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Abstract Background Chemotherapy‐induced anorexia is a common occurrence in patients undergoing treatment for advanced lung cancer. However, the relationship between chemotherapy‐induced anorexia and weight loss during platinum‐based chemotherapy combined with immune checkpoint inhibitors is unclear. This study explored the relationship between chemotherapy‐induced anorexia and therapeutic outcomes in patients with stage IV non‐small‐cell lung cancer undergoing platinum‐based chemotherapy combined with immune checkpoint inhibitors. Methods The study retrospectively reviewed the medical records of 106 patients with stage IV non‐small‐cell lung cancer treated with platinum‐based chemotherapy and immune checkpoint inhibitors between January 2019 and October 2022. The incidence of weight loss and its association with treatment efficacy was assessed in the chemotherapy‐induced anorexia group. Chemotherapy‐induced anorexia, nausea, and vomiting were evaluated using Common Terminology Criteria for Adverse Events v 5.0. Progression‐free and overall survival were used to measure treatment efficacy. Results Chemotherapy‐induced anorexia was observed in 13.2% of patients. These patients exhibited significant weight loss at 6 and 9 weeks after treatment initiation compared to those in the non‐chemotherapy‐induced anorexia group. Progression‐free and overall survival were shorter in the chemotherapy‐induced anorexia group than in the non‐chemotherapy‐induced anorexia group, but the difference was not statistically significant. Conclusions Chemotherapy‐induced anorexia was associated with significant weight loss and reduced treatment efficacy in patients with stage IV non‐small‐cell lung cancer. These results highlight the importance of implementing robust supportive care for chemotherapy‐induced anorexia to mitigate weight loss and uphold treatment effectiveness during platinum‐based chemotherapy combined with immune checkpoint inhibitors.

Abstract Background The AmoyDx Pan lung cancer PCR panel (AmoyDx PLC panel) has been approved as a companion diagnostic tool for multiple anticancer agents in patients with non‐small cell lung cancer (NSCLC). However, the suitability of cytology specimens as samples for the AmoyDx PLC panel remains unclear. We evaluated the performance of frozen cell pellets from cytology specimens (FCPs) in the Amoy 9‐in‐1 assay, a preapproval assay of the AmoyDx PLC panel. Methods We retrospectively collected data of NSCLC patients enrolled in LC‐SCRUM‐Asia from the Shizuoka Cancer Center between September 2019 and May 2021. Results A total of 49 cases submitted FCPs for evaluation of oncogenic driver alterations and were assessed using Amoy 9‐in‐1 and next‐generation sequencing (NGS) assays. The success rates of DNA and RNA analyses using the Amoy 9‐in‐1 were both 100%, compared with 86% and 45%, respectively, using NGS assays. Oncogenic driver alterations were detected in 27 (55%) and 23 (47%) patients using Amoy 9‐in‐1 and NGS, respectively. No inconsistent results were observed among 19 cases in which both assays showed successful detection. In the remaining 30 cases, 10 had inconsistent results: nine oncogenic driver alterations (3 MET, 2 ALK, 2 ROS1, and 2 KRAS) were detectable only in Amoy 9‐in‐1, and one epidermal growth factor receptor (EGFR) mutation was detectable only in NGS. Conclusion FCPs can be successfully used in the AmoyDx PLC panel, with higher success rate compared with the NGS assay. The AmoyDx PLC panel may be an option in cases when insufficient tissue sample is available for the NGS assay.

Introduction: EGFR tyrosine kinase inhibitors have been the standard treatment for patients with NSCLC who have sensitive EGFR mutations. This study revealed final analysis survival data, biomarkers, and resistance mechanisms of osimertinib plus bevacizumab or osimertinib monotherapy in previously untreated patients with advanced EGFR-positive nonsquamous NSCLC. Methods: We previously reported the primary results of a randomized, open-label, phase 2 study comparing osimertinib plus bevacizumab with osimertinib monotherapy for this population. In this exploratory analysis using tissue and plasma samples, we evaluated gene profiles at baseline and disease progression or the last dose using targeted deep sequencing. Results: The median progression-free survival (PFS) by the blinded independent central reviewer was 22.1 months for the osimertinib plus bevacizumab arm and 20.2 months for the osimertinib arm (hazard ratio [HR] = 0.864, 95% confidence interval [CI]: 0.549–1.359). The 3-year overall survival was not different between the two arms (osimertinib plus bevacizumab: 57.1%; osimertinib monotherapy: 65.0%; HR 1.271, 95% CI: 0.727–2.223). A total of 94 patients had assessable plasma samples at baseline, and 40 had assessable pretreatment tissue samples. EGFR mutations (76.6%) and TP53 mutations (44.7%) were detected in plasma samples at baseline. In patients with plasma TP53 mutations (n = 42), the median PFS by blinded independent central reviewer was 19.8 months for the osimertinib plus bevacizumab arm and 20.2 months for the osimertinib arm (HR = 1.107, 95% CI: 0.534–2.297). Conclusions: There was also no significant difference in the PFS between the two arms, even in patients with TP53 mutations.

An 18-year-old previously healthy Filipino male presented with abdominal pain, vomiting, dyspnoea and fever. Initial investigations revealed severe hepatosplenomegaly, pancytopaenia, elevated liver enzymes, coagulopathy and extremely high ferritin levels. Bone marrow biopsy confirmed an abnormal CD8+ T-cell population with haemophagocytosis. Extensive workup was performed, and he was ultimately diagnosed with haemophagocytic lymphohistiocytosis (HLH) secondary to Epstein-Barr virus-positive T-cell lymphoma of childhood (EBV-TCL), a rare and aggressive malignancy. Despite the initiation of modified dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE) chemotherapy along with high-dose glucocorticoids, the patient did not respond to the treatment and expired. This case underscores the critical importance of early recognition and prompt intervention in EBV-TCL-associated HLH which is a unique condition and a rare entity. The diagnosis of this entity can be particularly challenging, given its rapid progression and high mortality rate. Therefore, timely diagnosis and the initiation of appropriate therapy are essential for improving patient outcomes. General medicine providers play a key role in identifying warning signs to avoid delays in treatment initiation.

ABSTRACT Background Mutations in the epidermal growth factor receptor (EGFR) gene are the most common targetable gene alterations in non‐small cell lung cancer (NSCLC). In Japan, approximately 40% of patients who undergo surgical resection for non‐squamous NSCLC have EGFR mutations. However, no long‐term studies have been conducted including a large number of EGFR‐positive NSCLC patients with postoperative recurrence (PR). Methods We conducted a retrospective observational study of the data of EGFR‐positive NSCLC patients with PR who had undergone surgery at the Shizuoka Cancer Center between October 2002 and November 2017. We evaluated post‐recurrence overall survival (PRS) and postoperative overall survival (POS) using the Kaplan–Meier method and identify any associations between the clinical variables at recurrence and PRS using univariate and multivariate analysis. Results We enrolled 162 patients. The median observation time for PRS was 4.95 years (range, 0.82–13.25) and POS was 5.81 years (range, 2.84–16.71). The median PRS was 5.17 years (95% confidence interval [CI], 3.90–5.61) and POS was 7.07 years (95% CI, 5.88–8.01). Univariate analysis identified male sex (median PRS: 3.32 vs. 5.39 years; p

Abstract The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647–1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648–1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.

