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Study Design: Retrospective observational study.Purpose: We investigated the correlation between T2 relaxation times and clinical symptoms in patients with cervical radiculopathy caused by cervical disk herniation.Overview of Literature: There are currently no imaging modalities that can assess the affected cervical nerve roots quantitatively.Methods: A total of 14 patients with unilateral radicular symptoms and five healthy subjects were subjected to simultaneous apparent T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement signaling (SHINKEI-Quant) using a 3-Tesla magnetic resonance imaging. The Visual Analog Scale (VAS) score for neck pain and upper arm pain was used to evaluate clinical symptoms. T2 relaxation times of the cervical dorsal root ganglia of the brachial plexus were measured bilaterally from C4 to C8 in patients with radicular symptoms and from C5 to C8 in healthy controls. The T2 ratio was calculated as the affected side to unaffected side.Results: When comparing nerve roots bilaterally at each spinal level, no significant differences in T2 relaxation times were found between patients and healthy subjects. However, T2 relaxation times of nerve roots in the patients with unilateral radicular symptoms were significantly prolonged on the involved side compared with the uninvolved side (p

PURPOSE To investigate the efficacy of gefitinib as an adjuvant therapy for non–small-cell lung cancer patients with EGFR mutation. PATIENTS AND METHODS IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252 ), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non–small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS). RESULTS Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively. CONCLUSION Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial.

Immune checkpoint inhibitors can often trigger immune‐related adverse events (irAEs), such as relapse of pre‐existing interstitial pneumonia. Here, we report the case of an 88‐year‐Japanese man diagnosed with advanced lung adenocarcinoma with a high tumor proportion score of programmed death‐ligand 1. Six years earlier, he had developed organizing pneumonia (OP), a subtype of interstitial pneumonia, that was treated with steroid pulse therapy maintained with prolonged prednisolone administration. We initiated pembrolizumab as the first‐line treatment. One month after the first pembrolizumab administration, high resolution computed tomography (HRCT) of the chest demonstrated ground‐glass opacities and consolidations. We suspected pembrolizumab‐induced OP relapse, an irAE. His oxygenation was normal; therefore, we discontinued pembrolizumab without additional treatment for OP relapse. Four months after OP relapse, HRCT showed no new findings. After significant amelioration of OP, although the size of the tumor shadow remained the same on HRCT, positron emission tomography‐computed tomography demonstrated the disappearance of the standardized uptake value of the primary tumor, mediastinal lymph nodes, and pleural nodules. In conclusion, this is the first report of a dramatic, significant metabolic response after a single pembrolizumab treatment despite the relapse of pre‐existing OP in a patient with advanced lung adenocarcinoma., High resolution computed tomography findings of the chest at (a) organizing pneumonia (OP) occurrence, (b) after OP amelioration, (c) diagnosis of lung cancer, (d) relapse of OP induced by pembrolizumab treatment, and (e) after amelioration of OP relapse.

Introduction: Chronic low back pain (CLBP) is a leading cause of disability, yet there is limited high-quality evidence to identify the most suitable pharmacological therapy. The purpose of this Japanese nationwide, multicenter, prospective study was to compare the effectiveness of four representative drug therapies―acetaminophen, celecoxib, loxoprofen, and a tramadol and acetaminophen (T+A) combination drug―to establish evidence for a drug of choice for CLBP. Methods: Patients with CLBP (N=471) received one of the four treatments and were evaluated, prospectively and comprehensively, once every month for six months using a visual analog scale (VAS) for LBP, the Japanese Orthopedic Association (JOA) score, the JOA Back Pain Evaluation Questionnaire (JOABPEQ), the Roland-Morris Disability Questionnaire (RDQ), the EuroQol five-dimensions three-levels (EQ-5D-3L), and the Short Form-8 item health survey (SF-8). We conducted multivariable linear regression analyses of the four drugs at 1 and 6 months after drug allocation. Differences with P

Aims/Introduction Islets have microvessels that might develop pathological alterations similar to microangiopathy in type 2 diabetes patients. It remains unclear, however, whether the changes correlate with endocrine cell deficits or whether the presence of macroangiopathy influences the islet microvasculature in Japanese type 2 diabetes patients. In this study, we characterized changes of the islet microvessels and endocrine cells in Japanese non‐obese patients with type 2 diabetes who died of acute myocardial infarction (AMI). Materials and Methods Clinical profiles and islet pathology were examined for 35 diabetes patients who died of AMI (DM + AMI) and 13 diabetes patients who were free from AMI (DM). A total of 13 age‐matched, individuals without diabetes who died of AMI and 16 individuals without diabetes who were free from AMI were also studied. Pancreata were subjected to morphometric evaluation of islets, including microvascular alterations of immunostained sections. Results Body mass index in DM + AMI was comparable to those in DM. Compared with DM, DM + AMI showed greater glycated hemoglobin levels, higher prevalence of renal failure, hypertension, smaller β‐cell volume density and greater amyloid area. DM + AMI showed an increased microvascular area and density compared with other groups. There was a significant increase in vascular basement membrane thickness and loss of pericytes in DM and DM + AMI compared with individuals without diabetes in each group, and the extent of thickening was correlated with the amyloid area and occurrence of β‐cell loss in DM + AMI. Conclusions Islet microangiopathy was associated with augmented β‐cell loss and amyloid deposition in non‐obese Japanese type 2 diabetes patients who died of AMI., Islet microvessels are assumed to regulate function and morphology of islets. Vascular changes in islets similar to microangiopathy were evident in diabetes complicated with macroangiopathy. Islet microangiopathy was associated with β‐cell deficit in non‐obese Japanese type 2 diabetes patients.

Background An effective strategy for weight loss in patients who are overweight or obese is to reduce body fat mass while maintaining skeletal muscle mass. Adiponectin and myostatin are affected through changes in body composition due to weight loss, and examining their dynamics may contribute to strategies for maintaining skeletal muscle mass through weight loss. We aimed to examine the relationships among myostatin, adiponectin, and body composition, depending on the extent of weight loss, in patients with obesity undergoing a weight loss program. Methods We examined 66 patients with obesity (age: 46.8 ± 14.0 years, body mass index: 34.3 [31.0–38.4] kg/m2) attending a hospital weight loss program. We categorized the patients into two groups, namely an L group (those with a weight reduction of 5% from baseline). All patients underwent blood tests and were assessed for body composition, insulin resistance, adipocytokine and myokine levels, exercise tolerance, and muscle strength at baseline and post-intervention. Results Serum myostatin and adiponectin levels increased post-intervention in both groups. Body weight and %fat decreased, and the rate of lean body mass (%LBM) increased in both groups. Exercise capacity and muscle strength improved in the M group only. Change in (⊿) myostatin correlated with ⊿%fat, ⊿%LBM, and ⊿adiponectin. ⊿adiponectin (β = − 0.262, p = 0.035) was an independent predictor of ⊿myostatin. Conclusions Myostatin and adiponectin might cross-talk and regulate changes in skeletal muscle and fat mass with or without successful weight loss. These findings indicate that evaluating serum myostatin and adiponectin levels in clinical practice could be used to predict the effects of weight loss and help prevent skeletal muscle mass loss.

