Linear dichroism reveals the perpendicular orientation of DNA bases in the RecA and Rad51 recombinase filaments: A possible mechanism for the strand exchange reaction.

Linear dichroism spectroscopy is used to investigate the structure of RecA family recombinase filaments (RecA and Rad51 proteins) with DNA for clarifying the molecular mechanism of DNA strand exchange promoted by these proteins and its activation. The measurements show that the recombinases promote the perpendicular base orientation of single-stranded DNA only in the presence of activators, indicating the importance of base orientation in the reaction. We summarize the results and discuss the role of DNA base orientation.

Human Rad51 Protein Requires Higher Concentrations of Calcium Ions for D-Loop Formation than for Oligonucleotide Strand Exchange.

Human Rad51 protein (HsRad51)-promoted DNA strand exchange, a crucial step in homologous recombination, is regulated by proteins and calcium ions. Both the activator protein Swi5/Sfr1 and Ca2+ ions stimulate different reaction steps and induce perpendicular DNA base alignment in the presynaptic complex. To investigate the role of base orientation in the strand exchange reaction, we examined the Ca2+ concentration dependence of strand exchange activities and structural changes in the presynaptic complex. Our results show that optimal D-loop formation (strand exchange with closed circular DNA) required Ca2+ concentrations greater than 5 mM, whereas 1 mM Ca2+ was sufficient for strand exchange between two oligonucleotides. Structural changes indicated by increased fluorescence intensity of poly(dεA) (a poly(dA) analog) reached a plateau at 1 mM Ca2+. Ca2+ > 2 mM was required for saturation of linear dichroism signal intensity at 260 nm, associated with rigid perpendicular DNA base orientation, suggesting a correlation with the stimulation of D-loop formation. Therefore, Ca2+ exerts two different effects. Thermal stability measurements suggest that HsRad51 binds two Ca2+ ions with KD values of 0.2 and 2.5 mM, implying that one step is stimulated by one Ca2+ bond and the other by two Ca2+ bonds. Our results indicate parallels between the Mg2+ activation of RecA and the Ca2+ activation of HsRad51.

Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

Impact of immune-related adverse events on survival outcomes in extensive-stage small cell lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors have recently become the standard of care in the first-line treatment of extensive-stage small cell lung cancer. Although immune-related adverse events have been reported to influence prognosis in non-small cell lung cancer patients, few studies have investigated the prognostic value of immune-related adverse events in small cell lung cancer patients. In this study, we evaluated the prognosis of patients who developed immune-related adverse events after first-line treatment with immune checkpoint inhibitor-based chemotherapy for extensive-stage small cell lung cancer. METHODS: We enrolled 90 patients with extensive-stage small cell lung cancer who received immune checkpoint inhibitor-based chemotherapy as first-line treatment from September 2019 to December 2022 in six hospitals in Japan. The patients were categorized into groups with and without immune-related adverse events. RESULTS: There were 23 patients with and 67 without immune-related adverse events. Seventeen patients had grade 1-2 immune-related adverse events, and nine (including overlapping cases) had grade ≥3. The most frequent immune-related adverse event was a skin rash. The median survival time was 22 months in patients with immune-related adverse events and 9.3 months in patients without immune-related adverse events. The hazard ratio was 0.40 (95% confidence interval: 0.19-0.83, p = 0.013). CONCLUSIONS: The results of this study show that immune-related adverse events are associated with improved survival outcomes in patients with extensive-stage small cell lung cancer.

Physical Activity Using a Wearable Device as an Alternative to Performance Status in Patients With Advanced Lung Cancer.

