Upfront Multiplex Gene Test Helps Prolong Survival in Advanced Non-small Cell Lung Cancer.

BACKGROUND/AIM: Detection of genetic abnormalities is crucial for selecting an appropriate therapy to effectively treat advanced non-small cell lung cancer (NSCLC). Multiplex genetic testing aids the selection of appropriate therapy and tailored treatments; however, its impact on survival remains unexplored. PATIENTS AND METHODS: Using data from 112 patients with advanced or recurrent NSCLC between February 2020 and April 2023, we investigated the impact of multiplex genetic tests, conducted before the initiation of systemic therapy, on survival. RESULTS: Multiplex genetic test was performed on 72 patients (MPL group). Among the remaining 40 patients (non-MPL group), 18 underwent ≥1 single-plex genetic test, including tests for EGFR (18), ALK (14), and ROS1 (8). The frequency of EGFR mutations in the MPL and non-MPL groups was similar (28% and 25%, respectively), whereas alterations in KRAS, ALK, MET, HER2, and RET levels (5, 4, 4, 4, and 1, respectively) were exclusively detected in the MPL group. The MPL group exhibited a significantly improved survival rate compared to the non-MPL group (median survival time 20.6 vs. 9.3 months, p=0.009). CONCLUSION: Multiplex genetic testing, before the initiation of systemic treatment, could potentially enhance prognosis by uncovering a wide range of non-EGFR gene abnormalities. Multiplex genetic tests could be crucial for the effective application of modern anticancer therapeutic strategies.

The effect of 1-hydroxy-vitamin D treatment in hospitalized patients with COVID-19: A retrospective study.

BACKGROUND & AIMS: The efficacy of vitamin D supplementation in coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to evaluate the effect of 1-hydroxy-vitamin D on the prevention of severe disease and mortality in patients hospitalized for COVID-19. METHODS: This retrospective study included 312 patients with COVID-19 who were admitted to our hospital between April 2021 and October 2021 (primarily the Delta variant) and between July 2022 and September 2022 (primarily Omicron variant). Serum 25-hydroxyvitamin D (25(OH)D) levels were measured at the time of admission and 1-hydroxy-vitamin D was prescribed by the treating physicians. The patients were divided into two groups: those administered 1-hydroxy-vitamin D (Vit D group) and those who were not (control group). The composite primary endpoint was the need for additional respiratory support, including high-flow oxygen therapy or invasive mechanical ventilation, and in-hospital mortality rate. RESULTS: Of 312 patients, 122 (39%) received 1-hydroxy-vitamin D treatment. Although the median age was not significantly higher in the Vit D group than in the control group (66 vs. 58 years old, P = 0.06) and there was no significant difference in the proportion of vitamin D deficiency (defined as serum 25(OH)D level less than 20 ng/mL, 77% vs. 65%, P = 0.07), patients in the control group had a more severe baseline profile compared to the Vit D group according to the Japanese disease severity definition for COVID-19 (P = 0.01). The proportion of those requiring more respiratory support and in-hospital mortality was significantly lower in the Vit D group than in the control group (6% vs. 14%, P = 0.01 log-rank test). After propensity score matching, a statistically significant difference in the primary endpoint was observed (P = 0.03 log-rank test). CONCLUSIONS: 1-hydroxy-vitamin treatment may improve outcomes in hospitalized patients with COVID-19, reducing composite outcomes including the need for additional respiratory support and in-hospital mortality.

Effect of eicosapentaenoic acid on prevention of lean body mass depletion in patients with exacerbation of chronic obstructive pulmonary disease: A prospective randomized controlled trial.

