Key issues in Japan's public health centers to prepare for future pandemics: a text mining study using a topic model.

BACKGROUND: In Japan, over 450 public health centers played a central role in the operation of the local public health system in response to the COVID-19 pandemic. This study aimed to identify key issues for improving the system for public health centers for future pandemics. METHODS: We conducted a cross-sectional study using an online questionnaire. The respondents were first line workers in public health centers or local governments during the pandemic. We solicited open-ended responses concerning improvements needed for future pandemics. Issues were identified from these descriptions using morphological analysis and a topic model with KHcoder3.0. The number of topics was estimated using Perplexity as a measure, and Latent Dirichlet Allocation for meaning identification. RESULTS: We received open-ended responses from 784 (48.6%) of the 1,612 survey respondents, which included 111 physicians, 330 nurses, and 172 administrative staff. Morphological analysis processed these descriptions into 36,632 words. The topic model summarized them into eight issues: 1) establishment of a crisis management system, 2) division of functions among public health centers, prefectures, and medical institutions, 3) clear role distribution in public health center staff, 4) training of specialists, 5) information sharing system (information about infectious diseases and government policies), 6) response to excessive workload (support from other local governments, cooperation within public health centers, and outsourcing), 7) streamlining operations, and 8) balance with regular duties. CONCLUSIONS: This study identified key issues that need to be addressed to prepare Japan's public health centers for future pandemics. These findings are vital for discussions aimed at strengthening the public health system based on experiences from the COVID-19 pandemic.

Immunotherapy With Radiotherapy for Brain Metastases in Patients With NSCLC: NEJ060.

Introduction: Immune checkpoint inhibitor (ICI)-based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29-0.72], OW-adjusted HR = 0.52 [95% CI: 0.35-0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70-1.48], OW-adjusted HR = 0.93 [95% CI: 0.65-1.33]). Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.

Postoperative Airway Management after Anterior Cervical Spine Surgery: Retrospective Neurosurgical Multicenter Study.

Airway complications that occur after anterior cervical spine surgery pose a life-threatening risk, which encompasses complications including prolonged intubation, unplanned reintubation, and/or necessity of tracheostomy. The present study aimed to identify the surgical risks associated with postoperative airway complications in neurosurgical training institutes. A retrospective, multicenter, observational review of data from 365 patients, who underwent anterior cervical spine surgery between 2018 and 2022, at three such institutes was carried out. Postoperative airway complication was defined as either the need for prolonged intubation on the day of surgery or the need for unplanned reintubation. The perioperative medical information was obtained from their medical records. The average age of the cohort was over 60 years, with males comprising approximately 70%. Almost all surgeries predominantly involved anterior cervical discectomy and fusion or anterior cervical corpectomy and fusion, with most surgeries occurring at the level of C5/6. In total, 363 of 365 patients (99.5%) were extubated immediately after surgery, and the remaining two patients were kept under intubation because of the risk of airway complications. Of the 363 patients who underwent extubation immediately after surgery, two (0.55%) required reintubation because of postoperative airway complications. Patients who experienced airway complications were notably older and exhibited a significantly lower body mass index. The results of this study suggested that older and frailer individuals are at an elevated risk for postoperative airway complications, with immediate postoperative extubation generally being safe but requiring careful judgment in specific cases.

Association between workaholism and headaches causing presenteeism: A cross-sectional study in Japan.

OBJECTIVES: This study investigates the association between workaholism and headaches causing presenteeism among Japanese employees. METHODS: Used data from self-reporting questionnaire and annual health checkups. Workaholism was assessed using the Dutch Workaholic Scale and headaches causing presenteeism were identified as the symptom hindering work. We performed a logistic regression analysis adjusted for covariates. RESULTS: Among 5,802 respondents, 3.7% cited headaches as the symptom hindering work. We found an association between workaholism and such headaches (Odds ratios [OR]: 1.05, 95% confidence intervals [CI]: 1.03-1.08). Both working excessively (OR: 1.08, 95% CI: 1.04-1.12) and working compulsively (OR: 1.10, 95% CI: 1.05-1.15) subscales were also related. CONCLUSIONS: Workaholism may lead to productivity loss due to headaches, and addressing workaholism can prevent this loss. Combining health examination data with work hours data may enable the early detection of workaholism.

Surgical Outcomes and Medical Costs Associated with Spinal Cord Tumors: Comparison of Extramedullary and Intramedullary Tumors.

