Onset of takotsubo syndrome induced by osimertinib in a patient with lung adenocarcinoma.

The cardiotoxicity of osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, has been recently reported when treating EGFR mutation-positive non-small cell lung cancer. In this report, we describe a case of an 81-year-old female patient diagnosed with Takotsubo syndrome (TTS). TTS occurred despite the patient receiving osimertinib retreatment at reduced doses and having no history of cardiac or respiratory disease. The findings of this case suggest that clinicians should consider the possibility of TTS induced by osimertinib.

Trifluridine and Tipiracil Hydrochloride Combination-Induced Interstitial Pneumonia: A Case Report.

We report a case of a 62-year-old male who was diagnosed with advanced rectal cancer. The attending gastro-enterologist initiated chemotherapy using capecitabine plus oxaliplatin and bevacizumab; however, this treatment regimen was discontinued, as the patient developed a skin rash. Once the skin rash improved, chemotherapy was re-initiated using a combination of trifluridine and tipiracil hydrochloride (TAS-102). The patient developed high fever and dyspnea 2 months after initiation of TAS-102. Chest high-resolution computed tomography showed bilateral diffuse ground glass opacities in all lung lobes with traction bronchiectasis. At this time, the gastro-enterologist consulted our department. The patient was put on non-invasive positive pressure ventilation due to worsening respiratory symptoms. The patient was suspected to develop TAS-102-induced interstitial pneumonia based on positive TAS-102 drug-induced lymphocyte stimulation test. The patient's respiratory symptoms and radiological findings improved after corticosteroid treatment. The corticosteroid dose was gradually decreased by 5 mg. Thereafter, chemotherapy was re-initiated using different anti-cancer agents.

Current situation of management of spontaneous pneumothorax in Japan: A cross-sectional cohort study.

BACKGROUND: Limited epidemiological information is available on spontaneous pneumothorax. To address this gap, the Japan Society for Pneumothorax and Cystic Lung Disease (JSPCLD) conducted a nationwide retrospective survey to investigate the current epidemiology of spontaneous pneumothorax in Japan. METHODS: In this study, we conducted a retrospective cross-sectional cohort study to demonstrate the clinical features of spontaneous pneumothorax in one year from April 2019 to March 2020, compare patient characteristics and treatment outcomes between primary (PSP) and secondary spontaneous pneumothorax (SSP), and investigate the risk factors associated with in-hospital mortality among patients with SSP. RESULTS: A total of 1784 patients from 28 institutions were enrolled in the study, with PSP observed in 956 cases (53.6%) and SSP in 817 cases (45.8%). The age distribution showed a biphasic peak caused by the different peaks between PSP and SSP. In-hospital mortality occurred in 42 cases (2.4%) among all patients, with 0 cases (0%) in PSP and 42 cases (5.1%) in SSP. Multivariable analyses revealed that interstitial pneumonia as an underlying disease (odds ratio: 2.4700, 95% confidence interval: 1.1100 to 5.4800, p = 0.0269), performance status≧3 (odds ratio: 7.3900, 95% confidence interval: 3.1900 to 17.2000, p < 0.0001), and lower value of serum albumin on admission (odds ratio: 0.4060, 95% confidence interval: 0.2140 to 0.7690, p = 0.0057) were significantly associated with in-hospital mortality among patients with SSP. CONCLUSIONS: SSP patients with poor baseline conditions are at a higher risk for in-hospital mortality. It is crucial to provide close and meticulous management for SSP patients with compromised conditions.

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.

Pneumatosis intestinalis with free air in the abdominal cavity caused by nintedanib.

This is the first case confirmed the association between PI development and nintedanib by the reproducibility of PI development. In patients taking a combination treatment with corticosteroid and nintedanib, clinicians should be careful regarding the development of PI although the patient improved only after discontinuation of nintedanib treatment.

Late relapse of ulcerative colitis presenting as tracheobronchitis: a case report.

BACKGROUND: Lung involvement in inflammatory bowel diseases usually follows colitis. However, the time to lung involvement onset varies depending on the case, and pulmonary lesions are usually not parallel to exacerbations of the colitis. CASE PRESENTATION: A 67-year-old Asian woman with a 38-year history of ulcerative colitis presented to our hospital with a complaint of prolonged dry cough for 2 months. The colitis had remained quiescent for > 35 years with low-dose salazosulfapyridine treatment. Chest computed tomography indicated circumferential thickening of the tracheal wall, while bronchoscopy examination revealed widespread erythematous edema and diffuse narrowing of the bronchial lumen. Biopsy of the bronchial mucosa showed submucosal lymphocytic infiltration. She was diagnosed with ulcerative-colitis-related tracheobronchitis and successfully treated with corticosteroids. CONCLUSIONS: Tracheobronchitis, in our case, occurred despite the longest remission period previously reported. Careful follow-up is necessary for the early recognition and treatment of pulmonary disease in patients with ulcerative colitis, regardless of the disease duration and long-term remission of colitis.