BACKGROUND & AIMS: Systemic inflammation plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD), resulting in depletion of lean body mass (LBM) and muscle mass. Both frequent exacerbation of COPD and low LBM are associated with poor prognosis. This study aimed to evaluate whether supplementation of eicosapentaenoic acid (EPA) prevents depletion of LBM and muscle mass in hospitalized patients with exacerbation of COPD. METHODS: This was a prospective randomized controlled trial, conducted between November 2014 and October 2017. Fifty patients were randomly assigned to receive 1 g/day of EPA-enriched oral nutrition supplementation (ONS) (EPA group) or EPA-free ONS of similar energy (control group) during hospitalization. The LBM index (LBMI) and the skeletal muscle mass index (SMI) were measured using a bioelectrical impedance analyzer at the time of admission and at the time of discharge. Patients underwent pulmonary rehabilitation and wore a pedometer to measure step counts and physical activity. RESULTS: Forty-five patients that completed the experiment were analyzed. Baseline characteristics were similar between the EPA (n = 24) and control groups (n = 21). There were no significant differences in energy intake, step counts, physical activity, or length of hospitalization between the two groups. Although the plasma levels of EPA significantly increased only in the EPA group, we found an insignificant increase in LBMI and SMI in the EPA group compared with the control group (LBMI: +0.35 vs. +0.19 kg/m2, P = 0.60, and SMI: +0.2 vs. -0.3 kg/m2, P = 0.17, respectively). The change in the SMI was significantly correlated with the length of hospitalization in the EPA group, but not in the control group (r = 0.53, P = 0.008, and r = -0.09, P = 0.70, respectively). CONCLUSIONS: EPA-enriched ONS in patients with exacerbation of COPD during short-time hospitalization had no significant advantage in preservation of LBM and muscle mass compared with EPA-free ONS. EPA supplementation for a longer duration might play an important role in the recovery of skeletal muscle mass after exacerbation of COPD.

[Successful lobectomy in 3 lung cancer cases with severe COPD after treatment with tiotropium bromide].

It is well known that lung cancer patients with severe chronic obstructive pulmonary disease (COPD) have a higher risk of postoperative complications than patients without COPD. However, the information regarding preoperative treatment to improve pulmonary function of the lung cancer patients with severe COPD is limited. Here, we report 3 lung cancer cases with severe COPD. Although all patients received medication without tiotropium bromide in combination with pulmonary rehabilitation for 1 or 2 months, their pulmonary function did not improve and the predicted postoperative FEV1/predicted FEV1 was below 40% in all cases. After the approval in Japan for use of tiotropium bromide in the treatment of COPD, all patients were treated with tiotropium bromide. The pulmonary function in all patients improved 2-4 weeks after the start of tiotropium bromide, and we performed lobectomy safely. Currently all patients maintain good pulmonary function without recurrence of lung cancer. We propose that treatment of tiotropium bromide might be one of the effective preoperative methods to improve pulmonary function of lung cancer patients with severe COPD.

[A possible case of drug-induced pneumonia due to L-carbocisteine].

A 70-year-old man presented with a deteriorating fever and productive cough after the administration of drugs including L-carbocisteine against the common cold. Since chest radiograph revealed pulmonary infiltrates in the right lower lung field, he was admitted to our hospital, then L-carbocisteine was continued and antibiotics started. However, his symptoms, laboratory findings, and hypoxia worsened. Pulmonary infiltrates on his chest radiograph increased and chest CT demonstrated pulmonary consolidation with traction bronchiectasis and ground glass opacity with thickened of interlobular septae in the right lung field. Analysis of bronchoalveolar lavage fluid showed elevated numbers of total cells, neutrophils and eosinophils, and the CD4/CD8 ratio was 5.65. Under a suspected diagnosis of drug-induced pneumonia, we halted L-carbocisteine administration stopped and began corticosteroid therapy. Subsequently his symptoms and findings markedly improved. The drug lymphocyte stimulation test for L-carbocisteine using peripheral blood lymphocytes showed positive results. On the basis of the clinical course, laboratory and radiographic findings, we considered this case to possibly be drug-induced pneumonia due to L-carbocisteine. To our knowledge, this is possibly the first case of L-carbocisteine-induced pneumonia to be reported.

[Bronchial asthma attack with lactic acidosis and hypokalemia in a case receiving high dose inhalation of procaterol hydrochloride].

We report a case of bronchial asthma attack with lactic acidosis and hypokalemia in a patient receiving high-dose inhalation of procaterol hydrochloride. A 28-year-old man was transferred to our hospital because of adynamia, nausea and dyspnea. He had used inhaled procaterol hydrochloride with a pressurized metered dose inhaler about 20 times before admission. On admission, there were no signs of shock state or hypoxemia and laboratory data showed hypokalemia, hyperglycemia and metabolic acidosis with elevated anion gap. Lactic acidosis was identified as the reason for the metabolic acidosis with elevated anion gap. Lactic acidosis improved after 12 hours. Lactic acidosis due to high dose inhalation of procaterol hydrochloride was suggested.

