Real-world evidence of efficacy of pembrolizumab plus chemotherapy and nivolumab plus ipilimumab plus chemotherapy as initial treatment for advanced non-small cell lung cancer.

BACKGROUND: For advanced non-small cell lung cancer (NSCLC), combination therapies including a PD-1 inhibitor plus chemotherapy or a PD-1 inhibitor, CTLA-4 inhibitor, and chemotherapy are standard first-line options. However, data directly comparing these regimens are lacking. This study compared the efficacy of pembrolizumab plus chemotherapy (CP) against nivolumab plus ipilimumab and chemotherapy (CNI) in a real-world setting. METHODS: In this multicenter retrospective study, we compared the efficacy and safety of CP and CNI as first-line therapies in 182 patients with stage IIIB-IV NSCLC. Primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included the response rate (RR) and safety profiles. Kaplan-Meier survival curves and Cox proportional hazards models were utilized for data analysis, adjusting for confounding factors such as age, gender, and PD-L1 expression. RESULTS: In this study, 160 patients received CP, while 22 received CNI. The CP group was associated with significantly better PFS than the CNI group (median 11.7 vs. 6.6 months, HR 0.56, p = 0.03). This PFS advantage persisted after propensity score matching to adjust for imbalances. No significant OS differences were observed. Grade 3-4 adverse events occurred comparably, but immune-related adverse events were numerically more frequent in the CNI group. CONCLUSIONS: In real-world practice, CP demonstrated superior PFS compared with CNI. These findings can inform treatment selection in advanced NSCLC.

Improved diagnostic accuracy with three lung tumor markers compared to six-marker panel.

Background: Combining multiple tumor markers increases sensitivity for lung cancer diagnosis in the cost of false positive. However, some would like to check as many as tumor markers in the fear of missing cancer. We though to propose a panel of fewer tumor markers for lung cancer diagnosis. Methods: Patients with suspected lung cancer who simultaneously underwent all six tests [carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA), squamous cell carcinoma-associated antigen (SCC), neuron-specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP), and sialyl Lewis-X antigen (SLX)] were included. Tumor markers with significant impact on the lung cancer in a logistic regression model were included in our panel. Area under the curve (AUC) was compared between our panel and the panel of all six. Results: We included 1,733 [median 72 years, 1,128 men, 605 women, 779 (45%) confirmed lung cancer]. Logistic regression analysis suggested CEA, CYFRA, and NSE were independently associated with the lung cancer diagnosis. The panel of these three tumor markers [AUC =0.656, 95% confidence interval (CI): 0.630-0.682, sensitivity 0.650, specificity 0.662] had better (P<0.001) diagnostic performance than six tumor markers (AUC =0.575, 95% CI: 0.548-0.602, sensitivity 0.829, specificity 0.321). Conclusions: Compared to applying all six markers (at least one marker above the upper limit of normal), the panel with three markers (at least one marker above the upper limit of normal) led to a better predictive value by lowering the risk of false positives.

ILD-GAP combined with the monocyte ratio could be a better prognostic prediction model than ILD-GAP in patients with interstitial lung diseases.

BACKGROUND: The ILD-GAP scoring system is known to be useful in predicting prognosis in patients with interstitial lung disease (ILD). An elevated monocyte count was associated with increased risks of IPF poor prognosis. We examined whether the ILD-GAP scoring system combined with the monocyte ratio (ILD-GAPM) is superior to the conventional ILD-GAP model in predicting ILD prognosis. METHODS: In patients with ILD treated between April 2013 and April 2017, we were retrospectively assessed the relationships between baseline clinical parameters, including age, sex, Charlson Comorbidity Index score (CCIS), ILD diagnosis, blood biomarkers, pulmonary function test results, and disease outcomes. In ILD patients were included idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), collagen vascular disease-related interstitial pneumonia (CVD-IP), chronic hypersensitivity pneumonitis (CHP), and unclassifiable ILD (UC-ILD). We also assessed the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPM models. RESULTS: A total of 179 patients (mean age, 73 years) were assessed. All of them were taken pulmonary function test, including percentage predicted diffusion capacity for carbon monoxide. ILD patients included 56 IPF cases, 112 iNSIP and CVD-IP cases, 6 CHP cases and 5 UC-ILD cases. ILD-GAPM provided a greater area under the receiver-operating characteristic curve (0.747) than ILD-GAP (0.710) for predicting 3-year ILD-related events. Furthermore, the log-rank test showed that the Kaplan-Meier curves in ILD-GAPM were significantly different by stage (P = 0.015), but not by stage in ILD-GAP (P = 0.074). CONCLUSIONS: The ILD-GAPM model may be a more accurate predictor of prognosis for ILD patients than the ILD-GAP model.

