齋藤 合

In clinical clerkship (CC), medical students can practice evidence-based medicine (EBM) with their assigned patients. Although CC can be a valuable opportunity for EBM education, the impact of EBM training, including long-term behavioral changes, remains unclear. One hundred and nine fourth- and fifth-year medical students undergoing CC at a medical school in Japan attended a workplace-based learning program for EBM during CC (WB-EBM), which included the practice of the five steps of EBM. The program's effect on the students' attitudes toward EBM in CC was assessed through questionnaires. A total of 88 medical students participated in the program. Responses to the questionnaire indicated high satisfaction with the WB-EBM program. The most common theme in students' clinical problems with their assigned patients was the choice of treatment, followed by its effect. Based on the responses in the post-survey for the long-term effects of the program, the frequency of problem formulation and article reading tended to increase in the 'within six months' group comprising 18 students who participated in the WB-EBM program, compared with the control group comprising 34 students who did not. Additionally, the ability to self-assess problem formulation was significantly higher, compared with the control group. However, among 52 students who participated in the WB-EBM program more than six months later, EBM-related behavioral habits in CC and self-assessments of the five steps of EBM were not significantly different from those in the control group. The WB-EBM program was acceptable for medical students in CC. It motivated them to formulate clinical questions and enhanced their critical thinking. Moreover, the WB-EBM program can improve habits and self-evaluations about EBM. However, as its effects may not last more than six months, it may need to be repeated across departments throughout CC to change behavior in EBM practice.

PURPOSE: Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKIs). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells. EXPERIMENTAL DESIGN: Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-RTK antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET-fusion-positive lung cancer were analyzed for pre-treatment YAP expression and correlated with treatment outcomes. RESULTS: In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/TEAD inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pre-treatment YAP expression in clinical specimens obtained from patients with RET-fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes. CONCLUSION: The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.

BACKGROUND: The optimal subsequent treatment strategy for locally advanced non-small cell lung cancer (LA-NSCLC) after chemoradiotherapy (CRT) and consolidative durvalumab therapy remains unknown. We aimed to determine the optimal subsequent treatment strategy for this clinical population. MATERIALS AND METHODS: We retrospectively enrolled 523 consecutive patients with LA-NSCLC treated with CRT and analyzed the treatment outcomes of subsequent therapy after progression following CRT and consolidative durvalumab therapy. Patients who received tyrosine kinase inhibitors as subsequent therapy were excluded. RESULTS: Out of 122 patients who received subsequent chemotherapy, 55% underwent platinum-based, 25% non-platinum-based, and 20% immune checkpoint inhibitor (ICI)-containing therapies. In the platinum-based group, patients with a durvalumab-progression-free survival (Dur-PFS) ≥ 1 year had a significantly longer median subsequent therapy-PFS (SubTx-PFS) than those with Dur-PFS < 1 year (13.2 months vs. 4.7 months; hazard ratio, 0.45; 95% confidence interval, 0.21-0.97; P = .04). Furthermore, among patients receiving non-platinum-based chemotherapy, the median SubTx-PFS was longer in the combined with angiogenesis inhibitor group than in the without group, although the difference was not statistically significant. No significant difference of SubTx-PFS was observed between the reason for durvalumab discontinuation and the outcomes of ICI-containing therapy. CONCLUSION: In clinical practice, platinum-based chemotherapy rechallenge is frequently employed following progression subsequent to CRT and consolidative durvalumab therapy for LA-NSCLC. Optimal treatment strategies may consider Dur-PFS and angiogenesis inhibitor feasibility. Further research is warranted to identify clinical biomarkers that can help identify patients who would benefit from ICI rechallenge.

