Mid-term Outcome of Superior Capsular Reconstruction Using Fascia Lata Autograft (At Least 6 mm in Thickness) Results in High Retear Rate and No Improvement in Muscle Strength.

PURPOSE: (1) To report and evaluate clinical and radiologic outcomes of superior capsular reconstruction (SCR) using fascia lata autograft in patients with irreparable rotator cuff tears (IRCTs) over a mid-term duration and (2) to assess the overall survival rate of the graft. METHODS: We retrospectively reviewed patients who underwent SCR with fascia lata autograft between June 2017 and August 2018. The graft, folded 3 or 4 times, achieved a minimum thickness of 6 mm during the surgical procedure. The inclusion criteria encompassed patients with isolated supraspinatus IRCTs or posterosuperior IRCTs exhibiting poor muscle quality (Goutallier grade ≥3) and without arthritis (Hamada grade ≤ 2). The exclusion criteria included lack of follow-up data or magnetic resonance imaging. Clinical assessments included the visual analog scale score, Constant score, and American Shoulder and Elbow Surgeons (ASES) score; active range of motion; and strength. Radiographic analysis included the acromiohumeral distance, Hamada grade, and graft integrity at final follow-up. A Kaplan-Meier curve was generated to depict SCR graft survivorship. RESULTS: In total, 45 patients (mean age, 64.8 ± 5.7 years) were included, and the average follow-up duration was 63.2 ± 5.9 months (range, 50-79 months). There was significant improvement in pain (visual analog scale score of 4.4 ± 1.3 preoperatively vs 1.4 ± 0.4 at final follow-up, P < .001). Yet, 18 patients (40.0%) and 17 patients (37.7%) achieved the minimal clinically important difference in the ASES score and Constant score, respectively. Active forward elevation increased from 119° ± 23° to 137° ± 23° (P < .001), and external rotation at the side improved from 29° ± 11° to 36° ± 12° (P = .002). However, strength did not exhibit improvement in any direction. The acromiohumeral distance decreased from 8.5 ± 1.7 mm to 6.5 ± 1.9 mm (P < .001), and the Hamada grade increased from 1.1 ± 0.3 to 1.8 ± 1.1 (P < .001). Finally, the infection rate was 13.3% (n = 6). CONCLUSIONS: Despite a substantial graft retear rate of 62.2%, SCR led to a significant improvement in pain. Nonetheless, 18 patients (40.0%) and 17 patients (37.7%) achieved the minimal clinically important difference in the ASES score and Constant score, respectively. Forward elevation and external rotation at the side showed significant improvement, but no improvement in muscle strength was observed. Finally, significant arthritis progression was observed. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Joint-preserving treatment for global irreparable rotator cuff tears: combined anterior Latissimus dorsi and Teres major tendon transfer.

INTRODUCTION: Treating global irreparable rotator cuff tears (GIRCTs) that involve both antero-and postero-superior cuff tendon tears could be a challenging problem. There has been limited joint-preserving treatment options in high-demand patients with minimal glenohumeral arthritis. The study aims to assess the clinical outcome of combined anterior latissimus dorsi and teres major tendon (aLDTM) transfer for patients with both GIRCTs and minimal glenohumeral arthritis. MATERIALS AND METHODS: This retrospective study included patients who underwent combined aLDTM transfer for GIRCTs between 2018 May and 2020 October. Clinical outcomes include pain VAS, Constant, American Shoulder and Elbow Society (ASES), University of California Los Angeles (UCLA), activities of daily living requiring active internal rotation (ADLIR) score, active range of motion (aROM), strength, rates of pseudoparalysis or pseudoparesis reversal and return to work. Radiographic assessment included the acromiohumeral distance (AHD), Hamada grade, and transferred tendon integrity at final follow-up. RESULTS: 23 patients (mean age: 64.7 ± 5.9 years [55-74]) were included and the mean follow-up period was 28.2 ± 4.3 [24‒36] months. Postoperatively, VAS, Constant, ASES, UCLA, and ADLIR scores significantly improved at final follow-up (P < .001). Postoperative aROM was significantly improved in forward elevation (FE) to 129° ± 29°, abduction (ABD) to 105° ± t3°, and internal rotation (IR) at back to 5.9 ± 2.5. Strength of both FE and IR were also significantly improved (P < .001). Patients with preoperative pseudoparalysis (2 of 4 patients) and pseudoparesis (6 of 6 patients) experienced a reversal. No significant change in AHD and hamada grade was confirmed at final follow-up. 3 patients experienced partial tear of the transferred tendon. CONCLUSIONS: In this study, we found significant improvement in clinical outcomes with no significant progression of arthritis by final follow-up. The aLDTM transfer could be an alternative choice of joint-preserving treatment option for young and active patients with GIRCTs and minimal glenohumeral arthritis. However, large and long-term studies should be conducted to establish its adequacy. STUDY DESIGN: Case series. LEVEL OF EVIDENCE: IV.

