Amyloid conformation-dependent disaggregation in a reconstituted yeast prion system.

Disaggregation of amyloid fibrils is a fundamental biological process required for amyloid propagation. However, due to the lack of experimental systems, the molecular mechanism of how amyloid is disaggregated by cellular factors remains poorly understood. Here, we established a robust in vitro reconstituted system of yeast prion propagation and found that heat-shock protein 104 (Hsp104), Ssa1 and Sis1 chaperones are essential for efficient disaggregation of Sup35 amyloid. Real-time imaging of single-molecule fluorescence coupled with the reconstitution system revealed that amyloid disaggregation is achieved by ordered, timely binding of the chaperones to amyloid. Remarkably, we uncovered two distinct prion strain conformation-dependent modes of disaggregation, fragmentation and dissolution. We characterized distinct chaperone dynamics in each mode and found that transient, repeated binding of Hsp104 to the same site of amyloid results in fragmentation. These findings provide a physical foundation for otherwise puzzling in vivo observations and for therapeutic development for amyloid-associated neurodegenerative diseases.

Clinical outcomes and predictive value of programmed cell death-ligand 1 expression in response to anti-programmed cell death 1/ligand 1 antibodies in non-small cell lung cancer patients with performance status 2 or greater.

BACKGROUND: Anti-programmed cell death protein-1/ligand-1 (anti-PD-1/PD-L1) therapy is promising for patients with non-small-cell lung cancer (NSCLC); however, clinical trials have focused on patients with a performance status (PS) 0 or 1. This study aimed to evaluate the clinical outcomes and correlation between PD-L1 expression status and tumor response to anti-PD-1/PD-L1 therapy among NSCLC patients with poor PS (i.e., PS ≥ 2). METHODS: In total, 130 patients with NSCLC and PS ≥ 2 treated with anti-PD-1/PD-L1 monotherapy at 12 institutions between January 2016 and August 2019 were retrospectively reviewed. PD-L1 expression status was divided into four groups: < 1%, 1-49%, ≥ 50%, and unknown. RESULTS: The objective response rate and PS improvement rate were 23 and 21% and were higher in the PD-L1 ≥ 50% group than in other groups (P < 0.01). Median progression-free survival (PFS) was 62 days and was longer in the PD-L1 ≥ 50% group than in other groups (P = 0.03). Multivariate analyses revealed that PD-L1 expression is significantly associated with prolonged PFS (PD-L1 < 1%; reference; 1-49%, hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04-0.99, P = 0.05; ≥ 50%, HR 0.12, 95% CI 0.02-0.71, P = 0.02; unknown, HR 0.30, 95% CI 0.08-1.22, P = 0.09). CONCLUSIONS: NSCLC patients with poor PS and PD-L1 ≥ 50% are expected to benefit from anti-PD-1/PD-L1 therapy, despite a modest overall response among NSCLC patients with poor PS. Accordingly, PD-L1 expression provides useful information regarding decision-making for anti-PD-1/PD-L1 therapy even in these populations.

Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma.

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.

Protective effect of bevacizumab on chemotherapy-related acute exacerbation of interstitial lung disease in patients with advanced non-squamous non-small cell lung cancer.

BACKGROUND: Acute exacerbation of interstitial lung disease (AE-ILD) is the most serious complication in lung cancer patients with pre-existing ILD receiving chemotherapy. The role of vascular endothelial growth factor (VEGF) in pathogenesis of AE-ILD is conflicting. The influence of bevacizumab (Bev), a monoclonal antibody against VEGF, on lung cancer patients with pre-existing ILD remains unclear. We examined the effect of Bev on reducing AE-ILD risk in non-squamous non-small cell lung cancer (NSCLC) patients receiving chemotherapy. METHODS: We analysed incidence of AE-ILD and outcomes of 48 patients with advanced non-squamous NSCLC with ILD who received first-line chemotherapy with (Bev group, n = 17) and without (non-Bev group, n = 31) Bev between July 2011 and July 2016. Gray's test, which was competing risk analysis during the study period, was performed for both groups. RESULTS: The most common regimen used for first-line chemotherapy was the combination of carboplatin plus pemetrexed (PEM) in both groups. The incidences of chemotherapy-related AE-ILD 120 days after first-line chemotherapy initiation were significantly lower in the Bev than in the non-Bev groups (0% vs. 22.6%, p = 0.037, Gray's test). However, there were no differences in development of progressive disease of lung cancer and other events as the competing risk factors of AE-ILD between the two groups. Only patients receiving PEM-containing regimens also showed a significant difference in the incidence of AE-ILD between the two groups (p = 0.044). The overall-cumulative incidence of AE-ILD during the first-line and subsequent chemotherapy was 29.2% (14 of the 48). The median progression-free survival was significantly longer in the Bev than in the non-Bev groups (8.0 vs. 4.3 months, p = 0.026). CONCLUSIONS: The addition of Bev to chemotherapy regimens may reduce the risk of chemotherapy-related AE-ILD in patients with lung cancer.

Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters.

Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C>T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT-2677TT-3455TT, rs1128503 TT-rs2032582 TT-rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.

Pulmonary Nocardiosis With Endobronchial Involvement Caused by Nocardiaaraoensis.

We report a rare case of pulmonary nocardiosis with endobronchial involvement caused by Nocardia araoensis. A 79-year-old man with a history of asthma and a previous right upper lobectomy for lung cancer and organizing pneumonia presented with cough and dyspnea. He presented with right bronchial stenosis associated with various mucosal lesions, including ulcerative and exophytic lesions. N araoensis was detected in sputum samples collected via bronchoscopy. The mucosal lesions improved after a 2-week course of meropenem. After a further 6 months of oral sulfamethoxazole-trimethoprim treatment, the mucosal lesions completely disappeared. Based on bronchoscopic and pathophysiologic findings, the patient was diagnosed with pulmonary nocardiosis with endobronchial involvement. Nocardiosis should be considered in the differential diagnosis of endobronchial mucosal lesions.

Safety and efficacy of osimertinib rechallenge or continuation after pneumonitis: A multicentre retrospective cohort study.

INTRODUCTION: Although osimertinib is a standard first-line treatment for patients with advanced-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, the incidence rate of pneumonitis associated with osimertinib is high. However, there are few reports about the safety and efficacy of osimertinib rechallenge after the development of pneumonitis. METHODS: We conducted a retrospective multicentre cohort study of consecutive patients who developed pneumonitis associated with osimertinib as a first-line and received osimertinib rechallenge. The primary outcome was the incidence rate of any grade pneumonitis after osimertinib rechallenge. The secondary outcome was treatment efficacy in patients after osimertinib rechallenge. RESULTS: In total, 33 patients who received osimertinib rechallenge were included. Of them, 26 patients had grade 1, 6 patients had grade 2, and 1 patient had grade 3 initial pneumonitis. The median follow-up period after the osimertinib rechallenge was 16.9 months (interquartile range, 11.1-21.3 months). After the start of osimertinib rechallenge, five patients (15%) experienced mild relapsed pneumonitis. Three of the five patients had similar imaging patterns for initial and relapsed pneumonitis. No significant differences in characteristics were observed between patients with and without relapsed pneumonitis. The median progression-free survival after osimertinib rechallenge was not achieved (95% confidence interval: 10.3 months - not reached). CONCLUSION: Osimertinib rechallenge was feasible and effective for patients who developed initial pneumonitis associated with first-line osimertinib therapy. Osimertinib might be considered a treatment option even after the development of mild initial pneumonitis.

Osimertinib as first-line treatment for elderly patients with advanced EGFR mutation-positive non-small cell lung cancer in a real-world setting (OSI-FACT-EP).