Objective: In recent years, there has been an increase in research on the therapeutic effects of exergaming, but there have been few studies on these types of interventions for chronic low back pain. In this study, we hypothesized that the Nintendo Ring Fit Adventure (RFA) exergame would be effective for patients with chronic low back pain, and we conducted a randomized prospective longitudinal study. Materials and Methods: Patients with chronic low back pain were included in this study. Twenty randomly selected patients (9 males and 11 females, mean age 49.3 years) were included in the RFA group, and RFA exergaming was performed once a week for 40 minutes for 8 weeks. Twenty patients (12 males and 8 females, mean age 55.60 years) served as the control group and received oral treatment for 8 weeks. Pain and psychological scores (pain self-efficacy, pain catastrophizing, and kinesiophobia) were measured and analyzed before and after 8 weeks of treatment in both groups. Results: In the RFA group, low back pain, buttock pain, and pain self-efficacy were significantly improved after 8 weeks of RFA exergaming, but there was no significant improvement in lower limb numbness, pain catastrophizing, or kinesiophobia. In the control group, no significant improvement was observed after 8 weeks of oral treatment. Conclusion: RFA exergaming increased pain self-efficacy and reduced pain in patients with chronic low back pain. Future treatment protocols should be developed to improve pain self-efficacy. Approval code: 2894, School of Medicine, Chiba University.

Healthcare workers (HCWs) are highly exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The actual coronavirus disease (COVID-19) situation, especially in regions that are less affected, has not yet been determined. This study aimed to assess the seroprevalence of SARS-CoV-2 in HCWs working in a frontline hospital in Tokyo, Japan. In this cross-sectional observational study, screening was performed on consented HCWs, including medical, nursing, and other workers, as part of a mandatory health checkup. The screening test results and clinical characteristics of the participants were recorded. The antibody seroprevalence rate among the 4147 participants screened between July 6 and August 21, 2020, was 0.34% (14/4147). There was no significant difference in the seroprevalence rate between frontline HCWs with a high exposure risk and HCWs working in other settings with a low exposure risk. Of those seropositive for SARS-CoV-2, 64% (9/14) were not aware of any symptoms and had not previously been diagnosed with COVID-19. In conclusion, this study provides insights into the extent of infection and immune status in HCWs in Japan, which has a relatively low prevalence of COVID-19. Our findings aid in formulating public health policies to control virus spread in regions with low-intensity COVID-19.

Background Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is now a standard treatment of previously untreated EGFR-mutated advanced non–small-cell lung cancer (NSCLC). However, disease progression occurs within 19 months of treatment. In the NEJ009 study, gefitinib plus carboplatin plus pemetrexed demonstrated significantly better progression-free and overall survival compared with gefitinib monotherapy. Furthermore, the Lung Oncology Group in Kyushu and North East Japan Study Group, major clinical trial groups in Japan, conducted a randomized phase II study to evaluate the efficacy and safety of second-line osimertinib plus carboplatin plus pemetrexed versus osimertinib monotherapy for patients with disease progression during first-line EGFR tyrosine kinase inhibitor therapy and the EGFR T790M resistance mutation (TAKUMI trial; trial registration no., jRCTs071180062). In the first treatment course for the initial 24 patients, no safety issues were reported in the combination arm. Thus, we have planned this phase II study to evaluate the safety and preliminary efficacy of osimertinib plus cisplatin/carboplatin plus pemetrexed therapy for patients with previously untreated EGFR-mutated NSCLC. Patients and Methods A total of 66 patients will be enrolled, because this sample size will be adequate for assessing treatment safety and efficacy. The co-primary endpoints include safety and the objective response rate, and the secondary endpoints include the complete response rate, disease control rate, and progression-free survival. Conclusions This is the first study to explore the efficacy and safety of osimertinib combined with platinum-based chemotherapy in previously untreated NSCLC patients with EGFR-sensitizing mutations. Our findings could provide valuable information for phase III studies such as FLAURA2 and for developing treatment strategies for EGFR-mutated NSCLC.

Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by multiple thin-walled pulmonary cysts. The currently proposed diagnostic algorithm emphasizes the characteristic cystic appearance on high-resolution computed tomography (HRCT) so uncommon HRCT appearances present challenges to establishing the proper LAM diagnosis. The objective of this study is to accrue uncommon chest HRCT appearances, determine frequencies in both tuberous sclerosis complex (TSC)-associated LAM (TSC-LAM) and sporadic LAM (S-LAM) patients. 311 females referred to our hospital, including 272 S-LAM patients (mean age 39.2 years) and 39 TSC-LAM patients (mean age 38.3 years), were retrospectively evaluated. We found 2 types of radiologic findings likely to make HRCT cyst appearance atypical: characteristics of the cyst itself and uncommon findings in addition to cysts. We found that approximately 80% of LAM patients, whether TSC-associated or sporadic, showed typical HRCT appearance with mild to severe cystic destruction. The remaining 20% displayed unusual profiles in cyst appearance as well as additional findings aside from cyst: the former includes large cyst, thickened walls, and irregularly shaped whereas the latter includes ground glass attenuation and diffuse noncalcified nodules. It is important to be aware of various radiologic findings that make HRCT cystic appearance atypical of LAM.

Background Although Japanese radish (Raphanus sativus L.) is a common Japanese ingredient, there are few reports of IgE-mediated immediate food allergy caused by Japanese radish. Case presentation A 48-year-old woman developed urticarial lesions on her hands after grating Japanese radish and also developed lip edema and oral itching when she ate a salad composed of raw Japanese radishes. Skin prick testing was positive to extract of grated Japanese radish. Moreover, immunoblotting analysis showed IgE reactivity in the patient’s serum to a single band at the 18 kDa in grated Japanese radish, suggesting that the heat-labile 18 kDa protein of raw Japanese radish may be a radish-specific antigen. Conclusions To the best of our knowledge, this is the first case report of a patient with hand urticaria, lip angioedema, and oropharyngeal pruritus to raw Japanese radish through IgE-mediated immediate allergic reaction.

Background Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. Methods In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. Results The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. Conclusions ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.

Background Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab. Methods In this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1-21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state. Results Seventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naive patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation. Conclusions Afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated.

