Lymphangioleiomyomatosis as a potent lung cancer risk factor: Insights from a Japanese large cohort study.

BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease associated with the functional tumour suppressor genes TSC1 and TSC2 and causes structural destruction in the lungs, which could potentially increase the risk of lung cancer. However, this relationship remains unclear because of the rarity of the disease. METHODS: We investigated the relative risk of developing lung cancer among patients diagnosed with LAM between 2001 and 2022 at a single high-volume centre in Japan, using data from the Japanese Cancer Registry as the reference population. Next-generation sequencing (NGS) was performed in cases where tumour samples were available. RESULTS: Among 642 patients diagnosed with LAM (sporadic LAM, n = 557; tuberous sclerosis complex-LAM, n = 80; unclassified, n = 5), 13 (2.2%) were diagnosed with lung cancer during a median follow-up period of 5.13 years. All patients were female, 61.5% were never smokers, and the median age at lung cancer diagnosis was 53 years. Eight patients developed lung cancer after LAM diagnosis. The estimated incidence of lung cancer was 301.4 cases per 100,000 person-years, and the standardized incidence ratio was 13.6 (95% confidence interval, 6.2-21.0; p = 0.0008). Actionable genetic alterations were identified in 38.5% of the patients (EGFR: 3, ALK: 1 and ERBB2: 1). No findings suggested loss of TSC gene function in the two patients analysed by NGS. CONCLUSION: Our study revealed that patients diagnosed with LAM had a significantly increased risk of lung cancer. Further research is warranted to clarify the carcinogenesis of lung cancer in patients with LAM.

Pulmonary Erdheim-Chester Disease With BRAF-AGAP3 Fusion: Late-Onset Osteolytic Femoral Lesions Despite Long-Term Pulmonary Stabilization With Corticosteroid.

Erdheim-Chester disease (ECD) is a rare inflammatory myeloid neoplasm affecting multiple systems and organs. The patient is a 38-year-old male with ECD complicated with pulmonary and cutaneous manifestations but without bone lesions diagnosed in 2008. Initial treatment with oral and inhaled corticosteroids achieved persistent favorable disease remission. However, atypical late-onset bone lesions developed in the bilateral femur in 2021. Although BRAF-V600E mutation was negative in the lung specimen at diagnosis, the next-generation gene sequence using biopsied bone lesions revealed a rare BRAF-AGAP3 fusion, leading to the administration of trametinib. This is the first report describing ECD harboring BRAF-AGAP3 fusion successfully treated with trametinib. Our case presents a unique clinical course in which late-onset osteolytic bone lesions developed despite a long-term stabilization of pulmonary lesions with low-dose oral and inhaled corticosteroids.

An elderly woman with Birt-Hogg-Dubé syndrome having multiple pulmonary cysts mimicking lymphangioleiomyomatosis.

The characteristics of the pulmonary cysts on the high-resolution computed tomography (HRCT) chest images are an important diagnostic clue to distinguish among cystic lung diseases. The diagnostic accuracy of HRCT was reported to be as high as 90% by experienced pulmonologists and radiologists. Herein, we report the case of an elderly woman with Birt-Hogg-Dubé syndrome (BHDS) whose HRCT images displayed lymphangioleiomyomatosis-like features of the pulmonary cysts, rendering it difficult for us to diagnose BHDS. This case illustrates the significance of a thorough anamnesis, physical examination, and skin biopsy of facial papules to establish an accurate diganosis.

Extrapleural air secondary to idiopathic pulmonary fibrosis-related pneumomediastinum.

Extrapleural air is a rare condition that may concurrently develop with pneumomediastinum and pneumothorax, especially in older patients with fragile connective tissues. Physicians should consider extrapleural air to prevent inadvertent harm. Coronal reconstruction computed tomography images help appreciate extrapleural air and recognize the track of extrapulmonary air.

Postoperative hormonal therapies reduce the recurrence of thoracic endometriosis-related pneumothorax.