Increased serum vascular endothelial growth factor level in Churg-Strauss syndrome.

BACKGROUND: Churg-Strauss syndrome (CSS) is a rare form of systemic vasculitis occurring in patients with asthma and hypereosinophilia. For optimal treatment, prompt distinction of CSS from asthma is necessary; however, there are few serologic screening markers for this purpose. Vascular endothelial growth factor (VEGF), a vascular permeability factor, has been associated with other systemic vasculitis such as Wegener granulomatosis and giant-cell arteritis. OBJECTIVE: The aim of this study was to clarify the clinical value of the measurement of serum VEGF for the distinction of CSS from asthma. METHODS: We investigated serum VEGF levels in 18 CSS patients, 19 asthma patients, and 12 acute bronchitis patients. We also performed immunohistochemical analysis for VEGF. RESULTS: The serum VEGF levels of CSS patients were significantly higher than those of asthma patients and acute bronchitis patients. The sensitivity and specificity to distinguish CSS from asthma were 93.3% and 81.8%, respectively (cutoff, 600 pg/mL). Infiltrating eosinophils stained intensely positive for VEGF, and serum VEGF levels showed a significant correlation with peripheral eosinophil counts. Serum VEGF levels decreased significantly after therapy (p < 0.001). The infiltrating eosinophils in the CSS lesion stained positive for VEGF in the immunohistochemical analysis. CONCLUSION: VEGF is one of the useful screening markers for the distinction of CSS from asthma. We suggest that VEGF might be associated with the pathogenesis of CSS.

Increased serum vascular endothelial growth factor levels in microscopic poly angiitis with pulmonary involvement.

Microscopic polyangiitis (MPA) is a systemic necrotizing vasculitis that affects small vessels, resulting in a wide spectrum of organ involvement including the lungs. However, there are little serological markers that predict its prognosis or severity of pulmonary involvement. Vascular endothelial growth factor (VEGF) is an angiogenic mediator, which has been reported to be elevated in systemic vasculitis. In this study, we measured serum VEGF levels in 22 MPA patients with pulmonary involvement. We also investigated VEGF expression in pulmonary cells using flow cytometry analysis. We found that serum VEGF levels in MPA patients were significantly higher than those in respiratory or urinary tract infection. The serum VEGF levels decreased in parallel with the improvement of MPA symptoms. The serum VEGF levels in MPA patients who died within 5 years were significantly higher than those who survived more than 5 years. The sensitivity of VEGF levels to distinguish MPA patient with poor prognosis from those with good prognosis was 90.9%, and specificity was 81.8% (cutoff value = 802.5 pg/ml). The serum VEGF levels showed significant positive correlation with the composite physiological index, which indicates the severity of pulmonary lesion. In flow cytometry analysis, CD11b positive bronchoalveolar lavage fluid cells expressed VEGF. Immunohistochemically, alveolar macrophages, tissue infiltrating inflammatory cells and alveolar epithelial cells stained positive for VEGF. Measurement of serum VEGF levels in MPA might become one of the markers for prognosis and the severity of pulmonary involvement in MPA. VEGF might contribute to the development of pulmonary lesion of MPA.

[A case of bronchiolitis obliterans syndrome successfully treated by Tiotropium bromide].

A 48-year-old woman was admitted with dyspnea on effort. She suffered from adult T-cell leukemia and received peripheral blood stem cell transplantation (PBSCT). Eight months after the PBSCT, she developed dyspnea on effort and was treated with bronchodilator, inhaled corticosteroid, anti-leukotriene drug, theophylline and oxytropium bromide. However her symptoms progressed and she was admitted. We diagnosed bronchiolitis obliterans syndrome (BOS) because of obstructive pulmonary dysfunction, diffuse patchy high density of the lung field on chest computed tomography and decreased ventilation with peripheral patchy accumulation on ventilation scintigraphy. She was treated with corticosteroid and cyclosporine A and her symptoms and her pulmonary function were improved. However, in parallel with corticosteroid tapering, her symptoms and pulmonary functions worsened. Treatment with Tiotropium bromide was started and her pulmonary function improved significantly. Her pulmonary function did not worsen and tapering steroid dose was successfully achieved. PBSCT was reported to up-regulate the muscarinic receptor activity in lung. Tiotropium bromide might become one additional option for the treatment of BOS.