Abstract Introduction Non-invasive biofeedback of pelvic floor muscle training (PFMT) is required for continuous training in home care. Therefore, we considered self-performed ultrasound (US) in adult women with a handheld US device applied to the bladder. However, US images are difficult to read and require assistance when using US at home. In this study, we aimed to develop an algorithm for the automatic evaluation of pelvic floor muscle (PFM) contraction using self-performed bladder US videos to verify whether it is possible to automatically determine PFM contraction from US videos. Methods Women aged ≥ 20 years were recruited from the outpatient Urology and Gynecology departments of a general hospital or through snowball sampling. The researcher supported the participants in their self-performed bladder US and videos were obtained several times during PFMT. The US videos obtained were used to develop an automatic evaluation algorithm. Supervised machine learning was then performed using expert PFM contraction classifications as ground truth data. Time-series features were generated from the x- and y-coordinate values of the bladder area including the bladder base. The final model was evaluated for accuracy, area under the curve (AUC), recall, precision, and F1. The contribution of each feature variable to the classification ability of the model was estimated. Results The 1144 videos obtained from 56 participants were analyzed. We split the data into training and test sets with 7894 time series features. A light gradient boosting machine model (Light GBM) was selected, and the final model resulted in an accuracy of 0.73, AUC = 0.91, recall = 0.66, precision = 0.73, and F1 = 0.73. Movement of the y-coordinate of the bladder base was shown as the most important. Conclusion This study showed that automated classification of PFM contraction from self-performed US videos is possible with high accuracy.

Evans syndrome (ES) is a rare autoimmune disorder characterised by autoimmune haemolytic anaemia (AIHA), immune thrombocytopenia and autoimmune neutropenia. The precise pathogenesis of ES remains unclear, but it is believed to involve immune-mediated destruction of erythrocytes and platelets. Thrombotic complications, such as stroke, are critical yet largely unrecognised in ES. Here, we present a case of an 80-year-old male with ES who developed multiple strokes, emphasising the complex management challenges associated with this condition. The patient, known for stage IIB lung adenocarcinoma, presented with right-sided weakness and was diagnosed with a stroke of undetermined aetiology. He was started on warfarin for secondary prevention alongside intravenous immunoglobulin (IVIG) and corticosteroids for ES. Stroke in ES is rarely reported, and the optimal management remains inconclusive due to its rarity. The patient’s management was guided by existing guidelines for stroke prevention and anticoagulation in the setting of antiphospholipid syndrome. While anticoagulants are recommended for venous thromboembolism prophylaxis in AIHA, there are no clear guidelines for stroke prevention in ES. This case underscores the necessity of individualised treatment approaches and highlights the gaps in evidence regarding stroke management in ES. Future research is essential to determine the optimal management of stroke in this complex clinical scenario.

Abstract Background Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)‐SCLC, to assess whether conventional NE markers are predictive of ICIs. Methods Patients with untreated ED‐SCLC who received first‐line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first‐line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI‐chemo group) and with chemotherapy alone (chemo group). Results A total of 227 patients were included in the ICI‐chemo and chemo groups, respectively. The progression‐free survival (PFS) tended to be better in patients in the ICI‐chemo group than those treated with chemotherapy alone in patients with NE marker‐positive SCLC. In particular, it was statistically significant in patients with chromogranin A‐positive SCLC (p = 0.036). In patients with NE marker‐negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. Conclusion Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker‐negative SCLC.

Abstract Objective Becker muscular dystrophy (BMD) is a milder variant of Duchenne muscular dystrophy (DMD), a lethal X‐linked muscular disorder. Here, we aim to investigat the clinical involvement of skeletal, respiratory, cardiac, and central nervous systems in patients with BMD, as well as genotype–phenotype relationships. Methods This nationwide cohort study investigated the clinical manifestations and genotype–phenotype relationships in 225 patients with BMD having in‐frame deletion from 22 medical centers. The primary outcome was to elucidate the association of genotype with skeletal muscle, respiratory, cardiac, and central nervous system disorders. Descriptive statistics were used to analyze the data. Results The average age of the subjects was 31.5 (range, 1–81) years. Initial symptoms of BMD were muscular (60%), followed by asymptomatic hypercreatine kinasemia (32.4%) and central nervous system disorders (5.3%). Gait disturbance was observed in 53.8% of patients and the average age at wheelchair introduction was 36.5 years. The ventilator introduction rate was 6.7% at an average age of 36.6 years. More than 30% of patients had an abnormal electrocardiogram and approximately 15% had heart failure symptoms. Cardiac function on echocardiography varied significantly among the patients. The frequencies of seizures and intellectual/developmental disability were 8.0% and 16.9%, respectively. Exon 45–47deletion (del) was the most common (22.6%), followed by exon 45–48del (13.1%). Patients with exon 45–49del patients demonstrated severe skeletal muscle damage. Patients with exon 45–47del and exon 45–55del patients did not require ventilator use. Interpretation The study provides important prognostic information for patients and clinicians to establish therapy plans and to implement preventative medicine.

Abstract Background Amrubicin (AMR) regimens have shown efficacy as second‐line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia (FN) sometimes preclude their use. Further, the safety and efficacy of AMR with primary prophylactic pegfilgrastim (P‐PEG) have not been sufficiently evaluated. In this study, we evaluated the safety and efficacy of AMR with or without P‐PEG as second‐line chemotherapy for SCLC. Methods We retrospectively reviewed patients with SCLC who received AMR as second‐line chemotherapy at Shizuoka Cancer Center, between December 2014 and November 2021. Based on presence/absence of P‐PEG in their regimen, patients (n = 60) were divided into P‐PEG (n = 21) and non‐P‐PEG groups, and their clinical outcomes were evaluated. Results Median of AMR treatment cycles was five (range: 1–39 cycles) in P‐PEG group and four (range: 1–15 cycles) in non‐P‐PEG group. The incidence of FN (4.8% vs. 30.8%; p = 0.02) and AMR dose reduction because of adverse events (4.8% vs. 25.6%; p = 0.08) were lower in the P‐PEG group than in the non‐P‐PEG group. The objective response rates were 52.4% and 30.8%, and median progression‐free and overall survival were 4.7 and 3.0 months, and 9.6 and 6.8 months, in the P‐PEG and non‐P‐PEG groups, respectively. Conclusions AMR with P‐PEG as second‐line chemotherapy for SCLC reduced the incidence of FN at a maintained AMR dose intensity and was associated with favorable tumor responses and survival outcomes. P‐PEG should be considered for patients treated with AMR for SCLC including refractory relapsed SCLC.

Abstract Background Foreign body (FB) ingestion is a common event in children. The management of the ingested FB depends on the location, type, number, size of the FBs, patient age, and symptoms. Although most FBs pass spontaneously through the gastrointestinal tract without causing serious injuries, the ingestion of multiple high-powered magnetic pieces, especially neodymium magnets (NMs) increases the risks of morbidity and mortality. Supravesical hernia (SH) is rarely occurs in children, and few studies have reported SH in pediatric patients. We report an extremely rare case of ingested NMs that migrated into an internal SH in a pediatric patient. Case presentation A 3-year-old boy who had accidentally swallowed two NMs 3 days ago presented with vomiting and lower abdominal pain. X-ray imaging and computed tomography (CT) suspected the presence of a 1.0-cm radiopaque FB located in the terminal ileum dorsal side of the bladder. Although his abdominal pain was gradually getting better after oral feeding, repeat abdominal X-ray imaging showed that the FB was in a stagnant in position. Therefore, surgical intervention was planned to remove the FB 1 week after his admission. Under general anesthesia, laparoscopic and fluoroscopic examinations were performed and the cecum was found adhered to the retroperitoneum between the right medial umbilical fold and the right wall of the urinary bladder. The FB was presumed to be located at the tip of the incarcerated cecum in the retroperitoneal space. Peritoneum incision was started near the medial inguinal fossa, and the Retzius space was opened in a manner similar to the transabdominal pre-peritoneal approach for inguinal hernia repair. Consequently, the patient was diagnosed with internal SH with FB migration. The incarcerated cecum was pulled out, which revealed intestinal wall perforation. The FB remained in the retroperitoneal space in the pelvic cavity. The FB was easily removed using intestinal forceps and identified as combined two NMs. The postoperative course was good, and the patient was discharged on postoperative day 5. Conclusions We experienced an extremely rare case of a pediatric patient who swallowed multiple NMs that migrated into an internal SH, and the laparoscopic minimally invasive removal was successful.