Locoregional recurrence of non-small-cell lung cancer (NSCLC) after complete resection lacks standard treatment. Durvalumab after chemoradiotherapy (CRT) or CRT alone is often selected in daily clinical practice for patients with locoregional recurrence; however, the therapeutic efficacy of these treatments remains unclear, and we aimed to assess this. This retrospective observational study used data from patients with NSCLC diagnosed with locoregional recurrence after complete resection who subsequently underwent concurrent CRT followed by durvalumab (CRT-D group) or CRT alone (CRT group). We employed propensity score analysis with inverse probability treatment weighting (IPTW) to adjust for various confounders and evaluate efficacy in the CRT-D group. After IPTW adjustment, the CRT-D group contained 119 patients (64.7% male; 69.7% adenocarcinoma), and the CRT group contained 111 patients (60.5% male; 73.4% adenocarcinoma). Their mean ages were 66 and 65 years, respectively. The IPTW-adjusted median progression-free survival was 25.4 and 11.5 months for the CRT-D and CRT groups, respectively (hazard ratio, 0.44; 95% confidence interval, 0.30-0.64); the median overall survival was not reached in either group favoring CRT-D (hazard ratio, 0.49; 95% confidence interval, 0.24-0.99). Grade 3 or 4 adverse events were observed in 48.8% of patients during CRT, 10.7% after initiating durvalumab maintenance therapy in the CRT-D group, and 57.3% in the CRT group. Overall, the sequential approach of CRT followed by durvalumab is a promising treatment strategy for locoregional recurrence of NSCLC after complete resection.

OBJECTIVES: Certain guidelines recommend caution when administering immunotherapy in patients with pre-existing interstitial lung disease (ILD) owing to the high incidence of pneumonitis induced by anti-cancer therapy. A prospective clinical trial assessing the safety of chemoimmunotherapy in patients with small-cell lung cancer (SCLC) and pre-existing ILD is warranted. Therefore, this study evaluated the safety and efficacy of chemoimmunotherapy in patients with extensive-stage (ES)-SCLC and mild idiopathic interstitial pneumonia (IIP). METHODS: In this multicenter prospective trial, patients with ES-SCLC and pre-existing mild chronic fibrosing IIP were recruited. Mild IIP was defined as the exclusion of poor pulmonary function, a definite usual interstitial pneumonia (UIP) pattern, and positivity for autoantibodies in blood tests. The patients received durvalumab, etoposide, and carboplatin every three weeks (induction phase), followed by 1,500 mg durvalumab every four weeks (maintenance phase). The primary endpoint was severe pneumonitis-free rate. RESULTS: Twenty-one patients were included in the analysis. Among them, 13 patients displayed a probable UIP pattern, whereas eight patients exhibited an indeterminate for UIP pattern. Two patients (9.5 %) had pneumonitis of any grade during the induction phase; one had Grade 1 and the other had Grade 5 pneumonitis. No other patient developed pneumonitis during the maintenance phase. The severe pneumonitis-free rate was 95.2 % (95 % confidence interval (CI): 77.3-99.2 %). The median progression-free survival was 5.5 months (95 % CI: 3.6-6.4 months). Median overall survival was 10.7 months (95 % CI: 6.0 months to not reached). CONCLUSIONS: Chemoimmunotherapy is a feasible treatment approach for patients with ES-SCLC and mild IIP.

Although intrathoracic extramedullary haematopoiesis (EMH) is rare, its nodular lesions should be differentiated from malignancy. 111In-bone marrow scintigraphy can be useful for the non-invasive diagnosis of intrathoracic EMH because extramedullary accumulation of 111In can be determined as EMH.