A GRU-Based Model for Detecting Common Accidents of Construction Workers.

Fall accidents in the construction industry have been studied over several decades and identified as a common hazard and the leading cause of fatalities. Inertial sensors have recently been used to detect accidents of workers in construction sites, such as falls or trips. IMU-based systems for detecting fall-related accidents have been developed and have yielded satisfactory accuracy in laboratory settings. Nevertheless, the existing systems fail to uphold consistent accuracy and produce a significant number of false alarms when deployed in real-world settings, primarily due to the intricate nature of the working environments and the behaviors of the workers. In this research, the authors redesign the aforementioned laboratory experiment to target situations that are prone to false alarms based on the feedback obtained from workers in real construction sites. In addition, a new algorithm based on recurrent neural networks was developed to reduce the frequencies of various types of false alarms. The proposed model outperforms the existing benchmark model (i.e., hierarchical threshold model) with higher sensitivities and fewer false alarms in detecting stumble (100% sensitivity vs. 40%) and fall (95% sensitivity vs. 65%) events. However, the model did not outperform the hierarchical model in detecting coma events in terms of sensitivity (70% vs. 100%), but it did generate fewer false alarms (5 false alarms vs. 13).

Serum heme oxygenase-1 as a prognostic biomarker in patients with acute exacerbation of interstitial lung disease.

Serum heme oxygenase (HO)-1 level has been reported as a clinically reliable diagnostic biomarker for acute exacerbation of interstitial lung disease (ILD); however, its utility for predicting mortality among these patients is unclear. Serum HO-1 levels of patients newly diagnosed with acute exacerbation of ILD were measured at the time of initiating steroid pulse therapy. The relationship between serum HO-1 and various other serum biomarkers, change in HRCT findings, and disease prognosis at 12 weeks after diagnosis of acute exacerbation was evaluated in 51 patients, of whom 17 (33%) had idiopathic pulmonary fibrosis (IPF). Serum HO-1 was higher in patients with acute exacerbation of IPF than in patients with acute exacerbation of other ILDs. Serum HO-1 levels were higher in patients who died within these 12 weeks than in survivors. Among age, sex, comorbidities, IPF diagnosis, HRCT findings, and blood biomarkers, serum HO-1 was a primary predictor of 12-week mortality. In 41 patients who underwent repeat HRCT, serum HO-1 was higher in patients with honeycomb progression than in those without. Serum HO-1 measurement could be useful for evaluating disease mortality and morbidity of patients with acute exacerbation of ILDs.

Whole-genome sequencing predicting phenotypic antitubercular drug resistance: meta-analysis.

BACKGROUND: For simultaneous prediction of phenotypic drug susceptibility test (pDST) for multiple anti-tuberculosis drugs, the whole genome sequencing (WGS) data can be analyzed using either catalogue-based approach, wherein one causative mutation suggests resistance, (e.g., WHO catalog) or non-catalogue-based approach using complicated algorithm (e.g., TB-profiler, machine learning). The aim was to estimate the predictive ability of WGS-based tests with pDST as the reference, and to compare the two approaches. METHODS: Following the systematic literature search, the diagnostic test accuracies for 14 drugs were pooled using a random-effect bivariate model. RESULTS: Out of 779 articles, 44 articles with 16,821 specimens for meta-analysis and 13 articles not for meta-analysis were adopted. The areas under summary receiver operating characteristic curve suggested "excellent" (0.97-1.00) for 2 drugs (isoniazid 0.975, rifampicin 0.975), "very good" (0.93-0.97) for 8 drugs (pyrazinamide 0.946, streptomycin 0.952, amikacin 0.968, kanamycin 0.963, capreomycin 0.965, para-aminosalicylic acid 0.959, levofloxacin 0.960, ofloxacin 0.958), and "good" (0.75-0.93) for 4 drugs (ethambutol 0.926, moxifloxacin 0.896, ethionamide 0.878, prothionamide 0.908). The non-catalogue-based and catalogue-based approaches had similar ability for all drugs. CONCLUSION: WGS accurately identifies isoniazid and rifampicin resistance. For most drugs, positive WGS results reliably predict pDST positive. The two approaches had similar ability.