Increased latissimus dorsi and teres major muscle volume after anterior transfer for irreparable anterior superior rotator cuff tear: correlation with improved internal rotation strength.

INTRODUCTION: While the well-established correlation between increased muscle volume and enhanced muscle strength is widely recognized, there have been no studies assessing volumetric muscle changes in transfer surgery in the shoulder. This study aimed to evaluate changes in transferred muscle volume and their clinical implications in anterior latissimus dorsi and teres major (aLDTM) tendon transfer in patients with anterior superior irreparable rotator cuff tears (ASIRCTs). MATERIALS AND METHODS: The study retrospectively examined 40 patients who underwent aLDTM tendon transfers for ASIRCTs between August 2018 and January 2022. Using ImageJ software, the LDTM muscle was segmented in T2-weighted oblique axial images, and total muscle volume (tLDTMV) of both immediate and postoperative 1-year were calculated. Pearson correlation analysis was used to determine the correlation between ΔtLDTMV and ΔASES scores, Δactive-ROM, and Δstrength. RESULTS: The current study revealed an 11.4% increase in tLDTMV at 1-year postoperative. Patients were grouped based on postoperative ASES score: Group 1 (Optimal, n = 17) and Group 2 (Suboptimal, n = 23). Although tLDTMVimmediate postoperative values were similar between groups (P = 0.954), tLDTMV1-year postoperative value was significantly higher in Group 1 compared to Group 2 (P = 0.021). In correlation analysis, ΔtLDTMV showed significant correlations with ΔASES score (r = 0.525, P < 0.001), ΔaROM of forward elevation (FE) (r = 0.476, P = 0.002), ΔaROM of internal rotation (IR) at back (r = 0.398, P = 0.011), Δstrength of FE (r = 0.328, P = 0.039), Δ strength of IR at 90° abduction (r = 0.331, P = 0.037), and IR at side (r = 0.346, P = 0.029). CONCLUSIONS: Significant increase in tLDTMV was observed at 1-year postoperative for ASIRCT patients. Notably, greater ΔtLDTMV exhibited a correlation with better ASES scores, increased aROM and strength in both FE and IR. Nevertheless, further research is required by employing more robust standardized measurement tools and a larger sample size.

Mid-term outcomes of arthroscopically assisted lower trapezius tendon transfer using Achilles allograft in treatment of posterior-superior irreparable rotator cuff tear.

BACKGROUND: Arthroscopically assisted lower trapezius tendon (aLTT) transfer is one of the treatment options for posterior-superior irreparable rotator cuff tears (PSIRCTs). Although short-term clinical outcomes have shown promising results, there are currently no reported clinical outcomes over a longer follow-up period. This study evaluated the mid-term outcomes of aLTT transfer in patients with a diagnosis of PSIRCT. METHODS: This retrospective case-series study included patients who underwent aLTT transfer between May 2017 and May 2019. The clinical outcome assessment included the visual analog scale (VAS) pain score, Constant score, American Shoulder and Elbow Surgeons score, University of California-Los Angeles score, Activities of Daily Living Requiring Active External Rotation (ADLER) score, active range of motion, Single Assessment Numeric Evaluation score, and return-to-work rate. The radiographic analysis included the acromiohumeral distance, Hamada grade, and integrity of the transferred tendon at final follow-up. Subgroup analyses were performed based on the integrity of the transferred tendon and the trophicity of the teres minor (Tm). RESULTS: This study enrolled 36 patients with a mean age of 63.4 years who met the inclusion criteria and were followed up for a mean of 58.2 ± 5.3 months. At final follow-up, the patients showed significant improvement in mean VAS score, Constant score, American Shoulder and Elbow Surgeons score, University of California-Los Angeles score, ADLER score, and active range of motion in all directions except internal rotation. A decrease in the acromiohumeral distance and an increase in the Hamada grade were observed at final follow-up (P = .040 and P = .006, respectively). Retears of the transferred tendon occurred in 7 patients, and postoperative infections developed in 2 individuals. An interesting finding was that the retear group still demonstrated improvement in the VAS score but did not show improvement in external rotation at the side by the final follow-up. Compared with the Tm non-hypertrophy group, the Tm hypertrophy group showed significantly better improvement in external rotation at 90° of abduction and at the side, as well as the ADLER score. Of the study patients, 30 (83.3%) were able to successfully resume their previous work. CONCLUSION: In this study, aLTT transfer in patients with PSIRCTs demonstrated significant improvements in clinical and radiologic outcomes by the final follow-up. These findings provide support for the mid-term safety and effectiveness of aLTT transfer as a viable joint-preserving treatment option for PSIRCTs. However, larger and longer-term studies are still needed to further validate these findings.