IMPORTANCE: Chemoimmunotherapy is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). However, whether findings from pivotal trials can be extrapolated to the clinical practice setting remains unclear. OBJECTIVE: To compare treatment outcome gaps following first-line chemoimmunotherapy for patients with ES-SCLC between those who met and did not meet the eligibility criteria used in previous clinical trials. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted from September 1, 2019, to September 30, 2020, at 32 hospitals in Japan, with at least 12 months of follow-up. Participants included consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as first-line therapy. EXPOSURES: Patients who met eligibility criteria for pivotal phase 3 clinical trials were considered trial-eligible. MAIN OUTCOMES AND MEASURES: The primary outcome was 6-month progression-free survival. The secondary outcomes were differences in progression-free survival, overall survival, and safety according to whether key clinical trial eligibility criteria were met. RESULTS: A total of 207 patients were analyzed (median age, 72 years; range, 46-87 years; 170 [82%] were male). Sixty-four patients (31%) were older adults (age ≥75 years), and most (184 [89%]) had an Eastern Cooperative Oncology Group performance status of 0 or 1. There were 132 (64%) trial-eligible patients. The 6-month progression-free survival rate for all patients was 38.8% (95% CI, 32.4%-45.7%). The median progression-free survival was 5.1 months in trial-eligible patients and 4.7 months in trial-ineligible patients (hazard ratio, 0.72; 95% CI, 0.53-0.97; P = .03). The proportion of patients who achieved disease control was 93% (118 of 127) in trial-eligible patients and 77% (55 of 71) in trial-ineligible patients (P = .002). The median overall survival was 15.8 months in trial-eligible patients and 13.1 months in trial-ineligible patients (hazard ratio, 0.73; 95% CI, 0.51-1.07; P = .10). The rate of severe adverse events was numerically higher among trial-ineligible patients than among trial-eligible patients (39% vs 27%; P = .07). CONCLUSIONS AND RELEVANCE: In this cohort study, the overall treatment outcome was comparable to that reported in pivotal clinical trials. However, treatment outcomes after chemoimmunotherapy might differ between trial-eligible and trial-ineligible patients. These findings suggest that trial-eligibility criteria may be useful in clinical practice, and further studies using data from clinical practice settings are required to inform regulatory approval and clinical decision-making.

Introduction: Malignant pleural effusion (MPE) is associated with poor treatment outcome in patients with NSCLC receiving immune checkpoint inhibitors (ICIs). ICIs and chemotherapy (ICI/Chemo) combination therapy is currently the standard therapy for NSCLC, and some ICI/Chemo regimens for nonsquamous (non-Sq) NSCLC contain bevacizumab (BEV), which is effective for controlling MPE and may enhance immune response. This study aimed to determine the optimal first-line treatment for this clinical population. Methods: We retrospectively enrolled consecutive patients with non-Sq NSCLC with MPE who received ICI/Chemo or pembrolizumab monotherapy. Treatment outcomes were analyzed in patients with programmed death-ligand 1 (PD-L1) tumor proportion score more than or equal to 50% who were administered ICI/Chemo or pembrolizumab monotherapy (PD-L1 high cohort) and in patients with any PD-L1 status, treated with ICI/Chemo with or without BEV (ICI/Chemo cohort). We used propensity score matching (PSM) to reduce bias. Results: PD-L1 high and ICI/Chemo cohorts included 143 and 139 patients, respectively. In PD-L1 high cohort, 37 patients received ICI/Chemo. With PSM, the median progression-free survival was significantly longer in the ICI/Chemo group than in the pembrolizumab group (11.1 versus 3.9 mo, respectively, p = 0.0409). In the ICI/Chemo cohort, 23 patients received BEV. With PSM, no significant difference occurred in median progression-free survival between BEV and non-BEV groups (6.1 versus 7.4 mo, p = 0.9610). Conclusion: ICI/Chemo seemed more effective than pembrolizumab monotherapy for patients with non-Sq NSCLC with MPE. Nevertheless, the synergistic effect of BEV with ICI/Chemo may be limited. Further studies are needed to clarify the key factor in the tumor-induced immunosuppression environment in these patients.

BACKGROUND: Coronavirus disease (COVID-19) has induced an urgent need to train medical students not only in infection prevention control but also in the treatment of infectious diseases, including COVID-19. This study evaluates the impact of simulated clinical practice with peer role-plays and a lecture on clinical education for COVID-19. METHODS: The sample for the study included 82 fourth- and fifth-year medical students undergoing clinical clerkship in respiratory medicine. They answered questionnaires and participated in semi-structured focus group interviews (FGIs) regarding the advantages of simulated clinical practice with peer role-plays and lectures on clinical education for COVID-19. RESULTS: A total of 75 students participated in the COVID-19 education program between January and November 2021. The responses to the questionnaire revealed that the satisfaction level of students with COVID-19 education was high. No significant change was found among students concerning fear of COVID-19 before and after the program. The degree of burden of handling information on COVID-19 reduced significantly, while the degree with respect to the use of personal protective equipment (PPE), including appropriate wearing and removing of PPE, and care of patients with confirmed COVID-19 while taking steps to prevent infection, exhibited a decreasing trend. Nine FGIs were conducted (n = 74). The advantages of simulated clinical practice were segregated into five categories (infection prevention control, educational methods, burden on healthcare providers, self-reflection, and fear of COVID-19); and that of the lecture were segregated into four categories (information literacy, knowledge of COVID-19, educational methods, and self-reflection). CONCLUSIONS: Simulated clinical practice with peer role-plays and the lecture pertaining to COVID-19 can prove to be efficient and safe methods for learning about COVID-19 infection and prevention control for medical students. They can reduce the burden of COVID-19 patients' care. Moreover, they can also provide an opportunity for self-reflection, realize the burden of medical care, and acquire relevant information.

