Efficacy and safety of mRNA SARS-CoV-2 vaccines in lung transplant recipients.

BACKGROUND: To date, reports addressing the antibody response following mRNA SARS-CoV-2 vaccination in lung transplant (LTX) recipients are limited. Thus, the aim of this clinical study was to investigate the efficacy and safety of the vaccines in LTX recipients compared to controls. METHODS: An open-label, nonrandomized prospective study was conducted at Tohoku University Hospital. LTX recipients and controls who received either the BNT162b2 vaccine or the mRNA-1273 vaccine were recruited, and SARS-CoV-2 IgG was measured before and after vaccination. The adverse events were reviewed. Predictors of negative serology after vaccination were evaluated with logistic regression. RESULTS: Forty-one LTX recipients and 24 controls were analyzed. Although all controls had a positive antibody response to a SARS-CoV-2 mRNA vaccine, antibody response was found in 24.4% of LTX recipients (p < .0001). The amount of SARS-CoV-2 IgG following the 2nd dose significantly climbed to 6557 AU/mL in controls, whereas the increase in IgG in LTX recipients was 8.3 AU/mL (p < .0001). Fewer LTX recipients developed systemic fever than controls (p < .0001) despite equivalent overall adverse event percentages in both groups. A higher plasma concentration of mycophenolate was a significant predictor of negative serology (p = .032). CONCLUSIONS: An impaired antibody response to mRNA vaccines was significantly found in LTX recipients compared to controls and was associated with the plasma concentration of mycophenolate. While repeating mRNA vaccination may be one of the strategies to improve antibody response given the safety of the vaccines, emerging data on humoral immune responses based on immunosuppression regimens in LTX recipients should be studied (jRCT1021210009).

[The Management of Cytomegalovirus Infection after Lung Transplantation].

Cytomegalovirus( CMV) infection is one of the most common complications after lung transplantation which affects the morbidity and mortality. The transplantation society international CMV consensus group published the consensus guideline on the management, prevention, treatment and diagnostics of CMV infection. On the other hand, each lung transplant program in Japan manages the CMV infection in the lung transplant recipients according to the unique protocol. In this article, we introduce our protocol for prophylaxis and treatment for CMV infection after lung transplantation and compare it to the international guideline. We also report the conditions of CMV infections in the lung transplant recipients in our center and the outcomes of the treatment that we performed for CMV infections by our protocol.

Association of Airflow Limitation With Carotid Atherosclerosis in a Japanese Community　- The Hisayama Study.

BACKGROUND: There has been no large-scale observational study examining the association between chronic obstructive pulmonary disease (COPD) or airflow limitation and carotid atherosclerosis in the general population across a wide range of generations in Asia. In the present study we assessed the association between airflow limitation and carotid intima-media thickness (IMT) in a general Japanese population, with consideration of a comprehensive array of cardiovascular risk factors.Methods and Results:In all, 2,099 community-dwelling Japanese subjects were included in the study. Airflow limitation was defined by spirometry. Maximum and mean IMT values were measured using carotid ultrasonography. Among the subjects, 352 (16.8%) had airflow limitation. The geometric mean values of maximum IMT and mean IMT were significantly higher in subjects with than without airflow limitation (1.27 vs. 1.18 mm, respectively, for maximum IMT; 0.73 mm vs. 0.72 mm, respectively, for mean IMT) and increased with the severity of airflow limitation after adjustment for conventional risk factors, including smoking habits and serum high-sensitivity C-reactive protein. It should be noted that the magnitude of these associations was greater in the middle-aged (40-64 years) than elderly (≥65 years) subgroup. CONCLUSIONS: The findings of the present study suggest that airflow limitation is a significant risk factor for carotid atherosclerosis, especially in midlife, in the general Japanese population.

Letermovir prophylaxis for cytomegalovirus in lung-transplant recipients: a comprehensive study with literature review of off-label use and real-world experiences.

