Development of a Reverse-Yield Factor Database Disaggregating Japanese Composite Foods into Raw Primary Commodity Ingredients Based on the Standard Tables of Food Composition in Japan.

The reverse-yield factor (RF) database was developed for qualitatively and quantitatively disaggregating Japanese composite foods into raw primary commodity (RPC) ingredients. Representative equations for four types (dried, salted, fermented and mixed foods) were developed to calculate RFs using the food content and composition data for composite foods listed in the Standard Tables of Food Composition in Japan-2020-(STFCJ), published by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Out of 1150 composite foods identified in the STFCJ, RFs for 54 dried, 41 salted, 40 fermented and 818 mixed foods were obtained. RFs for 197 mixed foods could not be calculated because these foods were produced from ingredients with no specified information and/or through complex processing. The content and composition of Japanese composite foods would be interpreted representatively by RFs in the developed database.

Development of a processing factor prediction model for pesticides in processed tomato foods using elastic net regularization.

A novel regularized elastic net regression model was developed to predict processing factor (PF) for pesticide residues, which represents a change in the residue levels during food processing. The PF values for tomato juice, wet pomace and dry pomace in the evaluations and reports published by the Joint FAO/WHO Meeting on Pesticide Residues significantly correlated with the physicochemical properties of pesticides, and subsequently the correlation was observed in the present tomato processing study. The elastic net regression model predicted the PF values using the physicochemical properties as predictor variables for both training and test data within a 2-fold range for 80-100% of the pesticides tested in the tomato processing study while overcoming multicollinearity. These results suggest that the PF values are predictable at a certain degree of accuracy from the unique sets of physicochemical properties of pesticides using the developed model based on a processing study with representative pesticides.

Successful application of lorlatinib in a 23-year-old patient with anaplastic lymphoma kinase (ALK)-positive lung cancer and multiple brain metastases.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive lung cancer has a better long-term prognosis with ALK-inhibitor than other lung cancers. However, resistance to ALK-inhibitors and the control of metastases in the central nervous system (CNS) remain to be a challenge in the management of ALK-positive lung cancer. CASE: We present the case of a 23-year-old man who developed multiple brain metastases while receiving alectinib treatment for ALK-positive lung cancer. After 3 months of lorlatinib initiation, brain metastases disappeared, and complete response (CR) was maintained. CONCLUSION: While lorlatinib can be used as first line therapy, this drug may be considered as second line or later option for patients with multiple brain metastases if the patient has already been treated with other ALK-inhibitors since lorlatinib is thought to have good CNS penetration. This treatment option should be verified by further research.

High level of C-reactive protein as a predictive factor for immune-related adverse events of immune checkpoint inhibitors in non-small cell lung cancer: a retrospective study.

Background: Several risk factors for the immune-related adverse events (irAEs) during treatment with immune checkpoint inhibitors (ICIs) have been reported, of which include high levels of C-reactive protein (CRP). In this study, we aim to evaluate CRP levels before ICIs treatments as potential predictive biomarkers of irAEs incidence rate and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). Methods: Between December 1, 2015 to December 31, 2019, we retrospectively collected all adult patients with NSCLC who received at least one dose of an ICI targeting the PD-1/PD-L1 axis at the Iwate Medical University Hospital in Japan. In this study the patients were categorized into low and high groups with a cut-off value of 10 mg/L as the baseline level of CRP before the ICI treatment. The primary endpoint was relationship between CRP levels at baseline and incidence of irAEs. The secondary endpoints were the relationship of progression-free survival (PFS) and OS. Results: A total of 101 irAEs, and 25 severe irAEs were observed. The incidence of the most irAEs was higher in the high CRP group compared to the low CRP group (54.4% vs. 34.5%, respectively, P=0.003). The most frequent irAEs were skin rush (28.8%), followed by pneumonitis (19.2%), hypothyroidism (15.4%), and hepatotoxicity (9.6%). The most common grade 3 or 4 irAEs was pneumonitis (7.9%), which tended to be more frequent in the high CRP group. In multivariate analysis, patients with high CRP levels had an adjusted OR of 2.41 and were associated with an increased risk of developing irAEs (95% CI: 1.16-4.43, P=0.020). The high CRP group was related with shorter PFS compared to the low CRP group (2.2 vs. 3.3 months, respectively, P=0.006). The high CRP group were also related with shorter OS compared to the low CRP group (8.9 vs. 39.1 months, respectively, P<0.001). Conclusions: The results suggest that higher level of pretreatment CRP is involved in the development of irAE and poor prognosis. Identification of patients at high risk of irAEs would be of great help. Future multicenter prospective studies are needed to expand on this study.