Does a Positive Response to Transforaminal Epidural Steroid Injection Identify Patients Who Can Avoid Surgery for Two Years?

Background: Transforaminal epidural steroid injection (TFESI) is widely used to manage lumbar radiculopathy. In clinical settings, patients often undergo repeated transforaminal epidural injections with or without steroid administration. Objectives: To examine whether a positive response to TFESI at the first month, can in clinical settings, identify patients with radiculopathy who can avoid surgery for two years. Study Design/Setting. This prospective observational study was conducted at an academic medical center. Methods: Individuals aged ≥20 years who had been referred to our pain center by spine surgeons were enrolled. All patients were assessed using the Numerical Rating Scale (NRS) at baseline and 1 month after the first TFESI. Patients were divided into two groups according to the NRS decrement: the positive response (PR) group achieved a ≥2.0 decrease on the NRS 1 month after the first TFESI compared to baseline and the no response (NR) group achieved a <2.0 decrease on the NRS. The incidence rates of surgery over two years were compared between the two groups. In addition, we calculated the hazard ratio of the PR group to the NR group regarding the incidence of surgery over two years using the Cox proportional hazard model, adjusting for baseline NRS. Results: Seventy-six patients completed the two-year follow-up. In total, 8 and 68 patients had bilateral and unilateral radiculopathy, respectively. The PR and NR groups included 35 and 41 patients, respectively. The rate of surgery avoidance was 85.7% and 73.2% in the PR and NR groups, respectively. This difference was not statistically significant (p=0.26). After adjusting for baseline NRS, the hazard ratio of the PR group to the NR group regarding the incidence of surgery within two years was 0.35 (95% confidence interval: 0.11-1.11, p=0.08). Conclusion: A positive response to TFESI may not identify patients who can avoid surgery for two years.

Atezolizumab addition to platinum doublet: evaluating survival outcomes for patients with extensive disease small cell lung cancer.

BACKGROUND: The efficacy of adding atezolizumab to the platinum doublet regimen for extensive disease small cell lung cancer (ED-SCLC) remains marginally limited. METHODS: We retrospectively assessed the real-world efficacy and safety of atezolizumab in addition to carboplatin and etoposide (EP + A), versus carboplatin and etoposide (EP) alone in previously untreated ED-SCLC patients. RESULTS: From a total of 99 patients, 46 were assigned to the EP + A group, and 53 to the EP group. No significant difference was observed in progression-free survival between the groups. However, the overall survival (OS) was significantly longer in the EP + A group (20.8 vs 12.1 months; HR: 0.52; p = 0.0127). Patients older than 70 years, male, with performance status 0-1, without liver metastasis, and low levels of C-reactive protein and neutrophil-lymphocyte ratio, experienced longer OS in the EP + A group compared to the EP group. CONCLUSION: The addition of atezolizumab to the platinum doublet regimen significantly extended OS in ED-SCLC patients, particularly among certain subgroups, suggesting its potential value in personalized treatment strategies. Further investigation is warranted to validate these findings.

＜Editors' Choice＞ Comparison of clinical features between patients with acute exacerbation of idiopathic interstitial pneumonia and collagen vascular disease-associated interstitial pneumonia.

Acute exacerbation (AE) of interstitial pneumonia (IP) shows poor prognosis, due to the typical histological pattern of diffuse alveolar damage superimposed upon lung fibrosis. The previous reports comparing clinical features between AE of idiopathic interstitial pneumonias (IIPs) and those of IPs with known etiology are limited. We retrospectively compared clinical parameters including age, sex, Charlson Comorbidity Index score (CCIS), blood biomarkers at diagnosis of AE, treatment, and 3-month mortality between patients with AE of IIPs and collagen vascular disease-associated interstitial pneumonia (CVD-IP). We assessed 85 patients, comprising 66 patients with AE of IIPs (78%) and 19 patients with AE of CVD-IP (22%). The least absolute shrinkage and selection operator regression selected CCIS (hazard ratio, 1.281; 95% confidence interval, 1.055-1.556; P = 0.012) and log serum lactate dehydrogenase (LDH) (hazard ratio, 6.267; 95% confidence interval, 2.172-18.085; P < 0.001) as significant predictors of 3-month mortality among these patients. Also, the adjusted survival curves using sex, CCIS, and serum LDH showed no significant differences between these two groups. In conclusion, among AE patients, CCIS and serum LDH level may be more important prognostic factors for 3-month mortality rather than two classification of IP subtypes: IIPs and CVD-IP.