Objectives: The current standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiation therapy (CCRT) followed by durvalumab consolidation therapy. Although the trial revealed the survival benefit of adding an immune checkpoint inhibitor (ICI) to the population, the optimal treatment strategy and efficacy of subsequent treatment after relapse remain unclear. Materials and methods: We retrospectively collected data from patients with unresectable LA-NSCLC who completed platinum-based CCRT as first-line treatment. Patients who received molecular-targeted therapy for driver gene alterations or did not receive durvalumab as consolidation therapy following the approval were excluded. We assessed differences in regimen and efficacy of subsequent treatment in patients who underwent durvalumab consolidation therapy (D group) and those who did not (CR group). Results: Among the 62 eligible patients, 32 were assigned to the D group and 30 to the CR group. Patients in the CR group were more frequently treated with an immune checkpoint inhibitor (ICI)-containing regimen than those in the D group (57 % vs. 13 %, p < 0.001). The median overall survival from initiation of subsequent treatment was shorter in the D group than in the CR group (13.0 months vs. 26.7 months, hazard ratio 2.60; 95 % confidence interval: 1.28–2.56, p = 0.008). Conclusions: Patients with unresectable LA-NSCLC who relapsed after durvalumab consolidation therapy received an ICI-containing regimen less frequently, and the efficacy of the subsequent treatment was limited.

Background: Validation studies of diabetes definitions using nationwide healthcare databases are scarce. We evaluated the validity of diabetes definitions using disease codes and antidiabetic drug prescriptions in the Japanese Diagnosis Procedure Combination (DPC) data via medical chart review. Methods: We randomly selected 500 records among 15,334 patients who participated in the Japan Public Health Center-Based Prospective Study for the Next Generation in Yokote City and who had visited a general hospital in Akita between October 2011 and August 2018. Of the 500 patients, 98 were linked to DPC data; however, only 72 had sufficient information in the medical chart. Gold standard confirmation was performed by board-certified diabetologists. DPC-based diabetes definitions were based on the International Classification of Diseases, 10th Revision codes and antidiabetic prescriptions. Sensitivity, specificity, and the positive and negative predictive values (PPV and NPV, respectively) of DPC-based diabetes definitions were evaluated. Results: Of 72 patients, 23 were diagnosed with diabetes using chart review; 19 had a diabetes code, and 13 had both a diabetes code and antidiabetic prescriptions. The sensitivity, specificity, PPV, and NPV were 89.5% (95% confidence interval [CI], 66.9–98.7%), 96.2% (95% CI, 87.0–99.5%), 89.5% (95% CI, 66.9–98.7%), and 96.2% (95% CI, 87.0–99.5%), respectively, for (i) diabetes codes alone; 89.5% (95% CI, 66.9–98.7%), 94.3% (95% CI, 84.3–98.8%), 85.0% (95% CI, 62.1–96.8%), and 96.2% (95% CI, 86.8–99.5%) for (ii) diabetes codes and/or prescriptions; 68.4% (95% CI, 43.4–87.4%), 100% (95% CI, 93.3–100%), 100% (95% CI, 75.3–100%), and 89.8% (95% CI, 79.2–96.2%) for (iii) both diabetes codes and prescriptions. Conclusion: Our results suggest that DPC data can accurately identify diabetes among inpatients using (i) diabetes codes alone or (ii) diabetes codes and/or prescriptions.

Abstract Carboplatin plus etoposide is a standard treatment for older extensive‐stage small‐cell lung cancer (ES‐SCLC) patients with performance status (PS) 2. However, older patients often exhibit poor PS (3, 4), and the treatment effect in them is poorly understood. To determine the therapeutic efficacy and safety of carboplatin plus etoposide therapy for this population, we retrospectively analyzed 63 patients with ES‐SCLC with PS ≥2, aged ≥71 years, who had received first‐line carboplatin plus etoposide therapy. We compared the treatment efficacy and safety in patients with baseline PS 2 versus those with PS 3–4. In the PS 2 (38 patients) and PS ≥3 (25 patients) groups, the overall response rate was 71.1% and 72.0%, median progression‐free survival was 4.6 and 3.1 months, and overall survival was 7.7 and 5.1 months, respectively. PS improved to 0–1 post‐treatment in 65.8% and 48.0% of the patients in the PS 2 and PS ≥3 groups, respectively. Patients with PS ≥3 showing improved PS had a progression‐free survival of 6.1 months. A higher incidence of grade ≥3 decreased neutrophil counts, febrile neutropenia, and treatment‐related death was observed in the PS ≥3 group. The progression‐free survival of patients administered prophylactic granulocyte colony‐stimulating factor (G‐CSF) was 5.2 and 6.1 months in the PS2 and PS ≥3 groups. Overall, carboplatin plus etoposide therapy provided comparable tumor shrinkage, but shorter progression‐free and overall survival in older ES‐SCLC patients with PS ≥3 than in those with PS 2. Thus, supportive care, such as prophylactic G‐CSF administration, may be necessary to ensure safety and survival.

Abstract Adenosine-to-inosine RNA editing is a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family. It has been discovered recently as an epigenetic modification dysregulated in human cancers. However, the clinical significance of RNA editing in patients with liver metastasis from colorectal cancer (CRC) remains unclear. The current study aimed to systematically and comprehensively investigate the significance of adenosine deaminase acting on RNA 1 (ADAR1) expression status in 83 liver metastatic tissue samples collected from 36 patients with CRC. The ADAR1 expression level was significantly elevated in liver metastatic tissue samples obtained from patients with right-sided, synchronous, or RAS mutant-type CRC. ADAR1-high liver metastasis was significantly correlated with remnant liver recurrence after hepatic metastasectomy. A high ADAR1 expression was a predictive factor of remnant liver recurrence (area under the curve = 0.72). Results showed that the ADAR1 expression level could be a clinically relevant predictive indicator of remnant liver recurrence. Patients with liver metastases who have a high ADAR1 expression requires adjuvant chemotherapy after hepatic metastasectomy.

Abstract Background Programmed cell death 1 (PD‐1)/programmed cell death ligand (PD‐L1) inhibitors plus chemotherapy (ICI + Chemo) is the standard treatment for advanced non‐small‐cell lung cancer (NSCLC). However, the impact of tumour burden on the efficacy of ICI + Chemo remains unknown. Methods We retrospectively evaluated 92 patients with advanced NSCLC treated with ICI + Chemo. Tumour burden was assessed as the sum of the longest diameter of the target lesion (BSLD) and number of metastatic lesions (BNMLs). We categorised the patients into three groups based on the combined BSLD and BNML values. Results Sixty‐eight patients (74%) had progressive disease or died. Forty‐four patients (48%) in the low‐BSLD group had a median progression‐free survival (PFS) of 9.5 months, whereas patients in the high‐BSLD group had a median PFS of 4.6 months (hazard ratio [HR] = 0.54, p = 0012). Twenty‐five patients (27%) in the low‐BNML group had a median PFS of 9.6 months, whereas patients in the high‐BNML group had a median PFS of 6.5 months (HR = 0.51, p = 0.029). Low‐BSLD and low‐BNML were associated independently with improved PFS in multivariate analysis. Analysis of the tumour burden combined with BSLD and BNML revealed a trend towards improved PFS as the tumour burden decreased, with median PFS of 22.3, 8.7, and 3.9 months in the low‐ (N = 13), medium‐ (N = 42) and high‐burden (N = 37) groups respectively. Conclusions Our findings demonstrated that a high tumour burden negatively impacts the efficacy of ICI + Chemo in patients with advanced NSCLC.