OBJECTIVES: Thoracic endometriosis-related pneumothorax (TERP) frequently recurs even after surgery. Meanwhile, postoperative hormonal therapies (HTx) are believed to be effective for pelvic endometriosis. Therefore, we evaluated the relationship between postoperative TERP recurrence and postoperative HTx in a retrospective observational study. METHODS: We retrospectively reviewed the data of patients with TERP who underwent the first video-assisted thoracoscopic surgery between January 2011 and February 2022. RESULTS: Of the 248 patients eligible for this study, 67 (27.0%) experienced postoperative TERP recurrence. Postoperative HTx were administered to 70 patients (28.2%). Dienogest was the most frequently administered drug, given to 56.7% of patients. Following univariable analysis, postoperative hormonal therapies was closely related to reduce postoperative recurrence (P = 0.003). Likewise, the multivariable analysis revealed postoperative hormonal therapies were significantly associated with the risk reduction of recurrence (hazard ratio 0.28, P < 0.001). CONCLUSIONS: Postoperative HTx reduced TERP recurrence. We hypothesize that HTx may control residual endometrial tissues to avoid TERP if pleural endometrial tissues are resected as much as possible.

Clinicopathological Impacts of Expression of Neuronal Markers in Lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a tuberous sclerosis complex (TSC)-associated tumor, characterized by the expression of neural crest lineages including neuronal markers. Neural crest cells can differentiate into multiple cell types that contribute to tissues associated with TSC-related tumors, and TSC-related tumors could be specifically associated with distinct neural crest subtypes. This study aimed to clarify the clinicopathological effects of expression of neuronal markers in LAM. Lung tissues from 40 patients with LAM (of whom 13, 1, and 26 had undergone lung transplantation, lobectomy, and partial lung resection, respectively) were immunohistochemically analyzed. All patients were women, and their median age was 36 years (range: 24-62 y). All patients who underwent lung transplantation or lobectomy were classified as LAM histologic score (LHS)-3, whereas those who underwent partial lung resection were classified as LHS-1. LAM cells expressed peripherin (65%), and neuron-specific ßIII-tubulin (43%). A comparison of the early (LHS-1) and advanced (LHS-3) stages of LAM revealed that neuron-specific ßIII-tubulin was significantly expressed in the early stage of LAM ( P = 0.0009). Neuron-specific ßIII-tubulin-positive LAM was associated with younger age ( P < 0.0001), the coexistence of renal angiomyolipoma ( P = 0.027), and the absence of retroperitoneal LAM ( P = 0.045). Furthermore, based on the expression levels of immunohistochemical markers in LAM, 2 distinct clusters with different expression levels of neuronal markers were observed. Approximately 40% to 60% of patients with LAM expressed neuron-specific ßIII-tubulin and peripherin. Neuronal expression may be associated with disease severity.

Clinical and genetic features of 334 Asian patients with Birt-Hogg-Dubé syndrome (BHDS) who presented with pulmonary cysts with or without a history of pneumothorax, with special reference to BHDS-associated pneumothorax.

BACKGROUND: The clinical pulmonary manifestations and genetic features of Birt-Hogg-Dubé syndrome (BHDS) in Asian patients remained unclear. We aimed to clarify the clinical features of BHDS-associated pneumothorax (PTX) and retrospectively investigate potential contributing factors in the largest Asian cohort to date. METHODS: We reviewed the clinical and genetic data collected in 2006-2017, from the BHDS patients who were Asian and presented with pulmonary cysts with or without a history of PTX. RESULTS: Data from 334 (41.3% males; 58.7% females) patients from 297 unrelated families were reviewed. Among them, 314 (94.0%) patients developed PTX. The median age at the first occurrence of PTX was 32 years, which was significantly lower in males (P = 0.003) and patients without notable skin manifestations (P < 0.001). Seventy-six (24.2%) patients experienced their first PTX episode before the age of 25 years. PTX simultaneously occurred in the bilateral lungs of 37 (11.8%) patients. Among 149 patients who had their first PTX episode at least 10 years before BHDS diagnosis, PTX occurred more frequently in males (P = 0.030) and light smokers than in nonsmokers (P = 0.014). The occurrence of PTX peaked in the early 30s and gradually decreased with age but remained high in females (P = 0.001). We identified 70 unique FLCN germline variants, including duplications (46.4%), substitutions (7.1%), insertions/deletions (30.0%), and variants affecting splicing (12.5%). Approximately 80% of Asian patients suspected of having BHDS could be genetically diagnosed by examining FLCN exons 7, 9, 11, 12, and 13. No apparent genotype-phenotype correlation regarding pulmonary manifestations was identified. CONCLUSIONS: Our findings indicate that sex, smoking history, and skin manifestations at BHDS diagnosis significantly influence the clinical features of BHDS-associated PTX. These findings may contribute to the appropriate management and treatment of BHDS-associated PTX.