Letermovir, initially approved for cytomegalovirus (CMV) prophylaxis in hematopoietic stem-cell transplantation, has gained attention for off-label use in lung-transplant (LTx) recipients. Given the high susceptibility of LTx recipients to CMV infection, this study explores the effectiveness and safety of letermovir prophylaxis. A retrospective analysis of using letermovir for LTx recipients at Tohoku University Hospital (January 2000 to November 2023) was conducted. Case summaries from other Japanese transplant centers and a literature review were included. Six cases at Tohoku University Hospital and one at Kyoto University Hospital were identified. Prophylactic letermovir use showed positive outcomes in managing myelosuppression and preventing CMV replication. The literature review supported the safety of letermovir in high-risk LTx recipients. Despite limited reports, our findings suggest letermovir's potential as prophylaxis for LTx recipients intolerant to valganciclovir. Safety, especially in managing myelosuppression, positions letermovir as a promising option. However, careful consideration is important in judiciously integrating letermovir into the treatment protocol.

Small Intestine Metastasis Leads to the Diagnosis of Thoracic SMARCA4-Deficient Undifferentiated Tumor: A Case Report.

SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and aggressive malignancy characterized by the loss of SMARCA4 protein expression. It typically affects middle-aged male smokers and has a poor prognosis due to its rapid progression and metastatic potential. This case report presents a 73-year-old male diagnosed with a thoracic SMARCA4-UT. Initially diagnosed with stage IVA non-small cell lung cancer, the patient underwent brain tumor resection, radiation, and chemo-immunotherapy. Treatment was halted due to immune-related adverse events. During treatment, a progressing small intestine tumor was discovered, resected, and identified as SMARCA4-UT metastasis through immunohistochemistry, leading to a revised diagnosis of SMARCA4-UT with brain and small intestine metastases. The patient received multimodal treatment, including surgery, radiation, and chemo-immunotherapy. The small intestine metastasis showed resistance to systemic therapy, necessitating surgical intervention. This case highlights the diagnostic challenges and treatment complexities of SMARCA4-UT, emphasizing the importance of comprehensive diagnostic workup and personalized treatment strategies. It demonstrates the potential efficacy of combining systemic therapy with targeted interventions for oligoprogressive disease. The patient's progression-free survival at approximately two years post-diagnosis underscores the need for further research into optimal management strategies for this rare tumor.

A Rare Case of Platypnea-Orthodeoxia Syndrome in a Patient With Undiagnosed Atrial Septal Defect.

Platypnea-orthodeoxia syndrome (POS) is a rare condition characterized by dyspnea and oxygen desaturation that worsens in the upright position and improves when lying down. We report the case of a 67-year-old male who presented with a 14-month history of dyspnea in the sitting/standing position. Despite treatment for suspected asthma, his symptoms persisted, and he was referred to our hospital for further evaluation. Physical examination and arterial blood gas analysis confirmed the presence of POS, with a significant decrease in PaO2 and SpO2 when moving from a supine to an upright position. Contrast-enhanced CT showed no obvious embolism nor arteriovenous fistula, and ventilation-perfusion scintigraphy demonstrated ventilation-perfusion mismatch with a right-to-left shunt fraction of 9.4%, without any focal defect. Transthoracic echocardiography with a microbubble test demonstrated a right-to-left shunt that increased in the upright position. Transesophageal echocardiography revealed an atrial septal defect (ASD) with an atrial septal aneurysm and the presence of an inferior vena cava valve, causing a bidirectional shunt. The patient was diagnosed with POS secondary to ASD and was referred for percutaneous closure of the defect. Following the procedure, the shunt resolved, and the patient's orthostatic oxygen desaturation improved. This case highlights the importance of considering POS in patients with positional dyspnea and the value of performing diagnostic tests, such as echocardiography, in different positions to identify the underlying cause. Early recognition and appropriate management of POS can significantly improve patients' quality of life and prevent complications associated with chronic hypoxemia.

Clinical Association Between Immune-related Adverse Events and Treatment Efficacy in Patients With Non-small-cell Lung Cancer Treated With Nivolumab-Ipilimumab-based Therapy.