Abstract Background Despite improvement in the overall survival of patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, the effects of EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment on bone metastasis remain unclear. This study investigated radiological responses to gefitinib regarding bone metastasis in patients. Methods We treated 260 patients with NSCLC and symptomatic bone metastasis. Thirty-seven patients harboring EGFR mutation were treated with gefitinib for more than 30 days and followed up for more than 3 months (GEF group). We performed a retrospective observational study by selecting 36 cases without EGFR-TKI treatment, at least 3 months of follow-up, and at least two radiological evaluations as the control group. We assessed the best overall radiological response, interval from treatment initiation to appearance of a radiological response, and the local response maintenance rate. Results The best effect in the GEF group was 98% partial response or better, which was significantly higher than the 57% observed in the control group (p

Abstract The differences in genetic susceptibility to lung adenocarcinoma and squamous cell carcinoma remain unclear. We developed a customized, targeted gene sequencing panel for efficient and sensitive identification of germline variants, including whole-gene deletion types for cancer-related drug-metabolizing enzyme genes in lung adenocarcinoma and squamous cell carcinoma. The minor allele frequencies of the variants, confirmed as clinically significant in the Japanese population, did not differ significantly from those of normal participants listed in the public database. Genotype analysis comparing lung adenocarcinoma (n = 559) and squamous cell carcinoma (n = 151) indicated that the variants of DPYD (rs190771411, Fisher’s exact test, P = 0.045; rs200562975, P = 0.045) and ALDH2 (rs568781254, P = 0.032) were associated with an increased risk of squamous cell carcinoma compared to adenocarcinoma. Conversely, whole-gene deletion of CYP2A6 was associated with adenocarcinoma but not squamous cell carcinoma. Notably, whole-gene deletion of CYP2A6 was confirmed in 22 patients with lung adenocarcinoma but not in any patients with squamous cell carcinoma. Most patients with whole-gene deletion of CYP2A6 were female non-smokers. The discovery of a whole-gene deletion of CYP2A6 in patients with lung adenocarcinoma may have an important role in clinical practice and advance our understanding of CYP2A6 germline variants and their association with carcinogenesis or their susceptibility to lung adenocarcinoma.

Purpose: A postoperative pain management strategy for the enhanced recovery after surgery (ERAS) protocol has recently become more important in pediatric surgery and growing attention is being paid to perioperative use of intravenous acetaminophen (IV-A). In laparoscopic extraperitoneal closure (LPEC) procedure, postoperative pain is still occurring and optimal analgesia remains unclear. We aimed to evaluate the efficacy of preoperative IV-A (pIV-A) for postoperative analgesia after LPEC in children. Methods: After approval of the ethics committee of our hospital (#2,018,131), 40 consecutive pediatric patients with unilateral inguinal hernia were randomized into two group (20 each) and received LPEC procedure with pIV-A (group-A) and without (group-C). The pain scale score (PSS), the frequency of the postoperative acetaminophen bolus use (FPAB) and school start day (SSD) were assessed. Results: The PSS and the FPAB are significantly lower in group-A compared to group-C on POD0 and POD1, indicating a significant reduction in pain in group-A at an early stage after the operation. In addition, SSD after LPEC operation was shorter in group-A compared to group-C. Conclusion: Our results suggest that pIV-A for postoperative analgesia after LPEC in children is safe and useful for the ERAS.

Given the paucity of reports on all-inside reconstruction procedures via the transfemoral approach, we describe a minimally invasive, all-inside transfemoral technique that enables creating femoral and tibial sockets from the intra-articular cavity. Our transfemoral approach makes it possible to sequentially create femoral and tibial sockets using the same reamer bit, while a single drilling guide is set in place. Our custom socket drilling guide was designed to integrate with a tibial tunnel guide, which helped locate the tunnel exit at an anatomically acceptable location. The advantages of this method include easy and precise positioning of the femoral tunnel, narrow tibial tunnel, minimal damage to the intramedullary trabecular bone integrity, and low postoperative risks of pain, bleeding, and infections.

Abstract Background Cancer cachexia and tumor burden predict efficacies of programmed cell death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) inhibitors and chemotherapy or pembrolizumab in non‐small cell lung cancer (NSCLC). There are no predictive models that simultaneously assess cancer cachexia and tumor burden. Methods In the present retrospective study, we reviewed the medical records of patients with advanced NSCLC who received cancer immunotherapy as first‐line systemic therapy. Clinical immune predictive scores were defined according to multivariate analysis of progression‐free survival (PFS) and overall survival (OS). Results A total of 157 patients were included in the present study (75 treated with PD‐1/PD‐L1 inhibitors + chemotherapy; 82, pembrolizumab monotherapy). Multivariate analysis for PFS revealed that PD‐L1 tumor proportion scores

Background: Obstructed Hemivagina and Ipsilateral Renal Anomaly (OHVIRA) syndrome is characterized by duplicated uterus and vagina, obstructed hemivagina, and ipsilateral congenital renal malformation. Patients typically have progressive hematocolpos and hematometra when they first show up after menarche. Hematocolpos symptoms can be effectively treated with a vaginal septectomy and hematoma drainage. However, current described procedures to perform the vaginoscopic incision of the vaginal septum carry intraoperative complications in pediatric patients. We aim to discuss our novel operative procedure of vaginal septectomy using transvaginal endoscopic ultrasonography (EUS) for the children with OHVIRA syndrome. Case presentation: A 12-year-old girl was referred to our hospital because of excruciating abdominal pain after her menarche. Magnetic resonance imaging showed hematocolpos and hematometra, and OHVIRA syndrome was diagnosed. Elective vaginal septectomy was planned. With the use of a resectoscope and transvaginal EUS, we carried out transvaginal septectomy. The procedure was completed safely, and there were no postoperative problems. Conclusions: We discovered that EUS-guided transvaginal septectomy is a safe, technically feasible, and minimally invasive approach with low incidence of intraoperative complications for treating OHVIRA syndrome in children with hematocolpos.

Purpose: This study aimed to clarify the characteristics of and evaluate the risk factors for radiation pneumonitis (RP) induced by chemoradiation therapy (CRT) using accelerated hyperfractionated (AHF) radiation therapy (RT) in patients with limited-stage small cell lung cancer (LS-SCLC). Methods and Materials: Between September 2002 and February 2018, 125 patients with LS-SCLC were treated with early concurrent CRT using AHF-RT. Chemotherapy was comprised of carboplatin/cisplatin with etoposide. RT was administered twice daily (45 Gy/30 fractions). We collected data regarding onset and treatment outcomes for RP, and analyzed the relationship between RP and total lung dose–volume histogram findings. Uni- and multivariate analyses were performed to assess patient- and treatment-related factors for grade ≥2 RP. Results: The median age of patients was 65 years, and 73.6% of participants were men. In addition, 20% and 80.0% of participants presented with disease stage II and III, respectively. The median follow-up time was 73.1 months. Grades 1, 2, and 3 RP were observed in 69, 17, and 12 patients, respectively. Grades 4 to 5 RP were not observed. RP was treated with corticosteroids in patients with grade ≥2 RP, without recurrence. The median time from initiation of RT to onset of RP was 147 days. Three patients developed RP within 59 days, 6 within 60 to 89 days, 16 within 90 to 119 days, 29 within 120 to 149 days, 24 within 150 to 179 days, and 20 within ≥180 days. Among the dose–volume histogram parameters, the percentage of lung volume receiving >30 Gy (V30) was most strongly related to the incidence of grade ≥2 RP, and the optimal threshold to predict RP incidence was V30 ≥20%. On multivariate analysis, V30 ≥20% was an independent risk factor for grade ≥2 RP. Conclusions: The incidence of grade ≥2 RP correlated strongly with a V30 of ≥20%. Contrarily, the onset of RP induced by concurrent CRT using AHF-RT may occur later. RP is manageable in patients with LS-SCLC.