OBJECTIVE: This study aimed to clarify the differences in the perioperative data of patients with extramedullary and intramedullary tumors and estimate the impact of surgery on medical costs. METHODS: This single-center retrospective study included consecutive patients who underwent spinal tumor resection between September 2020 and December 2022. The perioperative medical information and medical costs for individual patients were obtained from their medical records. RESULTS: Thirty-two patients with extramedullary spinal cord tumors and 18 with intramedullary spinal cord tumors were included in the study. The 2 groups had no difference in surgery-related or major systemic complications. However, the operation time and the length of hospital stay were significantly longer and activities of daily living at discharge tended to worsen in the intramedullary tumor group compared to those in the extramedullary tumor group. As a result, the discharge outcome was significantly different between the 2 groups. The total medical costs for intramedullary tumors were approximately 1.43 times higher than those for extramedullary tumors. Further, a better functional outcome at discharge can save medical costs, regardless of extramedullary or intramedullary tumors. CONCLUSIONS: Surgery for intramedullary tumors can be performed with similar perioperative risks as for extramedullary tumors. However, intramedullary tumors are associated with concerns, such as prolonged hospitalization and worsening of activities of daily living at discharge, which ultimately result in higher medical costs.

Anti-neutrophil cytoplasmic antibody-negative granulomatosis with polyangiitis manifesting through pulmonary nodules and a genital lesion.

A 72-year-old female presented with bilateral pulmonary nodules before undergoing surgery for hysteroptosis. Transbronchial biopsy did not lead to a definitive diagnosis. The right mass in the upper lobe was resected through video-assisted thoracic surgery. Pathological findings showed granulomatosis with polyangiitis. However, the patient was negative for serum proteinase 3-anti-neutrophil cytoplasmic antibody. Although the nodule in the left lower lobe progressed, the serum inflammatory reaction yielded negative results. Resection of the nodule in the left lower lobe revealed identical pathological findings with those of the right pulmonary mass. Following total hysterectomy for hysteroptosis, the pathological findings indicated granulomatosis with polyangiitis.

Impact of Locoregional Therapies for Brain Lesions on Survival in Patients With Non-small Cell Lung Cancer With Multiple Extrathoracic Metastases.

BACKGROUND/AIM: The treatment of brain metastases in patients with non-small cell lung cancer (NSCLC) typically involves surgery, irradiation, and chemotherapy (single or combination therapy). However, the impact of these therapies on the survival of patients with NSCLC with multiple extrathoracic metastases has not yet been determined. Therefore, in the present study, we examined the prognostic effect of multimodal treatment for brain metastases in patients with NSCLC with multiple extrathoracic metastases in the absence of driver mutations. PATIENTS AND METHODS: Patients with NSCLC with multiple extrathoracic metastases (including at least one brain metastasis), who visited Saitama Medical Center, Saitama Medical University from January 1, 2010 to December 31, 2016, were enrolled in this study; follow-up was conducted until December 31, 2021. RESULTS: A total of 56 patients were enrolled, including 12 and 44 patients with single and multiple brain metastases, respectively. The median overall survival (OS) for all patients was 4.9 months, and did not differ significantly between patients with single and multiple brain metastases (3.0 vs. 4.9 months, respectively). The selection of locoregional treatment for brain metastases did not depend on Karnofsky performance status (p=0.0862). Among patients with multiple brain metastases, the OS for those who underwent craniotomy followed by whole brain radiation therapy (WBRT), those who received only WBRT, and those treated without locoregional therapy was 47.7, 3.9, and 15.9 months, respectively (p=0.00382). CONCLUSION: Surgical resection followed by radiation therapy is an effective treatment option for brain metastases in patients with multiple metastases. However, WBRT alone did not improve prognosis.

Inequality in workplace support for various types of precarious workers compared with permanent workers in Japan: A cross-sectional study.

