Fatal Hemoptysis Due to Endobronchial Aspergilloma in the Hyperinflated Native Lung after Single-Lung Transplantation for Lymphangioleiomyomatosis: A Case Report.

Pulmonary lymphangioleiomyomatosis accounts for the majority of cadaveric lung transplantation cases. Post-transplantation management is continuingly necessary not only to prevent the progression of LAM but also to address complications. A woman with lymphangioleiomyomatosis underwent cadaveric lung transplantation. She developed post-operative native lung hyperinflation and hemoptysis with cavity shadow in the native lung on computed tomography. Isolated Aspergillus from her sputum and positive Aspergillus galactomannan antigen in the blood led to a diagnosis of aspergillosis. Despite the reduction of hemoptysis by antifungal medication, she developed fatal hemoptysis. An autopsy showed an Aspergillus fungal mass in the bronchus in the native lung whilst the lung graft was free from lymphangioleiomyomatosis lesions. Endobronchial aspergilloma was suggested to be a cause of hemoptysis. This fatal clinical course suggested that hemoptysis due to endobronchial aspergilloma in the native lung should have been considered native lung pneumonectomy as a further intervention.

Feasibility Study of Adjuvant Chemotherapy with Carboplatin and Nab-Paclitaxel for Completely Resected NSCLC.

PURPOSE: Adjuvant chemotherapy with cisplatin (CDDP) plus vinorelbine is the standard regimen for the treatment of non-small cell lung cancer (NSCLC). However, CDDP elicits severe toxic effects, including emesis, neurotoxicity, and renal damage; carboplatin (CBDCA) may be a feasible alternative for CDDP-unfit patients. CBDCA plus paclitaxel (PTX) adjuvant chemotherapy showed a survival benefit for patients with stage IB tumors >4 cm in size, while CBDCA plus nanoparticle albumin-bound (nab)-PTX showed greater efficacy and lower neurotoxicity than CBDCA plus PTX in advanced NSCLC. Here, we investigated the feasibility of using CBDCA plus nab-PTX as adjuvant chemotherapy for NSCLC. PATIENTS AND METHODS: Patients with completely resected stage II or III NSCLC, with an Eastern Cooperative Oncology Group performance status of 0-1 and adequate kidney function, received four cycles of postoperative adjuvant chemotherapy with CBDCA (AUC=5 mg/mL/min, on day 1) and nab-PTX (100 mg/m2, on days 1, 8, and 15) administered every 4 weeks within 8 weeks after surgery. The study was designed as a prospective, single-center, Phase II study. The primary endpoint was the completion rate of chemotherapy; secondary endpoints were two-year relapse-free survival (RFS) and safety. The expected completion rate was 80%, with a 50% lower limit. RESULTS: Of 21 enrolled patients, 18 (85.7%) were CDDP-unfit owing to age (≥75 years old [n=11, 52.4%]) or mild renal impairment (n=7, 33.3%). Nineteen of the 21 enrolled patients were assigned to the intervention. The most common grade 3 or 4 adverse events were neutropenia (n=15, 78.9%) and anemia (n=3, 15.8%). The completion rate for the four cycles was 63.2% (95% CI, 38.4-83.7). Two-year RFS was 56.8% (95% CI, 29.7-76.9). CONCLUSION: The completion rate for CBDCA plus nab-PTX as adjuvant chemotherapy for CDDP-unfit NSCLC patients did not reach treatment feasibility. Further dose modifications may be required in future studies.

Overexpression of CD 133 and BCL-2 in non-small cell lung cancer with neuroendocrine differentiation after transformation in ALK rearrangement-positive adenocarcinoma.

Transformation to small cell lung cancer is one phenomenon of acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Few case reports have focused on other types of histological transformation. We report a case of transformation of ALK rearrangement-positive adenocarcinoma to NSCLC with neuroendocrine differentiation during alectinib therapy. A 36-year-old woman presented with a tumor in the left lower lobe and bone metastases. She was diagnosed with ALK rearrangement-positive adenocarcinoma by histopathology of the primary tumor. Alectinib had been effective for 8 months before new lesions appeared. Histopathological re-examination of a recurrent tumor revealed poorly differentiated carcinoma with insulinoma-associated protein 1 (INSM1) expression, which remained ALK-positive. Expression of CD133, BCL-2, and SOX2 was positive in comparison to the initial tumor. Expression of SOX2 became more strongly positive than it was before treatment. The immunohistochemical findings of these markers associated with cancer stem-like cells and/or neuroendocrine differentiation suggest that cancer stem cells play a role in the mechanisms of histological transformation and acquired resistance of ALK rearrangement-positive cancer. To our knowledge, this is the first report to suggest an association between cancer stem-like cells and histological transformation in ALK rearrangement-positive lung cancer.

Successful Treatment of ROS1-rearranged Lung Cancer Complicated by Hypertrophic Pulmonary Osteoarthropathy with Crizotinib Therapy.