OBJECTIVES: Osimertinib is the primary treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer. However, evidence of the outcomes of osimertinib treatment in patients over 75 years of age in the real-world setting is limited. MATERIALS AND METHODS: This retrospective study analyzed the data of 538 patients (203 elderly and 335 non-elderly) with EGFR mutation-positive lung cancer in whom osimertinib was initiated as first-line treatment between August 2018 and December 2019. Patients over 75 years of age were classified as elderly. The data cut-off date was February 28, 2022. RESULTS: The progression-free survival (PFS) did not significantly differ between the elderly and non-elderly groups [elderly group: median PFS, 16.9 months (95 % confidence interval (CI), 14.3-20.2); non-elderly group: median PFS, 22.1 months (95 % CI: 19.5-26.3); hazard ratio (HR) for the elderly against the non-elderly: 1.21 (95 % CI: 0.98-1.50), p = 0.079]. However, the time to treatment failure (TTF) was significantly shorter in the elderly than in the non-elderly [elderly group: median TTF, 14.0 months (95 % CI: 0.98-1.50); non-elderly group: median TTF, 21.8 months (95 % CI: 18.2-24.6); HR for the elderly against the non-elderly: 1.46 (95 % CI: 1.20-1.77), p < 0.001]. Furthermore, the rate of treatment discontinuation because of adverse events was 28.6 % in the elderly and 14.9 % in the non-elderly (p < 0.001). Among patients who discontinued treatment, the conversion rate to second-line treatment was 39.6 % in the elderly and 72.8 % in the non-elderly. In addition, the median overall survival was 30 months (95 % CI: 25.8-37.7) in the elderly and not reached (NR) (95 % CI: NR-NR) in the non-elderly (p < 0.001). CONCLUSION: In a real-world clinical setting, elderly patients receiving osimertinib as first-line treatment should be aware of the frequent inability to transition to second-line treatment due to adverse events.

Drug-Related Pneumonitis Induced by Osimertinib as First-Line Treatment for Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Real-World Setting.

BACKGROUND: Osimertinib has demonstrated impressive efficacy as a first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive (m+) lung cancer. Drug-related pneumonitis (DRP) is a potentially lethal complication of osimertinib treatment, but reliable real-world data currently are lacking. RESEARCH QUESTION: What is the prevalence of osimertinib-induced DRP in first-line settings? What are the characteristics, clinical impact, and risk factors of osimertinib-induced DRP? STUDY DESIGN AND METHODS: We conducted a retrospective multicenter cohort study of patients who received osimertinib as a first-line treatment for advanced EGFR m+ non-small cell lung cancer (NSCLC) between August 2018 and December 2019. All chest CT scans and clinical information during osimertinib exposure were collected until June 2020. The primary end point was DRP incidence identified through central review. RESULTS: A total of 452 patients from 18 institutions were evaluated. Eighty patients (18%) had a diagnosis of DRP (all grades), and 21 patients (4.6%) had a diagnosis of grade 3 or more DRP. Among the patients with DRP, 46% were identified as having transient asymptomatic pulmonary opacity (TAPO). Regarding the CT scan patterns, organizing pneumonia, simple pulmonary eosinophilia, hypersensitivity pneumonia, diffuse alveolar damage, and nonspecific interstitial pneumonia were found in 30, 21, 18, 9, and two patients (38%, 26%, 23%, 11%, and 3%), respectively. In multivariate analysis, smoking history was identified as an independent risk factor for DRP (hazard ratio, 1.72; 95% CI, 1.01-2.89; P = .046). In the 3-month landmark analysis, DRP was associated with poor treatment efficacy; however, the presence of TAPO did not affect treatment efficacy negatively. INTERPRETATION: For osimertinib treatment in first-line settings, the frequency of DRP was considerably elevated to 18 %, and half of these patients exhibited TAPO features.

Prospective analysis of factors precluding the initiation of durvalumab from an interim analysis of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small cell lung cancer in Japan (SAMURAI study).

Background: The standard of care for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC trial. Disease progression and pneumonitis were reported as the main reasons to preclude the initiation of durvalumab in multiple retrospective studies. However, the transition rate and the reasons for failure to proceed to consolidation therapy with durvalumab after CRT were not evaluated prospectively. Although phase II studies in Japan have shown high efficacy and tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has yet been reported. We therefore conducted a phase II study to verify the efficacy and safety of durvalumab following SP-based CRT. In this interim analysis, we report the transition rate and the reasons for its failure. Methods: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab every 2 weeks for up to 12 months. The primary endpoint was 12 month progression-free survival rate. Results: Fifty-nine patients were enrolled, of whom 86.4% (51/59) proceeded to durvalumab. All of them initiated durvalumab within 42 days after CRT [median 18 days (range: 3-38)], including 27.5% (14/51) in <14 days. Common reasons for failure to proceed to durvalumab were disease progression (2/59, 3.4%) and adverse events (6/59, 10.2%). Among the latter cases, four resumed treatment and proceeded to durvalumab within 42 days on off-protocol. The objective response rate and the disease control rate were 62.7% and 93.2%, respectively. The incidences of ⩾grade 3 pneumonitis, febrile neutropenia, and esophagitis were 0%, 8.5%, and 3.4%, respectively. Conclusion: Regarding durvalumab after CRT, this interim analysis of the SAMURAI study clarified the high transition rate, early introduction, and reasons for failure to proceed to consolidation therapy, which were not determined in the PACIFIC trial. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study): primary analysis.