BACKGROUND AND OBJECTIVE: Osimertinib as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR) mutations remains controversial. Sequential EGFR-tyrosine kinase inhibitor (TKI) might be superior to the first line osimertinib in patients at risk of developing acquired T790M mutations. METHODS: We enrolled consecutive patients with EGFR-mutated (deletion 19 or L858R) advanced NSCLC treated with first-line drugs and evaluated predictive markers using classification and regression tree (CART) for the detection of T790M mutations based on patient backgrounds prior to initial treatment. RESULTS: Patients without acquired T790M mutations had worse outcomes than those with T790M mutations (median OS: 798 days vs. not reached; HR: 2.70; P < 0.001). CART identified three distinct groups based on variables associated with acquired T790M mutations (age, CYF, WBC, liver metastasis, and LDH; AUROC: 0.77). Based on certain variables, CART identified three distinct groups in deletion 19 (albumin, LDH, bone metastasis, pleural effusion, and WBC; AUROC: 0.81) and two distinct groups in L858R (age, CEA, and ALP; AUROC: 0.80). The T790M detection frequencies after TKI resistance of afatinib and first-generation EGFR-TKIs were similar (35.3% vs. 37.4%, P = 0.933). Afatinib demonstrated longer PFS (398 vs. 279 days; HR: 0.67; P = 0.004) and OS (1053 vs. 956 days; HR: 0.68; P = 0.051) than first-generation EGFR-TKIs. CONCLUSION: Identification of patients at risk of acquiring T790M mutations after EGFR-TKI failure may aid in choice of first-line EGFR-TKI. Furthermore, afatinib may be the more effective 1st-line EGFR-TKI treatment for patients at risk of developing T790M as initial EGFR-TKI resistance.

INTRODUCTION: The real-world effectiveness of combination treatment with cytotoxic chemotherapy and programmed cell death protein-1 or programmed death-ligand 1 inhibitor for NSCLC, especially for the elderly (aged ≥75 y) or those with poor performance status (≥2), has not been fully elucidated. We investigated the real-world effectiveness and safety of this combination therapy in these populations. METHODS: This multicenter retrospective study evaluated patients who are chemo-naïve with advanced NSCLC who received a combination of platinum, pemetrexed, and pembrolizumab between December 2018 and June 2019. This was an updated prespecified secondary analysis with the primary objective of investigating the safety and effectiveness in this cohort. RESULTS: Overall, 299 patients were included. Multivariate analysis identified performance status (0-1) and programmed death-ligand 1 tumor proportion score (≥50%) as significant independent predictors of progression-free survival (p = 0.007, and p = 0.003, respectively). The incidence of severe adverse events (AEs) was higher in the elderly and those with poor performance status than in their younger and good performance status counterparts. A total of 71 patients developed AEs that led to treatment discontinuation, and AE-related treatment discontinuation occurred at a significantly higher rate in older patients (median [range]) (70 [46-82] y) than in younger patients (68 [31-84] y) (p <0.001). CONCLUSIONS: Combination treatment with pembrolizumab plus chemotherapy had low real-world effectiveness for poor performance status patients. Severe AEs occurred at a higher rate in the elderly and poor performance status patients, and the AE-related treatment discontinuation rate increased with age. Physicians should be cautious about using this regimen, especially in the elderly and poor performance status patients.

