Yasuhiro Kato

Objective: Evidence regarding the prognostic relevance of comorbidity burden and polypharmacy in older patients with oncogene-driven NSCLC receiving targeted therapy remains limited. We evaluated whether these factors were associated with survival and tumor-control outcomes. Methods: We retrospectively analyzed patients aged ≥ 65 years with advanced NSCLC harboring actionable genomic alterations who received targeted therapy at six institutions between 2020 and 2024. Patients were categorized by Charlson Comorbidity Index (CCI; 0–1 vs ≥ 2) and polypharmacy (< 5 vs ≥ 5 medications) and further classified into four combined groups. Overall survival (OS) was the primary endpoint and progression-free survival (PFS) the secondary endpoint. Results: Among 609 patients, high CCI was independently associated with worse OS in a multivariable Cox model including both CCI and polypharmacy (HR 1.40, 95% CI 1.05–1.86, P = 0.021), whereas polypharmacy was not (HR 1.19, 95% CI 0.93–1.51, P = 0.165). Neither CCI nor polypharmacy was independently associated with PFS. Compared with the High/High group, the High/Low (HR 0.56, 95% CI 0.32–0.97), Low/High (HR 0.58, 95% CI 0.40–0.84), and Low/Low groups (HR 0.54, 95% CI 0.38–0.77) had improved OS. Treatment response and major treatment-related toxicities were comparable across groups. In age-stratified analyses, associations appeared stronger among patients aged 65–74 years, although the interaction was not statistically significant (P = 0.056). Conclusion: Comorbidity burden and polypharmacy provided clinically relevant OS stratification without corresponding differences in PFS, treatment response, or major toxicity. These readily available measures may capture host vulnerability beyond tumor control in older patients receiving targeted therapy.

Background: The effect of type 2 diabetes mellitus (T2DM) on treatments for advanced non-small cell lung cancer (NSCLC) remains unelucidated. We aimed to assess the effect of T2DM on the treatment for advanced NSCLC. Methods: We retrospectively investigated clinicopathological character, treatment effect, and adverse events (AEs) in advanced NSCLC patients started on systemic treatment at Nippon Medical School Chiba-Hokusoh Hospital from 2018 to 2024. Results: The numbers of T2DM and non-T2DM patients among those undergoing immune checkpoint inhibitor (ICI) therapy, molecular targeted therapy (MTT), and cytotoxic chemotherapy (CTT) were 37 and 78, 30 and 86, 9 and 17, respectively. The overall survival (OS) of patients complicated T2DM was significantly worse in total (19.3 vs. 34.5 months, P=0.001), the ICI (11.5 vs. 34.2 months, P=0.005) and the MTT cohort (27.4 vs. 43.4 months, P=0.03). Median progression-free survival (PFS) was significantly poor for T2DM patients in the ICI cohort (5.7 vs. 12.5 months, P=0.04). However, a significant difference was not found for the MTT cohort (13.3 vs. 12.7 months, P=0.91). There were no significant differences in AEs in either cohort. Hemoglobin A1c (HbA1c) was significantly higher in patients with derived neutrophil lymphocyte ratio (dNLR) ≥3. The PFS in T2DM patients in the ICI cohort was investigated with regard to clinicopathological factors and T2DM treatments. Specialist consultation was identified as a factor that improved PFS of ICI. Conclusions: Our research suggests that T2DM is an independent poor prognostic factor in advanced NSCLC and affects ICI treatment.

Introduction: A neurotrophic tropomyosin receptor kinase (NTRK)‐tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK‐TKIs. Method: To investigate the mechanism of resistance to NTRK‐TKIs, we established cells resistant to three types of NTRK‐TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3‐NTRK1 rearrangement. Result: Overexpression of 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12‐LR, KM12‐ER, and KM12‐SR) by microarray analysis. Lower expression of sterol regulatory element‐binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12‐ER and KM12‐SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12‐LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK‐TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK‐TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK‐TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK‐TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. Conclusion: These results suggest that HMGCS2 overexpression induces resistance to NTRK‐TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

Background: The exosome-focused translational research for afatinib (EXTRA) study is the first trial to identify novel predictive biomarkers for longer treatment efficacy of afatinib in patients with epidermal growth factor receptor ( EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) via a comprehensive association study using genomic, proteomic, epigenomic, and metabolomic analyses. Objectives: We report details of the clinical portion prior to omics analyses. Design: A prospective, single-arm, observational study was conducted using afatinib 40 mg/day as an initial dose in untreated patients with EGFR mutation-positive NSCLC. Dose reduction to 20 mg every other day was allowed. Methods: Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. Results: A total of 103 patients (median age 70 years, range 42–88 years) were enrolled from 21 institutions in Japan between February 2017 and March 2018. After a median follow-up of 35.0 months, 21% remained on afatinib treatment, whereas 9% had discontinued treatment because of AEs. The median PFS was 18.4 months, with a 3-year PFS rate of 23.3%. The median afatinib treatment duration in patients with final doses of 40 ( n = 27), 30 ( n = 23), and 20 mg/day ( n = 35), and 20 mg every other day ( n = 18) were 13.4, 15.4, 18.8, and 18.3 months, respectively. The median OS was not reached, with a 3-year OS rate of 58.5%. The median OS in patients who did ( n = 25) and did not ( n = 78) receive osimertinib during the entire course of treatment were 42.4 months and not reached, respectively ( p = 0.654). Conclusions: As the largest prospective study in Japan, this study confirmed favorable OS following first-line afatinib in patients with EGFR mutation-positive NSCLC in a real-world setting. Further analysis of the EXTRA study is expected to identify novel predictive biomarkers for afatinib. Trial registration: UMIN-CTR identifier (UMIN000024935, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000028688