Prevalence, Trend, and Risk Factors for Early Chronic Obstructive Pulmonary Disease: An Analysis of the Nationwide Population-Based Survey from 2010 to 2019 in South Korea.

This study aimed to evaluate the prevalence, trends, and risk factors of early chronic obstructive pulmonary disease (COPD) by using a nationally representative sample. The datasets of the Korea National Health and Nutrition Examination Survey 2010-2019 were used, where 80,860 individuals were identified; of these, 9,045 participants aged 40-49 years who underwent spirometry with no missing data were analyzed. Early COPD was defined as forced expiratory volume in 1 s /forced vital capacity ratio < the lower limit of normal (2.5th percentile) in individuals aged <50 years without a history of asthma, inhaler therapy, or persistent respiratory symptoms. The prevalence and trend of early COPD were estimated according to features such as smoking status and pack-years. Joinpoint regression analysis was used to analyze the significant annual change in the trend according to sex, smoking status, and pack-years. A complex sample multivariable-adjusted regression model was used to identify factors affecting early COPD. The estimated population size during 2010-2019 was 82,326,178. Early COPD was present in 4.5% of patients (6.5% of men and 2.3% of women). It was present in 7.7% of current smokers, followed by former and never smokers. Among smokers with ≥ 10 pack-years, early COPD was present in 8.2%, whereas it was present in 2.6% of smokers with < 10 pack-years. Joinpoint regression analyses found a recent decrease in the trend of prevalence in males who were former and current smokers. The multivariable-adjusted logistic regression model showed that being male, lower educational level, smoking status, and pack-years were factors that affected the presence of early COPD. Continued surveillance of this pre-disease condition is required, and further research are warrant.

Overexpression of Interleukin-8 Promotes the Progression of Fatty Liver to Nonalcoholic Steatohepatitis in Mice.

Nonalcoholic steatohepatitis (NASH) is an advanced stage of fatty liver disease characterized by liver damage, inflammation, and fibrosis. Although neutrophil infiltration is consistently observed in the livers of patients with NASH, the precise role of neutrophil-recruiting chemokines and infiltrating neutrophils in NASH pathogenesis remains poorly understood. Here, we aimed to elucidate the role of neutrophil infiltration in the transition from fatty liver to NASH by examining hepatic overexpression of interleukin-8 (IL8), a major chemokine responsible for neutrophil recruitment in humans. Mice fed a high-fat diet (HFD) for 3 months developed fatty liver without concurrent liver damage, inflammation, and fibrosis. Subsequent infection with an adenovirus overexpressing human IL8 for an additional 2 weeks increased IL8 levels, neutrophil infiltration, and liver injury in mice. Mechanistically, IL8-induced liver injury was associated with the upregulation of components of the NADPH oxidase 2 complex, which participate in neutrophil oxidative burst. IL8-driven neutrophil infiltration promoted macrophage aggregate formation and upregulated the expression of chemokines and inflammatory cytokines. Notably, IL8 overexpression amplified factors associated with fibrosis, including collagen deposition and hepatic stellate cell activation, in HFD-fed mice. Collectively, hepatic overexpression of human IL8 promotes neutrophil infiltration and fatty liver progression to NASH in HFD-fed mice.

SARS-CoV-2 Breakthrough Infections after introduction of 4 COVID-19 Vaccines, South Korea, 2021.

We conducted a nationwide retrospective cohort study to estimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection among recipients of 4 different vaccines in South Korea. Age-adjusted breakthrough infection rate per month was highest for Janssen (42.6/100,000 population), followed by AstraZeneca (21.7/100,000 population), Pfizer-BioNTech (8.5/100,000 population), and Moderna (1.8/100,000 population).

