Geriatric Nutritional Risk Index is a predictor of tolerability of antifibrotic therapy and mortality risk in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung fibrosis of unknown aetiology. Epidemiological studies have suggested that IPF progression may negatively affect nutritional status. Weight loss during antifibrotic therapy is also frequently encountered. The association of nutritional status and outcome has not been fully evaluated in IPF patients. METHODS: This retrospective multicohort study assessed nutritional status of 301 IPF patients receiving antifibrotic therapy (Hamamatsu cohort, n = 151; Seirei cohort, n = 150). Nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI). The GNRI was calculated based on body mass index and serum albumin. The relationship between nutritional status and tolerability of antifibrotic therapy as well as mortality was explored. RESULTS: Of 301 patients, 113 (37.5%) had malnutrition-related risk (GNRI < 98). Patients with malnutrition-related risk were older, had increased exacerbations and worse pulmonary function than those without a GNRI status <98. Malnutrition-related risk was associated with a higher incidence of discontinuation of antifibrotic therapy, particulary due to gastrointestinal disturbances. IPF patients with malnutrition-related risk (GNRI < 98) had shorter survival than those without such risk (median survival: 25.9 vs. 41.1 months, p < 0.001). In multivariate analysis, malnutrition-related risk was a prognostic indicator of antifibrotic therapy discontinuation and mortality, independent of age, sex, forced vital capacity, or gender-age-physiology index. CONCLUSION: Nutritional status has significant effects on the treatment and outcome in patients with IPF. Assessment of nutritional status may provide important information for managing patients with IPF.

Hepatic Angiosarcoma with Peliosis Hepatis.

A 59-year-old woman presented to our hospital with liver dysfunction. Imaging revealed multiple lesions in the liver. The patient was diagnosed with peliosis hepatis using percutaneous and laparoscopic biopsies. However, her condition worsened with the appearance of new, obvious mass-forming lesions. Therefore, she underwent a second percutaneous biopsy of these lesions and was diagnosed with hepatic angiosarcoma. Her condition progressed rapidly, and she died two weeks after the diagnosis. Diagnosis of hepatic angiosarcoma in the early stages is difficult. It should be noted that hepatic angiosarcoma may be associated with the development of peliosis hepatis.

Associations of serum long-chain fatty acids with multiple organ involvement in patients with sarcoidosis.

BACKGROUND: Fatty acids have diverse immunomodulatory functions and the potential to be associated with inflammatory responses in sarcoidosis. METHODS: The serum levels of multiple long-chain fatty acids (LCFAs) were compared between 63 patients with sarcoidosis and 38 healthy controls. The associations of LCFAs with clinical outcomes of sarcoidosis were also evaluated. RESULTS: The patients with sarcoidosis had significantly lower levels of n-3 poly-unsaturated fatty acids (PUFAs) (p < 0.001) and n-6 PUFAs (p < 0.001) than the healthy controls. However, there were no significant differences in the levels of saturated fatty acids (SFAs) and mono-unsaturated fatty acids (MUFAs) between the two groups. On multivariate logistic analysis, lower levels of n-3 PUFAs, n-6 PUFAs, and n-3/n-6 ratio were predictive of sarcoidosis. Among the patients with sarcoidosis, those with multiple organ involvement had significantly lower levels of n-3 PUFAs and n-3/n-6 ratio than those with single organ involvement. There were no significant differences in the levels of n-6 PUFAs, SFAs, and MUFAs between the patients with multiple and single organ involvement. On multivariate logistic analysis, lower levels of SFAs and n-3/n-6 ratio were predictive of multiple organ involvement. The levels of LCFAs had no significant association with radiographic stage or spontaneous remission. CONCLUSIONS: Assessment of LCFA profiles may be useful for the diagnosis of sarcoidosis and evaluation of the disease activity.

Association of the Geriatric Nutritional Risk Index With the Survival of Patients With Non-Small Cell Lung Cancer After Nivolumab Therapy.