OBJECTIVES: The purpose of this study was to examine, by sex, whether precarious workers in Japan receive less support in the workplace than permanent workers. METHODS: We conducted a cross-sectional study using an online questionnaire in 2022. We stratified participants by sex and performed modified Poisson regression analysis. The outcomes were support from supervisors, co-workers, occupational health professionals, and no one. Adjusted prevalence ratios (aPR) were calculated for contract workers, part-time workers, and dispatched workers, using permanent workers as reference. RESULTS: This study had 21 047 participants. For men, 87.9% were permanent workers; for women, 50.7% were permanent workers and 37.3% were part-time workers. For workplace support, 47.5% of men and 45.2% of women selected superiors; 41.8% of men and 50.5% of women selected colleagues; 16.8% of men and 6.2% of women selected occupational health professionals. Female contract workers were less likely to receive support from their supervisors (aPR 0.88) or co-workers (aPR 0.89). Male part-time workers were less likely to be supported by their co-workers (aPR 0.86). Dispatched workers were less likely to be supported by their supervisors (men aPR 0.71, women aPR 0.84) and co-workers (men aPR 0.73, women aPR 0.77). Part-time and dispatched workers were less likely to receive support from occupational health professionals. CONCLUSIONS: Precarious workers could get less workplace support than permanent workers. This may contribute to occupational health problems with precarious workers.

Advice as a Form of Structural Coupling: Intersystem Organizations and Scientific Communication in the Japanese Response to COVID-19.

A critical issue in the study of scientific communication from a systems theoretical perspective is its role in multiple intersystem relationships. During COVID-19, politics has adopted scientific findings to inform political decisions. However, science has in response actively coordinated its operations for providing desired stimuli to politics. Luhmann identified advice as a form of structural coupling that links political and scientific systems. Advice is not a monolithic intervention by which one side acts on the other but is rather an interface that enables the two systems to relate through distancing. In this article, I empirically illustrate how the structural coupling of the political system and scientific system through advice manifests itself in an examination of the roles that various organizations (expert meeting and cluster task forces) have played in Japan's response to COVID-19. Through this analysis, I provide a theoretical insight regarding these organizations and a more detailed case analysis of the transformation of certain organizations to re-describe the system theoretical insights of advice in the form of scientific communication between politics and science.

Supervisors' Work Engagement Is Associated With Interactivity and Carefulness in Supporting Subordinates: A Cross-sectional Study Using Text Mining in Japan.

OBJECTIVE: This study aimed to structure supervisory support and clarify the relationship between supervisors' work engagement and support for their subordinates. METHODS: We conducted a cross-sectional study in a manufacturing company using a questionnaire survey. Supervisors provided open-ended responses regarding the provision of support for their subordinates. Using text mining, we structured these descriptions into multiple categories, assigned words to them, and analyzed frequently mentioned categories by the level of work engagement. RESULTS: We obtained responses from 729 participants that included 13,968 words. We structured supervisory support by three categories (contents, direction, and attitude toward support) and 11 subcategories. As supervisors' work engagement increased, the rates of mentioning information retrieval, information transmission, and carefulness increased. CONCLUSIONS: Supervisors with work engagement could communicate with each other and be careful in providing support to their subordinates.

The Safety of Spine Surgery in the Late-Stage Elderly of 75 Years of Age or Older: A Retrospective Multicenter Study.

OBJECTIVE: The objective of this study was to verify that spine surgery for late-stage elderly (LSE) (age 65-74 years) is as safe as that for early-stage elderly (ESE) (age 65-74 years). METHODS: This retrospective multicenter study included elderly patients aged ≥65 years who underwent spine surgery between 2018 and 2021. The medical information for individual patients was obtained from medical records. Activities of daily living (ADL) were estimated using a 5-grade scale based on the Eastern Cooperative Oncology Group performance status. Good outcome was defined as ADL grade 0 or 1 at discharge; poor outcome was defined as ADL grade 2 to 4 at discharge. The postoperative complications were listed with reference to the Common Terminology Criteria for Adverse Events v5.0. RESULTS: There were 311 patients in the ESE group and 395 patients in the LSE group. Reoperation during hospitalization was significantly higher in the LSE group (4.6%) than in the ESE group (1.6%). The total number of days of hospitalization was significantly longer in the LSE group than in the ESE group. However, there was no significant difference in the postoperative complications or ADL at discharge between the 2 groups. In the statistical analysis, preoperative American Society of Anesthesiologists physical status class 3-6, underlying heart or renal disease, and cervical or thoracic spine level of surgical procedures were significantly associated with poor ADL outcomes at discharge. CONCLUSIONS: Spine surgery even for LSE can be safely done, if perioperative risk factors are appropriately managed.

[Competencies expected of labor and social security attorneys in harmonizing work with diseases treatment].