Escherichia coli minicells with targeted enzymes as bioreactors for producing toxic compounds.

Formed by aberrant cell division, minicells possess functional metabolism despite their inability to grow and divide. Minicells exhibit not only superior stability when compared with bacterial cells but also exceptional tolerance-characteristics that are essential for a de novo bioreactor platform. Accordingly, we engineered minicells to accumulate protein, ensuring sufficient production capability. When tested with chemicals regarded as toxic against cells, the engineered minicells produced titers of C6-C10 alcohols and esters, far surpassing the corresponding production from bacterial cells. Additionally, microbial autoinducer production that is limited in expanding bacterial population was conducted in the minicells. Because bacterial population growth was nonexistent, the minicells produced autoinducers in constant amounts, which allowed precise control of the bacterial population having autoinducer-responsive gene circuits. When bacterial population growth was nonexistent, the minicells produced autoinducers in constant amounts, which allowed precise control of the bacterial population having autoinducer-based gene circuits with the minicells. This study demonstrates the potential of minicells as bioreactors suitable for products with known limitations in microbial production, thus providing new possibilities for bioreactor engineering.

Response-Guided Omission of Anthracycline in Patients with HER2-Positive Early Breast Cancer Treated with Neoadjuvant Taxane and Trastuzumab: 5-Year Follow-Up of Prognostic Study Using Propensity Score Matching.

BACKGROUND: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without fluorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). RESULTS: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. CONCLUSIONS: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.

Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking.

Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for detoxification the ethanol metabolite acetaldehyde, is recognized as a promising therapeutic target to treat alcohol use disorders (AUDs). Disulfiram, a potent ALDH2 inhibitor, is an approved drug for the treatment of AUD but has clinical limitations due to its side effects. This study aims to elucidate the relative contribution of different organs in acetaldehyde clearance through ALDH2 by using global- (Aldh2-/-) and tissue-specific Aldh2-deficient mice, and to examine whether liver-specific ALDH2 inhibition can prevent alcohol-seeking behavior. Aldh2-/- mice showed markedly higher acetaldehyde concentrations than wild-type (WT) mice after acute ethanol gavage. Acetaldehyde levels in hepatocyte-specific Aldh2 knockout (Aldh2Hep-/-) mice were significantly higher than those in WT mice post gavage, but did not reach the levels observed in Aldh2-/- mice. Energy expenditure and motility were dramatically dampened in Aldh2-/- mice, but moderately decreased in Aldh2Hep-/- mice compared to controls. In the 2-bottle paradigm and the drinking-in-the-dark model, Aldh2-/- mice drank negligible volumes from ethanol-containing bottles, whereas Aldh2Hep-/- mice showed reduced alcohol preference at high but not low alcohol concentrations. Glial cell- or neuron-specific Aldh2 deficiency did not affect voluntary alcohol consumption. Finally, specific liver Aldh2 knockdown via injection of shAldh2 markedly decreased alcohol preference. In conclusion, although the liver is the major organ responsible for acetaldehyde metabolism, a cumulative effect of ALDH2 from other organs likely also contributes to systemic acetaldehyde clearance. Liver-targeted ALDH2 inhibition can decrease heavy drinking without affecting moderate drinking, providing molecular basis for hepatic ALDH2 targeting/editing for the treatment of AUD.

Prediction of pathological complete response after neoadjuvant chemotherapy in breast cancer: comparison of diagnostic performances of dedicated breast PET, whole-body PET, and dynamic contrast-enhanced MRI.

