High Frequency of BRCA2 c.5576_5579del Carriers in Kakogawa, Japan.

Background/Aim: Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. Patients and Methods: This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. Results: A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. Conclusion: BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.

Pseudomesotheliomatous Carcinoma of the Lung with Morphological Characteristics of Signet Ring Cell Carcinoma: An Autopsy Case Report.

A 50-year-old woman presented with left pleural effusion. A pleural fluid cell-block specimen and longitudinal lymph node needle biopsy suggested signet ring cell carcinoma (SRCC). Although computed tomography showed a consolidation shadow in the left lower lobe, a left lung biopsy could not be performed. Upper gastrointestinal endoscopy revealed no malignancies. We administered carboplatin, pemetrexed, ipilimumab, and nivolumab for lung cancer; however, she died due to progressive respiratory failure. Pathological autopsy revealed that the left pleura was thickened as in mesothelioma, based on which pseudomesotheliomatous carcinoma of the lung (PMCL) was diagnosed. PMCLs exhibiting an SRCC morphology are rare.

Comprehensive genomic profiling of Japanese patients with thoracic malignancies: A single-center retrospective study.

BACKGROUND: Few studies have been conducted on comprehensive genomic profiling (CGP) panels in Japanese patients with thoracic malignancies after completing standard treatment. Consequently, its value in clinical practice remains unclear. METHODS: We conducted a retrospective study of Japanese patients with thoracic malignancies who underwent CGP between June 2019 and November 2022 at our hospital. We evaluated the detection rate of actionable genetic alterations and percentage of patients who received genomically-matched therapy. Furthermore, we examined the value of the CGP panel in patients who underwent multiplex gene-panel testing prior to their initial treatment. This study was performed in accordance with the principles of the Declaration of Helsinki. RESULTS: The study included 56 patients, of whom 47 (83.9%) had actionable genetic alterations and 8 (14.3%) received genomically-matched therapy. Of these, four patients were treated with approved drugs and three patients were treated with investigational agents. In addition, one patient was treated with approved drugs using the patient-directed care system. Of the 17 patients who had multiplex gene-panel testing performed at the start of their initial therapy, two (11.8%) were newly identified by the CGP panel and subsequently received genomically-matched therapy. EGFR L718Q and MET amplification were observed in two of the seven patients with epidermal growth factor receptor-tyrosine kinase inhibitor resistance. CONCLUSIONS: The CGP panel could identify genetic alterations, thereby facilitating genomically-matched therapy, even in patients with thoracic malignancies who could not be identified using multiplex gene-panel testing.

Dose reduction of docetaxel avoids the usage of pegfilgrastim in docetaxel plus ramucirumab therapy for recurrent nonsmall cell lung cancer.

BACKGROUND: Pegfilgrastim is recommended in docetaxel plus ramucirumab (DTX + RAM) therapy for recurrent nonsmall cell lung cancer (NSCLC) because of the associated frequency of febrile neutropenia (FN). However, the FN occurs less frequently when the dose of DTX is reduced because of other adverse events, such as appetite loss and oral mucositis. METHODS AND RESULTS: Twenty-two patients with recurrent NSCLC who received DTX + RAM therapy at the Hiroshima Prefectural Hospital. The cut-off value which is the most unlikely to cause FN without the combined use of pegfilgrastim was set using a receiver operating characteristic (ROC) curve. This was created according to the dose of DTX and the presence or absence of the onset of FN. We compared the incidence of FN when a DTX dose above and below the cut-off value was used. The ROC curve showed that 48 mg/m2 was the best cut-off value that predicted whether FN was likely to occur when pegfilgrastim was not used concurrently. The incidence of FN was 26.1% for DTX ≥48 mg/m2 and 5.1% for DTX <48 mg/m2 . CONCLUSIONS: Pegfilgrastim can be discontinued when the dose of DTX is reduced to <48 mg/m2 due to nonhematological toxicities.