A Case of Mediastinal Tuberculous Lymphadenitis in a Chronic Dialysis Patient Diagnosed by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA).

A 54-year-old woman on dialysis due to chronic renal failure had a fever lasting 2 weeks and was referred to a hospital. Non-enhanced CT and blood tests showed no remarkable findings. She was hospitalized and received an antibacterial drug. Although she was discharged after the fever subsided, she was hospitalized again due to a fever a few days later. A contrast-enhanced CT revealed mediastinal lymphadenopathy, and she was transferred to our hospital for a bronchoscopy. Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) for subcarinal lymph nodes was performed in our hospital. The Polymerase Chain Reaction (PCR) test of the obtained specimen was positive for mycobacterium tuberculosis, and histologically, caseous granulomas were found in the specimen. She was diagnosed with mediastinal tuberculous lymphadenitis, and HREZ (isoniazid, rifampicin, ethambutol, and pyrazinamide) treatment was started. The fever subsided immediately, and she was discharged from our hospital 2 weeks after the initiation of treatment. Thereafter, she received treatment as an outpatient. Since the use of a contrast medium was complicated by dialysis, a non-enhanced CT was performed at first, and it was difficult to make a diagnosis from this. We report this as an informative case that could be diagnosed with EBUS-TBNA, which was easily performed on a patient weakened by prolonged fever and dialysis.

Comprehensive analysis of a decade of cumulative radiocesium testing data for foodstuffs throughout Japan after the 2011 Fukushima Daiichi Nuclear Power Plant accident.

The unexpected accident at the Fukushima Daiichi Nuclear Power Station in Japan, which occurred on March 11th, 2011, after the Great East Japan Earthquake and tsunami struck the north-eastern coast of Japan, released radionuclides into the environment. Today, because of the amounts of radionuclides released and their relatively long half-life, the levels of radiocesium contaminating foodstuffs remain a significant food safety concern. Foodstuffs in Japan have been sampled and monitored for 134,137Cs since the accident. More than 2.5 million samples of foodstuffs have been examined with the results reported monthly during each Japanese fiscal year (FY, from April 1st to March 31st) from 2012 to 2021. A total of 5,695 samples of foodstuffs within the "general foodstuffs" category collected during this whole period and 13 foodstuffs within the "drinking water including soft drinks containing tea as a raw material" category sampled in FY 2012 were found to exceed the Japanese maximum permitted level (JML) set at 100 and 10 Bq/kg, respectively. No samples from the "milk and infant foodstuffs" category exceeded the JML (50 Bq/kg). The annual proportions of foodstuffs exceeding the JML in the "general foodstuffs" category varied between 0.37% and 2.57%, and were highest in FY 2012. The 134,137Cs concentration for more than 99% of the foodstuffs monitored and reported has been low and not exceeding the JML in recent years, except for those foodstuffs that are difficult to cultivate, feed or manage, such as wild mushrooms, plants, animals and fish. The monitoring data for foodstuffs show the current status of food safety risks from 134,137Cs contamination, particularly for cultured and aquaculture foodstuffs on the market in Japan.

Combination treatment with bevacizumab plus erlotinib for meningeal carcinomatosis of afatinib-resistant EGFR mutated lung cancer without T790M mutation: a case report.

Meningeal carcinomatosis in lung cancer is known to have a very poor prognosis. Here we report a case in which bevacizumab plus erlotinib (BE) was effective against meningeal carcinomatosis from afatinib-resistant EGFR mutation-positive lung cancer. A 61-year-old man started afatinib, a 2nd generation molecular targeting drug, as first-line treatment for lung adenocarcinoma cT1bN0M1a stage IVA harboring EGFR exon19 deletion mutation. This treatment shrank the tumor and allowed sustained control of tumor growth. After 19 months from the start of treatment, head MRI revealed brain metastasis in the cerebellum and meningeal carcinomatosis with loss of appetite and slurred speech, in response to which whole-brain irradiation was performed. Head MRI 1 month after whole-brain irradiation showed no change in the disseminated lesions of the cerebellum. In Japan, osimertinib treatment after failure of EGFR-TKI treatments requires the T790M mutation in the tumor, blood or body fluid, so BE treatment was started as second-line treatment. Brain MRI showed improvement in cerebellar disseminated lesions 1 month after the start of BE treatment. BE treatment controlled intrapulmonary metastases, pleural disseminated lesions and meningeal carcinomatosis for 6 months. BE treatment as second-line treatment should be considered as an option for meningeal carcinomatosis of EGFR tyrosine kinase inhibitor (TKI) -resistant EGFR mutated lung cancer.