Background: Childhood cancer survivors (CCSs) have a lifelong increased risk of chronic health problems, most of which are associated with the curative therapies. Recent studies have suggested that prospective active screening using comprehensive assessments for CCSs is superior in identifying undiagnosed chronic health problems. Methods: To assess the significance of active screening using comprehensive medical examinations for detecting chronic health problems in multiple organ systems in CCSs, we retrospectively compared the frequency and severity of health problems between two different cohorts of CCSs in a single institution: 110 CCSs who visited the outpatient clinic for regular follow-ups between December 2010 and December 2015 (regular follow-up group) vs. 58 CCSs who underwent comprehensive medical examinations between February 2016 and September 2019 (active screening group). CCSs were defined as patients aged ≥ 18 years who had been diagnosed as having childhood cancer ≥ 10 years before and had survived without cancer for ≥ 5 years. Results: Patient characteristics were similar between the two groups except for primary diagnosis (more brain tumors and embryonal tumors in the active screening group) and treatment history (more alkylating agents used and surgical interventions performed in the active screening group). The prevalence and the median number of health problems were significantly higher in the active screening group than in the regular follow-up group: 93% vs. 67% and 1.0 [0.0-8.0] vs. 2.0 [0.0-7.0] respectively. In term of organ-specific health problems, pulmonary dysfunction, neurocognitive impairment, ocular abnormalities, and dental abnormalities were identified more in the active screening group, partly because these problems had not been assessed in the regular follow-up group. Nevertheless, the prevalence of grade 3-5 health problems was similar between the two groups, except for pulmonary dysfunction. Conclusion: Active screening using comprehensive medical examinations was effective for identifying health problems in CCSs. Although the prevalence of severe problems identified by both approaches was similar, comprehensive medical examinations could detect overlooked problems such as severe pulmonary dysfunction, dental maldevelopment, and borderline intellectual functioning, which might have an impact on quality of life in CCSs.

Histologic transformation (HT) is a major cause of drug resistance to therapy in patients with lung cancer. HTs to small-cell lung cancer (SCLC) have been reported frequently in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer. Although HTs have an impact on the clinical outcomes in patients owing to a high refractoriness to treatments, there is limited data on the prevalence, causes, mechanisms, treatment efficacy, and future treatment strategies. In this review, we assess the literature regarding HTs comprehensively, including those describing EGFR-tyrosine kinase inhibitors, other molecular targeted drugs, and immune checkpoint inhibitors. Furthermore, we discuss the mechanisms of HTs and the lineage plasticity to SCLC and squamous cell carcinoma in lung cancer. In addition, we summarize the treatment efficacy and future perspectives of HTs in patients with lung cancer, and propose better management strategies for this group of patients.

千葉大学医学部附属病院呼吸器内科での医師臨床研修における取り組みの効果を検証した。2020年度より指導者間で研修医面談によるニーズ評価と日々の研修内容の情報共有を行い、研修の調整を行った。研修満足度や研修内容に関してアンケートで2019年度と比較した。2019年度と比較し研修満足度が有意に高くなり、経験できた項目や疾患が増加した。呼吸器内科への興味も有意に高かった。指導者間の学習者ニーズ評価、研修内容の情報共有は研修医の満足度を向上させ、研修の充実につながる。(著者抄録)

BACKGROUND: Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient. METHODS: We performed a retrospective multicentre cohort study for 538 EGFR mutation-positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS). RESULTS: The median observation period was 14.7 months (interquartile range 11.4-20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6-not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35-2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11-2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03-2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04-2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01-2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70-5.83, P < 0.001) were associated with PFS. PD-L1 expression of 1-49% (HR 1.66, 95% CI 1.05-2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17-4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05-2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%). CONCLUSION: During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation.