Prophylactic renal artery embolization before pregnancy in patients with lymphangioleiomyomatosis and renal angiomyolipoma.

OBJECTIVE: Pregnant patients with lymphangioleiomyomatosis (LAM) and renal angiomyolipomas (AMLs) require care for both renal AMLs and pulmonary dysfunction because AMLs can grow and rupture during pregnancy, potentially causing hemorrhagic shock and fetal death. This study examined whether prophylactic transcatheter arterial embolization (TAE) could prevent the pregnancy-associated growth and rupture of renal AMLs in patients with LAM. METHODS: This retrospective study included five women with 14 renal AMLs (initial diameter, ≥2 cm) first encountered between September 2010 and August 2015 who subsequently became pregnant. Seven tumors in five patients were embolized, and seven tumors in two patients were not treated. Changes in the volume of each tumor were evaluated. RESULTS: Untreated tumors were much more likely to grow than embolized tumors both during pregnancy (100% vs. 0%) and at the first follow-up visit after delivery (100% vs. 14%). One untreated hypervascular tumor grew rapidly during pregnancy to 409% of the pretreatment volume. No tumor ruptured. CONCLUSIONS: Prophylactic pre-pregnancy TAE decreased the growth and bleeding of renal AMLs during pregnancy in patients with LAM. TAE can be recommended for hypervascular tumors before pregnancy regardless of the size of the aneurysm.

Propylene glycol, a component of electronic cigarette liquid, damages epithelial cells in human small airways.

BACKGROUND: Electronic cigarettes (e-cigarettes) are used worldwide as a substitute for conventional cigarettes. Although they are primarily intended to support smoking cessation, e-cigarettes have been identified as a gateway to smoking habits for young people. Multiple recent reports have described the health effects of inhaling e-cigarettes. E-cigarette liquid (e-liquid) is mainly composed of propylene glycol (PG) and glycerol (Gly), and the aerosol generated by these devices primarily contains these two components. Thus, this study aimed to evaluate the effects of PG and Gly on human small airway epithelial cells (SAECs). METHODS: SAECs were exposed to PG or Gly, and cell proliferation, cell viability, lactate dehydrogenase (LDH) release, DNA damage, cell cycle, and apoptosis were evaluated. Additionally, SAECs derived from chronic obstructive pulmonary disease (COPD) patients (COPD-SAECs) were investigated. RESULTS: Exposure of SAECs to PG significantly inhibited proliferation (1%, PG, p = 0.021; 2-4% PG, p < 0.0001) and decreased cell viability (1-4% PG, p < 0.0001) in a concentration-dependent manner. Gly elicited similar effects but to a reduced degree as compared to the same concentration of PG. PG also increased LDH release in a concentration-dependent manner (3% PG, p = 0.0055; 4% PG, p < 0.0001), whereas Gly did not show a significant effect on LDH release. SAECs exposed to 4% PG contained more cells that were positive for phosphorylated histone H2AX (p < 0.0001), a marker of DNA damage, and an increased proportion of cells in the G1 phase (p < 0.0001) and increased p21 expression (p = 0.0005). Moreover, caspase 3/7-activated cells and cleaved poly (ADP-ribose) polymerase 1 expression were increased in SAECs exposed to 4% PG (p = 0.0054). Furthermore, comparing COPD-SAECs to SAECs without COPD in PG exposure, cell proliferation, cell viability, DNA damage and apoptosis were significantly greater in COPD-SAECs. CONCLUSION: PG damaged SAECs more than Gly. In addition, COPD-SAECs were more susceptible to PG than SAECs without COPD. Usage of e-cigarettes may be harmful to the respiratory system, especially in patients with COPD.

Long-term safety of Prolastin®-C, an alpha1-proteinase inhibitor, in Japanese patients with alpha1-antitrypsin deficiency.