Phase II Trial of Nivolumab in Metastatic Rare Cancer with dMMR or MSI-H and Relation with Immune Phenotypic Analysis (the ROCK Trial).

PURPOSE: Mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) are positive predictive markers for immune checkpoint inhibitors. However, data on the activity of nivolumab in advanced dMMR/MSI-H rare cancers and more accurate biomarkers are worth exploring. PATIENTS AND METHODS: We conducted a multicenter phase II, open-label, single-arm clinical trial to explore the effectiveness and safety of nivolumab monotherapy in patients with advanced rare cancers with dMMR/MSI-H, in parallel with immune phenotype analysis, to explore new biomarkers. A Bayesian adaptive design was applied. Characterization of peripheral blood mononuclear cells (PBMC) was characterized by multicolor flow cytometric analysis and CyTOF using samples collected before and after the intervention. The dMMR was identified by the complete loss of MLH1/MSH2/MSH6/PMS2. RESULTS: From May 2018 to March 2021, 242 patients were screened, and 11 patients were enrolled, of whom 10 were included in the full analysis. Median follow-up was 24.7 months (interquartile range, 12.4-31.5). Objective response rate was 60% [95% confidence interval (CI), 26.2-87.8] by central assessment and 70% (95% CI, 34.8-93.3) by local investigators. Median progression-free survival was 10.1 months (95% CI, 0.9-11.1). No treatment-related adverse events of grade 3 or higher were observed. Patients with a tumor mutation burden of ≥10/Mb showed a 100% response rate (95% CI, 47.8-100). Responders had increased T-bet+ PD-1+ CD4+ T cells in PBMC compared with nonresponders (P < 0.05). CONCLUSIONS: The trial met its primary endpoint with nivolumab, demonstrating clinical benefit in advanced dMMR/MSI-H rare solid cancers. Besides, the proportion of T-bet+ PD-1+ CD4+ T-cells may serve as a novel predictive biomarker.

Adverse events induced by durvalumab and tremelimumab combination regimens: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have shown remarkable therapeutic outcomes among cancer patients. Durvalumab plus tremelimumab (DT) is under investigation as a new ICI combination therapy, and its efficacy has been reported in various types of cancer. However, the safety profile of DT remains unclear, especially considering rare adverse events (AEs). Objective: We aimed to assess the frequency of AEs associated with DT. Design: This study type is a systematic review and meta-analysis. Data Sources and Methods: Four databases were searched for articles. Randomized trials, single-arm trials, and prospective and retrospective observational studies were included. The type of cancer, previous treatment, and performance status were not questioned. Major AE indicators such as any AE and the pooled frequency of each specific AE were used as outcomes. As a subgroup analysis, we also compared cases in which DT was performed as first-line treatment with those in which it was performed as second-line or later treatment. The protocol for this systematic review was registered on the University Hospital Medical Information Network (UMIN) Center website (ID: UMIN000046751). Results: Forty-one populations including 3099 patients were selected from 30 articles. Pooled frequencies of key AE indicators are shown below: any AEs, 77.8% [95% confidence interval (CI): 67.9-87.6]; grade ⩾ 3 AEs, 29.3% (95% CI: 24.2-34.4); serious AEs, 34.9% (95% CI: 28.1-41.7); AE leading to discontinuation, 13.3% (95% CI: 9.3-17.4); treatment-related deaths, 0.98% (95% CI: 0.5-1.5). AEs with a frequency exceeding 15% are shown below: fatigue, 30.1% (95% CI: 23.8-36.3); diarrhea, 21.7% (95% CI: 17.8-25.6); pruritus 17.9% (95% CI: 14.4-21.3); decreased appetite, 17.7% (95% CI: 13.7-22.0); nausea, 15.6% (95% CI: 12.1-19.6). There were no significant differences in these pooled frequencies between subgroups. Conclusions: The incidence of any AE in DT therapy was approximately 78%, and the incidence of grade 3 or higher AEs was approximately 30%, which was independent of prior therapy.

The clinical impact of comorbidities among patients with idiopathic pulmonary fibrosis undergoing anti-fibrotic treatment: A multicenter retrospective observational study.