Treatment with immune checkpoint inhibitors after EGFR-TKIs in EGFR-mutated lung cancer.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become the gold standard for EGFR-mutated non-small cell lung cancer (NSCLC) treatment. Immune checkpoint inhibitors (ICIs) have been developed for the treatment of several malignancies, including lung cancer. However, it is known that ICIs have poorer efficacy in EGFR-mutated NSCLC. METHODS: We collected data for patients with EGFR-mutated NSCLC receiving monotherapy with ICIs after EGFR-TKIs between December 2015 and March 2020 in three institutions, and retrospectively analyzed the association between patient characteristics and efficacy of ICIs. RESULTS: A total of 25 patients were included in this study. We defined responders as patients undergoing 90 days or longer of ICI treatment. Comparing characteristics between responders and non-responders, more tumors with L858R EGFR mutation were observed in responders than in non-responders (L858R: 66.7% and 25.0%, respectively, p < 0.05). There was no difference in incidence of T790M resistance mutation before ICI treatment. The PD-L1 positive rate was slightly higher in responders but not statistically significant (22.2% and 12.5%, respectively). Median duration of EGFR-TKI pretreatment was shorter in ICI responders compared with nonresponders (13.3 and 19.9 months, respectively). The survival of patients with L858R tumors was significantly longer than that of patients with exon 19 deletion (HR: 0.35, 95% CI: 0.13-0.93, p = 0.026). CONCLUSIONS: ICI treatment tends to have better efficacy in patients with L858R-mutated tumors. This study suggests that patients with L858R-mutated NSCLC are candidates for ICI treatment after EGFR-TKI treatment.

Impact of the genetic variants of GLCCI1 on clinical features of asthmatic patients.

BACKGROUND: Several gene variants are associated with a response to an inhaled corticosteroids (ICSs) treatment in patients with bronchial asthma. A variant of the glucocorticoid-induced transcript 1 (GLCCI1) genes has previously been associated with decreased lung function improvement upon treatment with ICSs in patients with bronchial asthma. Another report has also demonstrated that this genetic biomarker did not influence the change in flow volume in 1 second. However, no studies have considered the treatment content and the GLCCI1 variants. We were able to determine the relationship between the pulmonary function and clinical features and the variant of the GLCCI1 in Japanese asthmatic patients receiving long-term ICS treatment. MATERIALS AND METHODS: In this study, 405 patients with bronchial asthma, who were receiving ICS and living in Japan, were recruited, genotyped and underwent pulmonary function tests. To identify the GLCCI1 protein expression cells, endobronchial biopsy specimens were examined. RESULTS: We found that the pulmonary function was not significantly different in the homozygotes compared to the wild types. Also, the homozygotes increased the risk of a sustained step-up of the asthma treatment when compared to the wild type and heterozygotes. GLCCI1-positive cells were localized to the bronchial epithelial cells. The amount of GLCCI1 protein that cultured epithelial cells harboring GLCCI1 variants produced was less than the GLCCI1 wild type in the presence of a corticosteroid. CONCLUSIONS: A worsening of pulmonary function caused by GLCCI1 variants could be prevented due to recently used medications based on new action mechanisms.

Mitigation of tight junction protein dysfunction in lung microvascular endothelial cells with pitavastatin.

BACKGROUND: Statin use in individuals with chronic obstructive pulmonary disease (COPD) with coexisting cardiovascular disease is associated with a reduced risk of exacerbations. The mechanisms by which statin plays a role in the pathophysiology of COPD have not been defined. To explore the mechanisms involved, we investigated the effect of statin on endothelial cell function, especially endothelial cell tight junctions. METHOD: We primarily assessed whether pitavastatin could help mitigate the development of emphysema induced by continuous cigarette smoking (CS) exposure. We also investigated the activation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, which plays a role in maintaining endothelial functions, important tight junction proteins, zonula occludens (ZO)-1 and claudin-5 expression, and lung microvascular endothelial cell permeability. RESULTS: We found that pitavastatin prevented the CS-induced decrease in angiomotin-like protein 1 (AmotL1)-positive vessels via the activation of LKB1/AMPK signaling and IFN-γ-induced hyperpermeability of cultured human lung microvascular endothelial cells by maintaining the levels of AmotL1, ZO-1, and claudin-5 expression at the tight junctions. CONCLUSION: Our results indicate that the maintenance of lung microvascular endothelial cells by pitavastatin prevents tight junction protein dysfunctions induced by CS. These findings may ultimately lead to new and novel therapeutic targets for patients with COPD.