BACKGROUND: Routine positron emission tomography/computed tomography (PET/CT) has been recommended even for clinical stage I non-small-cell lung cancer (NSCLC). In spite of the progress in the screening procedure, and revisions to TNM classification, there is no evidence to support brain imaging screening of patients assessed with the current staging protocol including PET/CT. MATERIALS AND METHODS: We retrospectively investigated the frequency of extrathoracic metastasis in 466 consecutive patients with clinical stage T1-2 N0 NSCLC with the complete staging assessment comprised of thin-section CT, PET/CT, and brain contrast-enhanced magnetic resonance imaging between 2008 and 2016. All patients were reclassified according to the eighth edition of the tumor, node, and metastasis (TNM) classification. RESULTS: Among all patients, 70% of the tumors were pure solid and 30% had part-solid ground-glass opacity on thin-section CT, and 388 (83%) and 78 (17%) were classified into clinical stages T1 and T2, respectively. Eight patients (1.7%) had extrathoracic metastasis, including 3 (0.6%) with brain metastasis, and all showed pure-solid tumors. The frequency of extrathoracic and brain metastasis was 1.0% and 0.5% in 388 T1 patients, and 5.0% and 3.0% in 78 T2 patients. Although brain metastases were detected in 2 of 7 patients (29%) with PET/CT detectable extrathoracic metastases and 1 of 459 patients (0.2%) without PET/CT detectable extrathoracic metastasis, there were no neurologically asymptomatic brain metastases in patients with early-stage NSCLC confirmed by PET/CT. CONCLUSION: Routine screening of brain imaging is unnecessary in patients with early-stage NSCLC, assessed with the current staging protocol including PET/CT.

OBJECTIVES: The incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019. RESULTS: Median age was 70 (range: 40-87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P < 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study's rechallenge criteria and did not experience a severe pneumonitis relapse. CONCLUSION: High V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study's rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy.

PURPOSE: The risk factors for skeletal-related events (SREs) among non-small cell lung cancer (NSCLC) patients during treatment with bone-modifying agents (BMAs) are not yet well-understood. METHODS: The medical records of 238 consecutive NSCLC patients treated with BMAs, including zoledronic acid and denosumab, at the Chiba University Hospital from 2012 to 2016 were reviewed in the present study. SREs were defined as either pathologic fractures, spinal cord compression, the need for bone irradiation or surgery, or hypercalcemia. The risk factors for earlier occurrence of the first SRE from the time of the first bone metastasis diagnosis after the initiation of BMA treatment were identified. RESULTS: Of the 238 included patients, 92% (n = 220) had a performance status (PS) of 0-2 at diagnosis of bone metastasis. Forty-eight (20%) patients developed at least one SRE. The most common first SRE was the need for bone irradiation surgery (n = 27, 56%). Significant risk factors included poor PS (hazard ratio [HR]: 4.36; p = .024), male sex (HR: 2.17; p = .022), and the use of zoledronic acid (HR: 1.91; p = .032). The overall survival (OS) from the first bone metastasis diagnosis was 394 days (95% confidence interval [CI]: 331-465). The OS of patients with PS 3 and 4 at the diagnosis of bone metastasis (median: 36 days; 95% CI: 13-50) was significantly (p < 0.0001) shorter than that of patients with PS 0-2 (median: 411 days; 95% CI: 354-558) (HR: 4.53; 95% CI: 2.62-7.35). CONCLUSIONS: Careful observation is needed for patients with the identified risk factors, which include poor PS and male sex, despite the BMA treatment.

BACKGROUND: The COVID-19 pandemic has created a need for educational materials and methods that can replace clinical clerkships (CCs) for online simulated clinical practice (online-sCP). This study evaluates the impact of using simulated electronic health records (sEHR) for inpatients, and electronic problem-based learning (e-PBL) and online virtual medical interviews (online-VMI) for outpatients, for an online-sCP using a learning management system (LMS) and online meeting system facilitated by a supervising physician. METHODS: The sEHR was reviewed by medical students and subsequently discussed with a supervising physician using an online meeting system. In the e-PBL, medical students reviewed the simulated patients and discussed on the LMS. For the online-VMI, a faculty member acted as an outpatient and a student acted as the doctor. Small groups of students discussed the clinical reasoning process using the online meeting system. A mixed-method design was implemented. Medical students self-assessed their clinical competence before and after the online-sCP. They answered questionnaires and participated in semi-structured focus group interviews (FGIs) regarding the advantages and disadvantages of the practice. RESULTS: Forty-three students completed the online-sCP during May and June 2020. All students indicated significant improvement in all aspects of self-evaluation of clinical performance after the online-sCP. Students using sEHR reported significant improvement in writing daily medical records and medical summaries. Students using e-PBL and online-VMI reported significant improvement in medical interviews and counseling. Students also indicated CCs as more useful for learning associated with medical interviews, physical examinations, and humanistic qualities like professionalism than the online-sCP. Eight FGIs were conducted (n = 42). The advantages of online-sCP were segregated into five categories (learning environment, efficiency, accessibility, self-paced learning, and interactivity); meanwhile, the disadvantages of online-sCP were classified into seven categories (clinical practice experience, learning environment, interactivity, motivation, memory retention, accessibility, and extraneous cognitive load). CONCLUSIONS: Online-sCP with sEHR, e-PBL, and online-VMI could be useful in learning some of the clinical skills acquired through CC. These methods can be implemented with limited preparation and resources.