Pre-Existing Interstitial Lung Abnormalities Are Independent Risk Factors for Interstitial Lung Disease during Durvalumab Treatment after Chemoradiotherapy in Patients with Locally Advanced Non-Small-Cell Lung Cancer.

Introduction/Background: Chemoradiotherapy (CRT) followed by durvalumab, an immune checkpoint inhibitor, is the standard treatment for locally advanced non-small-cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a life-threatening toxicity caused by these treatments; however, risk factors for the ILD have not yet been established. Interstitial lung abnormalities (ILAs) are computed tomography (CT) findings which manifest as minor interstitial shadows. We aimed to investigate whether ILAs could be risk factors for grade-two or higher ILD during durvalumab therapy. Patients and Methods: Patients with NSCLC who received durvalumab after CRT from July 2018 to June 2021 were retrospectively enrolled. We obtained patient characteristics, laboratory data, radiotherapeutic parameters, and chest CT findings before durvalumab therapy. Results: A total of 148 patients were enrolled. The prevalence of ILAs before durvalumab treatment was 37.8%. Among 148 patients, 63.5% developed ILD during durvalumab therapy. The proportion of patients with grade-two or higher ILD was 33.8%. The univariate logistic regression analysis revealed that older age, high dose-volume histogram parameters, and the presence of ILAs were significant risk factors for grade-two or higher ILD. The multivariate analysis showed that ILAs were independent risk factors for grade-two or higher ILD (odds ratio, 3.70; 95% confidence interval, 1.69−7.72; p < 0.001). Conclusions: We showed that pre-existing ILAs are risk factors for ILD during durvalumab treatment after CRT. We should pay attention to the development of grade-two or higher ILD during durvalumab treatment in patients with ILAs.

Pigment epithelium-derived factor promotes peritoneal dissemination of ovarian cancer through induction of immunosuppressive macrophages.

Peritoneal dissemination of ovarian cancer (OC) correlates with poor prognosis, but the mechanisms underlying the escape of OC cells from the intraperitoneal immune system have remained unknown. We here identify pigment epithelium-derived factor (PEDF) as a promoting factor of OC dissemination, which functions through induction of CD206+ Interleukin-10 (IL-10)-producing macrophages. High PEDF gene expression in tumors is associated with poor prognosis in OC patients. Concentrations of PEDF in ascites and serum are significantly higher in OC patients than those with more benign tumors and correlated with early recurrence of OC patients, suggesting that PEDF might serve as a prognostic biomarker. Bromodomain and extraterminal (BET) inhibitors reduce PEDF expression and limit both OC cell survival and CD206+ macrophage induction in the peritoneal cavity. Our results thus implicate PEDF as a driver of OC dissemination and identify a BET protein-PEDF-IL-10 axis as a promising therapeutic target for OC.

High survival of bovine mature oocytes after nylon mesh vitrification, as assessed by intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) is an alternative technique to in vitro fertilization (IVF) for producing transferable blastocysts, especially in combination with cryopreserved oocytes, when the IVF system does not work sufficiently. The present study was conducted to directly compare the efficacy of producing bovine blastocysts by ICSI and IVF from vitrified-warmed and fresh oocytes. Denuded oocytes with a detectable first polar body were vitrified-warmed using a nylon mesh device. In the non-vitrified control group, blastocyst yields 8 days after IVF and ICSI were 32.0 and 26.8%, respectively. Oocyte vitrification and subsequent IVF resulted in an impaired blastocyst yield (15.0%); however, such a loss of efficacy due to vitrification was not observed in the ICSI group (blastocyst yield, 25.2%). The alignment of cortical granules beneath the oolemma was comparable between the fresh control and vitrified-warmed oocytes. Here, we report the high survival of vitrified-warmed bovine oocytes, as assessed by ICSI.

Switching Treatment from Mepolizumab to Benralizumab for Elderly Patients with Severe Eosinophilic Asthma: A Retrospective Observational Study.