Background: The standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC study. Although multiple Japanese phase II studies have shown high efficacy and tolerability of CRT with cisplatin plus S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported. Objectives: We conducted a multicenter phase II study of this approach, the interim analysis of which showed a high transition rate to durvalumab consolidation therapy. Here, we report the primary analysis results. Design: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m2, day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab (10 mg/kg) every 2 weeks for up to 1 year. Methods: The primary endpoint was 1-year progression-free survival (PFS). The expected 1-year PFS and its lower limit of the 80% confidence interval (CI) were set as 63% and 47%, respectively, based on the results of TORG1018 study. Results: In all, 59 patients were enrolled, with 51 (86.4%) proceeding to durvalumab. The objective response rate throughout the study was 72.9% (95% CI: 59.7-83.6%). After median follow-up of 21.9 months, neither median PFS nor OS was reached. The 1-year PFS was 72.5% (80% CI: 64.2-79.2%, 95% CI: 59.1-82.2%), while the 1-year overall survival was 91.5% (95% CI: 80.8-96.4%). No grade 5 adverse events were observed throughout the study. The most common adverse event during the consolidation phase was pneumonitis (any grade, 78.4%; grade ⩾3, 2.0%). Eventually, 52.5% of patients completed 1-year durvalumab consolidation therapy from CRT initiation. Conclusion: This study of durvalumab after SP-based CRT met its primary endpoint and found a 1-year PFS of 73% from CRT initiation. This study provides the first prospective data on the prognosis and tolerability of durvalumab consolidation from the initiation of CRT. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

[Methotrexate-related lymphomatoid granulomatosis in a patient with rheumatoid arthritis].

A 76-year-old man who was taking prednisolone and methotrexate for rheumatoid arthritis presented with gastric ulcers. Chest X-ray images showed multiple pulmonary nodules. Transbronchial lung biopsy specimens showed lymphocytic infiltrates but no malignant cells. The radiographic findings gradually ameliorated over a month, but then deteriorated 5 months later. We performed video-assisted thoracoscopic biopsy of the left lung, and the biopsy specimens showed lymphocytic infiltration with necrosis, in which the atypical lymphocytes were positive for Epstein-Barr virus-encoded small RNAs in situ hybridization (EBER-ISH). A diagnosis of lymphomatoid granulomatosis was determined. One year before this diagnosis, the patient was found to have an inflammatory liver tumor that had disappeared spontaneously within a month. A new pathological review of the liver and stomach lesions demonstrated EBER-ISH-positive lymphocytes, and therefore we assumed that they were pathological features of lymphomatoid granulomatosis. The chest radiographic findings improved gradually after the discontinuation of methotrexate. We therefore suggest that methotrexate treatment may be associated with the development of lymphomatoid granulomatosis in patients with rheumatoid arthritis. Lymphoproliferative disorders, including lymphomatoid granulomatosis, should be considered in patients with rheumatoid arthritis who are receiving methotrexate.

Osimertinib as first-line treatment for advanced epidermal growth factor receptor mutation-positive non-small-cell lung cancer in a real-world setting (OSI-FACT).

BACKGROUND: Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient. METHODS: We performed a retrospective multicentre cohort study for 538 EGFR mutation-positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS). RESULTS: The median observation period was 14.7 months (interquartile range 11.4-20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6-not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35-2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11-2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03-2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04-2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01-2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70-5.83, P < 0.001) were associated with PFS. PD-L1 expression of 1-49% (HR 1.66, 95% CI 1.05-2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17-4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05-2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%). CONCLUSION: During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation.

