Eating Disorders (2012) and has been covered by insurance since 2018. However, the neural mechanisms responsible for the effect of CBT have not been elucidated, and the use of biomarkers such as neuroimaging data would be beneficial.Methods and analysisThe Eating Disorder Neuroimaging Initiative is a multisite prospective cohort study. We will longitudinally collect data from 72 patients with eating disorders (anorexia nervosa and bulimia nervosa) and 70 controls. Data will be collected at baseline, after 21–41 sessions of CBT and 12 months later. We will assess longitudinal changes in neural circuit function, clinical data, gene expression and psychological measures by therapeutic intervention and analyse the relationship among them using machine learning methods.Ethics and disseminationThe study was approved by The Ethical Committee of the National Center of Neurology and Psychiatry (A2019-072). We will obtain written informed consent from all patients who participate in the study after they had been fully informed about the study protocol. All imaging, demographic and clinical data are shared between the participating sites and will be made publicly available in 2024.Trial registration numberUMIN000039841

Cementitious materials are commonly used to reinforce the bearing capacity of silty soils. However, there is very little data about how changes in arsenic (As) leaching from silty soils caused by the addition of cementitious materials. Therefore, batch leaching tests were conducted using As-bearing silty soil under different pH conditions. The pH was adjusted by changing the amount of slag cement added or the concentration of sodium hydroxide. This allows us to evaluate the effects of cement on As leaching. In addition, two different additives were applied to reduce As migration. The results show that high concentration of calcium ion (Ca2+) in leachates of soil-cement mixture has a significant effect in reducing the mobility of As even under hyperalkaline pH conditions. Arsenic immobilized by Ca2+ was observed in two patterns. The first mechanism was the help of Ca2+ to reduce the negative electrical potential on the surface of (hydr)oxide minerals under high pH conditions, thereby reducing the mobility of As by adsorption and coagulation of fresh precipitates of Fe and Al hydroxides. The second was the precipitation of calcium carbonate. This precipitate either directly adsorb/co-precipitate As or lower the concentration of strong competing ion, silica, both of which reduced the As mobility. When Ca- or Mg-based additive was added to the silty soil-cement mixture, As concentration in the leachate decreased. These findings are useful in developing sustainable soil-cement reinforcement techniques to avoid contamination.

Geranylgeranyl acetone (GGA) protects against various types of cell damages by upregulating heat shock proteins. We investigated whether GGA protects neuronal cells from cell death induced by oxidative stress. Glutamate exposure was lethal to HT-22 cells which comprise a neuronal line derived from mouse hippocampus. This configuration is often used as a model for hippocampus neurodegeneration in vitro. In the present study, GGA protected HT-22 cells from glutamate-induced oxidative stress. GGA pretreatment did not induce heat shock proteins (Hsps). Moreover, reactive oxygen species increased to the same extent in both GGA-pretreated and untreated cells exposed to glutamate. In contrast, glutamate exposure and GGA pretreatment increased mitochondrial membrane potential. However, increases in intracellular Ca2+ concentration were inhibited by GGA pretreatment. In addition, the increase of phosphorylated ERKs by the glutamate exposure was inhibited by GGA pretreatment. These findings suggest that GGA protects HT-22 cells from glutamate-provoked cell death without Hsp induction and that the mitochondrial calcium buffering capacity plays an important role in this protective effect.

Safely postponing the use of chemotherapy is important for quality of life maintenance in patients with hormone receptor-positive advanced breast cancer. In previous studies, a combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and fulvestrant prolonged the time to chemotherapy (TTC). In this study, we used real-world data to evaluate TTC in the context of CDK4/6i therapy.We performed a retrospective chart review of women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated at the Aichi Cancer Center Hospital. The patients were categorized into having received CDK4/6i therapy first (n = 41), second (n = 33), and none at all (n = 67). The change in TTC among the groups was examined.The median follow-up time was 13.8, 27.5, and 30.3 months in the CDK4/6i (first), CDK4/6i (second), and non-CDK4/6i groups, respectively. The median progression-free survival (PFS) with first-line therapy for metastasis was 30.0, 11.9, and 13.0 months, respectively (CDK4/6i [first] vs. non-CDK4/6i;Although PFS was significantly longer in the CDK4/6i (first) group than in the non-CDK4/6i group, TTC did not significantly differ among the three groups in real-world data. The non-CDK4/6i group showed a long TTC in patients with late recurrence and low risk at the primary lesion site, who benefited greatly from hormone monotherapy.