Objective Switching from mepolizumab to benralizumab has been reported to significantly improve both asthma control and the lung function. However, the data on its efficacy in elderly patients with severe eosinophilic asthma are limited. This study aimed to assess whether elderly patients with severe eosinophilic asthma could experience an improved asthma control and lung function when switching directly from mepolizumab to benralizumab. Methods In this single-center, retrospective study conducted between February 2017 and September 2018, we assessed the effect of switching the treatment directly from mepolizumab to benralizumab on eosinophil levels, exacerbation rates, and lung function. We compared the treatment responses between the two groups using either Fisher's exact test or Mann-Whitney U-test, as appropriate. Patients We enrolled 12 elderly patients (age ≥65 years) with severe eosinophilic asthma treated with mepolizumab at Hiroshima Prefectural Hospital (Hiroshima, Japan) during the study period. Six patients were switched from mepolizumab to benralizumab, and six continued with the mepolizumab treatment. Results The switch from mepolizumab to benralizumab caused a near-complete reduction in the eosinophil count (p=0.008). The annual rate of clinically relevant exacerbations and hospitalizations diminished as well, albeit with no statistical significance. We found no improvement in the lung function after switching treatment and no difference in the treatment response between the groups. Conclusion Although this study is based on a small sample of participants, the results indicate that both mepolizumab treatment and switching from mepolizumab to benralizumab treatment without a washout period have clinically relevant asthma control benefits for elderly patients with severe eosinophilic asthma.

Phase 2 study of first-line pembrolizumab monotherapy in elderly patients with non-small-cell lung cancer expressing high PD-L1.

BACKGROUND: Pembrolizumab is the recommended first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, its efficacy and safety for patients ≥75 years have not been prospectively investigated; this was the aim of this study. METHODS: This multicenter and open-label single-arm phase II study was conducted at 12 institutions. Chemotherapy-naïve patients with advanced NSCLC and a PD-L1 TPS of ≥50% without EGFR mutations or translocation of the ALK received pembrolizumab every 3 weeks. The primary endpoint was progression-free survival (PFS) with a threshold of 4.3 months. The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and quality of life. RESULTS: Twenty-six patients were enrolled between October 2017 and March 2020. The median PFS was 9.6 (95% confidence interval [CI] 2.1-20.6) months. The lower limit of the 95% CI did not exceed the target. The median OS was 21.6 months. The ORR and DCR were 41.7% and 70.8%, respectively. The proportion of patients with grade ≥3 treatment-related adverse events was 15.4%. The quality of life score did not change significantly during treatment. CONCLUSION: While this study showed that pembrolizumab was a tolerable treatment for elderly patients, the safety requires further confirmation in a larger study. Although the primary endpoint, the median PFS (9.6 months), was slightly shorter than that (10.3 months) of the previous phase III study (KEYNOTE-024 study), the median PFS did not achieve the expected value.

Effect of baricitinib in patients with coronavirus disease 2019 and respiratory failure: A propensity score-matched retrospective cohort study.

In this retrospective cohort study, we evaluated the efficacy of baricitinib in the treatment of coronavirus disease 2019 (COVID-19). Among 404 adult patients with COVID-19 who were admitted to our hospital between October 23, 2020, and July 31, 2021, 229 patients with respiratory failure were included. Among these, 41 patients in the baricitinib group and 41 patients in the control group were selected by propensity score matching to adjust for background factors. We compared the survival rates of the two groups at 30 and 60 days after admission. The 30-day survival rate was significantly higher in the baricitinib group than in the control group. However, there was no significant difference in 60-day survival in the two groups. Baricitinib may improve the early prognosis of patients with respiratory failure associated with COVID-19. However, efforts should be made to improve the long-term prognosis.

ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors.

Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

Drug-induced Neuropsychiatric Adverse Events Using Post-Marketing Surveillance.