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study).

BACKGROUND: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study. METHODS: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80-120 mg/body, Days 1-14) + cisplatin (60 mg/m2, Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate. DISCUSSION: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.

[A case of bronchial glomus tumor].

A 67-year-old man was admitted to our hospital because of a cough and hemoptysis. Chest CT and bronchoscopy demonstrated a polypoid tumor in the truncus intermedius. The pathological diagnosis of the biopsy specimens was glomus tumor, which is an extremely rare tumor of the respiratory tract. We performed a successful bronchoscopic removal of the tumor using a high-frequency-wave snare and microwave coagulation. After one year of follow-up, there was no recurrence. To the best of our knowledge, this is only the 24th report of a tracheobronchial glomus tumor.

Severe pulmonary alveolar proteinosis with respiratory failure treated by intrapulmonary percussive ventilation.

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by abnormal accumulation of surfactant in the alveoli. Whole lung lavage (WLL) is the standard treatment for severe autoimmune PAP (aPAP); however, it is highly invasive. Intrapulmonary percussive ventilation (IPV) is a non-invasive technique that delivers small bursts of high-flow respiratory gas into the lung and mobilizes secretions. As IPV is beneficial for chronic respiratory diseases such as cystic fibrosis and bronchiectasis to reduce sputum, it was hypothesized that IPV will ameliorate aPAP by mobilizing and removing accumulated surfactant and foamy macrophages. Here, we report the case of a 52-year-old female with severe aPAP and progressive respiratory failure. She received intermittent IPV therapy for six months and thereby showed improvement in assessments of chest computed tomography (CT), lung function, and oxygenation. We suggest that IPV should be used as an alternative therapy for patients with aPAP and respiratory failure.

Prognostic impact of pre-existing interstitial lung disease in non-HIV patients with Pneumocystis pneumonia.

BACKGROUND: The increasing incidence of life-threatening Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients is a global concern. Yet, no reports have examined the prognostic significance of pre-existing interstitial lung disease (ILD) in non-HIV PCP. METHODS: We retrospectively reviewed the medical records of non-HIV PCP patients with (ILD group) or without (non-ILD group) pre-existing ILD. The clinical features and outcomes of the ILD group were compared with those of the non-ILD group. Cox regression models were constructed to identify prognostic factors. RESULTS: 74 patients were enrolled in this study. The 90-day mortality was significantly higher in the ILD group than in the non-ILD group (62.5% versus 19.0%, p<0.001). In the ILD group, patients with a higher percentage of bronchoalveolar lavage fluid neutrophils had worse outcomes compared to those having a lower percentage (p=0.026). Multivariate analyses revealed that pre-existing ILD (p=0.002) and low levels of serum albumin (p=0.009) were independent risk factors for 90-day mortality. Serum levels of ß-d-glucan were significantly reduced after treatment of PCP in both groups, whereas levels of Krebs von den Lungen-6 (KL-6) significantly increased in the ILD group. In the ILD group, the 90-day mortality of patients with increasing KL-6 levels after treatment was significantly higher than those with decreasing levels (78.9% versus 0%, p=0.019). CONCLUSION: In non-HIV PCP patients, pre-existing ILD is associated with a poorer prognosis. Prophylaxis for PCP is needed in patients with pre-existing ILD under immunosuppression.

[A case of lymphomatoid granulomatosis].

An 83-year-old man was found to have multiple pulmonary nodules and ground-glass opacities after a left upper lobectomy for non-small-cell lung cancer. After bronchoalveolar lavage and transbronchial lung biopsy, he was put on a regimen of steroids for a tentative diagnosis of organizing pneumonia. Over the course of 3 months, the radiographic findings improved; however, they progressively deteriorated during the steroid tapering period and new skin lesions also appeared. Skin biopsy specimens showed lymphohistiocytic infiltration in which the atypical lymphocytes were positive for EBV encoding small RNAs by in situ hybridization; we therefore diagnosed lymphomatoid granulomatosis. The pulmonary and cutaneous lesions responded to steroid and cyclophosphamide therapy, but the patient died unexpectedly due to a rapid onset of massive pulmonary thromboembolism.