BACKGROUND: Among patients with idiopathic pulmonary fibrosis (IPF), few studies have investigated the clinical impact of anti-fibrotic treatment (AFT) with and without comorbidities. The aim of the study was to determine whether Charlson Comorbidity Index score (CCIS) can predict the efficacy of AFT in patients with IPF. METHODS: We retrospectively assessed data extracted from the medical records of IPF patients who received anti-fibrotic agents between 2009 and 2019. The collected data included age, sex, CCIS, pulmonary function test, high-resolution computed tomography (HRCT) pattern, gender/age/physiology (GAP) score, and 3-year IPF-related events defined as the first acute exacerbation or death within 3 years after starting AFT. RESULTS: We assessed 130 patients (median age, 74 years) who received nintedanib (n = 70) or pirfenidone (n = 60). Median duration of AFT was 425 days. Patients were categorized into high (≥ 3 points) and low (≤ 2 points) CCIS groups. There was no significant difference between the groups in terms of age, sex, duration of AFT, GAP score, or incidence of usual interstitial pneumonia pattern on HRCT except percentage predicted diffusion capacity of lung for carbon monoxide. Also, significant difference was not seen between the groups for 3-year IPF-related events (P = 0.75). Especially, in the low CCIS group but not the high CCIS group, the longer duration of AFT had better disease outcome. CONCLUSION: In the present study, we could not show any relation between CCIS and IPF disease outcomes in patients undergoing AFT, though the longer duration of AFT might be beneficial for IPF outcomes among patients with low CCIS.

Spatiotemporal expression patterns of R-spondins and their receptors, Lgrs, in the developing mouse telencephalon.

Development of the mammalian telencephalon, which is the most complex region of the central nervous system, is precisely orchestrated by many signaling molecules. Wnt signaling derived from the cortical hem, a signaling center, is crucial for telencephalic development including cortical patterning and the induction of hippocampal development. Secreted protein R-spondin (Rspo) 1-4 and their receptors, leucine-rich repeat-containing G-protein-coupled receptor (Lgr) 4-6, act as activators of Wnt signaling. Although Rspo expression in the hem during the early stages of cortical development has been reported, comparative expression analysis of Rspos and Lgr4-6 has not been performed. In this study, we examined the detailed spatiotemporal expression patterns of Rspo1-4 and Lgr4-6 in the embryonic and postnatal telencephalon to elucidate their functions. In the embryonic day (E) 10.5-14.5 telencephalon, Rspo1-3 were prominently expressed in the cortical hem. Among their receptors, Lgr4 was observed in the ventral telencephalon, and Lgr6 was highly expressed throughout the telencephalon at the same stages. This suggests that Rspo1-3 and Lgr4 initially regulate telencephalic development in restricted regions, whereas Lgr6 functions broadly. From the late embryonic stage, the expression areas of Rspo1-3 and Lgr4-6 dramatically expanded; their expression was found in the neocortex and limbic system, such as the hippocampus, amygdala, and striatum. Increased Rspo and Lgr expression from the late embryonic stages suggests broad roles of Rspo signaling in telencephalic development. Furthermore, the Lgr+ regions were located far from the Rspo+ regions, especially in the E10.5-14.5 ventral telencephalon, suggesting that Lgrs act via a Rspo-independent pathway.

Inductive effect of SORT1 on odontoblastic differentiation of human dental pulp-derived stem cells.

This study investigated the expression of sortilin 1 (SORT1) in cultured human dental pulp-derived stem cells (hDPSCs) and its role in their odontoblastic differentiation. Permanent teeth were extracted from five patients, and the dental pulp was harvested for explant culture. Fluorescence-activated cell sorting was used to analyze the outgrowth of adherent cells and cells that had migrated from the tissue margin. SORT1 expression was detected in hDPSCs simultaneously expressing the mesenchymal stem cell markers CD44 and CD90. The odontoblastic differentiation potential of SORT1-positive hDPSCs was examined via staining for alkaline phosphatase (ALP), an early odontoblastic differentiation marker. ALP staining was more intense in SORT1-positive than in SORT1-negative hDPSCs. Consistently, the expression of mRNA encoding SORT1 and p75NTR, a binding partner of SORT1, increased in SORT1-positive hDPSCs during odontoblastic differentiation. In addition, pro-nerve growth factor (NGF), a ligand for SORT1-p75NTR co-receptor, promoted ALP expression in SORT1-positive hDPSCs, and the interaction between SORT1 and p75NTR was detected using a coimmunoprecipitation assay. The function of SORT1 in odontoblastic differentiation was examined via RNA interference using shRNA targeting SORT1. ALP staining intensity in SORT1/shRNA-transfected cells was markedly lower than in control/shRNA-transfected cells. SORT1 knockdown decreased JUN phosphorylation and recruitment of phosphorylated JUN to the ALP promoter. Collectively, these results indicate that SORT1 is involved in the odontoblastic differentiation of hDPSCs through the JUN N-terminal kinases (JNK)/JUN signaling pathway and that the binding of SORT1 and p75NTR plays an important role in this process.