PURPOSE: To compare the diagnostic performance of ring-type dedicated breast PET (dbPET), whole-body PET (WBPET), and DCE-MRI for predicting pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). METHODS: This prospective study included 29 women with histologically proven breast cancer on needle biopsy between July 2016 and July 2019 (age: mean 55 years; range 35-78). Patients underwent WBPET followed by ring-type dbPET and DCE-MRI pre- and post-NAC for preoperative evaluation. pCR was defined as an invasive tumor that disappeared in the breast. Standardized uptake values corrected for lean body mass (SULpeak) were calculated for dbPET and WBPET scans. Maximum tumor length was measured in DCE-MRI images. Reduction rates were calculated for quantitative evaluation. Two radiologists independently evaluated the qualitative findings. Reduction rates and qualitative findings were compared between the pCR (n = 7) and non-pCR (n = 22) groups for each modality. Differences in quantitative and qualitative data between the two groups were analyzed statistically. RESULTS: Significant differences were observed in the reduction rates of dbPET and DCE-MRI (P = 0.01 and 0.03, respectively) between the two groups. Univariate and multiple logistic regression analyses revealed that SULpeak reduction rates in WBPET and dbPET (P = 0.02 and P = 0.01, respectively) and in dbPET (odds ratio, 16.00; 95% CI 1.57-162.10; P = 0.01) were significant indicators associated with pCR, respectively. No between-group differences were observed in qualitative findings in the three modalities. CONCLUSION: SULpeak reduction rate of dbPET > 82% was an independent indicator associated with pCR after NAC in breast cancer.

Protective and Detrimental Roles of p38α Mitogen-Activated Protein Kinase in Different Stages of Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Neutrophil infiltration is a hallmark of nonalcoholic steatohepatitis (NASH), but how this occurs during the progression from steatosis to NASH remains obscure. Human NASH features hepatic neutrophil infiltration and up-regulation of major neutrophil-recruiting chemokines (e.g., chemokine [C-X-C motif] ligand 1 [CXCL1] and interleukin [IL]-8). However, mice fed a high-fat diet (HFD) only develop fatty liver without significant neutrophil infiltration or elevation of chemokines. The aim of this study was to determine why mice are resistant to NASH development and the involvement of p38 mitogen-activated protein kinase (p38) activated by neutrophil-derived oxidative stress in the pathogenesis of NASH. APPROACH AND RESULTS: Inflamed human hepatocytes attracted neutrophils more effectively than inflamed mouse hepatocytes because of the greater induction of CXCL1 and IL-8 in human hepatocytes. Hepatic overexpression of Cxcl1 and/or IL-8 promoted steatosis-to-NASH progression in HFD-fed mice by inducing liver inflammation, injury, and p38 activation. Pharmacological inhibition of p38α/ß or hepatocyte-specific deletion of p38a (a predominant form in the liver) attenuated liver injury and fibrosis in the HFD+Cxcl1 -induced NASH model that is associated with strong hepatic p38α activation. In contrast, hepatocyte-specific deletion of p38a in HFD-induced fatty liver where p38α activation is relatively weak exacerbated steatosis and liver injury. Mechanistically, weak p38α activation in fatty liver up-regulated the genes involved in fatty acid ß-oxidation through peroxisome proliferator-activated receptor alpha phosphorylation, thereby reducing steatosis. Conversely, strong p38α activation in NASH promoted caspase-3 cleavage, CCAAT-enhancer-binding proteins homologous protein expression, and B cell lymphoma 2 phosphorylation, thereby exacerbating hepatocyte death. CONCLUSIONS: Genetic ablation of hepatic p38a increases simple steatosis but ameliorates oxidative stress-driven NASH, indicating that p38α plays distinct roles depending on the disease stages, which may set the stage for investigating p38α as a therapeutic target for the treatment of NASH.

Interleukin-22 Ameliorates Neutrophil-Driven Nonalcoholic Steatohepatitis Through Multiple Targets.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. At present, how simple steatosis progresses to NASH remains obscure and effective pharmacological therapies are lacking. Hepatic expression of C-X-C motif chemokine ligand 1 (CXCL1), a key chemokine for neutrophil infiltration (a hallmark of NASH), is highly elevated in NASH patients but not in fatty livers in obese individuals or in high-fat diet (HFD)-fed mice. The aim of this study was to test whether overexpression of CXCL1 itself in the liver can induce NASH in HFD-fed mice and to test the therapeutic potential of IL-22 in this new NASH model. APPROACH AND RESULTS: Overexpression of Cxcl1 in the liver alone promotes steatosis-to-NASH progression in HFD-fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as apoptosis signal-regulating kinase 1 and p38 mitogen-activated protein kinase) activation. Myeloid cell-specific deletion of the neutrophil cytosolic factor 1 (Ncf1)/p47phox gene, which encodes a component of the NADPH oxidase 2 complex that mediates neutrophil oxidative burst, markedly reduced CXCL1-induced NASH and stress kinase activation in HFD-fed mice. Treatment with interleukin (IL)-22, a cytokine with multiple targets, ameliorated CXCL1/HFD-induced NASH or methionine-choline deficient diet-induced NASH in mice. Mechanistically, IL-22 blocked hepatic oxidative stress and its associated stress kinases via the induction of metallothionein, one of the most potent antioxidant proteins. Moreover, although it does not target immune cells, IL-22 treatment attenuated the inflammatory functions of hepatocyte-derived, mitochondrial DNA-enriched extracellular vesicles, thereby suppressing liver inflammation in NASH. CONCLUSIONS: Hepatic overexpression of CXCL1 is sufficient to drive steatosis-to-NASH progression in HFD-fed mice through neutrophil-derived reactive oxygen species and activation of stress kinases, which can be reversed by IL-22 treatment via the induction of metallothionein.