OBJECTIVES: Labor and social security attorneys (LSSAs) are involved in various positions in harmonizing work with disease treatment; however, their qualification requirements do not include knowledge about the same. Expectations of their involvement in harmonizing work with disease treatment are insufficient. This study aimed to identify the competencies expected of the labor and social security LSSAs in harmonizing work with disease treatment. METHODS: In step 1, semi-structured interviews were conducted with LSSAs in this field. In step 2, a draft competency list was created based on the interview results. In step 3, the Delphi method was used to conduct a questionnaire survey among LSSAs who had over 10 consultation cases on harmonizing work with disease treatment, and they were asked about the level of importance (how important they thought it was to promote harmonizing work with disease treatment) and level of achievement (how much they had achieved). We also asked them about the competencies they considered necessary and added them as additional items in the draft. In step 4, the results of the previous step were presented to the participants who had given valid answers in step 3, and they were asked whether they would adopt the items as competencies. Items with an agreement rate of 80% or higher were considered competency items. Additionally, we asked them about the level of importance and level of achievement of the additional items created in step 3. RESULTS: In step 1, 24 LSSAs participated, and in step 2, a draft competency list of six major items, 18 medium items, and 71 minor items was created. In step 3, 49 LSSAs participated and 41 cooperated (response rate: 83.6%). Five items were selected for the draft competency list to be newly added. In step 4, 30 LSSAs cooperated (response rate: 73.1%). None of the items had an agreement rate of less than 80%, and over 40% of the items had an agreement rate of 100%. As a result, six major items, 18 medium items, and 76 minor items were selected for the competency list. CONCLUSIONS: This study identified the competencies expected of labor and social security LSSAs in harmonizing work with disease treatment. The results of this study can be used as a reference for developing a systematic training curriculum for LSSAs in this field in the future.

Nintedanib induces gene expression changes in the lung of induced-rheumatoid arthritis-associated interstitial lung disease mice.

Nintedanib is a multi-tyrosine kinase inhibitor widely used to treat progressive fibrosing interstitial lung diseases because it slows the reduction in forced vital capacity. However, the prognosis for patients treated with nintedanib remains poor. To improve nintedanib treatment, we examined the effects of nintedanib on gene expression in the lungs of induced-rheumatoid arthritis-associated interstitial lung disease model mice, which develop rheumatoid arthritis and subsequent pulmonary fibrosis. Using next-generation sequencing, we identified 27 upregulated and 130 downregulated genes in the lungs of these mice after treatment with nintedanib. The differentially expressed genes included mucin 5B and heat shock protein 70 family genes, which are related to interstitial lung diseases, as well as genes associated with extracellular components, particularly the myocardial architecture, suggesting unanticipated effects of nintedanib. Of the genes upregulated in the nintedanib-treated lung, expression of regulatory factor X2, which is suspected to be involved in cilia movement, and bone morphogenetic protein receptor type 2, which is involved in the pathology of pulmonary hypertension, was detected by immunohistochemistry and RNA in situ hybridization in peripheral airway epithelium and alveolar cells. Thus, the present findings indicate a set of genes whose expression alteration potentially underlies the effects of nintedanib on pulmonary fibrosis. It is expected that these findings will contribute to the development of improved nintedanib strategies for the treatment of progressive fibrosing interstitial lung diseases.

Initial rapidity of tumor growth as a prognostic factor for the therapeutic effect of immune-checkpoint inhibitors in patients with non-small cell lung cancer: evaluation for linear and non-linear correlation.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have been increasingly used for non-small cell lung cancer (NSCLC) treatment in recent years. Although insufficient, the rate of programmed death-ligand 1 expression has been adopted as a predictor of ICI efficacy. We evaluated tumor growth rate as a clinically easy-to-use predictor of the therapeutic effect of ICIs. METHODS: This study is a single-institution retrospective study in Japan. NSCLC patients treated with nivolumab, pembrolizumab, or atezolizumab at Saitama Medical Center from January 1, 2016 to December 31, 2018 were enrolled, and followed until December 31, 2020. We defined and calculated the initial rapidity of tumor progression (IRP) as: the increase in the sum of the diameters of intrathoracic tumors and lymph nodes on two series of chest computed tomography (CT) scans (one obtained at an initial checkup and the other obtained immediately before the first treatment) divided by the number of days between these CT scans. Two coefficients were calculated: the maximal information coefficient (MIC) between IRP and time to treatment failure (TTF) using the Python package with minepy library, and the Spearman's rank correlation coefficient. RESULTS: A total of 55 patients (median age, 70 years; 47 men) were enrolled. The median TTF with ICIs was 126 days, and four patients continued to receive ICI treatment at the end of the follow-up. The MIC between IRP and TTF was 0.302 with weak correlation, and the Spearman's rank correlation coefficient was -0.347 (P=0.00938). CONCLUSIONS: The initial tumor growth rate had a negative linear correlation with the therapeutic effect of ICIs.