Summary Background Mizagliflozin is a novel oral sodium-glucose cotransporter 1 (SGLT1) inhibitor that increases luminal glucose and water. This study assessed the efficacy and safety of mizagliflozin in patients with functional constipation. Methods In this multicentre, randomised, double-blind phase 2 trial at 32 hospitals and community outpatient clinics in Japan, we enrolled patients with functional constipation or constipation-predominant irritable bowel syndrome, aged 20 years or older. Patients were randomly assigned (1:1:1), by use of an independent centralised registration system and dynamic allocation method, to receive mizagliflozin 5 mg, mizagliflozin 10 mg, or placebo, orally once daily for 4 weeks. Patients, investigators, staff, and the sponsor were blinded to the group assignments. The primary outcome was the change from baseline in the number of spontaneous bowel movements per week after 1 week. Efficacy analysis was done in all patients except those who deviated from good clinical practice, did not receive at least one dose of the study drug, withdrew before starting treatment, were ineligible, or for whom the primary outcome could not be assessed, and safety was assessed in all patients except those who deviated from good clinical practice, who did not receive the study drug, or who withdrew before receiving treatment. This trial is registered with ClinicalTrials.gov , number NCT02281630 , and is completed. Findings Between Oct 15, 2014, and March 7, 2015, 258 patients with functional constipation were randomly assigned: 86 patients per group. Two patients from the placebo group and three from the 10 mg mizagliflozin group were excluded because the primary outcome could not be assessed, and one patient from the 5 mg mizagliflozin group was excluded for not receiving the study drug; therefore 84 patients in the placebo group, 85 in the 5 mg mizagliflozin group, and 83 in the 10 mg mizagliflozin group were included in the full analysis population. Mean change from baseline in the number of spontaneous bowel movements per week after 1 week with mizagliflozin 5 mg (3·85 [SD 3·96]) and mizagliflozin 10 mg (5·85 [6·01]) was significantly greater than those in the placebo group (1·80 [1·80]; p Interpretation The SGLT1 inhibitor mizagliflozin showed favourable efficacy and tolerability at 5 mg and 10 mg doses in patients with functional constipation, providing a potential alternative therapy to available drugs. Funding Kissei Pharmaceutical.

Aim To examine thyroid function and clinical features of hypothyroidism in autoimmune pancreatitis (AIP) patients. Methods We examined thyroid function in 77 patients with type 1 AIP (50 males, 27 females; median age 68 years, range 33-85) diagnosed according to the Japanese diagnostic criteria for AIP 2011. We compared clinical and serological findings between patients with and without various categories of hypothyroidism. The change in hypothyroidism after steroid therapy was also examined. Results Eight patients (10%) had hypothyroidism of 6 patients had subclinical hypothyroidism with a normal serum free thyroxine (FT4) and high thyroid stimulating hormone (TSH) level, and 2 patients had central hypothyroidism with low serum free triiodothyronine (FT3), FT4 and TSH levels. A significant goiter of the thyroid was not observed in any patient. There were no significant differences in age; male to female ratio; serum concentrations of IgG and IgG4-related disease (IgG4-RD); presence of anti-thyroglobulin antibody, antinuclear antigen or rheumatoid factor; or presence of extrapancreatic lesions between the 6 patients with subclinical hypothyroidism and patients with euthyroidism. After steroid therapy, both subclinical and central hypothyroidism improved with improvement of the AIP. Conclusion Hypothyroidism was observed in 8 (10%) of 77 AIP patients and was subclinical in 6 patients and central in 2 patients. Further studies are necessary to clarify whether this subclinical hypothyroidism is another manifestation of IgG4-RD.

Immediate breast reconstruction (IBR) has been become a standard treatment for patients with breast cancer undergoing mastectomy. However, whether IBR is appropriate in patients undergoing neoadjuvant chemotherapy (NAC) is still unclear. Therefore, in this study we examined the rates of operative adverse events (AEs), risk factors for operative AEs, and effects on chemotherapy and radiotherapy of IBR with NAC. Between January 2012 and March 2018, 593 patients underwent IBR at the Aichi Cancer Center Hospital. We retrospectively obtained clinical data of all these patients from their medical records and identified 56 patients (65 breasts) who had received NAC (NAC group) and 537 patients (568 breasts) who had not (non-NAC group). We compared the rates of operative AEs, risk factors for operative AEs, chemotherapy-related AEs, and duration to radiotherapy between the NAC and non-NAC cohorts. The rate of operative AEs was significantly higher in the NAC than the non-NAC group (35% vs. 22%, p

We report the case ofan elderly patient with squamous cell carcinoma(SCC)ofthe breast, which showed negative conversion after endocrine therapy. An 82-year-old woman with a diagnosis ofER -positive SCC(cT1N0M0, StageⅠ)received primary endocrine therapy with 5 hormonal medicines. Following the endocrine therapy, she underwent mastectomy and axillary node resection. Histological examination confirmed a diagnosis of ER-negative SCC. At 10 months after the operation, she was doing well with no evidence ofdisease without postoperative adjuvant therapy. Thus, clinicians should be aware that the ER status may change after primary endocrine therapy. For elderly patients with breast cancer, it is important to be aware that primary endocrine therapy can become ineffective due to ER-negative conversion and aging due to prolonged treatment.