The nutritional status has the potential to affect cancer immunity. We evaluated the relationship between the nutritional status and the efficacy of nivolumab in patients with non-small cell lung cancer (NSCLC). This study was a post hoc analysis of a prospective, multicenter cohort study conducted at 14 institutions in Japan between July 2016 and December 2018. The Geriatric Nutritional Risk Index (GNRI), calculated from body weight and serum albumin, was evaluated in 158 patients with NSCLC who received nivolumab. GNRI was graded as low, moderate, and high. Low GNRI was associated with significantly shorter progression-free survival [median, 1.9 mo; 95% confidence interval (CI)=0.6-3.3 mo] than moderate (median, 4.0 mo; 95% CI=2.3-5.8 mo; P=0.017) and high GNRI (median, 3.0 mo; 95% CI=1.9-7.2 mo; P=0.014). Low GNRI was also linked to significantly shorter overall survival (OS) (median, 7.8 mo; 95% CI=2.6-12.0 mo) than moderate (median, 13.0 mo; 95% CI=9.6-15.2 mo; P=0.006) and high GNRI (median, 20.6 mo; 95% CI=15.6 mo-not reached; P<0.001). High GNRI was associated with significantly longer OS than moderate GNRI (P=0.015). In multivariate Cox proportional hazard analyses, increased GNRI was predictive of longer progression-free survival and OS, similarly as tumor programmed cell death-ligand 1 expression. In patients with NSCLC receiving nivolumab. GNRI was predictive of survival and may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.

Association of the Geriatric Nutritional Risk Index with the survival of patients with non-small-cell lung cancer after platinum-based chemotherapy.

BACKGROUND: The nutritional status can potentially affect the efficacy of cancer therapy. The Geriatric Nutritional Risk Index (GNRI), a simple index for evaluating nutritional status calculated from body weight and serum albumin levels, has been reported to be associated with the prognosis of various diseases. However, the relationships between GNRI and the efficacy of platinum-based chemotherapy in patients with non-small-cell lung cancer (NSCLC) are unknown. METHODS: The pretreatment levels of GNRI were retrospectively evaluated in 148 chemo-naïve patients with advanced NSCLC who received first-line platinum-based chemotherapy and scored as low or high. RESULTS: Patients with a high GNRI had a significantly higher overall response rate (ORR; 44.5% [95% confidence interval {CI} = 35.6%-53.9%] vs. 15.8% [95% CI = 7.4%-30.4%, p = 0.002), longer median progression-free survival (PFS; 6.3 months [95% CI = 5.6-7.2 months] vs. 3.8 months [95% CI = 2.5-4.7 months], p < 0.001), and longer median overall survival (OS; 22.8 months [95% CI = 16.7-27.2 months] vs. 8.5 months [95% CI = 5.4-16.0 months], p < 0.001) than those with low GNRI. High GNRI was independently predictive of better ORR in multivariate logistic regression analysis and longer PFS and OS in multivariate Cox proportional hazard analyses. In 71 patients who received second-line non-platinum chemotherapy, patients with high GNRI exhibited significantly longer PFS and OS than those with low GNRI (both p < 0.001). CONCLUSIONS: GNRI was predictive of prolonged survival in patients with NSCLC who received first-line platinum-based chemotherapy and second-line non-platinum chemotherapy. Assessment of the nutritional status may be useful for predicting the efficacy of chemotherapy.

Impairment of the Hypothalamus-Pituitary-Thyroid Axis Caused by Naturally Occurring GATA2 Mutations In Vitro.

The transcription factor GATA2 regulates gene expression in several cells and tissues, including hematopoietic tissues and the central nervous system. Recent studies revealed that loss-of-function mutations in GATA2 are associated with hematological disorders. Our earlier in vitro studies showed that GATA2 plays an essential role in the hypothalamus-pituitary-thyroid axis (HPT axis) by regulating the genes encoding prepro-thyrotropin-releasing hormone (preproTRH) and thyroid-stimulating hormone ß (TSHß). However, the effect of GATA2 mutants on the transcriptional activity of their promoters remains unelucidated. In this study, we created five human GATA2 mutations (R308P, T354M, R396Q, R398W, and S447R) that were reported to be associated with hematological disorders and analyzed their functional properties, including transactivation potential and DNA-binding capacity toward the preproTRH and the TSHß promoters. Three mutations (T354M, R396Q, and R398W) within the C-terminal zinc-finger domain reduced the basal GATA2 transcriptional activity on both the preproTRH and the TSHß promoters with a significant loss of DNA binding affinity. Interestingly, only the R398W mutation reduced the GATA2 protein expression. Subsequent analysis demonstrated that the R398W mutation possibly facilitated the GATA2 degradation process. R308P and S447R mutants exhibited decreased transcriptional activity under protein kinase C compared to the wild-type protein. In conclusion, we demonstrated that naturally occurring GATA2 mutations impair the HPT axis through differential functional mechanisms in vitro.