Motoyasu Kato,1 Shinichi Sasaki,1,2 Misa Tateyama,1 Yuta Arai,1 Hiroaki Motomura,1 Issei Sumiyoshi,1 Yusuke Ochi,1 Junko Watanabe,1 Hiroaki Ihara,1 Shinsaku Togo,1 Kazuhisa Takahashi1 1Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; 2Department of Respiratory Medicine, Juntendo University Urayasu Hospital, Urayasu, Chiba, JapanCorrespondence: Motoyasu KatoDepartment of Respiratory Medicine, Juntendo University, Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-Ku, Tokyo 113-8431, JapanTel +81-3-5802-1063Fax +81-3-5802-1617Email mtkatou@juntendo.ac.jpPurpose: The INPULSIS-ON study suggested the safety and tolerability of long-term nintedanib treatment for idiopathic pulmonary fibrosis (IPF). However, there are no real-world studies on long-term nintedanib treatment. The main aim of the study was to investigate the efficacy and the tolerability of long-term treatment with nintedanib for IPF in clinical practice.Patients and Methods: This retrospective study enrolled 104 IPF patients who underwent treatment with nintedanib. Among these patients, 51 were able to receive nintedanib for more than 12 months (ie, treatment with nintedanib over 12 months was possible [P group]) and 53 were not able to receive nintedanib for more than 12 months (ie, treatment with nintedanib over 12 months was impossible [I group]). The tolerability and efficacy of nintedanib were compared between the two groups.Results: In the I group, 29 patients were unable to continue nintedanib therapy because of adverse effects, including diarrhea and nausea/anorexia. In addition, 19 and four patients could not continue nintedanib treatment because of IPF progression and worsening of performance status (PS), respectively. One patient suddenly died during nintedanib treatment. The incidence of nausea/anorexia in the I group was significantly higher than in the P group (49.06 vs 25.49%). The survival time was significantly longer in the P group than in the I group (35 vs 12 months). The decline in forced vital capacity was significantly larger in the I group than in the P group (165 vs 10 mL/year). Poor PS at nintedanib initiation was the only significant risk factor for nintedanib treatment discontinuation over 12 months. Finally, the survival time was significantly longer in patients with good PS than in those with poor PS (27 vs 13 months).Conclusion: Poor PS can result in discontinuation of nintedanib after 12 months. Long-term nintedanib treatment may be effective for survival.Keywords: idiopathic pulmonary fibrosis, nintedanib, real-world setting, performance status, nausea

Background Thymic malignancies are a model of rare cancer. However, little clinical data is available based on the large database. We aimed to clarify the prognostic factors, particularly the metastatic sites, for thymic malignancies using one of the largest, representative, multi-institutional databases, the NEJ023 database. Patients and Methods Patients with Stage IVA/IVB or recurrent thymic carcinoma were enrolled between 1995 and 2014. Clinicopathologic information was evaluated, and the patients were subdivided according to the metastatic organs of involvement (serosal dissemination, liver, lymph node, pulmonary, and bone metastasis). A Kaplan-Meier analysis and multivariate Cox regression were used to evaluate survival. Results Two hundred and seventy-nine patients with metastases and a predominantly squamous histology (66.7%) were included. Most patients (53.0%) had serosal dissemination, whereas 26.5%, 21.9%, 19.7%, and 15.8% had pulmonary, lymph node, bone and liver metastases, respectively. Over a median follow-up time of 21.5 months, the median overall survival (mOS) was 30.7 months. When the subjects were grouped according to involved metastatic sites, patients with more than 3 involved metastatic organs had the worst survival outcome. Among patients with isolated involvement, those with bone metastasis had the poorest survival, followed by patients with liver metastasis. Subjects with hypoalbuminemia also had poor survival outcomes. When patients treated with platinum and anthracycline-containing pharmacotherapy were compared with those treated with platinum and non-anthracycline-containing pharmacotherapy, no significant difference was observed. Bone metastasis (P = 0.0005), liver metastasis (P = 0.047), and hypoalbuminemia (P = 0.0021) were identified as prognostic factors in a multivariate analysis. Conclusion The site of metastatic involvement affects the survival outcomes of patients with thymic carcinoma, and this result may reflect the sensitivity of metastatic sites to pharmacotherapy. As a next step, controlling liver metastasis with pharmacotherapy could help to improve the prognosis of patients with thymic carcinoma.

Objectives Most patients with small-cell lung cancer (SCLC) experience relapse because of the emergence of drug-resistant tumor cells. Therefore, second-line therapy is subsequently required to prolong their survival. However, it is unclear whether second-line chemotherapy can provide a survival benefit to elderly patients with relapsed SCLC. Therefore, this study aimed to evaluate survival and identify prognostic factors in an elderly population. Materials and methods Based on a nationwide registry database of patients with SCLC (the Japanese Joint Committee of Lung Cancer Registry), we retrospectively reviewed medical records of patients aged ≥ 75 years with relapsed SCLC who subsequently received second-line chemotherapy. Survival time since the initiation of second-line chemotherapy was evaluated. Results Among 731 patients aged ≥ 75 years with SCLC who were accumulated by the nationwide registry database, this study included 228 patients, comprising 190 men and 38 women with a median age of 78 years. The number of patients with performance status (PS) of 0−1 and 2−4 was 196 and 32, respectively. The overall survival (OS) and 1-year survival rates were 7.5 months and 24 %, respectively. A multivariate analysis identified PS, clinical stage at the time of starting first-line therapy, and the interval from the start of first-line therapy to that of second-line therapy as independent prognostic factors. Conclusion This study with the nationwide registry database showed that among the relapsed elderly SCLC patients who received second-line chemotherapy, a substantial OS may be expected in patients with good PS, at an early clinical stage at the time of starting first-line therapy, and with a longer interval from the start of first-line therapy to that of second-line chemotherapy.

Introduction: Chronic low back pain (CLBP) is a major health burden worldwide and requires patient satisfaction with treatment. Consultation length can be an important factor in patient satisfaction, but few studies have investigated the impact of consultation length on satisfaction in patients with CLBP. This study tried to elucidate the impact of consultation length on clinical outcomes in patients with CLBP. Methods: This study is part of an analysis using the database of the nationwide, multicenter cohort for CLBP performed by the Project Committee of the Japanese Society for Spine Surgery and Related Research. A total of 427 patients aged 20-85 years (median age, 73.0 years; female, 58.6%) with CLBP were prospectively followed-up monthly for 6 months. Multivariable nonlinear regression analyses were performed to assess the effect of consultation length on outcome measures including subjective satisfaction score, EuroQol 5-dimension, Japanese Orthopaedic Association (JOA) score, Roland-Morris Disability Questionnaire, JOA Back Pain Evaluation Questionnaire, visual analog scale (VAS) and Medical Outcome Survey short-form 8-item health survey that evaluated at the next phase. Furthermore, we assessed whether the effect of consultation length on patient satisfaction was modified by the baseline Brief Scale for Psychiatric Problems in Orthopaedic Patients (BS-POP) score for patient and physician versions. Results: VAS for CLBP was the only score that correlated significantly with consultation length (P = 0.018). Satisfaction score showed a significant positive correlation with consultation length in patients with the highest baseline BS-POP scores (P < 0.2). Moreover, consultation lengths more than 7.6 min and 15.1 min offered increase of satisfaction if patients show the highest BS-POP scores on patient and physician versions, respectively. Conclusions: These findings suggest that a sufficiently long consultation is an important factor for subjective satisfaction in the patients with CLBP, particularly in patients with psychological problems.