BACKGROUND: Safety and pharmacokinetics (PK) of alpha1-proteinase inhibitor, modified process (Alpha-1 MP), was evaluated in a clinical trial of Japanese patients with alpha1-antitrypsin deficiency (AATD). The present study aimed to evaluate the long-term safety of weekly intravenous infusions of 60 mg/kg Alpha-1 MP in Japanese patients with AATD. METHODS: This was a multi-center, open-label extension (OLE) study that enrolled adult patients with AATD, who had completed the preceding safety and PK clinical trial. Patients were administered with Alpha-1 MP (60 mg/kg) weekly, for 52 weeks, and this could be renewed annually. Alpha1-MP trough levels (Cmin) were evaluated, and safety endpoints include: treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs potentially related to Alpha-1 MP, chronic obstructive pulmonary disease (COPD) exacerbations, laboratory parameters, vital signs, and pulmonary function tests (forced expiration volume in 1 s [FEV1] and forced vital capacity [FVC]). RESULTS: Four patients underwent Alpha-1 MP intravenous infusions at a mean (SD) of 210.8 (9.54) for 213 weeks (four years), with a Cmin of 55.73 (4.99) mg/dL. A total of fifty-four TEAEs were reported in four patients, in which most of them were mild (n = 52, 96.3%). Two patients had five SAEs, and all were unrelated to treatment. Three mild TEAEs were potentially related to treatment with Alpha-1 MP. No clinically significant findings in laboratory parameters, COPD exacerbations, or vital signs were observed. There were no identifiable differences in FEV1 and FVC throughout the study period. CONCLUSIONS: Long-term weekly intravenous infusions of 60 mg/kg Alpha-1 MP are generally safe and well-tolerated in Japanese patients with AATD. CLINICALTRIALS: GOV: NCT02870348; JAPIC CTI: JapicCTI-163194.

Perioperative management of thoracic surgery in patients with lymphangioleiomyomatosis.

BACKGROUND: General surgery for patients with lymphangioleiomyomatosis (LAM) is infrequent, however, general surgeons also occasionally experience it. Only a few reports have described the specific perioperative management appropriate for patients with LAM. Hence, in this case series, we aimed to investigate the surgical outcomes of LAM patients and their characteristics. CASE PRESENTATION: Medical records of 4482 patients who underwent thoracic surgery between 2009 and 2017 at our institution were assessed. Twelve patients were diagnosed with LAM. Details of the postoperative courses and surgical outcomes of LAM patients were retrospectively examined. All LAM patients were female (age 41.3 ± 10.6 years). Surgeries were performed for patients undergoing biopsy (n = 4) and those with pneumothorax (n = 3), lung cancer (n = 2), and other conditions (n = 3). The mortality rate was 0% and the length of hospital stay was 27.4 ± 8.9 days. Ten postoperative complications occurred in six patients (50%): hypoxemia (n = 5), chylothorax (n = 2), and prolonged air leakage (n = 3). CONCLUSIONS: Thoracic surgery may pose a risk of postoperative complications and long hospitalization for patients with LAM, although it lowers the risk of fatality. Management of perioperative air and chyle leakages and lymphatic stasis in the lungs is important for preventing morbidities.

Antibody response and seroprevalence in healthcare workers after the BNT162b2 vaccination in a University Hospital at Tokyo.

In 2020, we reported a low seroprevalence of N-specific antibodies in 4147 health care workers (HCWs) at a frontline hospital in Tokyo, Japan. In Japan, a vaccine campaign was launched in early 2021. We re-evaluated seroprevalences of N- and S-specific antibodies in 2202 HCWs who took two doses of the BNT162b2 vaccine. In 2021, N-specific seroprevalence remains as low as 1.59%. The seroprevalences were comparable among all HCWs regardless of exposure levels. Almost all of the HCWs elicited S-specific antibodies after vaccination. However, the HCWs who had COVID-19 elicited higher S-specific antibody titers than those who did not have COVID-19. In the HCWs without a history of COVID-19, 1.1% (23 out of 2185) were seropositive with N-specific antibodies, indicating the existence of asymptomatic infections. Also, S-specific antibody titers were higher in females and younger HCWs, and in those who had severe side effects. However, S-specific antibody titers were lower depending on the number of days after the second dose of vaccination specifically in elderly individuals. In conclusion, this study indicates N-specific seroprevalence remains low in HCWs at a frontline hospital in Tokyo. The mRNA vaccine elicited S-specific antibody in HCWs, however, the titers decreased as the days proceeded.

Increased delta variant SARS-CoV-2 infections in a highly vaccinated medical center in Japan.

The Delta variant has dominated SARS-CoV-2 infections in Tokyo, Japan from June 2021 to date. We conducted a retrospective cohort study to assess BNT162b2 vaccine effectiveness during the surge in Delta among 3,911 healthcare workers (HCWs) at a medical center of Tokyo with a high vaccination rate of 84.1%. With strict infection control protocols including universal masking, only a small number of cases among vaccinated and unvaccinated HCWs were identified before June. As Delta spread in Tokyo, 16 cases among 3,289 fully vaccinated HCWs and 11 cases among 574 unvaccinated HCWs were reported in July and August (case rate in August: 4.0 vs. 19.2 per 1,000). All breakthrough cases were confirmed as Delta. While our study confirms a robust vaccine effectiveness of BNT162b2 vaccine against Delta, rising breakthrough cases suggest that continued infection control measures are warranted in higher risk environments, even when high rates of vaccination coverage are achieved.

