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.