Correlation between pain catastrophizing in acute herpes zoster and postherpetic neuralgia: a retrospective analysis.

PURPOSE: The objective of this study was to examine the association between pain catastrophizing in acute phase herpes zoster and the development of postherpetic neuralgia. METHODS: The medical records of all patients diagnosed with herpes zoster between February 2016 and December 2021 were retrieved. Inclusion criteria were patients aged > 50 years who visited our pain center within 60 days after rash onset and reported a pain intensity of ≥ 3 in a numerical rating scale. Patients with a score of 30 or more in the pain catastrophizing scale at baseline were assigned to the catastrophizer group, and those with a score < 30 were assigned to the non-catastrophizer group. We defined patients with "postherpetic neuralgia" and "severe postherpetic neuralgia" as those with a numerical rating scale score of 3 or more and 7 or more at 3 months after baseline, respectively. RESULTS: Data of 189 patients were available for complete analysis. Age, baseline numerical rating scale, and prevalence of anxiety and depression were significantly higher in the catastrophizer than those in the non-catastrophizer group. Incidence of postherpetic neuralgia did not differ significantly between the groups (p = 0.26). Multiple logistic regression analysis showed that age, severe pain at baseline, and immunosuppressive state were the factors which were independently associated with developing postherpetic neuralgia. Severe pain at baseline was the only factor related to developing severe postherpetic neuralgia. CONCLUSION: Pain catastrophizing in the acute phase of herpes zoster may not be related to the development of postherpetic neuralgia.

Identifying highly active anti-CCR4 CAR T cells for the treatment of T-cell lymphoma.

A challenge when targeting T-cell lymphoma with chimeric antigen receptor (CAR) T-cell therapy is that target antigens are often shared between T cells and tumor cells, resulting in fratricide between CAR T cells and on-target cytotoxicity on normal T cells. CC chemokine receptor 4 (CCR4) is highly expressed in many mature T-cell malignancies, such as adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL), and has a unique expression profile in normal T cells. CCR4 is predominantly expressed by type-2 and type-17 helper T cells (Th2 and Th17) and regulatory T cells (Treg), but it is rarely expressed by other T helper (Th) subsets and CD8+ cells. Although fratricide in CAR T cells is generally thought to be detrimental to anticancer functions, in this study, we demonstrated that anti-CCR4 CAR T cells specifically depleted Th2 and Tregs, while sparing CD8+ and Th1 T cells. Moreover, fratricide increased the percentage of CAR+ T cells in the final product. CCR4-CAR T cells were characterized by high transduction efficiency, robust T-cell expansion, and rapid fratricidal depletion of CCR4-positive T cells during CAR transduction and expansion. Furthermore, mogamulizumab-based CCR4-CAR T cells induced superior antitumor efficacy and long-term remission in mice engrafted with human T-cell lymphoma cells. In summary, CCR4-depleted anti-CCR4 CAR T cells are enriched in Th1 and CD8+ T cells and exhibit high antitumor efficacy against CCR4-expressing T-cell malignancies.

Recurrent Transient Asymptomatic Pulmonary Opacity with Long-Term Afatinib: A Case Report.