Dose-Dependent Influence of Antithyroid Drugs on the Difference in Free Thyroxine Levels between Mothers with Graves' Hyperthyroidism and Their Neonates.

BACKGROUND: Several guidelines have recommended that the use of the lowest effective dose of antithyroid drugs (ATDs) that maintains maternal serum free thyroxine (FT4) levels at or moderately above the upper limit of the reference range is appropriate for fetal euthyroid status. However, little is known about whether ATD dosage affects the difference in serum FT4 levels between the mother and neonate. We conducted a retrospective study at a tertiary hospital in Japan to investigate the dose-dependent influence of ATDs on both maternal and fetal thyroid hormone status. MATERIALS AND METHODS: We retrospectively examined 62 pregnant women who delivered between 2007 and 2016 and were treated for Graves' hyperthyroidism with ATD at any stage during pregnancy. We selected individuals whose data on maternal FT4 level within 4 weeks of their deliveries and cord FT4 level of their infants at the time of delivery were available. Those with multiple pregnancies, iodine or glucocorticoid treatment, and fetal goiter detected by ultrasonography were excluded. RESULTS: After the exclusion criteria were applied, we recruited 40 individuals. The cord FT4 levels were significantly lower than the maternal FT4 levels in patients treated with high-dosage ATDs (methimazole >5 mg daily or propylthiouracil >100 mg daily). However, there were no significant differences between maternal and cord FT4 levels in patients treated with low-dosage ATDs (methimazole ≤5 mg daily or propylthiouracil ≤100 mg daily). We selected 35 individuals whose data on maternal thyrotropin receptor-binding inhibitory immunoglobulin (TBII) level were available. Multiple linear regression analysis adjusted for ATD dosage, maternal TBII level, and gestational period found that ATD dosage was a significant predictor of the difference in serum FT4 levels between the mother and neonate. In terms of maternal complications, multiple logistic regression analysis identified maternal free triiodothyronine (FT3) level as a significant predictor of the incidence of preterm delivery. CONCLUSIONS: We found a dose-dependent influence of ATDs on the difference in serum FT4 levels between mothers with Graves' hyperthyroidism and their neonates. Further studies to evaluate the optimal target FT4 and FT3 levels for the mother and neonate during pregnancy may improve the outcome of pregnant women with Graves' hyperthyroidism.

Pneumonitis with Diffuse Alveolar Hemorrhage Induced by Sho-seiryu-to.

A 78-year-old man presented with acute-onset fever and dyspnea. He had been taking Sho-seiryu-to for allergic rhinitis. A chest radiograph showed diffuse bilateral ground-glass opacities with subpleural sparing, crazy-paving pattern, and traction bronchiectasis. The patient's bronchoalveolar lavage fluid was bloody and transbronchial lung biopsy specimens showed alveolitis, organizing pneumonia, and type 2 alveolar epithelial cell proliferation. There were no clinical and laboratory findings suggestive of respiratory tract infection or connective tissue disease. Based on the clinical course and the exclusion of other etiologies, Sho-seiryu-to-induced pneumonitis with diffuse alveolar hemorrhage was considered. The patient's pneumonitis resolved after the discontinuation of the drug and the administration of systemic corticosteroid therapy.

Distribution Analysis via Mass Spectrometry Imaging of Ephedrine in the Lungs of Rats Orally Administered the Japanese Kampo Medicine Maoto.