Development of Prediction Model Including MicroRNA Expression for Sentinel Lymph Node Metastasis in ER-Positive and HER2-Negative Breast Cancer.

BACKGROUND: The aim of our study is to find microRNAs (miRNAs) associated with sentinel lymph node metastasis (SLNM) and to develop a prediction model for SLNM in ER-positive and HER2-negative (ER+/HER2-) breast cancer. PATIENTS AND METHODS: In the present study, only ER+/HER2- primary breast cancer was considered. The discovery set for SLNM-associated miRNAs included 10 tumors with and 10 tumors without SLNM. The training and validation sets both included 100 tumors. miRNA expression in tumors was examined comprehensively by miRNA microarray in the discovery set and by droplet digital PCR in the training and validation sets. RESULTS: In the discovery set, miR-98, miR-22, and miR-223 were found to be significantly (P < 0.001, fold-change > 2.5) associated with SLNM. In the training set, we constructed the prediction model for SLNM using miR-98, tumor size, and lymphovascular invasion (LVI) with high accuracy (AUC, 0.877). The accuracy of this prediction model was confirmed in the validation set (AUC, 0.883), and it outperformed the conventional Memorial Sloan Kettering Cancer Center nomogram. In situ hybridization revealed the localization of miR-98 expression in tumor cells. CONCLUSIONS: We developed a prediction model consisting of miR-98, tumor size, and LVI for SLNM with high accuracy in ER+/HER2- breast cancer. This model might help decide the indication for SLN biopsy in this subtype.

Real-world effectiveness of post-trastuzumab emtansine treatment in patients with HER2-positive, unresectable and/or metastatic breast cancer: a retrospective observational study (KBCSG-TR 1917).

BACKGROUND: Trastuzumab emtansine (T-DM1) is a second-line standard therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Evidence regarding post-T-DM1 treatments is currently lacking. We evaluated the effectiveness of post-T-DM1 drug therapy in patients with HER2-positive, unresectable and/or metastatic breast cancer. METHODS: In this multicenter, retrospective, observational study, real-world clinical data of female patients with HER2-positive breast cancer who had a history of T-DM1 treatment were consecutively collected from five sites in Japan. We investigated the effectiveness of post-T-DM1 therapy by evaluating the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Tumor response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines. Subgroup and exploratory analyses according to background factors were also undertaken. RESULTS: Of the 205 patients who received T-DM1 treatment between 1 January 2014 and 31 December 2018, 128 were included in this study. Among the 128 patients analyzed, 105 (82%) patients received anti-HER2 therapy and 23 (18%) patients received regimens without anti-HER2 therapy. Median (95% confidence interval [CI]) rwPFS, TTF, and OS were 5.7 (4.8-6.9) months, 5.6 (4.6-6.4) months, and 22.8 (18.2-32.4) months, respectively. CBR and ORR (95% CI) were 48% (38.8-56.7) and 23% (15.1-31.4), respectively. Cox-regression analysis showed that an ECOG PS score of 0, a HER2 immunohistochemistry score of 3+, recurrent type, ≥12 month duration of T-DM1 therapy, and anti-HER2 therapy were independent variables for rwPFS. An exploratory subgroup analysis of regimens after T-DM1 showed that those with anti-HER2 therapy had a median rwPFS of 6.3 and those without anti-HER2 therapy had a median rwPFS of 4.8 months. CONCLUSIONS: In the real-world setting in Japan, several post-T-DM1 regimens for patients with unresectable and/or metastatic HER2-positive breast cancer, including continuation of anti-HER2 therapy, showed some effectiveness; however, this effectiveness was insufficient. Novel therapeutic options are still needed for further improvement of PFS and OS in later treatment settings. TRIAL REGISTRATION: UMIN000038296 ; registered on 15 October 2019.