Relationship between impaired work function and coping behaviors in workers with low back pain.

OBJECTIVES: The aim of the present study was to clarify the relationship between work functional impairment levels and three coping behaviors of workers with low back pain, which were about seeking medical attention, taking over-the-counter drugs, and taking self-care. METHODS: We conducted a cross-sectional study on 14 Japanese companies in 2016. Work function impairment was measured using the Work Functioning Impairment Scale. Logistic regression analyses were conducted for the three coping behaviors and odds ratios (ORs) calculated for work functional impairment levels. RESULTS: We analyzed 2232 subjects; 226 were women and 790 worked on production lines. 688 workers had sought medical attention, 436 had taken over-the-counter medication, and 1225 had engaged in self-care. Those seeking medical attention were associated with severe work function impairment compared with no work function impairment (adjusted OR = 2.84, 95% confidence interval: 1.82-4.45, p < .001). We observed a trend for the association between over-the-counter drug use with high levels of work function impairment (adjusted OR: 1.19 for low, 1.35 for moderate, 1.65 for severe). There was no apparent relationship between self-care and the degree of work functional impairment. CONCLUSION: In workers with low back pain, severe work functional impairment may promote medical attention and over-the-counter medication use, but it would not encourage self-care, such as stretching or exercise. Therefore, workplaces need to provide special support to help them take care of themselves. Therefore, it is desirable to provide good support for self-care in the workplace.

Functional inhibition of heat shock protein 70 by VER-155008 suppresses pleural mesothelioma cell proliferation via an autophagy mechanism.

BACKGROUND: Pleural mesothelioma, a devastating asbestos-associated malignancy, urgently requires a novel effective therapy. Heat shock protein 70 (HSP70), which is synthesized in the cell response to protein damage, is expected to be a new target for antitumor treatment. In addition to its well-known protein refolding function, HSP70 regulates cell proliferation through different pathways, including PI3K/AKT/mTOR, and autophagy in malignant cells. In this study, we attempted to clarify the effects of VER-155008, an HSP70 inhibitor, on pleural mesothelioma. METHODS: Human pleural mesothelioma cell lines 211H, H2452 and H28 were cultured with VER-155008, and protein expression, cell proliferation, colony formation, cell cycle, synergistic effect with cisplatin, and autophagy induction were analyzed. RESULTS: In mesothelioma cell lines, VER-155008 (5.0 µM or more) inhibited cell growth and colony formation, accompanied by G1 cell cycle arrest. According to western blot analysis, VER-155008 reduced p-AKT expression. However, VER-155008 failed to show a synergistic effect with cisplatin on cell growth. Mesothelioma cells transfected with the novel plasmid pMRX-IP-GFP-LC3-RFP-LC3ΔG, which was developed for the quantitative and statistical estimation of macroautophagy, showed enhanced macroautophagy upon treatment with VER-155008 and gefitinib which is an EGFR-tyrosine kinase inhibitor. In addition, fetal bovine serum deprivation induced macroautophagy was further enhanced by VER-155008. CONCLUSIONS: On the basis of these results, functional HSP70 inhibition by VER-155008 suppressed cell growth in pleural mesothelioma cells, accompanied by enhanced macroautophagy. HSP70 inhibition is thus expected to become a new strategy for treating mesothelioma. KEY POINTS: Significant findings of the study In pleural mesothelioma cells, inhibition of HSP70 function by VER-155008 suppressed cell proliferation accompanied by induction of autophagy which was synergistically enhanced under the starvation condition, whereas gefitinib, an EGFR-TKI, did not show the same synergistic effect in autophagy. What this study adds The inhibition of HSP70 induced autophagy and suppressed cell proliferation in mesothelioma cells.

SH3P2 suppresses osteoclast differentiation through restricting membrane localization of myosin 1E.