[Two lung adenocarcinoma patients with multiple brain metastasis treated with Gefitinib and surviving more than 2 years].

Case 1 is a 78-year-old woman in whom lung adenocarcinoma with multiple brain metastasis (cT2N3M1, stage IV) was diagnosed. She was treated with Gefitinib alone. Her lung tumor and metastatic brain lesions decreased 6 months after the start of therapy. She has no recurrence and is still alive with a good performance status after 25 months. Case 2 is an 80-year-old woman in whom lung adenocarcinoma with multiple brain (cT2N3M1, stage IV) was diagnosed. She was also treated with Gefitinib alone and her lung tumor and metastatic brain becomes improved 6 months after the start of therapy. She maintained a good performance status for more than 2 years (29 months). However, 29 months after beginning treatment, she had recurrence in bone and died 2 months later, 31 months after the start of therapy. The prognosis of non-small cell lung cancer with multiple brain metastasis is very poor and the efficacy of chemotherapy for the treatment of multiple brain metastases is limited, and longterm survival remains disappointing. We report two lung adenocarcinoma patients with multiple brain metastasis who survived more than 2 years by treatment with Gefitinib alone.

Discoidin domain receptor 1: a new class of receptor regulating leukocyte-collagen interaction.

Previous studies demonstrated that type I collagen, a major component of the extracellular matrix, could influence the differentiation and function of leukocytes; however, it is not clear whether those effects of collagen were based on its interaction with the classic collagen receptors, alpha1beta1 and alpha2beta1 integrins. We recently detected significant upregulation of discoidin domain receptor 1 (DDR1), a new class of collagen receptor, in human leukocytes, including neutrophils, monocytes, and lymphocytes, in vitro, leading to the hypothesis that the leukocyte-activating effects of collagen might be owing to its interaction with DDR1. In this review, we summarize our recent findings demonstrating that DDR1-collagen interaction facilitates the adhesion, migration, differentiation/maturation, and cytokine/chemokine production of leukocytes. We also describe the intracellular signaling pathways activated by DDR1 interaction with collagen.

Effects of omega-3 polyunsaturated fatty acids on inflammatory markers in COPD.

BACKGROUND: COPD, the fifth-leading cause of death worldwide, is characterized by chronic inflammation. However, no available agent can effectively cure this inflammation. A dietary supplement containing omega-3 polyunsaturated fatty acids (PUFAs) has anti-inflammatory effects. In this study, we hypothesized that nutritional support with omega-3 PUFA-rich diets may be useful for treating COPD, and we compared the clinical features and inflammatory mediator levels between the COPD patients who received an omega-3 PUFA-rich supplement and those who received a nonrich supplement. METHODS: Sixty-four COPD patients received 400 kilocalories per day of an omega-3 PUFA-rich supplement (n-3 group) or an omega-3 PUFA-nonrich supplement (n-6 group) for 2 years. We prospectively investigated the clinical features of these patients and measured the levels of inflammatory mediators. RESULTS: In 6-min walk testing, the dyspnea Borg scale and decrease of arterial oxygen saturation measured by pulse oximetry significantly improved in the n-3 group. Leukotriene B4 levels in serum and sputum and tumor necrosis factor-alpha and interleukin-8 levels in sputum decreased significantly in the n-3 group, while there was no significant change in the n-6 group. Two patients in the n-3 group and three patients in the n-6 group had mild diarrhea, and three patients in the n-3 group and three patients in the n-6 group had nausea; however, their symptoms were controllable and they improved with treatment. With multiple regression analysis, it was proved that the omega-3 PUFA-rich diet significantly contributed to the change in cytokine levels in this study. CONCLUSION: We suggest nutritional support with an omega-3 PUFA-rich diet as a safe and practical method for treating COPD.

Interaction of discoidin domain receptor 1 isoform b (DDR1b) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages.