Abstract Background Adipose tissue induces inflammation, which desensitizes the efficacy of immunotherapy. However, several reports show that the therapeutic effect of programed cell death 1 (PD‐1)/programed death‐ligand 1 (PD‐L1) inhibitor(s) monotherapy is significantly better in obese patients. Therefore, the effect of adipose tissue on immunotherapy is unclear. Methods In this study, we retrospectively reviewed patients with advanced non‐small cell lung cancer (NSCLC) who received PD‐1/PD‐L1 inhibitor monotherapy between May 2016 and December 2018. We classified patients into total adipose tissue maintenance or loss groups according to adipose tissue change during the 6 months before treatment and compared the therapeutic effect of PD‐1/PD‐L1 inhibitors between these groups along with the presence or absence of cachexia, a poor prognostic factor. Results Of the 74 patients, 40 (54.1%) were cachexic. Among cachexic patients, we found no clear difference in the overall response rate (ORR) and progression‐free survival (PFS) between the total adipose tissue maintenance and loss group. However, among noncachexic patients, the total adipose tissue loss group had a higher ORR (64.7% vs. 23.5%, p

Abstract Background The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. TRPV2 overexpression in the sarcolemma of skeletal and cardiac myocytes causes calcium influx into the cytoplasm, which triggers myocyte degeneration. In animal models of cardiomyopathy and muscular dystrophy (MD), TRPV2 inhibition was effective against heart failure and motor function. Our previous pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Thus, this single-arm, open-label, multicenter study aimed to evaluate the safety and efficacy of tranilast for heart failure. Methods The study enrolled MD patients with advanced heart failure whose serum BNP levels were > 100 pg/mL despite receiving standard cardioprotective therapy. Tranilast was administered orally at 100 mg, thrice daily. The primary endpoint was the change in log (BNP) (Δlog [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous multicenter study of carvedilol results in a mean population Δlog (BNP) of 0.18. TRPV2 expression on peripheral blood mononuclear cell surface, cardiac events, total mortality, left ventricular fractional shortening, human atrial natriuretic peptide, cardiac troponin T, and creatine kinase, and pinch strength were also assessed. Results Because of the poor general condition of many patients, only 18 of 34 patients were included and 13 patients could be treated according to the protocol throughout the 6-month period. However, there were no serious adverse events related to tranilast except diarrhea, a known adverse effect, and the drug was administered safely. TRPV2 expression on the mononuclear cell surface was elevated at baseline and reduced after treatment. Cardiac biomarkers such as BNP, human atrial natriuretic peptide, and fractional shortening remained stable, suggesting a protective effect against the progression of heart failure. In the per protocol set group, Δlog [BNP] was − 0.2 and significantly lower than that in the null hypothesis. Conclusions Tranilast is safe and effective in inhibiting TRPV2 expression, even in MD patients with advanced heart failure. Further trials are needed to evaluate the efficacy of tranilast in preventing myocardial damage, heart failure, motor impairment, and respiratory failure. Clinical trial registration The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: http://www.umin.ac.jp/ctr/ ) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: https://jrct.niph.go.jp/ ) [November 12, 2021]. Patient registration was started in December 19, 2018.

Abstract Purpose This study aimed to evaluate short‐term outcomes at least 2 years after dome‐shaped high tibial osteotomy (HTO) combined with all‐inside anterior cruciate ligament reconstruction (ACL) in patients with persistent ACL insufficiency accompanied by pain due to varus deformity. Methods The study enrolled 19 knees of 18 patients. The mean age was 58.4 ± 13.4 years and the mean postoperative follow‐up period was 31.4 ± 6.6 months (24–49 months). JOA(Japanese Orthopaedic Association)‐OA(osteoarthritis) score, Lysholm score, radiographic outcomes such as femoro‐tibia angle (FTA) in a standing position, side‐to‐side difference in KT‐1000 measurements were evaluated at pre op. and post operative final follow up. And arthroscopic evaluation was evaluated at the time of the HTO plate‐removal procedure. Results Before surgery, the mean JOA‐OA score was 65.0 ± 13.5, the mean Lysholm score was 47.2 ± 16.2, the mean femoro‐tibia angle (FTA) in a standing position was 183.8 ± 3.4° (range;180–190°), and the mean side‐to‐side difference in KT‐1000 measurements was 4.1 ± 1.3 mm. After surgery, the mean JOA‐OA score, Lysholm score, and side‐to‐side difference in KT‐1000 measurements improved to 93.1 ± 6.0 (P

Abstract Background Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are currently the primary treatment option for patients with EGFR‐mutant non‐small cell lung cancer (NSCLC). However, the effect of EGFR‐TKIs are eventually weakened due to resistance, and there is also a differential efficacy based on EGFR mutation subtypes. The combination of angiogenesis inhibitor (AI) with EGFR‐TKI has shown better efficacy than EGFR‐TKI monotherapy, regardless of the mutation subtypes. Nevertheless, the effect of AI eligibility on overall survival (OS) and progression‐free survival (PFS) remains to be elucidated. Thus, we assessed this impact on patients with NSCLC harboring EGFR mutation. Methods In this study, the data for 450 patients with EGFR‐mutant NSCLC, who were treated with EGFR‐TKI monotherapy, were retrospectively analyzed for AI eligibility. The patients were categorized into AI‐eligible (AI fit) and ineligible groups (AI unfit). Results The median PFS of the AI fit group was 12.9 months, compared to 9.6 months in the unfit group (p = 0.007), and OS was also significantly longer in the AI fit group (median OS = 33.0 months) compared to that in the unfit group (18.5 months, p

Abstract 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

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

Abstract Background Patients with lung cancer and interstitial lung disease treated with radiotherapy are at risk of developing radiation pneumonitis. However, the association between interstitial lung abnormalities (ILAs) and radiation pneumonitis in patients with limited-stage small-cell lung cancer (LS-SCLC) remains unclear. Furthermore, the prognosis is uncertain for patients with SCLC and ILAs treated with chemoradiotherapy. We investigated the impact of ILAs on radiation pneumonitis and assessed the prognosis of patients with LS-SCLC and ILAs treated with chemoradiotherapy. Methods We retrospectively reviewed the medical records of 149 patients with LS-SCLC who received first-line treatment between January 2009 and December 2016. Results In the univariate analysis, the patients with ILAs showed a higher incidence rate of radiation pneumonitis compared with those without ILAs (64% vs. 10%, P

Abstract Venous thromboembolism (VTE) is frequently observed in patients with advanced cancer. The objective of this prospective observational study was to estimate, based on intensive screening, using computed tomography, lower‐extremity ultrasonography, and D‐dimer testing, the prevalence of VTE in patients with advanced cancer. Patients with metastatic or locally advanced cancer without anticoagulant therapy, who were planning to receive chemotherapy during 4 weeks, were eligible. Evaluations of VTE were performed at pretreatment, 12 weeks, and 24 weeks after the start of chemotherapy. Primary endpoint was cumulative incidence of VTE for 24 weeks. Secondary endpoints included incidence of VTE (pretreatment, 12 weeks, and 24 weeks after the start of chemotherapy), VTE according to primary cancer site, symptomatic VTE, pulmonary thromboembolism (PE), and treatment of VTE. We enrolled 860 patients with a median age of 68 years, including 34% female and 71% lung cancer. Cumulative incidence of VTE for 24 weeks was 22.6% (95% confidence interval: 19.8%–25.5%) (194 of 860 patients). Incidence of VTE was 11.3% pretreatment, 16.8% 12 weeks, and 14.1% 24 weeks. Symptomatic VTE was observed in 4.0% and PE in 1.0% of patients. By multivariate analysis, sex, D‐dimer level, and platelet count were independent risk factors of VTE for 24 weeks. This large prospective observational study showed that cumulative incidence of VTE was high in advanced cancer patients, mainly lung cancer. Although most patients showed asymptomatic VTE, intensive screening of VTE may be considered in advanced cancer patients, especially in women with high level of D‐dimer and decreased platelet count (UMIN000015243).