Exposure to the heated tobacco product IQOS generates apoptosis-mediated pulmonary emphysema in murine lungs.

Pulmonary emphysema is predominantly caused by chronic exposure to cigarette smoke (CS). Novel tobacco substitutes, such as heated tobacco products (HTPs), have emerged as healthier alternatives to cigarettes. IQOS, the most popular HTP in Japan, is advertised as harmless compared with conventional cigarettes. Although some studies have reported its toxicity, few in vivo studies have been conducted. Here, 12-wk-old C57BL6/J male mice were divided into three groups and exposed to air (as control), IQOS aerosol, or CS for 6 mo. After exposure, the weight gain was significantly suppressed in the IQOS and CS groups compared with the control (-4.93 g; IQOS vs. air and -5.504 g; CS vs. air). The serum cotinine level was significantly higher in the IQOS group than in the control group. The neutrophils and lymphocyte count increased in the bronchoalveolar lavage fluid of the IQOS and CS groups compared with those in the control group. Chronic IQOS exposure induced pulmonary emphysema similar to that observed in the CS group. Furthermore, expression levels of the genes involved in the apoptosis-related pathways were significantly upregulated in the lungs of the IQOS-exposed mice. Cytochrome c, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase-1 were overexpressed in the IQOS group compared with the control. Single-stranded DNA and TdT-mediated dUTP nick-end labeling-positive alveolar septal cell count significantly increased in the IQOS group compared with the control. In conclusion, chronic exposure to IQOS aerosol induces pulmonary emphysema predominantly via apoptosis-related pathways. This suggests that HTPs are not completely safe tobacco products.

Vasohibin-1 and -2 in pulmonary lymphangioleiomyomatosis (LAM) cells associated with angiogenic and prognostic factors.

Lymphangioleiomyomatosis (LAM) is a rare pulmonary neoplasm, clinically associated with dyspnea and respiratory failure. Current therapeutic modalities do not necessarily reach satisfactory outcome and novel therapeutic approaches are currently warranted. Therefore, in this study, we focused on vasohibin-1 (VASH1) and -2 (VASH2); VASH1 terminated and VASH2 promoted angiogenesis. In addition, both VASH1/2 were reported to influence the progression of various human malignancies. We first performed hierarchical clustering analysis to attempt to classify 36 LAM cases into three different clusters according to immunoreactivity of VASH1/2 and other angiogenic and prognostic factors of LAM; VEGFR1/2/3, p-mTOR, p-S6, p-4EBP, ERα, PgR, MMP2, and MMP9. The cluster harboring higher angiogenic factors had higher VASH1/2 status. VASH1 was significantly positively correlated with VEGFR2, MMP9, and p-mTOR (p-value <0.05), and VASH2 with both angiogenic and prognostic factors including VEGFR1, PgR, MMP9, p-mTOR, p-S6, and p-4EBP (p-value <0.05). Subsequent PCR array of angiogenic genes demonstrated that high VASH1 mRNA was significantly positively associated with the status of SPHK1 and TYPM, lower EGF and EFNB2 (p-value <0.05), and high VASH2 mRNA negatively with MMP2 (p-value <0.05). VASH1 was considered to be up-regulated by activation of angiogenesis, whereas VASH2 could influence the angiogenesis and progression of LAM.

Reactogenicity following two doses of the BNT162b2 mRNA COVID-19 vaccine: Real-world evidence from healthcare workers in Japan.