Caspase-1 is a cysteine protease responsible for the processing of the proinflammatory cytokine interleukin-1β and activated by the formation of inflammasome complexes. Although several investigations have found a link between diet-induced obesity and caspase-1, the relationship remains controversial. Here, we found that mice deficient in caspase-1 were susceptible to high-fat diet-induced obesity with increased adiposity as well as normal lipid and glucose metabolism. Caspase-1 deficiency clearly promoted the infiltration of inflammatory macrophages and increased the production of C-C motif chemokine ligand 2 (CCL2) in the adipose tissue. The dominant cellular source of CCL2 was stromal vascular fraction rather than adipocytes in the adipose tissue. These findings demonstrate a critical role of caspase-1 in macrophage-driven inflammation in the adipose tissue and the development of obesity. These data provide novel insights into the mechanisms underlying inflammation in the pathophysiology of obesity.

Various dietary phytochemicals seem to display antioxidant activity through the NF-E2-related factor 2 (Nrf2) pathway. However, few studies have demonstrated its antioxidant effect and Nrf2 dependency at the animal level. We constructed a zebrafish-based assay system to analyze the in vivo antioxidant activity of phytochemicals and examined the activity of 10 phytochemicals derived from spices, using this system as a pilot study. Hydrogen peroxide and arsenite were used as oxidative stressors, and Nrf2 dependency was genetically analyzed using an Nrf2-mutant zebrafish line. The activities of curcumin, diallyl trisulfide and quercetin were involved in the reduction of hydrogen peroxide toxicity, while those of cinnamaldehyde, isoeugenol and 6-(methylsulfinyl)hexyl isothiocyanate were involved in the reduction of arsenite toxicity. The antioxidant activities of these phytochemicals were all Nrf2 dependent, with the exception of cinnamaldehyde, which showed strong antioxidant effects even in Nrf2-mutant zebrafish. In summary, we succeeded in constructing an assay system to evaluate the in vivo antioxidant activity of various phytochemicals using zebrafish larvae. Using this system, we found that each spice-derived phytochemical has its own specific property and mechanism of antioxidant action.

Film Bulk Acoustic Resonator (FBAR) will become commonplace for the frequency filter used in mobile communication. AIN films were used for piezoelectric material of FBAR. High piezoelectricity of ScAlN films have attracted much attention as FBAR material. However, negative ion generation at Sc metal target induces degradation of the crystallinity due to the ion bombardment on ScAlN films during the sputtering growth. Large amount of O- and CN-ions generation at sputtering target were observed. In this study, we compared the energy distributions of negative ions of arc-melted and sintered ScAl alloy targets which have different oxygen and carbon concentration. The c-axis orientation and electromechanical coupling coefficient kt2of ScAlN films fabricated with these different targets were also compared. As a result, the kt2of two targets was larger than our previous report. There were the large differences in amount of O- and CN- ions generation in the two targets. However, it does not significantly affect the results of the crystallization and kt2of the ScAlN films.

We report the case of a patient with triple negative breast cancer(TNBC)who showed isolated brain metastasis relatively soon after pathological complete response(pCR)to neoadjuvant chemotherapy. A 45-year-old woman with a diagnosis of TNBC(T2N1M0, Stage II B)received neoadjuvant chemotherapy with 5-FU/epirubicin/cyclophosphamide(FEC), followed by docetaxel. After the neoadjuvant chemotherapy, she underwent mastectomy and axillary lymph node dissection. Histological examination of the resected specimens revealed pCR. Brain metastasis, however, developed 7 months after the resection. She underwent total removal of the brain tumor and 50 Gy irradiation to the right frontal lobe. Histological examination confirmed a diagnosis of metastasis from TNBC. She is doing well with no evidence of disease 81 months after resection of the brain metastasis. This case and a review of the literature suggest that the clinician should be aware that brain metastasis from breast cancer may develop even after achieving pCR to neoadjuvant chemotherapy. Surgical resection followed by radiotherapy may provide a survival benefit for selected patients with isolated brain metastasis from breast cancer.