Ribociclib, a CDK 4/6 inhibitor, plus endocrine therapy in Asian women with advanced breast cancer.

The ongoing, Phase Ib MONALEESASIA study is evaluating the efficacy and safety of ribociclib plus endocrine therapy in Asian patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Eligible patients from Japan, Hong Kong, and Singapore were enrolled in this 2-phase study consisting of a dose-escalation phase to determine the maximum-tolerated dose and the recommended Phase II dose of ribociclib plus letrozole, and a dose-expansion phase to evaluate safety and tolerability of ribociclib plus letrozole, fulvestrant, or tamoxifen. An exploratory biomarker analysis evaluating expression of target genes was also conducted. In the dose-escalation phase, the maximum-tolerated/recommended Phase II doses of ribociclib were lower in Japanese patients (300 mg) than in Asian non-Japanese patients (600 mg). Ribociclib plus endocrine therapy at the recommended Phase II dose had a manageable safety profile, with neutropenia and elevated liver transaminases being the most common adverse events leading to dose modifications or discontinuations, and it demonstrated evidence of clinical activity in both Japanese and Asian non-Japanese patients. Preliminary efficacy in Asian populations is similar to that observed in White populations studied in previous ribociclib (MONALEESA) trials. Biomarker analysis demonstrated suppression of pharmacodynamic biomarker gene expression, indicating inhibition of target genes by ribociclib combined with endocrine therapy. Results from the ongoing study support the use of ribociclib in combination with letrozole in Asian non-Japanese patients at the same dose (600 mg) as White patients. In Japanese patients, a lower dose of ribociclib (300 mg) should be considered. Clinicaltrials.gov: NCT02333370.

MicroRNA-223 Ameliorates Nonalcoholic Steatohepatitis and Cancer by Targeting Multiple Inflammatory and Oncogenic Genes in Hepatocytes.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases ranging from simple steatosis to more severe forms of liver injury including nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). In humans, only 20%-40% of patients with fatty liver progress to NASH, and mice fed a high-fat diet (HFD) develop fatty liver but are resistant to NASH development. To understand how simple steatosis progresses to NASH, we examined hepatic expression of anti-inflammatory microRNA-223 (miR-223) and found that this miRNA was highly elevated in hepatocytes in HFD-fed mice and in human NASH samples. Genetic deletion of miR-223 induced a full spectrum of NAFLD in long-term HFD-fed mice including steatosis, inflammation, fibrosis, and HCC. Furthermore, microarray analyses revealed that, compared to wild-type mice, HFD-fed miR-223 knockout (miR-223KO) mice had greater hepatic expression of many inflammatory genes and cancer-related genes, including (C-X-C motif) chemokine 10 (Cxcl10) and transcriptional coactivator with PDZ-binding motif (Taz), two well-known factors that promote NASH development. In vitro experiments demonstrated that Cxcl10 and Taz are two downstream targets of miR-223 and that overexpression of miR-223 reduced their expression in cultured hepatocytes. Hepatic levels of miR-223, CXCL10, and TAZ mRNA were elevated in human NASH samples, which positively correlated with hepatic levels of several miR-223 targeted genes as well as several proinflammatory, cancer-related, and fibrogenic genes. Conclusion: HFD-fed miR-223KO mice develop a full spectrum of NAFLD, representing a clinically relevant mouse NAFLD model; miR-223 plays a key role in controlling steatosis-to-NASH progression by inhibiting hepatic Cxcl10 and Taz expression and may be a therapeutic target for the treatment of NASH.

Adipocyte Death Preferentially Induces Liver Injury and Inflammation Through the Activation of Chemokine (C-C Motif) Receptor 2-Positive Macrophages and Lipolysis.