This study provides the benchmark statistics on medically treated patients with non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in Japan. Demographic background, treatment, and prognosis were obtained from patients with lung cancer pathologically diagnosed in 2012, who received nonsurgical treatment. Descriptive statistics and their associations with survival were analyzed. In total, 12 320 patients were registered from 314 institutions in Japan. The median age was 70 years, and 73% of the patients were male. The number (%) of stages I, II, III, and IV diseases were 468 (3.8%), 421 (3.4%), 3260 (26.5%), and 8171 (66.3%), respectively. NSCLC and SCLC accounted for 9872 (80.1%) and 2353 (19.1%) patients, respectively. Thoracic radiotherapy‐based therapy, chemotherapy, and palliative care alone were administered to 2572 (20.9%), 7790 (63.2%), and 1952 (15.8%) patients, respectively. Clinical TNM stage was one of the strongest prognostic factors with the 3‐year survival rates of 62.9%, 47.3%, 40.0%, 27.8%, 37.5%, 26.5%, and 18.2% for stages IA, IB, IIA, IIB, IIIA, IIIB, and IV, respectively. Among 6158 patients with NSCLC treated with chemotherapy, the 3‐year survival rate was 33.4% in patients receiving epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) at some point in their clinical course, whereas it was 17.4% in patients who did not. The 3‐year survival rate of SCLC was only 15.9%. In conclusion, approximately two‐thirds of the patients were diagnosed as stage IV at the initial diagnosis. Use of EGFR‐TKIs significantly improved the survival of patients with NSCLC., This study provides the benchmark statistics on medically treated patients with lung cancer in Japan. Here, 3‐year survival rates of patients treated with concurrent chemoradiotherapy (n = 1689), sequential chemoradiotherapy (n = 221), thoracic radiotherapy alone (n = 662), chemotherapy alone (n = 7790) and palliative care alone (n = 1952) were 43.6%, 29.1%, 40.0%, 19.9%, and 0.3.4%, respectively.

The anti-programmed cell death-1 protein monoclonal antibody, pembrolizumab is an immune checkpoint inhibitor. While it improves the prognoses of patients with advanced non-small-cell lung cancer, it has been reported to induce various kinds of immune-related adverse events, including hepatotoxicity. Despite the frequency of hepatotoxicity, there is only limited information available regarding the pathophysiology and treatment. We herein report a 48-year-old man with lung adenocarcinoma who was treated with pembrolizumab and developed cholestatic liver injury. In this case, the importance of evaluating the histology of hepatotoxicity and the effectiveness of ursodeoxycholic acid for cholestatic liver injury is indicated.

Background Immunodeficient patients are recommended to receive pneumococcal vaccination. However, there is limited evidence showing effectiveness of the polysaccharide vaccine. Polysaccharide vaccination has shown an association with cardiovascular event risk reduction. We assessed the efficacy of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in relation to the risk of hospitalization and death due to pneumonia and acute cardiac events. Methods The medical records of all dialysis patients attending our 8 study centers in 2010 were studied, and we selected 1038 consecutive patients. One-to-one propensity score matching was used to correct for potential selection bias in a PPSV23-vaccinated group versus a non-vaccinated group, and a total of 510 patients were identified for outcome analysis. Time to first admission, or deaths due to all-cause pneumonia or cardiac events until 2015 were compared between both groups. Results The all-cause death rate was significantly decreased in the PPSV23-vaccinated group, (hazard ratio [HR] 0.62, 95% confidence interval [CI]; 0.46–0.83, P = 0.002). All-cause death was considered to be a competing risk for the other outcomes. Further outcomes were evaluated by competing risk analysis adjusting for mortality. There was no statistically significant difference in the hospitalization rate for pneumonia; however, the hospitalization rate due to cardiac events was significantly lower in the PPSV23-vaccinated group than in the non-vaccinated group (HR 0.44, 95% CI; 0.20–0.96, P = 0.040). There was no statistically significant difference in the death rate due to pneumonia; however, the rate of cardiac death was significantly lower in the PPSV23-vaccinated group than in the non-vaccinated group (HR 0.36, 95% CI; 0.18–0.71, P = 0.003). Conclusions The PPSV23 vaccination is associated with a good prognosis and a low-risk of cardiac events in dialysis patients; however, there was no evidence indicating enhanced protective efficacy against pneumonia, suggesting the PPSV23 vaccination might improve the prognosis by directly preventing cardiovascular events.

Background Local ablative therapy (LAT) may be beneficial for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with oligo-residual disease after treatment with EGFR tyrosine kinase inhibitor (EGFR-TKI). However, this has not been fully established. This study aimed to evaluate the predominant progressive disease (PD) pattern limited to residual sites of disease after treatment with EGFR-TKI. Methods Patients with advanced EGFR-mutated NSCLC treated with EGFR-TKIs as first-line therapy were retrospectively analysed during a 7-year period. Oligo-residual disease was defined as the presence of 1 – 4 lesions (including the primary site) at 3 months from the start of EGFR-TKI treatment. The predictive factors of PD patterns after EGFR-TKI treatment were evaluated. Results A total of 207 patients were included. Three months after the start of EGFR-TKI treatment, 66 patients (32%) had oligo-residual disease. A total of 191 patients had PD, 60 with oligo-residual disease and 131 with non-oligo-residual disease. Regarding the pattern, 44 patients (73%) with oligo-residual disease and 37 patients (28%) with non-oligo-residual disease had PD limited to the residual sites. Multivariate logistic regression analysis at 3 months from the start of EGFR-TKI treatment revealed that oligo-residual disease (P P = 0.032), and initial treatment with osimertinib (P = 0.028) were independent predictors of PD limited to residual disease sites. Conclusions This study provided a rationale for LAT to all sites of residual disease in patients with oligo-residual disease during EGFR-TKI treatment.