Objective: Days spent at home (DASH) near the end of life is considered an important patient-centered goal and outcome because many patients want to stay at home toward the end of life. This study aimed to estimate the individual DASH near the end of life and identify its early predictors, including muscle mass and physical function, among elderly patients with advanced non-small-cell lung cancer (NSCLC). Methods: We conducted a post hoc analysis of the prospective observational study (UMIN000009768) that recruited patients aged ≥ 70 years who were scheduled to undergo first-line chemotherapy because of advanced NSCLC. We measured the muscle mass by bioelectrical impedance analysis at baseline. DASH was calculated as 30 days minus the number of days spent in hospitals, palliative care facilities, or nursing homes during the last 30 days of life. We performed linear regression analyses to evaluate the predictors of DASH. Results: Altogether, 16 women and 28 men with a median overall survival of 15.5 months (range: 2.9–58.9) were included. The median DASH in the last 30 days of life was 8 days (range: 0–30, interquartile range: 0–23). Men had longer DASH than women by 7.3 days. Patients who had good trunk muscle mass index and hand-grip strength had significantly longer DASH than those who did not (4.7 days per kg/m2 increase [P = 0.017] and 0.4 days per kg increase [P = 0.032], respectively). Conclusions: Most elderly patients with advanced NSCLC had a limited DASH near the end of life. The risk factors for reduced DASH were women, reduced muscle mass, and poor physical function at the time of diagnosis of advanced NSCLC. Our findings would encourage early discussions about end-of-life care for patients with advanced cancers with risk factors for short DASH at the time of diagnosis, and thus, improve the quality of end-of-life care.

Objectives Complications due to peripheral intravenous catheters (PIVC) can be assessed using ultrasound imaging; however, it is not routinely conducted due to the need for training in image reading techniques. This study aimed to develop and validate a system that automatically measures blood vessel diameters on ultrasound images using artificial intelligence (AI) and provide recommendations for selecting an implantation site.Design Pilot study.Setting The University of Tokyo Hospital, Japan.Primary and secondary outcome measures First, based on previous studies, the vessel diameter was calculated as the mean value of the maximum long diameter plus the maximum short diameter orthogonal to it. Second, the size of the PIVC to be recommended was evaluated based on previous studies. For the development and validation of an automatic detection tool, we used a fully convoluted network for automatic estimation of vein location and diameter. The agreement between manually generated correct data and automatically estimated data was assessed using Pearson’s product correlation coefficient, systematic error was identified using the Bland-Altman plot, and agreement between catheter sizes recommended by the research nurse and those recommended by the system was evaluated.Results Through supervised machine learning, automated determination was performed using 998 ultrasound images, of which 739 and 259 were used as the training and test data set, respectively. There were 24 false-negatives indicating no arteries detected and 178 true-positives indicating correct detection. Correlation of the results between the system and the nurse was calculated from the 178 images detected (r=0.843); no systematic error was identified. The agreement between the sizes of the PIVC recommended by the research nurse and the system was 70.2%; 7% were underestimated and 21.9% were overestimated.Conclusions Our automated AI-based image processing system may aid nurses in assessing peripheral veins using ultrasound images for catheterisation; however, further studies are still warranted.t

Abstract Background It is unclear whether clinical factors and immune microenvironment (IME) factors are associated with tumor mutation burden (TMB) in patients with nonsmall cell lung cancer (NSCLC). Materials and methods We assessed TMB in surgical tumor specimens by performing whole exome sequencing. IME profiles, including PD‐L1 tumor proportion score (TPS), stromal CD8 tumor‐infiltrating lymphocyte (TIL) density, and stromal Foxp3 TIL density, were quantified by digital pathology using a machine learning algorithm. To detect factors associated with TMB, clinical data, and IME factors were assessed by means of a multiple regression model. Results We analyzed tumors from 200 of the 246 surgically resected NSCLC patients between September 2014 and September 2015. Patient background: median age (range) 70 years (39‐87); male 37.5%; smoker 27.5%; pathological stage (p‐stage) I/II/III, 63.5/22.5/14.0%; histological type Ad/Sq, 77.0/23.0%; primary tumor location upper/lower, 58.5/41.5%; median PET SUV 7.5 (0.86‐29.8); median serum CEA (sCEA) level 3.4 ng/mL (0.5‐144.3); median serum CYFRA 21‐1 (sCYFRA) level 1.2 ng/mL (1.0‐38.0); median TMB 2.19/ Mb (0.12‐64.38); median PD‐L1 TPS 15.1% (0.09‐77.4); median stromal CD8 TIL density 582.1/mm2 (120.0‐4967.6);, and median stromal Foxp3 TIL density 183.7/mm2 (6.3‐544.0). The multiple regression analysis identified three factors associated with higher TMB: smoking status: smoker, increase PET SUV, and sCEA level: >5 ng/mL (P

Abstract Background Suspensory cortical buttons are widely used for fixation of reconstructed ligaments during anterior cruciate ligament (ACL) reconstruction because they have high usability and a favorable fixing force. However, it is not always easy to fix a reconstructed ACL while maintaining appropriate ligament tension. Therefore, we developed an improved cortical button that provides temporary tension until suturing is completed. Methods Button holes of our improved EndoButton are not perpendicular to the bone surface on which the button is placed, but have an angle of 45 degrees so that the button can be temporarily fixed by applying tension to the suture. The improved EndoButton and the original EndoButton (Smith & Nephew Inc., Andover, Massachusetts) were each tied to FiberWire 5/7 metric (5 M) (manufactured by Arthrex). Ten cycles of preliminary loading (0–50 N) were applied to each suture, followed by test loading (0–250 N) for 500 or 1000 cycles. Then, a tensile test was performed at a displacement velocity of 20 mm/min. Results The breaking strength of the sutures of the improved EndoButton were tend to higher than those of the sutures of the original EndoButton after 1000 loading cycles (p = 0.067, d = 0.883). The moduli of rigidity of the sutures of the improved EndoButton were higher than those of the sutures of the original EndoButton after 500 loading cycles (p = 0.027) and remained almost the same regardless of the number of loading cycles. Conclusion We found that compared with the original cortical button, the improved cortical button was better able to retain suture breaking strength and modulus of rigidity, regardless of the number of load cycles.

Introduction: The phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46–0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. Methods: Patients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. Results: The Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431–0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424–1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317–0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). Conclusions: Clinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression.

Abstract Background Nivolumab is a programmed cell death 1 (PD‐1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non‐squamous (non‐SQ) non‐small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO‐4538‐05) and non‐SQ (ONO‐4538‐06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2‐42.1) and 22.4% (14.5‐32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long‐term safety and efficacy in patients with SQ and non‐SQ NSCLC by pooling data from these two trials. Methods SQ (N = 35) and non‐SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan–Meier method. A pooled analysis of SQ and non‐SQ patients was also performed. Results In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4‐25.2), and the estimated 1‐year, 2‐year, and 3‐year survival rates were 71.4% (53.4‐83.5), 37.1% (21.6‐52.7), and 20.0% (8.8‐34.4), respectively. In non‐SQ NSCLC patients, median OS was 17.1 months (13.3‐23.0), and the estimated 1‐, 2‐, and 3‐year survival rates were 68.0% (56.2‐77.3), 37.4% (26.5‐48.1), and 31.9% (21.7‐42.5), respectively. When SQ NSCLC and non‐SQ NSCLC data were pooled, the median OS was 17.1 months (14.2‐20.6), and the estimated 1‐, 2‐, and 3‐year survival rates were 69.1% (59.6‐76.8), 37.3% (28.3‐46.2), and 28.1% (20.0‐36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found. Conclusion Treatment with nivolumab improved long‐term survival and was well tolerated in patients with SQ and non‐SQ NSCLC. Trial registration JapicCTI‐132072; JapicCTI‐132073.