Background: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, causing widespread mortality. Many patients with COVID-19 have been treated in homes, hotels, and medium-sized hospitals where doctors were responsible for assessing the need for critical care hospitalization. This study aimed to establish a severity prediction score for critical care triage. Method: We analyzed the data of 368 patients with mild-to-moderate COVID-19 who had been admitted to Fussa Hospital, Japan, from April 2020 to February 2022. We defined a high-oxygen group as requiring ≥4 l/min of oxygen. Multivariable logistic regression was used to construct a risk prediction score, and the best model was selected using a stepwise selection method. Results: Multivariable analysis showed that older age (≥70 years), elevated creatine kinase (≥127 U/L), C-reactive protein (≥2.19 mg/dL), and ferritin (≥632.7 ng/mL) levels were independent risk factors associated with the high-oxygen group. Each risk factor was assigned a score ranging from 0 to 4, and we referred to the final overall score as the Fussa score. Patients were classified into two groups, namely, high-risk (total risk factors, ≥2) and low-risk (total risk score, < 0.0001). Conclusions: The Fussa score might help to identify patients with COVID-19 who require critical care hospitalization.

Antibody–drug conjugate (ADC) was novel type of anticancer drugs. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2) targeting ADC, can be a novel treatment option for HER2 alternation (mutation, expression, amplification) advanced-stage non-small-cell lung cancer (NSCLC) from DESTINY-Lung01 result. Herein, we report a successful treatment with T-DXd for NSCLC harboring HER2 exon 20 insertion mutation in a patient with poor performance status (PS). We presented a case of a 52-year-old heavily pretreated female patient diagnosed with lung adenocarcinoma (cT1bN3M0, stage IIIB). After fifth-line pretreatment of systemic chemotherapy, primary tumor recurrence, pleural effusion, and miliary lung metastases were observed. The patient presented with hypoxia requiring oxygen therapy via nasal cannula at a flow rate of 4 L per minute, cancer pain, and cachexia requiring opioid treatment. Her Eastern Cooperative Oncology Group PS score was assessed 3. Comprehensive genomic profiling revealed HER2 exon 20 insertion mutation. After treatment with T-DXd was approved by the ethical review committee of Nippon Medical School Hospital, treatment was started. The tumor size decreased significantly, and her PS score decreased from 3 to 1, with improvement of hypoxia, cancer pain, and cachexia. The patient is still receiving treatment, without disease progression 6 months after starting treatment with T-DXd. Despite cases of poor PS, NGS should be performed and target therapy including ADCs should be considered.

Introduction MET exon 14 skipping mutation, observed in 3–4% of non-small cell lung cancer (NSCLC), is emerging as a targetable alteration. In recent years, immune checkpoint inhibitors (ICI) have been effective in treating several NSCLCs. Our research aimed to investigate the characteristics of patients with NSCLCs harboring MET exon 14 mutations and their response to ICI in Japan. Methods Among the 1954 consecutive NSCLCs diagnosed at Saitama Cancer Center between 2010 and 2019, MET exon 14 skipping mutations were detected in 68 (3.5%) NSCLCs. We evaluated their characteristics such as programmed cell death ligand 1 (PD-L1) expression. Results Median age of patients with NSCLCs harboring MET exon 14 skipping mutations was 73 years. PD-L1 was highly expressed in 17 (70.8%) of the 24 patients examined. Seven patients received ICI monotherapy, and three out of seven had a remarkable treatment response, resulted in objective response rate (ORR) of 42.9% and progression-free survival of 24.7 months. Three patients with donor splice-site mutations showed a long-term treatment response, despite the fact that two with acceptor splice-site mutations demonstrated no response and experienced early disease progression with ICI monotherapy. Conclusion Our results indicated that patients with NSCLCs harboring MET exon 14 mutations presented with a high rate of positive PD-L1 expression. ICI treatment showed a high ORR and long-term efficacy for NSCLCs harboring MET exon 14 mutations. Variants of MET exon 14 splice-site mutations may be associated with ICI response.

Recovering of upper extremity functions is important for stroke patients to perform various tasks in daily life. For better rehabilitation outcomes and accurate measurement, robot assisted exercises have been developed. However, there are limited number of studies related to arm muscles activities corresponding to task complexity. We conducted a preliminary case study on strategy and activities of upper extremity muscles in a healthy volunteer at reaching exercise with haptic feedback by a robot with seven degree-of-freedom when a different target was presented in the virtual environment. Impedance control for Franka Emika Panda robot arm has been developed. The study protocol consisted of 4 sets of 40 reaching trials. The trials had two modes with two different feedback: big target task mode and the small target task mode. In each mode both options, with/without haptic feedback were tested. The preliminary results suggest that different distance to target and target’s size is related to the change of activation order and intensity of muscle activities at reaching task. Additionally, the haptic feedback required different activation order and higher intensity regardless of the task difficulty.

Background: Tuberculosis (TB) is considered to be an adverse effect of treatment with immune checkpoint inhibitors. Methodology & results: Our case was a 75-year-old woman diagnosed with unresectab...