Silicosis-related pleural effusion diagnosed using elemental analysis of the pleural fluid cell block: A case report.

Pleural disease in silicosis remains an underrecognized entity. Herein, we describe the case of an 85-year-old man with a 20-year history of silica exposure between the ages of 9-28 years. He presented with bilateral exudative pleural effusions, and chest computed tomography revealed typical silicosis findings. Thoracentesis was performed thrice, but did not reveal the cause of effusion. However, pleural fluid cell-block elemental analysis revealed a silicon compound, suggesting that silicosis-related pleural effusion had developed after a long latency period. Therefore, elemental analysis of the pleural fluid cell block may help diagnose occupational lung diseases with pleural effusion.

Pleural effusion as a rare presentation of foreign body aspiration.

Unsuspected, non-asphyxiating, aspirated foreign body often masquerades as unresolved pneumonia, bronchiolitis or bronchial asthma. We report herein an 82-year-old, male patient with pleural effusion. Although the patient received the diagnosis of heart failure and treatment with diuretics, the pleural effusion remained, and a productive cough and a low-grade fever developed. Thoracentesis showed an exudative effusion, and chest computed tomography revealed a pill-like object in the right bronchus intermedius. The foreign body proved to be an iron pill, and the patient finally died from obstructive pneumonia due to severe mucosal damage caused by the pill. The present case emphasizes that foreign body aspiration may mimic not only respiratory but also cardiovascular diseases and should be suspected if the treatment of the initially diagnosed condition fails to ameliorate the patient's condition.

Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells.

Birt-Hogg-Dubé syndrome (BHDS), an autosomal dominant inheritance disease caused by folliculin (FLCN) mutations, is associated with lung cysts and spontaneous pneumothorax. The possibility of FLCN haploinsufficiency in pleural mesothelial cells (PMCs) contributing to development of pneumothorax has not yet been clarified. Electron microscopy revealed exposed intercellular boundaries between PMCs on visceral pleura and decreased electron density around the adherens junctions in BHDS. To characterize cellular function of PMCs in BHDS patients (BHDS-PMCs), during surgery for pneumothorax, we established the flow cytometry-based methods of isolating high-purity PMCs from pleural lavage fluid. BHDS-PMCs showed impaired cell attachment and a significant decrease in proliferation and migration, but a significant increase in apoptosis compared with PMCs from primary spontaneous pneumothorax (PSP) patients (PSP-PMCs). Microarray analysis using isolated PMCs revealed a significant alteration in the expression of genes belonging to Gene Ontology terms "cell-cell adhesion junction" and "cell adhesion molecule binding". Gene set enrichment analysis demonstrated that CDH1, encoding E-cadherin, was identified in the down-regulated leading edge of a plot in BHDS-PMCs. AMPK and LKB1 activation were significantly impaired in BHDS-PMCs compared with PSP-PMCs. Our findings indicate that FLCN haploinsufficiency may affect the E-cadherin-LKB1-AMPK axis and lead to abnormal cellular function in BHDS-PMCs.

Isolation and characterisation of lymphatic endothelial cells from lung tissues affected by lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS). We found that LAM-LECs had significantly higher ability of proliferation and migration compared to control LECs. VEGF-D significantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis.

Uncommon radiologic computed tomography appearances of the chest in patients with lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by multiple thin-walled pulmonary cysts. The currently proposed diagnostic algorithm emphasizes the characteristic cystic appearance on high-resolution computed tomography (HRCT) so uncommon HRCT appearances present challenges to establishing the proper LAM diagnosis. The objective of this study is to accrue uncommon chest HRCT appearances, determine frequencies in both tuberous sclerosis complex (TSC)-associated LAM (TSC-LAM) and sporadic LAM (S-LAM) patients. 311 females referred to our hospital, including 272 S-LAM patients (mean age 39.2 years) and 39 TSC-LAM patients (mean age 38.3 years), were retrospectively evaluated. We found 2 types of radiologic findings likely to make HRCT cyst appearance atypical: characteristics of the cyst itself and uncommon findings in addition to cysts. We found that approximately 80% of LAM patients, whether TSC-associated or sporadic, showed typical HRCT appearance with mild to severe cystic destruction. The remaining 20% displayed unusual profiles in cyst appearance as well as additional findings aside from cyst: the former includes large cyst, thickened walls, and irregularly shaped whereas the latter includes ground glass attenuation and diffuse noncalcified nodules. It is important to be aware of various radiologic findings that make HRCT cystic appearance atypical of LAM.