Adipocyte death occurs under various physiopathological conditions, including obesity and alcohol drinking, and can trigger organ damage particularly in the liver, but the underlying mechanisms remain obscure. To explore these mechanisms, we developed a mouse model of inducible adipocyte death by overexpressing the human CD59 (hCD59) on adipocytes (adipocyte-specific hCD59 transgenic mice). Injection of these mice with intermedilysin (ILY), which rapidly lyses hCD59 expressing cells exclusively by binding to the hCD59 but not mouse CD59, resulted in the acute selective death of adipocytes, adipose macrophage infiltration, and elevation of serum free fatty acid (FFA) levels. ILY injection also resulted in the secondary damage to multiple organs with the strongest injury observed in the liver, with inflammation and hepatic macrophage activation. Mechanistically, acute adipocyte death elevated epinephrine and norepinephrine levels and activated lipolysis pathways in adipose tissue in a chemokine (C-C motif) receptor 2-positive (CCR2+ ) macrophage-dependent manner, which was followed by FFA release and lipotoxicity in the liver. Additionally, acute adipocyte death caused hepatic CCR2+ macrophage activation and infiltration, further exacerbating liver injury. Conclusion: Adipocyte death predominantly induces liver injury and inflammation, which is probably due to the superior sensitivity of hepatocytes to lipotoxicity and the abundance of macrophages in the liver.

Intraobserver and interobserver reliability in sonographic size measurements of gallbladder polyps.

OBJECTIVES: To evaluate the intraobserver and interobserver reliability of gallbladder polyp measurements using transabdominal US and the factors that affect reliability. METHODS: From November 2017 to February 2018, two radiologists measured the maximum diameter of 91 gallbladder polyps using transabdominal US. Intraobserver and interobserver agreement were determined using 95% Bland-Altman limits of agreement and intraclass correlation coefficients (ICCs). The effects of image settings, polyp location, and polyp size were evaluated by comparing ICCs using z tests. RESULTS: The intraobserver agreement rates were 0.960 (95% confidence interval [CI], 0.939-0.973) for observer 1 and 0.962 (95% CI, 0.943-0.975) for observer 2. The ICCs between the two observers were 0.963 (95% CI, 0.926-0.979) for the first measurement and 0.973 (95% CI, 0.950-0.984) for the second measurement. The 95% limits of agreement on repeated measurements were 22.3-25.2% of the mean, and those between the two observers were 25.5-34.2% of the mean. ICCs for large polyps (≥ 5 mm) were significantly higher than those for small polyps (< 5 mm). There were no significant differences in the ICCs between image settings and polyp location. CONCLUSIONS: Polyp size measurements using transabdominal US are highly repeatable and reproducible. Polyp size significantly affects the reliability of measurement. Diameter changes of approximately less than 25% may fall within the measurement error; this should be considered while interpreting the change in size during follow-up US, especially for small polyps. KEY POINTS: • Gallbladder polyp size measurement using transabdominal US is highly repeatable and reproducible. • Diameter changes of approximately less than 25% should be interpreted carefully, especially in small polyps.

Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids.

OBJECTIVE: Aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify acetaldehyde in the liver, exists in both active and inactive forms in humans. Individuals with inactive ALDH2 accumulate acetaldehyde after alcohol consumption. However, how acetaldehyde affects T-cell hepatitis remains unknown. DESIGN: Wild-type (WT) and Aldh2 knockout (Aldh2-/-) mice were subjected to chronic ethanol feeding and concanavalin A (ConA)-induced T-cell hepatitis. Effects of acetaldehyde on T-cell glucose metabolism were investigated in vitro. Human subjects were recruited for binge drinking and plasma cortisol and corticosterone measurement. RESULTS: Ethanol feeding exacerbated ConA-induced hepatitis in WT mice but surprisingly attenuated it in Aldh2-/- mice despite higher acetaldehyde levels in Aldh2-/- mice. Elevation of serum cytokines and their downstream signals in the liver post-ConA injection was attenuated in ethanol-fed Aldh2-/- mice compared to WT mice. In vitro exposure to acetaldehyde inhibited ConA-induced production of several cytokines without affecting their mRNAs in mouse splenocytes. Acetaldehyde also attenuated interferon-γ production in phytohaemagglutinin-stimulated human peripheral lymphocytes. Mechanistically, acetaldehyde interfered with glucose metabolism in T cells by inhibiting aerobic glycolysis-related signal pathways. Finally, compared to WT mice, ethanol-fed Aldh2-/- mice had higher levels of serum corticosterone, a well-known factor that inhibits aerobic glycolysis. Blockade of corticosterone partially restored ConA-mediated hepatitis in ethanol-fed Aldh2-/- mice. Acute alcohol drinking elevated plasma cortisol and corticosterone levels in human subjects with higher levels in those with inactive ALDH2 than those with active ALDH2. CONCLUSIONS: ALDH2 deficiency is associated with elevated acetaldehyde and glucocorticoids post-alcohol consumption, thereby inhibiting T-cell activation and hepatitis.