PurposeProgrammed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors plus chemotherapy has become the standard first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). However, few studies have explicitly focused on the impact of cancer cachexia on the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy. Thus, we evaluated the clinical implications of cancer cachexia on the survival outcomes in patients who received this treatment.MethodsWe conducted a retrospective review of medical records of patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors plus chemotherapy from December 2018 to December 2020. Cancer cachexia was diagnosed as an unintentional weight loss of 5% or more over six months. We evaluated the progression-free survival (PFS) and overall survival (OS) for patients with or without cancer cachexia who received PD-1/PD-L1 inhibitors plus chemotherapy.ResultsAmong the 80 included patients, 37 (46%) had cancer cachexia. Cachectic patients had a lower objective response rate (30 vs 51%, P P P

Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors plus chemotherapy have become the standard first line of treatment in patients with advanced non-small-cell lung cancer (NSCLC). However, few studies have explicitly focused on the impact of weight loss on the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy. Thus, we evaluated the clinical implications of weight loss on the survival outcomes in patients who received this treatment. We conducted a retrospective review of medical records of patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors plus chemotherapy from December 2018 to December 2020. Significant weight loss was defined as an unintentional weight loss of 5% or more over 6 months. We evaluated the progression-free survival (PFS) and overall survival (OS) of patients with or without weight loss. Among the 80 included patients, 37 (46%) had weight loss, and were associated with a lower objective response rate (30 vs 51%, P

Background The adeno-associated virus (AAV) vector is a promising vector for ocular gene therapy. Surgical internal limiting membrane peeling before AAV vector administration is useful for efficient retinal transduction. However, no report has investigated localization of AAV vectors after administration into a post-vitrectomy eye. This study investigated the effects of vitrectomy surgery on intravitreal-injected AAV vector-mediated gene expression in the anterior segment and examined the presence of neutralizing antibodies (NAbs) in serum before and after AAV vector administration. Methods Of six eyes from three female cynomolgus monkeys, four were vitrectomized (Group VIT) and two were non-vitrectomized (Group IV). All eyes were injected with 50 μL of triple-mutated self-complementary AAV2 vector (1.9 × 1013 v.g./mL) encoding green fluorescent protein (GFP). NAbs in the serum were examined before administration and at 2 and 6 weeks after administration. GFP expression was analyzed at 19 weeks after administration. Results Immunohistological analysis showed no GFP expression in the trabecular meshwork in any eye. The GFP genome copy in two slices of the anterior segment was 2.417 (vector genome copies/diploid genome) in Group VIT and 4.316 (vector genome copies/diploid genome) in group IV. The NAb titer was 1:15.9 (geometric mean) before administration, 1:310.7 at 2 weeks after administration, and 1:669.4 at 6 weeks after administration. Conclusion Previous vitrectomy surgery did not affect gene expression in the anterior segment after intravitreal injection of AAV vectors.

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

Objectives: In EGFR-mutated non-small cell lung cancer (NSCLC) patients, approximately 80–90% of leptomeningeal metastasis (LM) develops after failed initial epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) treatment. However, the efficacy of rechallenging previously administered EGFR-TKIs in patients with EGFR-mutated NSCLC and LM that develops after EGFR-TKI treatment failure remains unknown.Materials and Methods: We retrospectively reviewed the medical records of patients with EGFR-mutated NSCLC and LM from November 2011 to August 2019. Patients were classified into two groups according to LM treatment type: switched to previously unadministered EGFR-TKIs (Switch-TKI) and rechallenge with previously administered EGFR-TKIs (Rechallenge-TKI).Results: In total, 50 patients treated with EGFR-TKI after LM diagnosis were included; 35 were treated with Switch-TKI, and 15 with Rechallenge-TKI. The median overall survival (OS) from the time of LM diagnosis was 6.2 months in all study patients. According to the treatment type, the median OS from the time of LM diagnosis was 6.9 months in Switch-TKI patients and 4.9 months in Rechallenge-TKI patients. There was no significant difference in the OS between the Switch-TKI and Rechallenge-TKI groups (P = 0.864). Thirty-five patients were treated with erlotinib and 15 with osimertinib; Regardless of the type for EGFR-TKI, there was no significant difference in OS between patients treated with Switch-TKI and those treated with Rechallenge-TKI. Conclusion: Our findings suggest that rechallenge of previously administered EGFR-TKIs may be a therapeutic option for LM development after EGFR-TKI treatment failure in patients with EGFR-mutated NSCLC, not only switching to previously unadministered EGFR-TKIs.

Nausea and diarrhea are the most common adverse effects of nintedanib in patients with idiopathic pulmonary fibrosis (IPF). However, the clinical risk factors for these side effects remain unknown. In the present study, we investigated the characteristics of patients who developed gastrointestinal side effects during nintedanib treatment for IPF and determined the risk factors for these side effects. We enrolled 77 patients with IPF who received nintedanib between October 2015 and March 2018. Performance status (PS) as a patient’s general condition, body mass index (BMI), modified Medical Research Council Dyspnea Scale score, severity of IPF at nintedanib initiation, and gastrointestinal toxicity of nintedanib were evaluated. In total, 25 and 27 patients exhibited nausea and diarrhea, respectively, during the follow-up period. A poor PS, low BMI, and full dosage of nintedanib at treatment initiation were risk factors for nausea. A low BMI was a significant risk factor for diarrhea, which could be prevented by combination treatment with nintedanib and prednisolone. In addition, the mean annual rate of decline in forced vital capacity was significantly greater in patients with nausea than in patients without nausea. In conclusion, our findings suggest that patients with a low BMI and/or poor PS and those who receive the full nintedanib dosage at treatment initiation are more susceptible to gastrointestinal adverse effects during nintedanib treatment. Addition of prednisolone to the treatment regimen may prevent the development of diarrhea during treatment.

Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.

A basic study using a rodent model of sarcopenia.To elucidate the contribution of oxidative stress to muscle degeneration and the efficacy of antioxidant treatment for sarcopenia using an animal model of neurogenic sarcopenia.Oxidative stress has been reported to be involved in a number of pathologies, including musculoskeletal disorders. Its relationship with sarcopenia, one of the potential origins of lower back pain, however, is not yet fully understood.Myoblast cell lines (C2C12) were treated with H2O2, an oxidative stress inducer, and N-acetyl-L-cysteine (NAC), an antioxidant. Apoptotic effects induced by oxidative stress and the antioxidant effects of NAC were assessed by western blotting, immunocytochemistry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assays. An animal model of sarcopenia was produced via axotomy of the sciatic nerves to induce muscle atrophy. Twenty-four male Sprague-Dawley rats were divided into sham, sham+NAC, axotomy, and axotomy+NAC groups. Rats were provided water only or water containing NAC (1 g/L) for 4 weeks. The gastrocnemius muscle was isolated and stained with hematoxylin and eosin (HE) 2 weeks after axotomy, from which muscle cells were harvested and protein extracted for evaluation.Mitogen-activated protein kinases (MAPKs) were significantly activated by H2O2 treatment in C2C12 cells, which was ameliorated by NAC pretreatment. Furthermore, H2O2 induced apoptosis and death of C2C12 cells, which was prevented by NAC pretreatment. The weight of the gastrocnemius muscle was reduced in the axotomy group, which was prevented by NAC administration. Lastly, although muscle specimens from the axotomy group showed greater reductions in muscle fiber, the oral administration of NAC significantly inhibited amyotrophy via antioxidant effects.The current in vitro and in vivo study demonstrated the possible involvement of oxidative stress in sarcopenic pathology. NAC represents a potential anti-sarcopenic drug candidate, preventing amyotrophy and fatty degeneration.4.