BACKGROUND: Several studies reported that abnormal behavior was noted in pediatric patients receiving several drugs, including neuraminidase inhibitors (NIs). However, the information on drugs associated with abnormal behavior in a real-world setting remains limited. The purpose of this study was to clarify the drugs associated with abnormal behavior using a spontaneous reporting system database. METHODS: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio at 95% confidence interval were calculated. RESULTS: A total of 1,144 reports of abnormal behavior were identified. The signals were detected through the association of 4 neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) with the abnormal behaviour. These signals were stronger for oseltamivir than other neuraminidase inhibitors. The signals were also detected for acetaminophen and montelukast. CONCLUSION: Our results should be able to raise physicians' awareness of drugs associated with abnormal behavior, but further investigation of these medications is warranted.

Efficacy of mepolizumab in elderly patients with severe asthma and overlapping COPD in real-world settings: A retrospective observational study.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are the most common respiratory diseases, presenting overlapping prevalence with age. Mepolizumab is a humanized monoclonal antibody targeting interleukin-5. In major randomized clinical trials, this antibody reportedly reduced the circulating eosinophil count, exacerbation rate, and oral corticosteroid (OCS) dosage in patients with severe eosinophilic asthma. However, data regarding the efficacy of mepolizumab in elderly patients with asthma and overlapping COPD are limited. METHODS: This was a single-center, retrospective, observational study. Elderly patients (age ≥65 years) administered mepolizumab between August 2016 and March 2019 were enrolled and the effects of mepolizumab on the eosinophil level, exacerbation numbers, OCS dosage, and lung functions were assessed. We compared treatment responses in patients with asthma and COPD overlap (ACO) with responses observed in patients with severe asthma alone. Adverse events were also evaluated. RESULTS: Twenty patients (10 men and 10 women), with a mean age of 77.5 ± 1.3 years, were included. Mepolizumab significantly reduced the blood eosinophil count, as well as significantly decreased clinically significant exacerbation, in both populations. The OCS dosage was significantly reduced in patients treated receiving maintenance OCS therapy. However, mepolizumab did not improve lung function in either population, and no significant difference was observed in treatment responses between patients with asthma alone and ACO. CONCLUSIONS: Mepolizumab may be effective in elderly patients with eosinophilic asthma and ACO.

Safety profiles of new xanthine oxidase inhibitors: A post-marketing study.

INTRODUCTION: The development of new xanthine oxidase (XO) inhibitors, such as febuxostat and topiroxostat, could offer an alternative to treatment with allopurinol. The purpose of this study was to compare safety profiles of new XO inhibitors with allopurinol using a spontaneous reporting system database. MATERIALS AND METHODS: A retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. RESULTS: Among 7,305 reports of adverse events associated with XO inhibitors, 64.5% involved males, who were frequently in their 70s (25.9%). A large number of skin-related adverse events were detected with the use of allopurinol, but not with febuxostat or topiroxostat. As for individual XO inhibitors, the signal values showing associations between drug reaction with eosinophilia and systemic symptoms (DRESS) and allopurinol, drug-induced liver injury and febuxostat, and blood urea increase and topiroxostat were noteworthy. CONCLUSION: The strength of the associations of XO inhibitors with adverse events is variable, and further studies are required to evaluate the identified signals.

Comparison of Adverse Event Profiles of Tumor Necrosis Factor-Alfa Inhibitors: Analysis of a Spontaneous Reporting Database.

INTRODUCTION: Concerns over safety profiles of tumor necrosis factor (TNF)-alfa inhibitors have been raised. The purpose of this study was to clarify the adverse events associated with TNF-alfa inhibitors using a spontaneous reporting system database. MATERIALS AND METHODS: A retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. RESULTS: Among the 34,031 reports of adverse events associated with TNF-alfa inhibitors, 65.8% were women, who were frequently in their 60s (28.2%). Signals were detected for pneumonia (ROR, 5.36; 95% CI, 5.14-5.6), interstitial lung disease (ROR, 2.04; 95% CI, 1.95-2.15), pneumocystis jirovecii pneumonia (ROR, 11.8; 95% CI, 11.1-12.5), and herpes zoster (ROR, 6.4; 95% CI, 5.92-6.91) for TNF-alfa inhibitors as a class. There was variability in their signal strength across individual TNF-alfa inhibitors. CONCLUSION: The strength of the associations of TNF-alfa inhibitors with adverse events is variable, and further studies are required to evaluate the identified signals.