As the first authorized COVID-19 vaccine in Japan, the BNT162b2 mRNA COVID-19 vaccine is utilized for mass vaccination. Although efficacy has been proved, real-world evidence on reactogenicity in Japanese personnel is needed to prepare the public. Healthcare workers in a large academic hospital in Japan received two doses of the Pfizer-BioNTech vaccine from March 17 to May 19, 2021. Online questionnaires were distributed to registered recipients following each dose, from day 0 through day 8. Primary outcomes are the frequency of reactogenicity including local and systemic reactions. Length of absence from work was also analyzed. Most recipients self-reported reactogenicity after the first dose (97.3%; n = 3254; mean age [36.4]) and after the second dose (97.2%; n = 3165; mean age [36.5]). Systemic reactions following the second dose were substantially higher than the first dose, especially for fever (OR, 27.38; 95% CI, [22.00-34.06]; p < 0.001), chills (OR, 16.49; 95% CI, [13.53-20.11]; p < 0.001), joint pain (OR, 8.49; 95% CI, [7.21-9.99]; p < 0.001), fatigue (OR, 7.18; 95% CI, [6.43-8.02]; p < 0.001) and headache (OR, 5.43; 95% CI, [4.80-6.14]; p < 0.001). Reactogenicity was more commonly seen in young, female groups. 19.3% of participants took days off from work after the second dose (2.2% after the first dose), with 4.7% absent for more than two days. Although most participants reported reactogenicity, severe cases were limited. This study provides real-world evidence for the general population and organizations to prepare for BNT162b2 mRNA COVID-19 vaccination in Japan and other countries in the region.

Real-world evidence for the effectiveness and breakthrough of BNT162b2 mRNA COVID-19 vaccine at a medical center in Japan.

Evidence of BNT126b2 vaccine effectiveness and breakthrough has been primarily demonstrated in populations outside of Asia; studies in the Western Pacific region are limited. Our retrospective cohort study assessed SARS-CoV-2 cases after vaccine rollout starting from mid-March 2021 at a tertiary hospital in Tokyo. Of 8,749 staff members, no fully vaccinated staff demonstrated confirmed infection, versus 19 cases in unvaccinated or partially vaccinated staff, by the end of June. Three breakthrough cases were identified in July, correlating with spread of delta variant in Tokyo. While our findings confirm the effectiveness of BNT162b2 vaccine in Asian populations, the presence of breakthrough cases despite strict infection control regulations suggest that ongoing public hygiene measures are required even after vaccination.

Current opinion and comparison of surgical procedures for the treatment of primary spontaneous pneumothorax.

INTRODUCTION: Although three-port video-assisted thoracoscopic surgery (VATS) is the standard radical treatment for primary spontaneous pneumothorax (PSP), several issues need to be addressed as the postoperative recurrence rate remains relatively high. Although bullectomy is effective in preventing the postoperative recurrence of PSP, recurrent pneumothorax often occurs, requiring additional methods such as pleural covering with absorbable mesh sheets, surgical chemical pleurodesis, pleural abrasion, or pleurectomy. In addition, minimally invasive approaches that exceed three-port VATS are required according to the social demand. These approaches, such as uniportal VATS, reduced port surgery, and needlescopic surgery, have cosmetic merits, lower postoperative pain, and similar surgical results as three-port VATS. AREAS COVERED: We focused on conventional and novel treatments for PSP in this article. EXPERT OPINION: Effective methods that prevent postoperative recurrence and minimally invasive approaches will become popular in the near future.

Elevated depressive symptoms among newer and younger healthcare workers in Japan during the COVID-19 pandemic.

AIM: Depression is a frequent outcome of long-term stress, but no studies have examined depression rates among Japanese healthcare workers fighting the COVID-19 pandemic. Therefore, we conducted a web-based interview of hospital employees to assess depression prevalence and factors. METHODS: This observational cohort study was conducted from July to August, 2020, as part of a mandatory health checkup of Juntendo University Hospital employees (Tokyo, Japan). A total of 4239 participants completed a web-based questionnaire on medical history and current health status. The Center for Epidemiologic Studies Depression Scale (CES-D) was used for self-assessment, with a score of ≥16 considered to indicate depression. RESULTS: Among all employees, the proportion of depression was 31.3% in 2020, the highest measured in the last 10 years and substantially greater than the pre-pandemic value in 2019 (27.5%). The proportion of depression for 2020 was significantly higher in new recruits than in employees with more than 2 years of experience (47.0% vs 29.9%, respectively, P < .0001) and in new recruits in 2019 (26.4%, P < .0001). When subdivided by occupation, nurses demonstrated the highest depression rate (43.2%), followed by paramedics (35.1%) and clerks (31.6%), whereas residents (22.9%), doctors (20.4%), teaching staff (18.0%), and part-time staff (15.3%) reported lower depression rates. The positive CES-D score significantly correlated with age (P < .0001). CONCLUSIONS: Younger and newer employees demonstrated the highest rates of depression independent of occupation. Therefore, mental healthcare programs focusing on these vulnerable groups need to be established.