Importance: The Eastern Cooperative Oncology Group Performance Status (ECOG PS) is extensively used to guide treatment decisions in patients with advanced lung cancer. However, its assessment is subjective, potentially leading to discordance among observers. Objective: To investigate the association between measured physical activity and ECOG PS, as well as the potential prognostic value of physical activity measurements in patients with advanced lung cancer. Design, Setting, and Participants: This single-institution, prospective observational study enrolled 119 patients with advanced lung cancer scheduled to receive systemic therapy as outpatients at Matsusaka Municipal Hospital in Mie, Japan. Participants wore the wearable device amuelink (Sony) for up to 14 days to measure physical activity, including metabolic equivalent tasks, distance walked, and number of steps taken. ECOG PS was assessed at enrollment, which took place from December 2021 to August 2022. Main Outcomes And Measures: The primary end point was estimating the area under the curve (AUC) for classification into ECOG PS of 2 or higher using physical activity measurements. An analysis of the association with survival was also conducted. Results: Among the 119 patients (median [range] age, 72 (32-88) years; 71 [59.7%] male), mean distance walked (MDW) had the highest diagnostic value for classifying an ECOG PS of 2 or greater, with an AUC of 0.818 (95% CI, 0.703-0.934). Moreover, MDW was also associated with 6-month survival, with an AUC of 0.806 (95% CI, 0.694-0.918). Survival curves significantly diverged based on the MDW threshold, indicating a potential association with survival outcome (hazard ratio, 0.17; 95% CI, 0.05-0.57). Conclusions and Relevance: The cohort study suggests that MDW, as measured by a wearable device, was associated with ECOG PS and may serve as a predictor of health status alongside ECOG PS categories. It demonstrates the potential of objectively measured physical activity in complementing subjective ECOG PS assessments in patients with advanced lung cancer. Further research is needed to confirm the prognostic value of physical activity measurements.

Nintedanib plus Chemotherapy for Small Cell Lung Cancer with Comorbid Idiopathic Pulmonary Fibrosis.

Rationale: A fatal acute exacerbation (AE) occasionally develops during chemotherapy for small cell lung cancer (SCLC) with comorbid idiopathic pulmonary fibrosis (IPF).Objectives: This study aimed to assess the safety and efficacy of carboplatin, etoposide, and nintedanib combination therapy for unresectable SCLC with comorbid IPF.Methods: The NEXT-SHIP study is a multicenter, single-arm, phase 2 trial for unresectable SCLC with IPF (Japan Registry of Clinical Trials registry number jRCTs031190119). The patients received carboplatin, etoposide, and nintedanib (150 mg twice daily). The primary endpoint was the incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy, and the sample size was set at 33 (5.0% expected, 20.0% threshold).Results: A total of 33 patients were registered; 87.9% were male, the median age was 73 years, the median percentage forced vital capacity was 85.2%, and 51.5% had honeycomb lungs. The median observation period was 10.5 months. The incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy was 3.0% (90% confidence interval [CI], 0.2-13.6). The objective response rate was 68.8% (95% CI, 50.0-83.9). The median progression-free survival and overall survival times were 4.2 months (95% CI, 4.2-5.5) and 13.4 months (95% CI, 8.1-21.6), respectively. The most common adverse event of grade 3 or higher was neutropenia (81.8%), followed by leukopenia (39.4%) and thrombocytopenia (30.3%).Conclusions: This study met its primary endpoint regarding the incidence of IPF-AEs with promising results for efficacy. Carboplatin, etoposide, and nintedanib combination therapy may be one of the standard treatment options for SCLC with comorbid IPF.Clinical trial registered with the Japan Registry of Clinical Trials (jRCTs031190119).

Prophylactic pegfilgrastim reduces febrile neutropenia in ramucirumab plus docetaxel after chemoimmunotherapy in advanced NSCLC: post hoc analysis from NEJ051.

Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p < 0.001). The frequency of FN was 25 patients (10.1%) in the pegfilgrastim group and 10 (24.4%) in the control group (p = 0.018). The objective response rate was 31.2% and 14.6% in the pegfilgrastim and control groups (p = 0.039), respectively. The disease control rate was 72.9% in the pegfilgrastim group and 51.2% in the control group (p = 0.009). Median progression free survival was 4.3 months in the pegfilgrastim group and 2.5 months in the control group (p = 0.002). The median overall survival was 12.8 and 8.1 months in the pegfilgrastim and control groups (p = 0.004), respectively. Prophylactic pegfilgrastim for RD reduced the frequency of grade 3/4 neutropenia and febrile neutropenia and did not appear to be detrimental to patient outcome RD.Clinical Trial Registration Number: UMIN000042333.

Effectiveness and Safety of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in Pulmonary Sarcomatoid Carcinoma.

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC. Methods: This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan. Results: A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS. Conclusions: ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.

A Phase 2 Single-Arm Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis NSCLC: Results for the First-Line Cohort of the OCEAN Study (LOGIK 1603/WJOG 9116L).