The effects of total pleural covering on pneumothorax recurrence and pulmonary function in lymphangioleiomyomatosis patients without history of pleurodesis or thoracic surgeries for pneumothorax.

BACKGROUND: Total pleural covering (TPC) is an innovative surgical procedure in which the entire visceral pleura is wrapped with sheets of oxidized regenerated cellulose (ORC) mesh under video-assisted thoracoscopic surgery. We have previously reported that TPC could successfully prevent pneumothorax recurrence in patients with lymphangioleiomyomatosis (LAM). However, the actual efficacy and preventive effect of TPC on pneumothorax recurrence remains unclear as many LAM patients already had pleural adhesion prior to TPC that was induced by thoracic surgery and/or pleurodesis. The purpose of this study is to evaluate the effects of TPC on pneumothorax recurrence and pulmonary function in LAM patients with no history of thoracic surgeries or pleurodesis. METHODS: We retrospectively reviewed medical charts of 52 patients (60 hemithoraces) who underwent TPC at our center, from January 2003 to September 2019, as a first surgical intervention for pneumothorax. RESULTS: Pneumothorax recurrence occurred in 12 patients [14 of 60 hemithoraces (23.3%)] during the observation period [27 months (14.7; 56.4) = median (lower; upper quartiles)]. The probability of recurrence-free hemithorax post TPC was 81.1% at 2.5 years and 64.1% at 5 years. TPC did not produce a significant decrease in either VC %predicted (pred) or FEV1/FVC. The pre- vs. post-TPC median (lower; upper quartiles) VC %pred was 85.7% (79.7; 98.0) vs. 87.2% (72.3; 95.6), P=0.535 and the FEV1/FVC was 84.6% (75.7; 89.6) vs. 83.0% (71.8; 87.0), P=0.667. Mechanistic/mammalian target of rapamycin (mTOR) inhibitors (mTORI) were subsequently initiated in 19 patients (36.5%) because of the progression of LAM. The postoperative FEV1%pred was significantly lower in patients who required mTORI than in those who did not [68.1% (57.3; 82.9) vs. 88.7% (84.6; 89.8), P=0.020]; the decline rate in FEV1%pred/year from pre to post TPC was significantly greater in LAM patients who required mTORI than in those who did not [-9.37% (-4.73; 12.9) vs. -1.94% (1.52; -4.50), P=0.029]. Postoperative complications were found in 25 of 52 hemithoraces (48.1%). CONCLUSIONS: TPC can prevent pneumothorax recurrence without causing ventilatory impairment or severe pleural symphysis in LAM patients. TPC is an effective treatment option for LAM-associated pneumothorax based on its efficacy and safety.

Transbronchial lung biopsy for the diagnosis of lymphangioleiomyomatosis: the severity of cystic lung destruction assessed by the modified Goddard scoring system as a predictor for establishing the diagnosis.

BACKGROUND: A guide of patient selection for establishing the diagnosis of lymphangioleiomyomatosis (LAM) by transbronchial lung biopsy (TBLB) has not been established, although the pathological confirmation of LAM by lung biopsy is desirable, particularly when patients have no additional test results except typical findings of computed tomography (CT) of the chest. METHODS: We retrospectively reviewed the medical records of LAM patients who visited at our hospital from January 2010 to September 2018. We found 19 patients who underwent TBLB and collected the following data to investigate which parameters could predict the TBLB diagnostic positivity for LAM: age, degree of exertional dyspnea, pulmonary function test, cystic lung destruction visually assessed by the modified Goddard scoring system (MGS), serum level of vascular endothelial growth factor-D, and TBLB-related data. RESULTS: The diagnosis of LAM was established by TBLB in 15 of 19 patients (78.9%) and no serious complications occurred. MGS was significantly higher in the TBLB-positive group than the TBLB-negative group. In LAM patients without pulmonary lymphatic congestion on CT (N = 16), multivariable logistic regression analysis revealed that MGS and FEV1/FVC were independent contributing parameters for TBLB diagnostic positivity. However, the analysis of Bayesian inference demonstrated that MGS is a better predictor than FEV1/FVC; the probability of establishing diagnosis exceeds 80% if MGS is > 2 (i.e., area of cystic destruction occupies > 25% of lung parenchyma on CT). CONCLUSIONS: MGS may be a helpful and convenient tool to select candidates for TBLB to establish the diagnosis of LAM pathologically.