BACKGROUND/AIM: Nivolumab and ipilimumab combination therapy has been extensively explored for the treatment of advanced non-small-cell lung cancer (NSCLC) through the pivotal phase III trials CheckMate 227 and CheckMate 9LA. However, the relationship between immune-related adverse events (irAEs) and the effectiveness of nivolumab plus ipilimumab-based therapy in a real-world clinical setting remains uncertain. PATIENTS AND METHODS: We performed a retrospective analysis of 28 patients with advanced or recurrent NSCLC who underwent treatment with nivolumab plus ipilimumab, with or without platinum-doublet chemotherapy, from February 2021 to January 2023. The primary objective was to elucidate the clinical association between irAEs and treatment efficacy associated with nivolumab plus ipilimumab-based therapy. RESULTS: Among the 28 patients, 22 (78.6%) experienced irAEs. The median progression-free survival (PFS) was significantly longer for patients with irAEs than for those without (p=0.0158), as was overall survival (OS) (p=0.000394). The severity of irAEs had no significant influence on PFS or OS. The objective response rate tended to be higher in patients with irAEs than in those without (50.0% versus 0.0%, respectively; p=0.0549). Multivariate analysis indicated that irAE occurrence was an independent factor for improved PFS (hazard ratio=0.2084, p=0.01383) and OS (hazard ratio=0.0857, p=0.001588). Interstitial lung disease was inferior to other irAE profiles for both PFS and OS. CONCLUSION: Patients with advanced NSCLC experiencing irAEs demonstrated superior clinical outcomes when treated with nivolumab plus ipilimumab-based therapy compared with those without irAEs. However, immune-related interstitial lung disease may be less linked with PFS and OS than other irAE profiles.

TNFR1 Mediated Apoptosis Is Protective against Mycobacterium avium in Mice.

Mycobacterium avium is an intracellular proliferating pathogen that causes chronic refractory respiratory infection. Although apoptosis induced by M. avium has been reported in vitro, the role of apoptosis against M. avium infection in vivo remains unclear. Here, we investigated the role of apoptosis in mouse models of M. avium infection. Tumor necrosis factor receptor-1 knockout mice (TNFR1-KO) andTNFR2-KO micewere used. M. avium (1 × 107 cfu/body) was administered intratracheally to mice. Apoptosis in lungs was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling and lung histology as well as cell death detection kits using BAL fluids. TNFR1-KO mice were susceptible to M. avium infection compared with TNFR2-KO and wild type mice based on the bacterial number and lung histology. Higher numbers of apoptotic cells were detected in the lungs of TNFR2-KO and wild-type mice were compared with TNFR1-KO mice. The inhalation of Z-VAD-FMK deteriorated M. avium infection compared with vehicle-inhaled controls. Overexpression of Iκ-B alpha by adenovirus vector attenuated M. avium infection. Our study showed apoptosis had an important role in innate immunity against M. avium in mice. The induction of apoptosis in M. avium-infected cells might be a new strategy to control M. avium infection.

Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease.

AIM: Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver dysfunction and its incidence has increased markedly. However, the mechanisms involved in the pathogenesis of NAFLD in humans have not been thoroughly investigated. Sterol regulatory element binding protein (SREBP)-1c and carbohydrate responsive element binding protein (ChREBP) are transcriptional factors that regulate the expression of lipogenic genes, including acetyl-CoA carboxylases (ACCs) and fatty acid synthase (FAS). SREBP-1c and ChREBP are transactivated by liver X receptor (LXR), a nuclear receptor that regulates the metabolism of cholesterol and fatty acids. To understand the mechanisms involved in the pathogenesis of NAFLD, we investigated the transcriptional factors and lipogenic genes activated in the liver with NAFLD. METHODS: Real-time PCR was carried out on liver biopsy samples from 20 NAFLD patients. The target genes studied were: ACC1, FAS, SREBP-1c, ChREBP, AMP-activated protein kinase (AMPK), and LXRalpha. RESULTS: LXRalpha, SREBP-1c, ACC1, and FAS were upregulated in NAFLD patients. Expression levels of LXR were four times greater than those of the controls and correlated significantly with SREBP-1c, but not with ChREBP, levels. CONCLUSIONS: These findings suggest that LXR acts as one of the main regulators of lipid metabolism by regulating SREBP-1c expression in NAFLD.