Afatinib is the second generation EGFR-TKI. Recently, transient asymptomatic pulmonary opacity (TAPO) was reported in EGFR-mutation harboring NSCLC receiving osimertinib. However, TAPO related to other EGFR-TKI has not been reported. Here, we reported a case of TAPO related to afatinib in lung adenocarcinoma harboring EGFR mutation. A 64-year-old male had the diagnosis of stage IV (The 7th edition of the staging system by the Union for International Cancer Control) lung adenocarcinoma harboring EGFR del 19 mutation. He received afatinib 40 mg per day from May 2015. Partial response was achieved, though the dose was reduced to 30 mg per day due to grade 3 rash. In January 2016, CT showed ground glass opacity in the right middle lobe, which resolved spontaneously 2 weeks later. He had no symptom and laboratory findings were not remarkable. Thereafter, recurrent GGO was revealed with chest CT, but all opacity improved without any medication (i.e., corticosteroids) or stopping afatinib. Therefore, we diagnosed a series of opacity as recurrent TAPO with afatinib. TAPO could occur with EGFR-TKI other than osimertinib. Further study is needed to establish the management of new opacity suggesting TAPO under EGFR-TKI treatment.

Screening for Major Depressive Disorder Using a Wearable Ultra-Short-Term HRV Monitor and Signal Quality Indices.

To encourage potential major depressive disorder (MDD) patients to attend diagnostic sessions, we developed a novel MDD screening system based on sleep-induced autonomic nervous responses. The proposed method only requires a wristwatch device to be worn for 24 h. We evaluated heart rate variability (HRV) via wrist photoplethysmography (PPG). However, previous studies have indicated that HRV measurements obtained using wearable devices are susceptible to motion artifacts. We propose a novel method to improve screening accuracy by removing unreliable HRV data (identified on the basis of signal quality indices (SQIs) obtained by PPG sensors). The proposed algorithm enables real-time calculation of signal quality indices in the frequency domain (SQI-FD). A clinical study conducted at Maynds Tower Mental Clinic enrolled 40 MDD patients (mean age, 37.5 ± 8.8 years) diagnosed on the basis of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and 29 healthy volunteers (mean age, 31.9 ± 13.0 years). Acceleration data were used to identify sleep states, and a linear classification model was trained and tested using HRV and pulse rate data. Ten-fold cross-validation showed a sensitivity of 87.3% (80.3% without SQI-FD data) and specificity of 84.0% (73.3% without SQI-FD data). Thus, SQI-FD drastically improved sensitivity and specificity.

Regional differences in epidermal growth factor receptor-tyrosine kinase inhibitor therapy in lung cancer treatment using a national database in Japan.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are extensively used in the treatment of non-small cell lung cancer (NSCLC); hence, equal access to them is important. Therefore, this study aimed to identify regional differences in the prescription of EGFR-TKIs and the factors contributing to these differences. In this ecological study, we collected data using the National Database Open Data and the National Cancer Registry. The standardized claim ratio (SCR) was used as an indicator of the number of EGFR-TKI prescriptions. Additionally, we examined the association between SCR and various factors to identify the factors associated with this difference. The average SCR for the top three provinces was 153.4, while the average for the bottom three provinces was 61.6. Multivariate analysis used for evaluating the association of SCR with variables revealed that the number of designated cancer hospitals and radiation therapies were independent factors associated with the SCR of EGFR-TKIs. There were significant regional differences in the prescriptions of EGFR-TKIs in Japan based on the number of coordinated designated cancer hospitals and the number of patients receiving radiotherapy alone. These findings emphasize the need to implement policies to increase the number of hospitals to reduce regional differences.

Comparative Observation and Analysis of Preference Behavior Based on Three Types of Taxes and Locomotor Activity in the Goldfish, Carassius auratus.

Psychophysiological studies in vertebrates have focused on taxes as indicators of behavioral change. Actually, a considerable number of studies about anxiety-like and anti-anxiety-like behaviors involving geotaxis, scototaxis, and thigmotaxis have been conducted on fish. However, few analyses considering these behaviors based on taxes in fish have been conducted. Here, using goldfish, we measured the time spent in the bright or dark area of a horizontally long rectangular tank (HLRT), in the upper or lower area of a vertically long rectangular tank (VLRT), and in the central or edge area of a circular tank (CT), respectively, for the first 30 min and the last 30 min in a 3-h period after fish had been introduced to tanks. Dark, lower, and edge preference behaviors were observed for the first 30 min in all tanks. While dark and edge preference behaviors were maintained even for the last 30 min, the lower preference was lost. Swimming distance and the number of area crossings in each tank were also compared between the first 30 min and the last 30 min. Both decreased significantly or tended to decrease in the last 30 min in the HLRT and the CT, but no change was observed in the VLRT. These results suggest that, in goldfish, preference behavior is stable for a short time, and that environmental habituation may depend on the shape of the tank and the elapsed time.