背景.気管支鏡検査の鎮静における塩酸ペチジン単独(P群)に対するミダゾラム併用(M+P群)の有効性と安全性の違いについては明らかではない.方法.2015年9月から2017年3月までに,当院で入院気管支鏡検査を行った症例のうち,同意が得られた症例(209例)に対して,気管支鏡再検査の忍容性について,質問票を用いて検討した結果を報告している.今回はpost hoc解析として同研究の対象となった209例をP群とM+P群の2群に分け,患者背景,診断率,合併症および質問票への回答の再解析を行った.結果.全209例中,P群は81例(39%),M+P群は128例(61%)であった.P群とM+P群で比較し,診断率(65% vs 73%,p=0.21),合併症の発生率(14% vs 12%,p=0.67)に有意差はなかった.質問票への回答としては,P群に比してM+P群で有意に苦痛度が低く(2.2±1.1 vs 2.9±1.2,p<0.001),想定より苦しくなく(2.0±1.0 vs 2.6±1.3,p<0.001),再検査の忍容性が高かった(2.5±1.3 vs 3.0±1.3,p=0.010).検査中の苦痛について,P群に比して,M+P群では苦痛がなかったと答えた例が多かった(35% vs 51%,p=0.02).苦痛の内容として,P群では咳嗽を挙げた例が最多であったが(23%),M+P群では検査前の咽頭麻酔を挙げる例が多かった(29%).結語.気管支鏡検査におけるミダゾラムとペチジンの併用による鎮静は,本邦でのミダゾラムとフェンタニルによる鎮静の前向き介入試験で示された忍容性と安全性と類似した結果を示し,有力な鎮静法の一つと考えられた.(著者抄録)

BACKGROUND: Acute exacerbation (AE) is recognized as a life-threatening condition with acute respiratory worsening in idiopathic pulmonary fibrosis (IPF). AE also occurs in fibrotic interstitial lung disease (ILD) other than IPF, including other types of idiopathic interstitial pneumonias (IIPs), ILD associated with collagen vascular disease (CVD-ILD), and chronic hypersensitivity pneumonia (CHP). However, the clinical impact after AE in those patients is still unclear. METHODS: A retrospective review of 174 consecutive first-episodes with AE of ILD in our institution from 2002 to 2016 was performed. AE was defined according to the revised definition and diagnostic criteria proposed by an international working group in 2016. Clinical characteristics, 90-day survival, and the requirement of long-term oxygen therapy (LTOT) after AE were evaluated in each underlying ILD. RESULTS: There were 102 patients with AE of IPF (AE-IPF) and 72 with AE of ILD other than IPF, including non-IPF IIPs (n = 29) and secondary ILD (n = 43) [CVD-ILD (n = 39), CHP (n = 4)]. In CVD-ILD, rheumatoid arthritis (n = 17) was most common. The 90-day mortality after AE was 57% in IPF, 29% in non-IPF IIPs, and 33% in secondary ILD. After AE, ILD other than IPF had a significantly better survival rate than IPF (P < 0.001). Among survivors, the rates of patients requiring LTOT after AE were 63% in IPF, 35% in non-IPF IIPs, and 46% in secondary ILD, respectively. CONCLUSIONS: AE of ILD other than IPF might have a better prognosis than AE-IPF, but both are fatal conditions that cause chronic respiratory failure.