Maoto, a traditional Japanese Kampo medicine, has been used to treat various respiratory diseases, including respiratory infections and influenza. Ephedrine (EPD), the main ingredient in maoto, is also clinically used to treat respiratory diseases. However, the pharmacokinetics and distribution of EPD in the lungs after the administration of maoto have not been demonstrated. This study aimed to determine the concentrations, distribution, and pharmacokinetics of EPD and its precursor methylephedrine (MEPD) in the lungs of rats orally administered maoto (1 and 4 g/kg). We used liquid chromatography-electrospray ionization-tandem mass spectrometry to measure the ingredient concentrations. Both ingredients were detected in maoto-treated lung homogenates. Next, we examined the distribution of both ingredients in lung sections by using matrix-assisted laser desorption/ionization-mass spectrometry imaging, a powerful tool for the visualization of the distribution of biological molecules. The mass spectrometry imaging analysis detected only EPD and provided the first visual demonstration that EPD is distributed in the alveoli, bronchi, and bronchioles in the lungs of rats orally administered maoto (4 g/kg, three times at 2-h intervals). These results suggest that the pharmacological efficacy of maoto for the amelioration of respiratory symptoms is related to the distribution of EPD in the lung.

Predictive factors for long-term outcome in polymyositis/dermatomyositis-associated interstitial lung diseases.

BACKGROUND: Interstitial lung disease (ILD) is strongly associated with polymyositis (PM), dermatomyositis (DM), and clinically amyopathic dermatomyositis (CADM). It is also related to mortality. Previous studies have highlighted that the acute form of PM/DM/CADM-associated ILD (PM/DM/CADM-ILD) has a poor short-term prognosis. However, little is known about the long-term clinical features of patients with PM/DM/CADM-ILD. The aim of the present study is to clarify the clinical characteristics and the predictive factors for long-term outcomes in patients with PM/DM/CADM-ILD. METHODS: Thirty-four patients with PM/DM/CADM-ILD who were followed up for more than 12 months were analyzed retrospectively. The patients were classified as "stable" or "deterioration" according to respiratory symptoms, serial changes in forced vital capacity (FVC) or arterial oxygen pressure, and radiologic findings during the follow-up period. RESULTS: Twenty-six patients (76%) were in the stable group and eight patients (24%) were in the deterioration group. Home oxygen therapy was performed in six cases in the deterioration group because of chronic respiratory failure due to progression of ILD. The deterioration group, in comparison to the stable group, had a significantly lower %FVC and a higher positive rate for the anti-PL-7 antibody. Multivariate logistic regression analysis revealed that a positive anti-PL-7 antibody test and a lower %FVC were independently associated with deterioration during long-term follow-up. CONCLUSIONS: Patients with PM/DM/CADM-ILD are at risk for chronic respiratory failure due to the deterioration of ILD during long-term follow-up. The presence of anti-PL-7 antibody and a lower %FVC at initial diagnosis may predict long-term deterioration in patients with PM/DM/CADM-ILD.

Japanese herbal medicine-induced pneumonitis: A review of 73 patients.

BACKGROUND: The number of reports concerning Japanese herbal medicine (JHM)-induced pneumonitis has increased. However, comprehensive data are lacking in this regard, and the clinical characteristics of the disease remain unclear. METHODS: A literature review was performed using PubMed and Ichushi-Web-the database of the Japan Medical Abstracts Society-to identify articles published between 1996 and 2015 describing patients with JHM-induced pneumonitis. The final cohort included 73 patients in 59 articles (7 in English; 52 in Japanese). RESULTS: Among the various JHMs reported, sho-saiko-to was the most frequently used drug (26%), followed by sairei-to (16%), seishin-renshi-in (8%), and bofu-tsusyo-san (8%). These drugs commonly contain ougon (skullcap) and kanzo (liquorice). The mean age at pneumonitis diagnosis was 63.2 ± 15.5 years (range: 7-89 years). The male/female ratio was 44/29. Sixty-five patients (89%) developed pneumonitis within 3 months of beginning JHM treatment. Bilateral ground-glass attenuations on chest computed tomography, as well as lymphocytosis with a low CD4/CD8 T-cell ratio in bronchoalveolar lavage fluid, were common findings. Twenty-six patients (36%) recovered from the pneumonitis after simply discontinuing the causative JHM. However, the remainder required immunosuppressive therapy, and 13 patients (18%) received mechanical ventilation. Importantly, three patients (4%) did not survive, with two showing pathological diffuse alveolar damage upon autopsy. CONCLUSIONS: Clinicians should be cautious regarding JHM-induced pneumonitis, particularly when using drugs/ingredients known to cause this complication, and during the early treatment period. Although most events are non-severe, critical cases should be recognized.