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen. DDR1 is constitutively expressed in a variety of normal and transformed epithelial cells and plays a role in cell migration and differentiation through as yet unidentified signaling pathways. We previously reported inducible expression of DDR1 in human leukocytes and suggested a role for the DDR1a isoform in leukocyte migration through extracellular matrix. Here, we evaluated the contribution of DDR1 in the differentiation of the human monocytic THP-1 cells overexpressing these isoforms and of primary macrophages. Interestingly, collagen activation of DDR1b, but not DDR1a, further promoted phorbol ester-induced differentiation of THP-1 cells as determined by reduced cell proliferation and up-regulated expression of HLA-DR, CD11c, CD14, and CD40. Collagen activation of DDR1b also induced the recruitment and phosphorylation of Shc and subsequent phosphorylation of p38 mitogen-activated protein (MAP) kinase and its substrate ATF2. A p38 MAP kinase inhibitor, SB203580, completely inhibited DDR1b-mediated HLA-DR expression. Activation of DDR1 endogenously expressed on macrophages also up-regulated their HLA-DR expression in a p38 MAP kinase-dependent manner. Thus, DDR1b in response to collagen transduces signals that promote maturation/differentiation of HLA-DR-positive antigen-presenting cells and contributes to the development of adaptive immunity in a tissue microenvironment.

Hermansky-Pudlak syndrome with a novel mutation.

We report a case of Hermansky-Pudlak syndrome (HPS) with a novel mutation in the HPS1 gene. This case showed oculocutaneous albinism and lysosomal ceroid accumulation, however platelet dysfunction was not observed. Histopathological findings of the biopsied lung tissue were compatible with HPS. Sequencing analysis showed the insertion of C in the codon 178 (739 bp) of the HPS1 gene forming a stop codon at codon 181. To the best of our knowledge, this is a novel HPS1 gene mutation.

Vascular endothelial growth factor and proinflammatory cytokines in pleural effusions.

To evaluate the predictive value of vascular endothelial growth factor (VEGF) in the differential diagnosis of pleuritis and its association with other proinflammatory cytokines in pleural effusion, we measured VEGF together with interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and soluble intercellular adhesion molecule-1 (sICAM-1) in pleural effusions. We investigated 127 patients with pleural effusion (congestive heart failure: 21; parapneumonic: 27; tuberculous: 41; malignant: 38). We examined standard parameters of pleural effusion and measured pleural effusion VEGF, IL-1beta, TNF-alpha and sICAM-1 using enzyme-linked immunosorbent assay. VEGF level was significantly higher in malignant effusion than in other groups. TNF-alpha level was significantly higher in tuberculous pleurisy than in other groups. In tuberculous pleurisy VEGF level showed significant positive correlations with mononuclear cell counts and all investigated cytokines. The sensitivity and specificity of VEGF in the diagnosis of malignancy was 100 and 84%, respectively (cutoff = 2000 pg/ml). The sensitivity and specificity of VEGF and TNF-alpha in the diagnosis of tuberculous pleurisy (VEGF titer <2000 pg/ml and TNF-alpha titer > 55 pg/ml) was 88.9 and 77.1%, respectively. We propose that measurement of VEGF together with TNF-alpha is helpful in differentiating between tuberculous pleurisy and malignant pleural effusion and that VEGF correlates with proinflammatory cytokines especially in tuberculous pleurisy. We also propose that measurement of pleural VEGF is helpful for the diagnosis of malignant pleural effusion.

Pleural cryptococcosis with idiopathic CD4 positive T-lymphocytopenia.

A 19-year-old man was admitted to our hospital because of chest pain. He was diagnosed as having pleural cryptococcosis by pleural biopsy. His CD4 positive T-lymphocyte count was low (< 300 microl) and there was no evidence of human immunodeficiency virus infection. He was successfully treated with fluconazole. However, his CD4 positive lymphocyte counts remained low after the recovery and he was diagnosed as idiopathic CD4 positive T-lymphocytopenia. Pleural cryptococcosis is rare and its predisposing condition is still controversial. To our knowledge, this is the first case of pleural cryptococcosis associated with idiopathic CD4 positive T lymphocytopenia.

[Intense 18F-fluorodeoxyglucose uptake caused by pulmonary Mycobacterium intracellulare infection].

A 70-year-old woman was admitted to our hospital for the evaluation of a pulmonary nodule in the left S5 segment. On 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET), the nodule showed substantial uptake of 18F-fluorodeoxyglucose. Bronchoscopy was performed, but the cytology was negative. For a pathological diagnosis, a lung biopsy was carried out using video-associated thoracoscopy. The biopsy specimen showed granuloma formation with multinuclear giant cells. An acid-fast bacteria culture of the specimen was positive for Mycobacterium intracellulare. An atypical mycobacterium infection should be considered as a possibility when the 18FDG-PET of patients with pulmonary nodules is interpreted.