Introduction: Osimertinib may be effective in treating central nervous system (CNS) metastasis, but its efficacy in treating radiation therapy (RT)-naive metastasis is unclear. The OCEAN study assessed the efficacy of osimertinib against RT-naive CNS metastasis in patients previously treated (T790M cohort) and untreated patients (first-line cohort) with EGFR mutation. Here, we report the results of the first-line cohort. Methods: Previously untreated patients with RT-naive CNS metastasis and EGFR mutation-positive NSCLC were treated with osimertinib. The brain metastasis response rate (BMRR), progression-free survival (PFS), and overall survival in the first-line cohort were secondary end points. Results: A total of 26 patients were enrolled in the study between September 2019 and July 2020. The median age was 72.0 years with 80.8% female. There were 20 patients who had multiple CNS metastases. BMRR assessed by PAREXEL criteria was 76.9% (90% confidence interval [CI]: 63.3%-90.5%), BMRR assessed by Response Evaluation Criteria in Solid Tumors was 76.9% (95% CI: 54.0%-99.8%), and median PFS of CNS metastasis was 22.0 months (95% CI: 9.7 mo-not reached). The overall response rate was 64.0% (95% CI: 45.2%-82.8%), median PFS was 11.5 months (95% CI: 6.9 mo-not reached), and median survival time was 23.7 months (95% CI: 16.5 mo-not reached). Paronychia and increased creatinine level were the most frequent nonhematological toxicities observed in 13 patients (50%). Grade three and higher adverse events were less than 10%, and there were no treatment-related deaths. Pneumonitis was observed in five patients (19.2%). Conclusions: These results suggest that osimertinib is effective in untreated patients with RT-naive asymptomatic CNS metastasis in a clinical practice first-line setting. Trial registration: UMIN identifier: UMIN000024218. jRCT identifier: jRCTs071180017.

Clinicopathological and Molecular Characteristics Promoting PD-L1 Expression in Early-stage Lung Adenocarcinoma and Squamous Cell Carcinoma.

BACKGROUND/AIM: Lung adenocarcinoma and lung squamous cell carcinoma represent the most prevalent subtypes of non-small cell lung cancer eligible for surgery in the early stages. The emergence of immune checkpoint inhibitors as adjuvant therapy has shown promising potential in improving the postoperative prognosis of patients with lung cancer. Hence, a comprehensive understanding of the clinicopathological and molecular features of programmed cell death ligand-1 (PD-L1) expression in lung adenocarcinoma and squamous cell carcinoma is crucial. PATIENTS AND METHODS: In this retrospective study, we conducted a comparative analysis of clinicopathological features associated with the expression of PD-L1, stratifying patients who underwent surgical resection into two distinct groups: 289 patients with lung adenocarcinoma and 66 with lung squamous cell carcinoma. Furthermore, we investigated the associations between the expression of PD-L1 and genetic alterations in well-established oncogenic driver mutations. RESULTS: Among the cases, 52.9% exhibited negative PD-L1 expression, 32.9% had low PD-L1 expression, and 12.3% had high PD-L1 expression in adenocarcinoma, while the PD-L1 expression in squamous cell carcinoma showed a near-even distribution. Notably, male sex, smoking history, the presence of invasive pathological factors, and disease progression significantly influenced PD-L1 expression in adenocarcinoma, whereas none of these factors were associated with PD-L1 expression in squamous cell carcinoma. Additionally, the distribution of PD-L1 expression varied based on the type of specific driver gene mutation in adenocarcinoma. CONCLUSION: The present study revealed clinicopathological and molecular differences between lung adenocarcinoma and squamous cell carcinoma patients promoting the expression of PD-L1.

Highly potent, orally active novel small-molecule HPK1 inhibitor DS21150768 induces anti-tumor responses in multiple syngeneic tumor mouse models.