A novel GABA-mediated corticotropin-releasing hormone secretory mechanism in the median eminence.

Corticotropin-releasing hormone (CRH), which is synthesized in the paraventricular nucleus (PVN) of the hypothalamus, plays an important role in the endocrine stress response. The excitability of CRH neurons is regulated by γ-aminobutyric acid (GABA)-containing neurons projecting to the PVN. We investigated the role of GABA in the regulation of CRH release. The release of CRH was impaired, accumulating in the cell bodies of CRH neurons in heterozygous GAD67-GFP (green fluorescent protein) knock-in mice (GAD67(+/GFP)), which exhibited decreased GABA content. The GABAA receptor (GABAAR) and the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1), but not the K(+)-Cl(-) cotransporter (KCC2), were expressed in the terminals of the CRH neurons at the median eminence (ME). In contrast, CRH neuronal somata were enriched with KCC2 but not with NKCC1. Thus, intracellular Cl(-) concentrations ([Cl(-)]i) may be increased at the terminals of CRH neurons compared with concentrations in the cell body. Moreover, GABAergic terminals projecting from the arcuate nucleus were present in close proximity to CRH-positive nerve terminals. Furthermore, a GABAAR agonist increased the intracellular calcium (Ca(2+)) levels in the CRH neuron terminals but decreased the Ca(2+) levels in their somata. In addition, the increases in Ca(2+) concentrations were prevented by an NKCC1 inhibitor. We propose a novel mechanism by which the excitatory action of GABA maintains a steady-state CRH release from axon terminals in the ME.

Anaphylaxis caused by tipepidine hibenzate, a central antitussive drug.

Tipepidine hibenzate, a central antitussive drug, is widely used in the management of cough and is generally safe and well tolerated. We present here a case of anaphylaxis caused by this drug. When the patient had caught a cold over the previous 10 years, she had received medications, including tipepidine hibenzate, from her family doctor. However, this time, she developed dyspnea, skin eruption, and anaphylactic shock after taking a Chinese herbal medicine and this drug. After her conditions improved due to adequate treatment, she was referred to our hospital to confirm the causative drug. Double-blind placebo-controlled oral challenge tests were performed after obtaining informed consent. Oral challenge with one-third tablet dose of tipepidine hibenzate caused a positive reaction. Urinary leukotriene E4 rose during the challenge with tipepidine hibenzate, but not with control. Clinicians should keep in mind that common antitussive drug use can cause anaphylactic reactions in very rare cases and can be harmful.

Green tea polyphenol EGCG induces lipid-raft clustering and apoptotic cell death by activating protein kinase Cδ and acid sphingomyelinase through a 67 kDa laminin receptor in multiple myeloma cells.

EGCG [(-)-epigallocatechin-3-O-gallate], the major polyphenol of green tea, has cancer chemopreventive and chemotherapeutic activities. EGCG selectively inhibits cell growth and induces apoptosis in cancer cells without adversely affecting normal cells; however, the underlying molecular mechanism in vivo is unclear. In the present study, we show that EGCG-induced apoptotic activity is attributed to a lipid-raft clustering mediated through 67LR (67 kDa laminin receptor) that is significantly elevated in MM (multiple myeloma) cells relative to normal peripheral blood mononuclear cells, and that aSMase (acid sphingomyelinase) is critical for the lipid-raft clustering and the apoptotic cell death induced by EGCG. We also found that EGCG induces aSMase translocation to the plasma membrane and PKCδ (protein kinase Cδ) phosphorylation at Ser664, which was necessary for aSMase/ceramide signalling via 67LR. Additionally, orally administered EGCG activated PKCδ and aSMase in a murine MM xenograft model. These results elucidate a novel cell-death pathway triggered by EGCG for the specific killing of MM cells.

[Two cases of pneumonitis caused by Seishinrenshiin, Chinese herbal medicine].