Osteoclasts are multinucleated cells responsible for bone resorption. Src homology 3 (SH3) domain-containing protein-2 (SH3P2)/osteoclast-stimulating factor-1 regulates osteoclast differentiation, but its exact role remains elusive. Here, we show that SH3P2 suppresses osteoclast differentiation. SH3P2 knockout (KO) mice displayed decreased femoral trabecular bone mass and enhanced localization of osteoclasts on the tibial trabecular bone surface, suggesting that SH3P2 suppresses bone resorption by osteoclasts. Osteoclast differentiation based on cellular multinuclearity induced by macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL) was enhanced in bone marrow-derived macrophages lacking SH3P2. RANKL induced SH3P2 dephosphorylation, which increased the association of actin-dependent motor protein myosin 1E (Myo1E) with SH3P2 and thereby prevented Myo1E localization to the plasma membrane. Consistent with this, Myo1E in the membrane fraction increased in SH3P2-KO cells. Together with the attenuated osteoclast differentiation in Myo1E knocked down cells, SH3P2 may suppress osteoclast differentiation by preventing their cell-to-cell fusion depending on Myo1E membrane localization.

Vascular Ehlers-Danlos Syndrome with a Novel Missense Mutation in COL3A1: A Man in His 50s with Aortic Dissection after Interventional Treatment for Hemothorax as the First Manifestation.

Type III collagen is the major protein in the walls of blood vessels and hollow organs; it is decreased in patients with vascular Ehlers-Danlos syndrome (EDS). A 52-year-old man was admitted for severe back pain, and right hemothorax was suspected by chest computed tomography. Immediately after embolization for bleeding bronchial artery, aortic dissection occurred and was treated conservatively in the intensive-care unit. Vascular EDS with a mutation of COL3A1 cDNA (c.3175G>A) was diagnosed. When vascular EDS is suspected, the patient should be treated prophylactically, and a genetic examination should be performed to confirm the diagnosis.

Validation of prognostic impact of number of extrathoracic metastases according to the eighth TNM classification: a single-institution retrospective study in Japan.

BACKGROUND: In the eighth edition of the TNM classification of lung cancer, the M1b and M1c descriptors are newly defined by the number of extrathoracic metastases. To verify the prognostic value of these descriptors in Japan, we reclassified our cases and re-evaluated prognosis in M1b and M1c patients. METHODS: All non-small cell lung cancer (NSCLC) patients with extrathoracic metastases who visited Saitama Medical Center from 2010 to 2016 were evaluated, divided according to the eighth edition of the TNM classification criteria into two groups (M1b, patients with single extrathoracic metastasis, and M1c, patients with multiple extrathoracic metastases), and followed up until December 31, 2017. Survival time analysis was performed using the Kaplan-Meier method, and between-group differences in overall survival time (OS) were evaluated by the log-rank test. RESULTS: A total of 231 NSCLC patients were divided into 57 patients with M1b and 174 with M1c. Median OS was 15.2 months (95% confidence interval [CI]: 9.3-19.9) and 7.3 months (95% CI 5.7-10.7) for M1b and M1c, respectively, with no significant between-group difference (P = 0.239). However, after excluding patients with epidermal growth factor receptor (EGFR) mutation or echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene, median OS was 12.9 months (95% CI 7.2-19.9) for M1b and 5.4 months (95% CI 3.8-6.3) for M1c, respectively, showing a significant difference (P = 0.029). CONCLUSIONS: The effect of therapy directed toward EGFR mutation or EML4-ALK fusion gene might obscure the significant prognostic difference between M1b and M1c.

Hepatic and Intrahepatic Targeting of Hydrogen Sulfide Prodrug by Bioconjugation.

Hydrogen sulfide (H2S) is an endogenous gaseous transmitter known to play an important role in biological functions. For the hepatic and intrahepatic targeting of H2S prodrug at the cellular level, we developed two types of sulfo-albumins, in which five sulfide groups (source of H2S) were covalently bound to succinylated (Suc) or galactosylated (Gal) bovine serum albumin (BSA). Sulfo-BSA-Suc and polyethylene glycol (PEG)-Sulfo-BSA-Gal, both released H2S in the 5 mM glutathione solution, but not in the plasma. Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal were taken up by RAW264.7 cells (mouse macrophage-like cells) and Hep G2 cells (human hepatocellular carcinoma cells), respectively, and H2S was released. These results indicate that Sulfo-BSA-Suc and PEG -Sulfo-BSA-Gal selectively released H2S intracellularly. In a biodistribution study, up to 80% of 111In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal rapidly accumulated in the liver, 30 min after intravenous injection in mice. Furthermore, 111In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal predominantly accumulated in liver nonparenchymal (endothelial cells and Kupffer cells) and parenchymal cells (hepatocytes), respectively. These findings suggest that targeted delivery of H2S prodrug to a specific type of liver cells was successfully achieved by bioconjugation.