Augmenting T-cell activity is a promising approach to enhance the efficacy of cancer immunotherapy treatment. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in immune cells and negatively regulates T-cell receptor signaling. It is reported that inhibition of the kinase function of HPK1 results in tumor growth suppression by enhancing cancer immunity. Thus, developing HPK1 inhibitors has attracted considerable attention as a future cancer immunotherapy approach. However, despite recent progress in HPK1 biology and pharmacology, various challenges still remain, such as developing HPK1 inhibitors with favorable pharmacological profiles and identifying tumor characteristics that can be applied to define susceptibility to HPK1 inhibition. Here, we present the identification and pharmacological evaluation of DS21150768, a potent small-molecule HPK1 inhibitor with a novel chemical scaffold. DS21150768 shows remarkable inhibition of HPK1 kinase activity, and in vitro studies demonstrated its potent activity to enhance T-cell function. DS21150768 is orally bioavailable and shows sustained plasma exposure, which leads to enhanced cytokine responses in vivo. We conducted a comparison of the anti-tumor efficacy of DS21150768 alone or in combination with anti-PD-1 antibody in 12 different mouse cancer cell models, and observed that the treatments suppressed tumor growth in multiple models. Furthermore, Gene Set Enrichment Analysis demonstrated significant enrichment of immune-related gene signatures in the tumor models responsive to DS21150768 treatment. Our results provide a path forward for the future development of HPK1 inhibitors and fundamental insights into biomarkers of HPK1-targeted therapy.

Efficacy and safety of second-line therapy of docetaxel plus ramucirumab after first-line platinum-based chemotherapy plus immune checkpoint inhibitors in non-small cell lung cancer (SCORPION): a multicenter, open-label, single-arm, phase 2 trial.

Background: Immune checkpoint inhibitors (ICI) plus platinum-based chemotherapy has been recognized as a standard first-line therapy in non-small cell lung cancer (NSCLC); however, no prospective clinical trials of docetaxel (DTX) plus ramucirumab (RAM) following first-line ICI plus platinum-based chemotherapy has been reported. Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients with NSCLC from eight centres in Japan. Patients with metastatic NSCLC with disease progression after platinum-based chemotherapy plus ICI were eligible for the study. Patients were intravenously treated with 60 mg/m2 of DTX and 10 mg/kg of RAM on day 1 with a strong recommendation of pegfilgrastim administration on day 2 every 3 weeks. The primary end point was objective response rate (ORR) in efficacy analysis population. Safety was assessed in all patients treated at least one dose. The ORR of the null and alternative hypotheses were 10% and 30%, with α error of 0.1 and ß error of 0.1. This trial is registered with the Japan Registry for Clinical Trials, jCRTs041190077. Findings: Between 16 January, 2020, and 24 August, 2021, 33 patients (median age 66 [range 42-79] years) were enrolled. Thirteen patients (41%) had Eastern Cooperative Oncology Group performance status of 1. Twenty-five patients (78%) had an interval of <60 days after the last administration of ICI. In the efficacy analysis population (n = 32), the primary endpoint was met as 11 patients achieved partial response (PR), with ORR of 34.4% (80% CI, 23.1-47.2). Grade ≥3 anaemia and febrile neutropenia were observed in 2 (6%) and 3 (9%) patients, respectively. No treatment-related deaths and no new safety signals were observed. Interpretation: DTX plus RAM demonstrated encouraging antitumor activity with a manageable safety profile in patients who have progressed on front-line ICIs plus platinum-based chemotherapy. The results of this trial can be a helpful reference in conducting further phase III trials of new second-line treatment options. Funding: Eli Lilly Japan K.K.

A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T.

Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-α (G6Pase-α, encoded by G6PC), which is primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves life expectancy, patients still experience intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a but potentially require complicated glycemic management throughout life. Here, we present an oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. We generated a mouse strain with homozygous knockin of this variant that well reflected the pathophysiology of patients with GSD1a. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b had long-lasting efficacy of more than 12 weeks in mice that received a single dose and had favorable pharmacokinetics and tolerability in mice and monkeys. These findings together indicate that this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.

Effect of Flavanol-Rich Cacao Extract on the Profile of Mood State in Healthy Middle-Aged Japanese Women: A Randomized, Double-Blind, Placebo-Controlled Pilot Study.