We report two cases of pneumonitis caused by Seishinrenshiin. A 54-year-old woman and a 80-year-old man had taken Seishinrenshiin for cystitis and benign prostatic hypertrophy. Their chest radiograph showed diffuse ground-glass shadows in the whole lung fields and chest CT showed diffuse ground-glass-opacities predominantly in the lower lung fields of both lungs. Biochemical tests revealed mild liver dysfunction and inflammatory reactions. Their abnormal chest shadows disappeared after discontinuation of Seishinrenshiin. We should be aware that Seishinrenshiin, as well as other Chinese herbal medicine, could be cause of drug-induced pneumonitis.

Mucosal vaccine using CTL epitope-pulsed dendritic cell confers protection for intracellular pathogen.

Effective protective immunity against respiratory infections with intracellular pathogens requires pathogen-specific cytotoxic T cells (CTL) in the lung. However, vaccines that induce pathogen-specific CTL in the lung are poorly explored. Dendritic cells (DC) have increasingly been exploited as vaccines against infections. However, few studies have investigated the ability of mucosal DC vaccines to elicit protective CTL responses in the lung. Our objective was to develop an efficacious mucosal DC vaccine to generate protective CTL against respiratory infections with intracellular pathogens. Bone marrow-derived DC (BM-DC) pulsed with a single immunodominant CTL epitope, listeriolysin O (LLO) 91-99, of Listeria monocytogenes (LM) were intratracheally administered into mice. The frequency and function of epitope-specific CTL in mediastinal lymph nodes (MLN) and spleen were assessed for their ability to protect against LM infection. After intratracheal administration, lipopolysaccharide (LPS)-treated LLO 91-99-loaded BM-DC (LPS-LLO DC) more frequently migrated to MLN than LPS-untreated LLO 91-99-loaded BM-DC (LLO DC). Using tetrameric H2-K(d)/LLO 91-99 peptide complex, specific CD8(+) T cells were found in MLN as well as the spleen in LPS-LLO DC-immunized mice, but not in LLO-DC-immunized mice. Both MLN and spleen cells obtained from LPS-LLO DC-immunized mice produced large amounts of IFN-gamma in response to LLO 91-99 with high epitope-specific CTL activities. Vaccination with LPS-LLO DC, but not LLO DC, protected mice against lethal respiratory infection with LM. These data suggest that mucosal vaccination with LPS-treated immunodominant CTL epitope-loaded DC is a promising strategy for generating protective CTL against respiratory infections with intracellular pathogens.

[A case of pneumonitis caused by Seisin-renshi-in, herbal medicine].

We report a case of pneumonitis induced by Seisin-renshi-in. A 62-year-old man began to complain of cough, dyspnea and fever 45 days after starting to take Seisin-renshi-in for benign prostate hypertrophy. Chest radiograph showed diffuse ground-glass shadows in the bilateral middle and lower lung fields. Chest CT showed diffuse ground-glass opacities in both lung fields. The serum KL-6 level was elevated. Arterial blood gas analysis revealed hypoxia. Lymphocyte stimulation test with peripheral blood lymphocytes for Seisin-renshi-in was positive. A mild increase of lymphocytes, neutrophils and eosinophils was observed in the cell population of bronchoalveolar lavage fluids. Transbronchial lung biopsy specimen showed lymphocytic infiltration into the alveolar septa, desquamative alveolar lining cells and fibrinous exudate in the alveolar spaces. On the basis of a diagnosis of Seisin-renshi-in-induced pneumonitis, steroid therapy was introduced. Three courses of steroid pulse therapy were required because of prolonged hypoxia. His respiratory condition then improved and predonisolone was tapered from 30 mg. We should be aware that over-the-counter drugs could be causal agents of severe pneumonitis.

[A case of severe intestinal tuberculosis, treated with ciprofloxacin, kanamycin and prednisolone].

A 31-year-old man was admitted to our hospital because of frequent diarrhea. Colonoscopy showed ring ulcers on the rectum and ascending colon and chest X-ray showed abnormal shadows which were diagnosed as tuberculosis by sputum PCR. He started treatment with isoniazid (INH), rifampicin (RFP), pyrazinamide (PZA) and streptomycin (SM), however, eruption and ileus were seen. Then, he was retreated with ciprofloxacin (CPFX), kanamycin sulfate (KM) and prednisolone (PSL). Subsequently, we added RFP and further added calcium para-aminosalicylate (PAS). All these treatment was effective, and he was discharged from the hospital.