In patients with overlap syndrome (OVS), the pathophysiologies of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease can interact with one another. Focusing on low arousal threshold, the authors evaluated polysomnographic features of OVS patients. This retrospective, multicenter study was conducted at three hospitals in Japan. Patients aged ≥ 60 years who underwent polysomnography and pulmonary function testing were reviewed. Severity of airflow limitation (AFL) was classified according to the Global Initiative for Chronic Obstructive Lung Disease criteria. Low arousal threshold was predicted based on the following polysomnography features: lower apnea-hypopnea index (AHI); higher nadir oxygen saturation, and larger hypopnea fraction of total respiratory events. These features were compared among patients with only OSA (n = 126), OVS with mild AFL (n = 16), and OVS with moderate/severe AFL (n = 22). A low arousal threshold was more frequently exhibited by OVS patients with moderate/severe AFL than by those with OSA only (p = 0.016) and OVS with mild AFL (p = 0.026). As forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) decreased in OVS patients, the mean length of apnea decreased (r = 0.388, p = 0.016), hypopnea fractions increased (r = − 0.337, p = 0.039), and AHI decreased (r = 0.424, p = 0.008). FEV1/FVC contributed to low arousal threshold independent of age, sex, smoking history, hospital, or body mass index in all subjects (OR 0.946 [95% CI 0.909–0.984]) and in OVS patients (OR 0.799 [95% CI 0.679–0.940]). This study first described peculiar polysomnographic features in OVS patients with moderate/severe AFL, suggesting a high prevalence of low arousal threshold.

Introduction: To investigate the risk of epidural hematoma after spinous process-splitting laminectomy (SPSL). Methods: A total of 137 cases (mean age, 72.4 years; 68 men) of SPSL were included. Of these, there were instances (3.7%; mean age, 70.5 years; all male) of postoperative development of new neurologic deficit due to epidural hematoma requiring reoperation. The 133 subjects (72.5 years; 64 men) with normal postoperative course were used as controls, and comparisons were made between both groups using chi-squared and Student's t-tests. Regarding our investigation of risk factors for epidural hematoma, logistic regression was conducted with presence or absence of hematoma as our primary outcome variable, and age, gender, disease duration, number of laminectomies, which levels were decompressed, blood loss, length of case, drain output, coagulopathy, and whether or not there was an intraoperative dural tear were our explanatory variables. Results: All cases of hematoma were single-level laminectomies; there was one case of T9-10 and 3 cases of L2-3. In our direct comparison of both groups (hematoma versus control), the proportion of men was significantly higher in the hematoma group (100% versus 48%, p < 0.05); levels decompressed were also significantly higher (p < 0.05) in the hematoma group, and drain outputs were significantly lower (113 mL versus 234 mL, p < 0.05). From our logistic regression analysis, the levels were significantly higher (χ2 = 15, p = 0.0001) and the drain outputs were smaller (χ2 = 4.6, p = 0.03) in the hematoma group. Conclusions: Single-level decompression higher than the L2-3 level and reduced drain output were risk factors for spinal epidural hematoma. With this method of spinous process suturing and reconstruction there is less decompression compared with more conventional methods; therefore, the effect of hematoma may be more pronounced at higher vertebral levels with reduced canal width, and drain failure may also occur with this limited space.

Background Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. Methods This was a multicenter, open-label trial in Japanese adults aged ≥20 years with AATD. Samples for evaluation of serum alpha1-PI concentration and PK parameters were collected at 10 time points until the seventh day after the last dose at Week 8: immediately before dosing, immediately after dosing (time 0), and 0.25, 2, 4, 8, 24, 48, 120, and 168 hours after dosing. Results Four subjects were analyzed. The median tmax was 0.534 h. Mean ± SD values for t½, Cmax, and AUC0–7days were 150.4 ± 36.18 h, 174.2 ± 30.51 mg/dL, and 14,913.2 ± 1633.45 mg*h/dL, respectively. Mean trough concentration at week 8 was 55.4 ± 7.23 mg/dL. Alpha-1 MP therapy was safe, with no serious adverse events or deaths reported. Two treatment-emergent adverse events of fatigue in one subject were considered to be possibly related. Conclusions The PK and safety of Alpha-1 MP in Japanese subjects with AATD were consistent with the Alpha-1 MP profile in non-Japanese subjects (ClinicalTrials.gov: NCT02870309; JAPIC CTI: JapicCTI-163160).

In sleep apnea syndrome (SAS), chronic intermittent hypoxia (CIH) is believed to activate the sympathetic nerve system, and is thus involved in cardiovascular diseases (CVD). However, since patients with SAS are often already obese, and have diabetes and/or hypertension (HT), the effects of CIH alone on sympathetic nerve activation and its impacts on CVD are largely unknown. We, therefore, examined the effects of CIH on sympathetic nerve activation in non-obese mice to determine whether renal sympathetic nerve denervation (RD) could ameliorate CIH-mediated cardiovascular effects. Male C57BL/6 (WT) mice were exposed to normal (FiO2 21%) or CIH (10% O2, 12 times/h, 8 h/day) conditions for 4 weeks with or without RD treatment. Increased urinary norepinephrine (NE), 8-OHdG, and angiotensinogen levels and elevated serum asymmetric dimethyl arginine levels were observed in the CIH model. Concomitant with these changes, blood pressure levels were significantly elevated by CIH treatment. However, these deleterious effects by CIH were completely blocked by RD treatment. The present study demonstrated that CIH-mediated renal sympathetic nerve activation is involved in increased systemic oxidative stress, endothelial dysfunction, and renin-angiotensin system activation, thereby contributing to the development of HT and CVD, thus could be an important therapeutic target in patients with SAS.

Key Clinical Message The incidence of spinal fusion surgery and associated adjacent segment disease (ASD) is steadily increasing. We report three cases of ASD after posterior fixation, treated by oblique lateral interbody fusion (OLIF). All cases had a good postoperative course. Altogether, OLIF surgery may be a viable option for treating ASD.

Background Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease that causes an obstructive ventilatory impairment similar to chronic obstructive pulmonary disease (COPD) and impairs the health-related quality of life (HRQoL). Here, we extended the use of the COPD assessment test (CAT) to patients with chronic respiratory diseases other than COPD. Specifically, the CAT was administered to patients with LAM for the first time. Methods Using data from 25 patients with LAM at Juntendo University who participated in the Multicenter Lymphangioleiomyomatosis Sirolimus Trial for Safety (MLSTS), we evaluated changes in pulmonary function, responses to HRQoL questionnaires (the CAT, St. George׳s Respiratory Questionnaire [SGRQ], EuroQOL Visual Analogue Scale [EuroQOL-VAS], and Functional Performance Inventory [FPI]), and the association between pulmonary function and HRQoL during a 24-month period of sirolimus treatment. Results Forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC), and CAT total scores improved over the 24 months of sirolimus treatment (5.33 ± 1.20 ml/month, 2.61 ± 1.16 ml/month, and −0.127 ± 0.022 score/month, respectively), whereas SGRQ total score, EuroQOL-VAS score, and FPI score did not. Most pulmonary functions at baseline were associated with the CAT breathlessness score during the first year. Longitudinal changes in FEV 1 , FEV 1% predicted, or FEV 1 /FVC correlated significantly with the scores of CAT total, CAT breathlessness, and SGRQ activity. When analyzed by stepwise multivariate regression within a linear mixed-effects model, CAT breathlessness and confidence scores were significantly associated with a change in FEV 1 from the baseline value ( P = 0.0011, and P = 0.0441). Conclusion Our results suggest that the CAT is a useful instrument for assessing HRQoL in sirolimus-treated patients with LAM.