目的:クリニカルクラークシップ(CC)における文献検索の現状と講義の効果を検証した。方法:対象は2019年5〜12月に呼吸器内科CCに参加した医学生67名。CC中に文献検索に関するアンケートと講義を実施した。結果:医学生はPubMedの使用頻度が多いが、利用する文献は日本語教科書、ガイドラインが多く、文献の吟味、英語読解に困難を感じていた。また、講義の前後で文献検索リテラシーの自己評価は有意に向上し、課題への引用文献数が前年度から増加した。結論:医学生は英語も含め文献検索は行うが文献の吟味や英語読解に困難を感じていた。また、講義でも文献検索リテラシーの向上が得られる可能性が示唆された。(著者抄録)

BACKGROUND: Pirfenidone (PFD), an oral antifibrotic drug, is conditionally recommended for the treatment of idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the prognostic factors in IPF patients treated with PFD and clarify the clinical significance of marginal physiological changes after PFD therapy. METHODS: We retrospectively reviewed 96 consecutive IPF patients treated with PFD. The physiological evaluation was performed at 3-6 months after PFD therapy, and the findings were classified into three groups based on the presence of a 5% change in %forced vital capacity (%FVC): improved, stable, and worsened. The clinical characteristics and prognostic outcomes were compared among groups, and the prognostic factors were evaluated by Cox proportional hazards analysis. RESULTS: Of the 96 patients, 25 (26.0%) showed acute exacerbation (AE) and 40 (41.6%) died during the observation period (median, 17 months). Physiological responses could be evaluated in 80 patients and the findings were as follows: improved, 23%; stable, 36%; and worsened, 41%. Time to the first AE and the survival rate were significantly shorter and lower, respectively, in the worsened group than in the improved/stable group (P = 0.002, P < 0.001, respectively). The prognostic analysis revealed that low %FVC at baseline (hazard ratio [HR]: 0.973 [0.950-0.996]), use of supplemental oxygen (HR: 2.180 [1.041-4.622]), and a "worsened" status after PFD therapy (HR: 5.253 [2.541-11.400]) were significantly associated with a poor prognosis. CONCLUSIONS: An early marginal decline in FVC may be important for survival outcomes in PFD-treated IPF patients.

A 68-year-old woman was admitted to our hospital with fever and pleural effusion. Her thoracentesis showed eosinophilic pleural effusion (EPE) without any evidence of malignancy, infection, or trauma. Pleural biopsy revealed pleuritis and intercostal myositis. Characteristic skin manifestations, including Gottron's sign, interstitial lung disease, and pericardial effusion, appeared later in the clinical course. She was finally diagnosed with anti-PL-7 antisynthetase syndrome (ASS) based on the presence of anti-PL-7 antibody, and she fulfilled the diagnostic criteria for dermatomyositis. These clinical manifestations improved with immunosuppressive therapy. EPE might therefore be one of the characteristic features of anti-PL-7 ASS.

A 64-year-old man was admitted to our hospital with an abnormal chest shadow. The patient was a current-smoker and had a past illness of autoimmune pancreatitis with a high serum level of IgG4, 348 mg/dL. Chest CT showed upper-lobe emphysema, and lower-lobe reticulation with honeycombing, suggestive of combined pulmonary fibrosis with emphysema (CPFE). Surgical lung biopsy was revealed a usual interstitial pneumonia pattern with marked infiltration of IgG4-positive plasma cells. The patient was diagnosed with IgG4 related disease (IgG4-RD) presenting with CPFE. Pulmonary manifestation was improved by corticosteroid therapy. IgG4-RD may be an underlying condition in patient with CPFE.

Small cell lung cancer (SCLC) is a neuroendocrine tumor, and the median age of onset is about 70 years old. A 20-year-old non-smoking man with known systemic sclerosis presented with discomfort in his left chest. Chest X-ray showed a mass shadow in the left upper zone. A transbronchial lung biopsy revealed small cell carcinoma, and imaging studies reached the diagnosis of extensive disease small cell lung cancer. He had concurrent interstitial lung disease with a non-specific interstitial pneumonia pattern and anti-Scl-70 antibodies. He died eight months after the diagnosis during fifth-line chemotherapy. We herein report the youngest case to date of SCLC with systemic sclerosis.