A total pleural covering of absorbable cellulose mesh prevents pneumothorax recurrence in patients with Birt-Hogg-Dubé syndrome.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a recently recognized inherited multiple cystic lung disease causing recurrent pneumothoraces. Similarly to the lesions in patients with lymphangioleiomyomatosis (LAM), the pulmonary cysts are innumerable and widely dispersed and cannot all be removed. We recently described a total pleural covering (TPC) that covers the entire visceral pleura with oxidized regenerated cellulose (ORC) mesh. TPC successfully prevented the recurrence of pneumothorax in LAM patients. The purpose of this study was to evaluate the effect of an ORC pleural covering on pneumothorax recurrence in BHDS patients. RESULTS: This retrospective study enrolled a total of 81 pneumothorax patients with the diagnosis of BHDS who underwent 90 covering surgeries from January 2010 to August 2017 at Tamagawa Hospital. During the first half of the study period, a lower pleural covering (LPC) which covered the affected area with ORC mesh was mainly used to treat 38 pneumothoraces. During the second half of the study period, TPC was primarily performed for 52 pneumothoraces. All the thoracoscopic surgeries were successfully performed without serious complications (≥ Clavien-Dindo grade III). The median follow-up periods after LPC/TPC were 66/34 months, respectively. Pneumothorax recurrence rates after LPC at 2.5/5/7.5 years postoperatively were 5.4/12/42%, respectively; none of the patients who had underwent TPC developed postoperative pneumothorax recurrence (P = 0.032). CONCLUSIONS: TPC might be an effective option for surgical treatment of intractable pneumothorax in patients with BHDS.

Pneumothorax caused by cystic and nodular lung metastases from a malignant uterine perivascular epithelioid cell tumor (PEComa).

Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with immunoreactivity for both melanocytic and smooth muscle markers. PEComas occur at multiple sites, and malignant PEComas can undergo metastasis, recurrence and aggressive clinical courses. Although the lung is a common metastatic site of PEComas, they usually appear as multiple nodules but rarely become cystic or cavitary. Here, we describe a female patient whose lungs manifested multiple cystic, cavity-like and nodular metastases 3 years after the resection of uterine tumors tentatively diagnosed as epithelioid smooth muscle tumors with uncertain malignant potential. This patient's subsequent pneumothorax necessitated video-assisted thoracoscopic surgery, and examination of her resected lung specimens eventually led to correcting the diagnosis, i.e., to a PEComa harboring tuberous sclerosis complex 1 (TSC1) loss-of-heterozygosity that originated in the uterus and then metastasized to the lungs. The administration of a gonadotropin-releasing hormone analogue later stabilized her clinical course. To the best of our knowledge, the present case is the first in the literature that associates PEComas with a TSC1 abnormality. Additionally, the pulmonary manifestations, including imaging appearance and pneumothorax, somewhat resembled those of lymphangioleiomyomatosis, a representative disease belonging to the PEComa family. Although PEComas are rare, clinicians, radiologists and pathologists should become aware of this disease entity, especially in the combined clinical setting of multiple cystic, cavity-like, nodular lesions on computed tomography of the chest and a past history of the tumor in the female reproductive system.

Lung adenocarcinoma expressing receptor for advanced glycation end-products with primary systemic AL amyloidosis: a case report and literature review.

BACKGROUND: Receptor for advanced glycation end-products (RAGE), a receptor for amyloids, is constitutively expressed in lungs and generally observed to be downregulated in lung cancer tissues. However, increasing levels of RAGE or serum amyloids is associated with poor outcome in lung cancer patients. We report a rare case of primary systemic amyloid light-chain (AL) amyloidosis in biopsy-proven multiple organs with early-stage non-small cell lung cancer (NSCLC) that displayed strong staining for RAGE in the tumour tissue. Interestingly, compared with randomly selected lung cancer biopsy samples, including all representative histological subtypes of NSCLC and small-cell lung cancer, only the NSCLC in the present case showed strong expression for RAGE that can bind amyloids. CASE PRESENTATION: A 71-year-old woman was admitted to our hospital for comprehensive investigation of nephrotic syndrome. Computed tomography showed a small nodule in the right upper lung lobe with hilar mediastinal lymph node enlargement. Pathological examination of transbronchial biopsy samples of the nodule yielded a diagnosis of lung adenocarcinoma. Furthermore, the pathological detection of amyloid deposition in biopsy samples of a subcarinal lymph node, gastric and duodenal mucosa, cardiac muscle, and bone marrow led to a diagnosis of primary systemic AL amyloidosis with nephrotic syndrome and cardiomyopathy. In addition, RAGE was detected in lung tumour tissues surrounded by normal lung tissues with amyloid deposition. CONCLUSION: The RAGE positivity of the lung cancer cells in this case suggests an interaction between amyloid-containing tissues and RAGE-expressing cancer cells. Lung adenocarcinoma with RAGE expression may be a complication of underlying amyloidosis.