To investigate the effects of flavanol-rich cacao extract on healthy middle-aged women's fatigue and mood conditions, we conducted a randomized, double-blind, placebo-controlled study in women aged 40-60 years who had reported fatigue and had shown high levels of a serum oxidative stress marker. We randomized the participants (n = 60) into equal groups receiving either a beverage containing cacao flavanols (240 mg/200 mL/day) or a placebo for 8 weeks. Before and after the 8-week treatment, we determined the participants' Chalder fatigue scale (CFS) scores, various mood states, autonomic nervous system (ANS) activity levels, and their ANS balance. The results demonstrated that among the mood states, the indicators of negative mood (e.g., depression, fatigue, and anger) and the total mood disturbance score were significantly lower in the cacao group compared to the placebo group after the treatment (p < 0.05). The change in the index of positive mood (i.e., vigor) from baseline to 8 weeks was significantly higher in the cacao group versus the placebo group (p < 0.05). There were no significant between-group differences in the changes in the CFS score or ANS activity level. The consumption of flavanol-rich cacao extract both suppressed negative moods and promoted positive moods in healthy middle-aged women. These results suggest that cacao flavanols may be a useful food material that can improve variable mood conditions in middle-aged women and support their active lives.

Close-to-lesion transbronchial biopsy: a novel technique to improve suitability of specimens for genetic testing in patients with peripheral pulmonary lesions.

Bronchoscopy with radial-probe endobronchial ultrasound, a guide sheath, and electromagnetic navigation can improve the diagnostic yield of peripheral lung nodules. However, the suitability of specimens for genetic analysis remains unsatisfactory. We hypothesized that a transbronchial biopsy performed after closely approaching the bronchoscope tip to the lesion might provide more suitable specimens for genetic analysis. We enrolled 155 patients with peripheral pulmonary lesions who underwent bronchoscopy with a thin or ultrathin bronchoscope. Bronchoscopy was performed using virtual bronchoscopic navigation and radial-probe endobronchial ultrasound with a guide sheath. The bronchoscope tip was placed closer to the lesion during bronchoscopy to collect larger specimens with higher malignant cell content. The patients who underwent a close-to-lesion biopsy had higher rates of overall diagnostic yield, histopathological diagnostic yield, and specimen quality for genetic testing than those who did not. The significant determinants of the specimen's suitability were the close-to-lesion approach, within-the-lesion image, the use of standard 1.9-mm-forceps, and the number of cancer-cell-positive specimens. The significant predictors of the specimen's suitability for genetic analysis were close-to-lesion biopsy and the number of malignant cell-positive tissue samples. This study demonstrates that the close-to-lesion transbronchial biopsy significantly improves the suitability of bronchoscopic specimens for genetic analysis.

Low Young's Modulus TiNbSn Alloy Locking Plates Accelerate Osteosynthesis in Rabbit Tibiae.

A new beta TiNbSn alloy with a low Young's modulus of approximately 40 GPa has been developed to resolve the stress shielding by Young's modulus divergence. In this study, the efficacy of TiNbSn alloy locking plates on bone repair is compared to that of commercially pure titanium (CP-Ti). The TiNbSn alloy and CP-Ti, which have Young's moduli of 49.1 GPa and 107 GPa, respectively, were compared. Male Japanese white rabbits were anesthetized, and osteotomy and osteosynthesis with locking plates were performed on the right tibia. The bone repair was assessed using micro-computed tomography (CT), histomorphometry, immunohistochemistry, and mechanical testing. Micro-CT, histomorphometry, immunohistochemistry, and mechanical testing were performed four weeks after osteotomy. Six weeks after surgery, micro-CT and mechanical testing were performed. Micro-CT analysis at four weeks after surgery showed that the intramedullary fracture callus in the TiNbSn alloy group had more bone volume and numerous bridging structures compared to the CP-Ti group (CP-Ti vs. TiNbSn alloy, 34.3 ± 13.1 mm3 vs. 61.3 ± 19.6 mm3, p = 0.02; mean ± standard deviation). At four weeks post-osteotomy, the healed tibia showed significantly higher strength in the TiNbSn alloy group compared with CP-Ti (CP-Ti vs. TiNbSn alloy, 81.3 ± 31.2 N vs. 133.7 ± 46.6 N, p = 0.04). TiNbSn alloy locking plates had a more positive impact on bone formation and bone strength restoration than the CP-Ti locking plates during the early phase of bone healing.

Clinical importance of the range of detectable variants between the Oncomine Dx target test and a conventional single-gene test for EGFR mutation.