Introduction: Thus far, few reports have described the time series histological variations in injured paravertebral muscle tissues for long durations, considering the type of pain. The purpose of this study is to evaluate histological changes in injured paravertebral muscles and dominant nerves considering the type of pain. Methods: We used 59 eight-week-old male Sprague-Dawley rats. A 115-g weight was dropped from a height of 1 m on the right paravertebral muscle. Fluoro-Gold (FG), a sensory nerve tracer, was injected into this muscle. Hematoxylin and eosin (HE) staining and nerve growth factor (NGF) immunostaining of the muscle were performed for histological evaluation. L2 dorsal root ganglia (DRG) on both sides were resected, and immunohistochemical staining was performed for calcitonin gene-related peptide (CGRP, a pain-related neuropeptide) and for activating transcription factor 3 (ATF3, a neuron injury marker). Each examination was performed at 3 days, 1-3 weeks, and 6 weeks after injury. Results: HE staining of the paravertebral muscle indicated infiltration of inflammatory cells and the presence of granulation tissue in the injured part on the ipsilateral side at 3 days and 1 week after the injury. Fibroblasts and adipocytes were present at 2-3 weeks. At 6 weeks, the injured tissue was almost completely repaired. NGF was detected at 2-3 weeks post injury and appeared to colocalize with fibroblasts, but was not observed at 6 weeks post injury. The percentage of cells double-labeled with FG and CGRP in FG-positive cells of the primary muscle was significantly higher in the injured side at 3 days and 1-3 weeks post injury (P < 0.05). However, at 6 weeks, no significant difference was observed. No significant expression of ATF3 was observed. Conclusions: These results suggest that sensitization of the dominant nerve in the DRG, in which NGF may play an important role, can protract pain in injured muscles.

Cancer cachexia is a multifactorial syndrome characterized by weight loss leading to immune dysfunction that is commonly observed in patients with advanced non-small cell lung cancer (NSCLC). We examined the impact of cachexia on the prognosis of patients with advanced NSCLC receiving pembrolizumab and evaluated whether the pathogenesis of cancer cachexia affects the clinical outcome. Consecutive patients with advanced NSCLC treated with pembrolizumab were retrospectively enrolled in the study. Serum levels of pro-inflammatory cytokines and appetite-related hormones, which are related to the pathogenesis of cancer cachexia, were analyzed. Cancer cachexia was defined as (1) a body weight loss > 5% over the past 6 months, or (2) a body weight loss > 2% in patients with a body mass index

BackgroundAcute exacerbation of chronic fibrosing idiopathic interstitial pneumonias (AE-IIPs) is known to be associated with a poor prognosis. In Japan, polymyxin B-immobilized fiber column-direct hemoperfusion (PMX-DHP) therapy is often used along with corticosteroids for the treatment of patients with AE-IIPs. However, the serum marker that predicts treatment response to PMX-DHP is still unknown. Our aim was to evaluate the serum marker that predicts the outcome in patients with AE-IIPs undergoing PMX-DHP therapy.MethodsWe retrospectively collected the medical records of 104 patients who developed AE-IIPs for the first time and visited Juntendo University Hospital between April 2009 and July 2020. Among these patients, 33 patients who received PMX-DHP were identified. Among the patients who received PMX-DHP, 18 patients who survived for over 30 days since the initiation of PMX-DHP therapy were classified into the “survival group,” and 15 patients who succumbed to the condition in less than 30 days were categorized into the “non-survival group.” We evaluated data on the patients’ background, survival, and differences in the serum markers associated with AE-IIPs and in oxygenation markers between the groups.ResultsAmong patient characteristics, median forced vital capacity was significantly higher in the survival group than in the non-survival group. Among serum markers, 7 days after the initiation of PMX-DHP therapy, serum lactate dehydrogenase (LDH) levels, white blood cell counts, and D-dimer levels were significantly higher and serum lymphocyte count was significantly lower in the non-survival group than in the survival group. PaO2/FiO2 ratio (P/F ratio) and alveolar-arterial oxygen difference (Aa-DO2) were significantly different between the two groups. The changes in LDH level (ΔLDH), P/F ratio, and Aa-DO2 were significantly different from day 1 to 7 days after the initiation of PMX-DHP between the two groups. Multivariate analysis revealed that ΔLDH was the only risk factor associated with poor prognosis. The cut-off value of ΔLDH was calculated as −8. The median survival time (MST) was significantly longer in patients with low ΔLDH values (−8).ConclusionsChanges in serum LDH levels are reasonable markers for evaluating the prognosis of PMX-DHP therapy.

BackgroundAdiponectin has been reported to be associated with lower skeletal muscle mass and skeletal strength and may be involved in skeletal muscle regulation along with myostatin. This study aims to evaluate the association between serum adiponectin and myostatin levels and identify independent factors using body composition and metabolic parameters in patients with obesity.MethodsOverall, 148 patients (age, 45.9 ± 14.3 years, body mass index, 37.2 ± 8.0 kg/m2) who initially visited the outpatient clinic of obesity between November 2013 and November 2019 were included. Body composition was measured using InBody 720 and dual energy X-ray absorptiometry. In addition, muscle strength, vascular function, and metabolic parameters were measured. Serum levels of adiponectin, leptin, myostatin, and irisin were measured from blood samples.ResultsThe serum adiponectin level was 2.9 μg/mL (1.7–4.1 μg/mL), and the serum myostatin level was 2398.4 pg/mL (1,777.1–2952.5 pg/mL). The stepwise regression analysis revealed less leg strength, homeostasis model assessment of insulin resistance, and C-reactive protein as an independent predictor of serum adiponectin levels based on the significance of the univariate analysis (R2= 0.190, P < 0.001). A high appendicular lean mass/body weight, reactive hyperemia index, and irisin were independent factors for serum myostatin levels (R2= 0.260, P < 0.001)ConclusionThe serum adiponectin level was associated with less muscle strength. Although serum myostatin was associated with a high appendicular lean mass, it is possible that myostatin was regulated by the percentage of body weight from appendicular lean mass.