Study Design Multicenter, prospective study. Purpose To investigate the effects of diabetes mellitus (DM) on surgical outcomes in patients with cervical myelopathy. Overview of Literature To date, few studies have investigated the influence of postoperative blood glucose or glycated hemoglobin (HbA1c) levels on surgical outcomes. Methods The participants were patients who underwent surgery for the treatment of cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament. The 61 cases were evaluated preoperatively and 1 year postoperatively using the Japanese Orthopaedic Association (JOA) scores and the JOA Cervical Myelopathy Evaluation Questionnaire (JOACMEQ). The study variables included fasting blood glucose and HbA1c levels measured preoperatively and at 1 week, 4 weeks, and 1 year postoperatively; the F-wave conduction velocity, latency, rate of occurrence, and M-wave latency in the ulnar and tibial nerves were measured preoperatively and at 1 year postoperatively. The patients were divided into a group without diabetes (N group, 42 patients) and a group with diabetes (DM group, 19 patients). We then assessed the associations between the surgical outcomes and each of the study variables. Results JOA scores significantly improved in both groups; however, no significant between-group differences were found. There was no significant improvement in the JOACMEQ scores, which assessed cervical function, upper and lower limb function, and bladder function in both groups. We then subdivided the DM group into those with a good control of HbA1c after 1 year (DMG group, 12 patients) and those with HbA1c deterioration after 1 year (DMB group, seven patients), prior to comparing the surgical outcomes. The JOACMEQ scores for upper and lower limb function significantly improved in the DMG group (p

Abstract Background Sporadic inclusion body myositis (sIBM) is the most prevalent muscle disease in elderly people, affecting the daily activities. sIBM is progressive with unknown cause and without effective treatment. In 2015, sIBM was classified as an intractable disease by the Japanese government, and the treatment cost was partly covered by the government. This study aimed to examine the changes in the number of patients with sIBM over the last 10 years and to elucidate the cross-sectional profile of Japanese patients with sIBM. Methods The number of sIBM patients was estimated through a reply-paid postcard questionnaire for attending physicians. Only patients diagnosed as “definite” or “probable” sIBM by clinical and biopsy sIBM criteria were included in this study (Lancet Neurol 6:620-631, 2007, Neuromuscul Disord 23:1044-1055, 2013). Additionally, a registered self-administered questionnaire was also sent to 106 patients who agreed to reply via their attending physician, between November 2016 and March 2017. Results The number of patients diagnosed with sIBM for each 5-year period was 286 and 384 in 2011 and 2016, respectively. Inability to stand-up, cane-dependent gait, inability to open a plastic bottle, choking on food ingestion, and being wheelchair-bound should be included as sIBM milestones. Eight patients were positive for anti-hepatitis C virus antibody; three of them were administered interferon before sIBM onset. Steroids were administered to 33 patients (31.1%) and intravenous immunoglobulin to 46 patients (43.4%). From 2016 to 2017, total of 70 patients applied for the designated incurable disease medical expenses subsidy program. Although the treatment cost was partly covered by the government, many patients expressed psychological/mental and financial anxieties. Conclusions We determined the cross-sectional profile of Japanese patients with sIBM. Continuous support and prospective surveys are warranted.

Abstract Background Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study. Methods Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development. Discussion This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer. Trial registration Registered at August 23, 2017. Registry number: UMIN000028801.

Abstract Background Mesentero-axial gastric volvulus (MAGV) is a rare but critical condition as delay in treatment can lead to lethal situations. Although the report of the surgical treatment with laparoscopic approach for MAGV has recently come to be seen, no standard procedures have been established. We aim to describe our operative technique of single-incision laparoscopic gastropexy (SILG) for MAGV and review the relevant literature to ascertain the most appropriate treatment option in these patients. Case presentation Three patients were referred to our hospital because abdominal pain and vomiting suddenly occurred. Acute MAGV was diagnosed by upper gastrointestinal study. After overnight gastric decompression with a nasal tube, the GV was resolved spontaneously. Elective SILG was planned. Single incision at the umbilicus was made and three 5-mm trocars were inserted. The anterior wall of the body of the stomach was sutured to the peritoneum using 6 × 4-0 non-absorbable sutures for prevention of recurrence of GV and occurrence of internal hernia through the space created between the sutures. Two boys and a girl with mean age 4 ± 2 years underwent SILG. The mean time of the operation was 48 ± 23 min. All of the procedures were completed safely, and there were no postoperative complications. The mean time of postoperative hospitalization was 4 ± 1 days. All patients had good cosmetic and clinical results. Conclusion We found SILG is a safe, technically feasible, and minimally invasive approach with low incidence of postoperative complication and the best cosmetic result for the patients with MAGV.

Abstract Background Combinations of exercise and nutritional interventions might improve the functional prognosis for cachectic cancer patients. However, high attrition and poor compliance with interventions limit their efficacy. We aimed to test the feasibility of the early induction of new multimodal interventions specific for elderly patients with advanced cancer Nutrition and Exercise Treatment for Advanced Cancer (NEXTAC) programme. Methods This was a multicentre prospective single‐arm study. We recruited 30 of 46 screened patients aged ≥70 years scheduled to receive first‐line chemotherapy for newly diagnosed, advanced pancreatic, or non‐small‐cell lung cancer. Physical activity was measured using pedometers/accelerometer (Lifecorder®, Suzuken Co., Ltd., Japan). An 8 week educational intervention comprised three exercise and three nutritional sessions. The exercise interventions combined home‐based low‐intensity resistance training and counselling to promote physical activity. Nutritional interventions included standard nutritional counselling and instruction on how to manage symptoms that interfere with patient's appetite and oral intake. Supplements rich in branched‐chain amino acids (Inner Power®, Otsuka Pharmaceutical Co., Ltd., Japan) were provided. The primary endpoint of the study was feasibility, which was defined as the proportion of patients attending ≥4 of six sessions. Secondary endpoints included compliance and safety. Results The median patient age was 75 years (range, 70–84). Twelve patients (40%) were cachectic at baseline. Twenty‐nine patients attended ≥4 of the six planned sessions (96.7%, 95% confidence interval, 83.3 to 99.4). One patient dropped out due to deteriorating health status. The median proportion of days of compliance with supplement consumption and exercise performance were 99% and 91%, respectively. Adverse events possibly related to the NEXTAC programme were observed in five patients and included muscle pain (Grade 1 in two patients), arthralgia (Grade 1 in one patient), dyspnoea on exertion (Grade 1 in one patient), and plantar aponeurositis (Grade 1 in one patient). Conclusions The early induction of multimodal interventions showed excellent compliance and safety in elderly patients with newly diagnosed pancreatic and non‐small‐cell lung cancer receiving concurrent chemotherapy. We are now conducting a randomized phase II study to measure the impact of these interventions on functional prognosis.

Abstract Background Laparoscopic percutaneous extraperitoneal closure (LPEC) has become a common procedure for repairing inguinal hernia. As a laparoscopic approach, pediatric surgical trainees require more training to learn LPEC than a traditional open approach. This study aimed to clarify the experience needed to acquire the skill to perform LPEC adequately. Methods This descriptive single-center study used clinical data from patients who underwent LPEC between May 2009 and May 2016. The mean operative time for ten consecutive unilateral repairs was used as an index of proficiency with the procedure. The number of repairs performed before the mean operative time became less than 20 min was evaluated for each trainee. Results During the study period, six pediatric surgical trainees participated in the training independently. The number of the patients was 987. The total number of repairs was 1436, including 538 unilateral repairs and 449 concurrent bilateral repairs. Overall, the mean operative time was 21.8 ± 8.1 min for unilateral repair and 31.4 ± 9.7 min for concurrent bilateral repairs. The mean number of repairs performed before the acquisition of skill for dexterous LPEC was 125.1 ± 29.5. Conclusions Although there were individual differences, all trainees acquired the skill to perform LPEC adequately within one year. With appropriate guidance, LPEC can become a standard technique for pediatric surgical trainees, along with traditional open surgery. These results provide valuable information for planning LPEC training.