Although we have experienced some cases with discordant results between the Oncomine Dx target test (ODxTT) and conventional single gene tests for detecting EGFR alterations, the clinical efficacy of EGFR-TKIs in these discordant cases remains little known. We retrospectively reviewed consecutive patients with non-small-cell lung cancer whose FFPE samples were simultaneously submitted for the ODxTT, and a PNA-LNA PCR clamp test. We evaluated the clinical efficacy of EGFR-TKIs in patients with discordant results between the two tests, focusing on the common EGFR mutations. Among 444 successful results, 10 patients had discordant results for common EGFR mutations (9 Ex 19 deletion and 1 Ex 21 L858R mutation), and all of these were detected only by the PNA-LNA PCR clamp test. Among six discordant cases treated with EGFR-TKI, the mutations detected in 3 patients were not included in the list of detectable variants that are reportable by the ODxTT, while the mutations detected in the other 3 patients were included in the list. For all three discordant cases harboring the mutations not reportable by the ODxTT, good clinical responses were demonstrated. However, among the other three discordant cases harboring the mutations reportable by the ODxTT, only one patient had a clinical response with short duration. Among the discordant cases for common EGFR mutations between the ODxTT and the conventional single gene test, there are a certain number of suitable patients responsive to EGFR-TKIs, especially when the cause of the discordant results comes from the difference in the range of detectable variants that are reportable between the tests.

Refractory response to entrectinib for ROS-1 rearranged NSCLC with concurrent de novo TP53 mutation showing good response to CNS lesion, but poor duration of response: A case report.

Entrectinib, a ROS-1 inhibitor, has been shown to be effective for patients with ROS-1 fused NSCLC, and has been established as the standard of care for this population. Entrectinib has been shown to achieve a better response to brain metastasis due to the characteristic of the drug having a weak interaction with P-glycoprotein and, even in prospective studies, the intracranial response is higher. Patients have been known to acquire resistance to molecularly targeted drugs such as EGF-TKIs or ALK-TKIs during targeted therapy. Similarly, the mechanisms of resistance to entrectinib have been reported, but information about the effects of TP53 mutation with entrectinib are still limited. Here, we experienced a case of a patient with ROS-1 fusion and concurrent TP53 mutation who was treated with entrectinib, resulting in a response to brain metastasis but rapid resistance to entrectinib. Our case demonstrates both the intracranial activity of entrectinib and the potential for resistance to entrectinib due to TP53 mutation.

Physical Activity Estimated by the Wearable Device in Lung Disease Patients: Exploratory Analyses of Prospective Observational Study.

Background. Physical activity is a potential parameter to assess the severity or prognosis of lung disease. However, the differences in physical activity between healthy individuals and patients with lung disease remain unclear. Methods. The analyses in this report are a combined analysis of four cohorts, including a healthy control cohort, in a prospective study designed to evaluate wearable device-estimated physical activity in three cohorts: the lung cancer cohort, the interstitial pneumonia cohort, and the COPD cohort (UMIN000047834). In this report, physical activity in the lung disease cohort was compared with that in the healthy cohort. Subgroup analyses were performed based on age, sex, duration of wearable device use, and lung disease subtype. Results. A total of 238 cases were analyzed, including 216 patients with lung disease and 22 healthy cases. Distance walked and number of steps were significantly lower in the patient group compared to the healthy control group. ROC analysis for the diagnostic value of lung disease by mean distance walked and mean number of steps showed AUC of 0.764 (95%CI, 0.673 to 0.856) and 0.822 (95%CI, 0.740 to 0.905), respectively. There was a significant difference in physical activity by age, but not by gender nor by duration based on the threshold of 7 days of wearing the device. Conclusions. Lung disease decreases physical activity compared to healthy subjects, and aging may bias the estimation of physical activity. The distance walked or number of steps is recommended as a measure of physical activity, with a period of approximately one week and adjusted for age for future investigation.

Alternating Therapy With Osimertinib and Afatinib Blockades EGFR Secondary Mutation in EGFR-Mutant Lung Cancer: A Single-Arm Phase II Trial.

BACKGROUND: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial. METHODS: Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment. RESULTS: Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected. CONCLUSION: The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment. CLINICAL TRIAL REGISTRATION: jRCTs051180009.