The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma.

Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. SIGNIFICANCE: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4439/F1.large.jpg.

First-line immune checkpoint therapy in metastatic squamous cell lung cancer harboring both EGFR mutation and high expression of PD-L1: A case report.

A 90-year-old female was admitted to our hospital with a history of a dry cough. Chest computed tomography (CT) scan showed a tumor shadow, and CT-guided lung biopsy revealed squamous cell carcinoma harboring an EGFR mutation. In addition, programmed death-ligand 1 (PD-L1) was highly expressed with a tumor proportion score (TPS) of >75%. Pembrolizumab therapy in the first-line setting was not effective, and the patient died at six months from the first visit. Squamous cell lung cancers (SCLCs) with both EGFR mutation and high expression of PD-L1 are very rare.

Efficacy of Upper Gastrointestinal Endoscopic Examination to Identify Patients with Obstructive Sleep Apnea Syndrome: A Retrospective Cross-Sectional Study.

BACKGROUND/AIMS: Despite the high prevalence of obstructive sleep apnea syndrome (OSAS), most individuals are unaware of its diagnosis. We assessed whether an upper gastrointestinal (GI) endoscopy can accurately predict the incidence of OSAS. METHODS: After endoscopic evaluation of laryngo-pharyngeal collapse, a total of 154 subjects with laryngo-pharyngeal collapse and 52 control subjects underwent polysomnography. Based on the modified Fujita Classification, upper airway obstruction was classified into 3 different types: oropharyngeal, supraglottic and combined type, and associations between upper airway obstruction and OSAS were evaluated. RESULTS: Of 154 subjects with laryngo-pharyngeal collapse, 108 (70.1%) were diagnosed as OSAS, while only 4 (7.7%) control subjects were diagnosed as OSAS (p < 0.001). The sensitivity and specificity of endoscopic diagnosis were 96.4 and 51.1%, respectively. Oropharyngeal involvement was frequently found in 90.2% of the subjects (139/154). The severity of upper airway obstruction was significantly correlated with the apnea-hypopnea index score (r = 0.55, p < 0.001). A multivariate logistic regression analysis revealed that a male sex (OR 5.20; 95% CI 2.65-10.2, p < 0.001), body mass index ≥25 kg/m2 (OR 4.98; 95% CI 2.23-11.2, p = 0.02) and severe obstruction (OR 7.79; 95% CI 3.34-18.2, p < 0.001) were significant independent predictors of severe OSAS. CONCLUSION: A conventional upper GI endoscopic examination might be useful as a diagnostic modality for OSAS.

Periostin antisense oligonucleotide suppresses bleomycin-induced formation of a lung premetastatic niche for melanoma.

Metastasis is the leading cause of cancer death. A tumor-supportive microenvironment, or premetastatic niche, at potential secondary tumor sites plays an important role in metastasis, especially in tumor cell colonization. Although a fibrotic milieu is known to promote tumorigenesis and metastasis, the underlying molecular contributors to this effect have remained unclear. Here we show that periostin, a component of the extracellular matrix that functions in tissue remodeling, has a key role in formation of a fibrotic environment that promotes tumor metastatic colonization. We found that periostin was widely expressed in fibrotic lesions of mice with bleomycin-induced lung fibrosis, and that up-regulation of periostin expression coincided with activation of myofibroblasts positive for α-smooth muscle actin. We established a lung metastasis model for B16 murine melanoma cells and showed that metastatic colonization of the lung by these cells was markedly promoted by bleomycin-induced lung fibrosis. Inhibition of periostin expression by giving an intratracheal antisense oligonucleotide targeting periostin mRNA was found to suppress bleomycin-induced lung fibrosis and thereby to attenuate metastatic colonization of the lung by melanoma cells. Our results indicate that periostin is a key player in the development of bleomycin-induced fibrosis and consequent enhancement of tumor cell colonization in the lung. Our results therefore implicate periostin as a potential target for prevention or treatment of lung metastasis.