We retrospectively analyzed the characteristics and outcomes of five patients with COVID‐19 who were received glucocorticoid (with or without pulse therapy) and therapeutic plasma exchange. The efficacy of the treatment was determined by whether the patient was able to be transferred from the COVID‐19 exclusive ICU to the general ward. In comparing patients who received prednisolone pulse therapy (three cases) with those who did not (two cases), 2/3 (66%) and 0/2 (0%) patients could be discharged from the COVID‐19 dedicated ICU, respectively. Among five patients who was performed plasma exchange, two elderly male patients who underwent plasma exchange as early as within 8 days of disease exacerbation survived and were able to be transferred to the general ward. This observational study indicates that plasma exchange in conjunction with methylprednisolone pulse therapy at the appropriate time may be an effective treatment for elderly patients with severe COVID‐19.

Atezolizumab is an immune checkpoint inhibitor (ICI) that is often associated with the development of several immune‐related adverse events, including fulminant type 1 diabetes mellitus (F1DM). Here, we present the case of a 73‐year‐old woman who was diagnosed with lung adenocarcinoma after surgical lung lobectomy. Two years later, she developed pulmonary metastasis, and atezolizumab treatment was initiated after seven years. However, she only completed two cycles of atezolizumab treatment because of disease progression. Four months after the interruption of atezolizumab treatment, she presented to the emergency department with fatigue and vomiting. On admission, she had a serum glucose level of 962 mg/dL, metabolic acidosis, and elevated ketone body levels. She was diagnosed with diabetic ketoacidosis induced by atezolizumab treatment. Her symptoms improved by insulin therapy. When ICIs are administered, care should be taken regarding the development of F1DM., We present a case of atezolizumab‐induced fulminant type 1 diabetes mellitus (F1DM) that occurred four months after withdrawal of the drug in a 73‐year‐old Japanese woman highlighting the need for clinicians to closely and continuously monitor the development of immune‐related adverse events, including F1DM, irrespective of the number of treatment cycles or the interval after the last immune checkpoint inhibitor cycle.

Background Mycolicibacterium fortuitum is a species of the rapidly growing mycobacteria that can cause pulmonary infection. It is susceptible to multiple antibiotics both in vitro and in clinical practice, so that any combination of susceptible drugs is effective. However, we encountered a case of infection due to fluoroquinolone-resistant M. fortuitum. In this study, we report the case and describe the mechanism of resistance. Case presentation A 65-year-old man with a history of total gastrectomy and immunosuppressant treatment for rheumatoid arthritis developed a recurrence of pulmonary infection caused by M. fortuitum. He was treated with clarithromycin and levofloxacin as a first-line treatment, based on the favorable susceptibility at that time. After recurrence, a high minimum inhibitory concentration to fluoroquinolones was detected. DNA sequencing of the pathogen showed the substitution of serine for tryptophan at residue 83 in the gyrA gene. He was successfully treated with a combination of other antibiotics. Conclusion This is the first report on the treatment of fluoroquinolone-resistant M. fortuitum and investigation of the mechanism of resistance. We suggest that the susceptibility test remains effective for determining the next line of treatment after a pathogen has acquired resistance, and resistance to fluoroquinolones in M. fortuitum can be attributed to a single change of amino acid.

Objectives To determine the seroprevalence of anti-SARS-CoV-2 IgG and IgM antibodies in symptomatic Japanese COVID-19 patients. Methods Serum samples (n = 114) from 34 COVID-19 patients with mild to critical clinical manifestations were examined. The presence and titers of IgG antibody for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were determined by a chemiluminescent microparticle immunoassay (CMIA) using Alinity i SARS-CoV-2 IgG and by an immunochromatographic (IC) IgM/IgG antibody assay using the Anti-SARS-CoV-2 Rapid Test. Results IgG was detected by the CMIA in 40%, 88%, and 100% of samples collected within 1 week, 1–2 weeks, and 2 weeks after symptom onset in severe and critical cases, and 0%, 38%, and 100% in mild/moderate cases, respectively. In severe and critical cases, the positive IgG detection rate with the IC assay was 60% within one week and 63% between one and two weeks. In mild/moderate cases, the positive IgG rate was 17% within one week and 63% between one and two weeks; IgM was positive in 80% and 75% of severe and critical cases, and 42% and 88% of mild/moderate cases, respectively. On the CMIA, no anti-SARS-CoV-2 IgG antibodies were detected in COVID-19 outpatients with mild symptoms within 10 days from onset, whereas 50% of samples from severe inpatients were IgG-positive in the same period. The IC assay detected higher IgM positivity earlier from symptom onset in severe and critical cases than in mild/moderate cases. Conclusions A serologic anti-SARS-CoV-2 antibody analysis can complement PCR for diagnosing COVID-19 14 days after symptom onset.

Background Hermansky-Pudlak syndrome (HPS) is an extremely rare disease with pulmonary fibrosis (PF), oculocutaneous albinism, induced platelet dysfunction, and granulomatous colitis. Although patients with HPS-associated PF (HPS-PF) often receive treatment with anti-fibrotic agents, including pirfenidone, many HPS-PF cases are progressive. The development of pneumothorax is known to be rare in HPS-PF. Pneumothorax development is generally important for prognosis in patients with interstitial pneumonia. However, there are few reports regarding the development of pneumothorax in patients with HPS-PF. Case presentation A 50-year-old Japanese man with chestnut hair, white skin, and light brown squint eyes visited our hospital for interstitial pneumonia examination. Chest high-resolution computed tomography (HRCT) demonstrated diffuse bilateral reticular opacities along the bronchovascular bundles and traction bronchiectasis predominantly in the upper lung fields. He was definitively diagnosed with HPS because genetic analysis showed that he had a homozygous mutation, c.398 + 5G > A, in the HPS-1 gene. After diagnosis with HPS-PF, he initiated home oxygen therapy due to gradually progressive hypoxemia. Three months after the HPS-PF diagnosis, the patient suddenly developed severe chest pain and dyspnea and was admitted to our hospital on emergency. He was diagnosed with pneumothorax by chest radiological findings. He immediately received chest drainage; however, his pneumothorax did not improve. Therefore, he underwent video-assisted surgery by thoracic surgeons. The leak point was not detected, but multiple bullae were found, mainly in the upper lung lobes. Thus, the surgeons did not perform bullectomy and only covered the apical areas. Fifteen days after the surgery, the patient developed high fever and dyspnea with a new diffuse reticular shadow found through HRCT. We first initiated the patient on broad-spectrum antibiotics; however, the symptoms and radiological findings worsened. Therefore, we started treatment with pirfenidone for inhibition of PF progression. The patient re-developed pneumothorax with severe respiratory failure. Although he re-underwent chest drainage, he died of progressive respiratory failure. Conclusions We herein report the case of a rare HPS patient who developed pneumothorax with progressive PF. Pneumothorax may cause rapid progressive respiratory failure and may be associated with PF progression in HPS-PF.