Background Myotonic dystrophy type 1 involves cardiac conduction disorders. Cardiac conduction disease can cause fatal arrhythmias or sudden death in patients with myotonic dystrophy type 1. Methods and Results This study enrolled 506 patients with myotonic dystrophy type 1 (aged ≥15 years; >50 cytosine‐thymine‐guanine repeats) and was treated in 9 Japanese hospitals for neuromuscular diseases from January 2006 to August 2016. We investigated genetic and clinical backgrounds including health care, activities of daily living, dietary intake, cardiac involvement, and respiratory involvement during follow‐up. The cause of death or the occurrence of composite cardiac events (ie, ventricular arrhythmias, advanced atrioventricular blocks, and device implantations) were evaluated as significant outcomes. During a median follow‐up period of 87 months (Q1–Q3, 37–138 months), 71 patients expired. In the univariate analysis, pacemaker implantations (hazard ratio [HR], 4.35; 95% CI, 1.22–15.50) were associated with sudden death. In contrast, PQ interval ≥240 ms, QRS duration ≥120 ms, nutrition, or respiratory failure were not associated with the incidence of sudden death. The multivariable analysis revealed that a PQ interval ≥240 ms (HR, 2.79; 95% CI, 1.9–7.19, P

Introduction: Programmed cell death 1 (PD-1) inhibitors have become standard treatment for patients with advanced NSCLC. However, few studies have focused on the impact of cancer cachexia on the efficacy of PD-1 or programmed death-ligand 1 (PD-L1) inhibitors among patients with NSCLC. Methods: We retrospectively reviewed medical records of patients with advanced NSCLC who received PD-1 or PD-L1 inhibitor monotherapy from May 2016 to December 2018. We defined cancer cachexia as unintentional weight loss greater than 5% over 6 months and high PD-L1 as greater than 50% expression on tumor cells. We evaluated the objective response rates (ORRs) and progression-free survival (PFS). Results: Among 108 patients, 52 had cancer cachexia. Patients with cachexia had a lower ORR (15% versus 57%, p < 0.001) and shorter PFS (2.3 mo versus 12.0 mo, p < 0.001) than those without cachexia. Patients with low PD-L1 expression had a lower ORR (14% versus 53%, p < 0.001) and shorter PFS (2.8 mo versus 10.8 mo, p = 0.002) than those with high PD-L1 expression. Multivariate analysis revealed cancer cachexia and low PD-L1 expression as independent negative predictors of PFS. Among patients with cachexia, there was no significant difference in the ORR (p = 0.514) or PFS (p = 0.992) on the basis of PD-L1 expression. Conclusions: Our findings indicate that cancer cachexia might be a negative predictor of the efficacy of PD-1 or PD-L1 inhibitors and reduce the impact of PD-L1 expression on the effect of PD-1 or PD-L1 inhibitors in patients with advanced NSCLC. Further clinical and basic studies are needed.

Abstract Background A pyriform sinus fistula (PSF) is a rare branchial anomaly that causes recurrent cervical infections. Open neck surgery has widely been accepted as a definitive treatment for PSFs, and endoscopic surgery has been reported in recent years. However, both approaches are not satisfactory because of high recurrence rates and postoperative complications. Microlaryngoscopic surgery (MLS) is a transoral surgical technique involving the use of an operating microscope. In this report, we present a new procedure involving MLS for resection and closure of a PSF without a skin incision. Case presentation Technique: MLS was performed under general anesthesia with endotracheal intubation. The patient was placed in the supine position, and a direct laryngoscope was inserted to expose the pyriform sinus, which was then magnified using an operating microscope. The mucosal layer was carefully resected using scissors and cupped forceps with sharp edges. The fistula was securely sutured using absorbable suture material. Case 1: A 9-year-old boy with recurrent neck abscesses since 8 years of age presented to our hospital after receiving antibiotics and undergoing drainage in other hospitals. After admission to our hospital, barium esophagography and oral contrast coronal computed tomography showed a PSF on the left side, and open neck surgery was performed to resect the fistula. He was eventually discharged from the hospital without any problem. However, a PSF recurred 2 weeks later. As reoperation with the cervical approach was considered difficult owing to severe adhesions, we adopted MLS as a definitive operation. The postoperative course was uneventful. No recurrence was observed during an 18-month follow-up. Case 2: A 10-year-old girl presented to our hospital with recurrent left-sided neck swelling since 6 years of age. After inflammation control, a PSF was identified on the left side on barium esophagography and computed tomography. MLS was performed safely, and the postoperative course was uneventful. No recurrence was observed during a 10-month follow-up. Conclusions MLS allows excellent visualization and effective closure for PSFs, and this approach is suitable for recurrence after open neck surgery. Therefore, MLS might become a first-line treatment for PSFs in children.

Abstract Background Primary adenocarcinoma of the appendix is a rare disease in clinical practice. Moreover, primary adenocarcinoma of the appendix in the pediatric age group is even rarer with very little cases being published. Here, we report a case of primary adenocarcinoma of the appendix with local invasion into adjacent organs in a child who was initially diagnosed as having an acute appendicitis. Case presentation A 13-year-old girl presented with abdominal pain of 3-month duration. Imaging study showed a mass including the fecalith that occupied her pelvic and right lower abdominal cavity. Drainage of the abscess and appendectomy were performed by the preoperative diagnosis of an acute appendicitis with an appendiceal mass. Postoperative histopathological examinations revealed the appendiceal adenocarcinoma. She then received the whole mass resection, ileocecal resection with lymph node dissection. The masses were tightly adherent with infiltration into the sigmoid colon, uterus, and right ovary. These organs were all dissected, and subsequent sigmoid colostomy was performed. We preserved the left ovary for her fertility. The pathological findings demonstrated negative margins and no lymph node invasions, and final pathological stage was pT4(SI)N0M0, stage II. After the operation, she received the chemotherapy with 6 cycles of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (mFOLFOX6) and subsequent 6 cycles of simplified LV and 5-FU (sLV5FU2). The patient is doing well till today on follow-up without progression of the disease 5 years after the operation. Conclusion Primary adenocarcinoma of the appendix is exceedingly rare in children. In this report, we described one of the youngest primary adenocarcinomas of an appendix case ever reported. When encountering atypical cases of the appendicitis, we should consider the possibility of primary adenocarcinoma of the appendix as it has an extremely poor prognosis and is usually diagnosed in advanced stages.

Background: The combination of congenital tracheal stenosis (CTS) and unilateral pulmonary agenesis is rare and fatal. Especially, right lung agenesis is associated with dextrocardia and often causes tracheal alignment disorder. The mortality is estimated with 12.5–65%. Slide Tracheoplasty (ST) has been improved the prognosis, however, the postoperative course of CTS with single lung remains unclear. Here, we describe the postoperative challenging situation with bronchial intervention and other devices. Case presentation: A 9-month-old girl with CTS, right lung agenesis, dextrocardia, and bilateral superior vena cava underwent ST anterior to the aortic arch. On postoperative day 50, tracheostomy was performed for long-term airway pressure support. Six months after the ST, she showed severe bronchomalacia at the bifurcation of the lobar bronchi, which was sandwiched between the descending aorta and left pulmonary artery. Direct bronchopexy and mobilization of left pulmonary artery resolved the severe bronchomalacia. Additionally, the kinked trachea caused a tracheal ulcer and frequent accidental decannulations. The ulcer was made above the aortic arch by contact with the tracheal cannula. The customized Montgomery T-tube solved both problems and enabled the stable management for airway. Her condition eventually improved, and she was discharged home after 14 months of hospitalization. Conclusion: This case presented a very rare and critical condition. This is the first report to address the severe condition after ST anterior to the aortic arch. Surgical interventions or other devices for treatment are thought to be modified according to each condition. Keywords: Conjenital tracheal stenosis, Unilateral pulmonary agenesis, Dextorcardia, Bronchomalacia, Direct bronchopexy, Customized Montgomery T-tube