Hypertrophic pulmonary osteoarthropathy (HPO) is a paraneoplastic syndrome characterized by digital clubbing, arthritis, and periostitis. Tumor removal usually leads to the resolution of these symptoms. We herein report the efficacy of crizotinib treatment for treating the symptoms of HPO associated with c-ros oncogene 1 receptor tyrosine kinase (ROS1)-rearranged lung cancer. A 71-year-old woman presented with a pulmonary tumor and arthritis. She was diagnosed with a ROS1-rearranged lung adenocarcinoma [stage IIIB (cT4N2M0) ] with HPO. Crizotinib dramatically reduced the tumor size and resolved the symptoms. After two months of crizotinib treatment, she underwent lobectomy, and a pathological evaluation revealed ypstage IIIA (ypT3a, ypN1). Crizotinib treatment was effective for reducing the tumor size and improving the symptoms of HPO.

Role of S1P/S1PR3 axis in release of CCL20 from human bronchial epithelial cells.

BACKGROUND: Sphingosine kinase phosphorylates sphingosine to generate sphingosine 1 phosphate (S1P) following stimulation of the five plasma membrane G-protein-coupled receptors. The objective of this study is to clarify the role of S1P and its receptors (S1PRs), especially S1PR3 in airway epithelial cells. METHODS: The effects of S1P on asthma-related genes expression were examined with the human bronchial epithelial cells BEAS-2B and Calu-3 using a transcriptome analysis and siRNA of S1PRs. To clarify the role of CCL20 in the airway inflammation, BALB/c mice were immunized with ovalbumin (OVA) and subsequently challenged with an OVA-containing aerosol to induce asthma with or without intraperitoneal administration of anti-CCL20. Finally, the anti-inflammatory effect of VPC 23019, S1PR1/3 antagonist, in the OVA-induced asthma was examined. RESULTS: S1P induced the expression of some asthma-related genes, such as ADRB2, PTGER4, and CCL20, in the bronchial epithelial cells. The knock-down of SIPR3 suppressed the expression of S1P-inducing CCL20. Anti-CCL20 antibody significantly attenuated the eosinophil numbers in the bronchoalveolar lavage fluid (P<0.01). Upon OVA challenge, VPC23019 exhibited substantially attenuated eosinophilic inflammation. CONCLUSIONS: S1P/S1PR3 pathways have a role in release of proinflammatory cytokines from bronchial epithelial cells. Our results suggest that S1P/S1PR3 may be a possible candidate for the treatment of bronchial asthma.

Bronchoscopy Using Virtual Navigation and Endobronchial Ultrasonography with a Guide Sheath (EBUS-GS) with or without Fluoroscopy for Peripheral Pulmonary Lesions.

OBJECTIVE: Endobronchial ultrasonography and guide sheath (EBUS-GS) technique has high diagnostic yield in lung nodules. Virtual bronchoscopic navigation (VBN) can lead bronchoscope to the target bronchi. The aim of this prospective study was to compare the diagnostic yield of two bronchoscopic procedures: bronchoscopy under EBUS-GS and VBN with or without x-ray fluoroscopy in small peripheral pulmonary lesions (PPLs, ≤30mm) with apparent CT-bronchus sign. METHODS: 31 patients with PPLs which had apparent CT-bronchus sign were randomly assigned to the X-ray or the non-X-ray groups (18 with and 13 without fluoroscopy) between September 1, 2012, and September 30, 2015. A bronchoscope was introduced into the target bronchus using the VBN system. Sites of specimen sampling were verified using EBUS-GS with or without fluoroscopy. RESULTS: The overall diagnostic yield was 83.3% in the X-ray and 69.2% in the non-X-ray group. The diagnostic yield of malignancy was 88.2% and 81.8%, respectively. The duration of the examination and time elapsed until the first EBUS visualization were similar in the X-ray and the non-X-ray group (9.0 (5.8-20.) min vs 11.0 (5.3-17.3) min, and 2.5 (1.3-14.2) min vs 4.1 (1.4-8.1) min, respectively). The fluoroscopy exposure time was 3.7 (2.9-10.56) min. The only adverse event was mild pneumothorax in a patient from the non-X-ray group, who had consequent TBB under fluoroscopy. CONCLUSIONS: There was a possibility that VBN-guided EBUS-transbronchial diagnosis without fluoroscopy might be equivalent to that under fluoroscopy. Further multi-center randomized study may be desired. (UMIN000008592).

Lung squamous cell carcinoma associated with hypoparathyroidism with sensorineural deafness and renal dysplasia syndrome: a case report.

Hypoparathyroidism with sensorineural deafness and renal dysplasia (HDR) syndrome is an autosomal dominant condition caused by mutations of the gene encoding the dual zinc-finger transcription factor, GATA3. A previous study identified some patients with GATA3 gene variants and breast cancer, suggesting that GATA3 variants may contribute to tumorigenesis in estrogen receptor 1-positive breast tumors; however, these patients did not have HDR syndrome. A 32-year-old nonsmoking Japanese woman was histologically diagnosed with lung squamous cell carcinoma associated with HDR syndrome and a c.C952T>C (p.C318R) germline mutation in GATA3. This is the first report describing cancer in a patient with HDR syndrome. Our data indicates that GATA3 mutations may be a potential therapeutic target for lung cancer.

Successful Osimertinib Rechallenge with Steroid Therapy after Osimertinib-induced Interstitial Lung Disease.

A 62-year-old male with lung adenocarcinoma harboring an exon 19 deletion in the Epidermal growth factor receptor (EGFR) was treated with EGFR-tyrosine kinase inhibitors (TKIs) and several cytotoxic agents. After administering a fifth-line chemotherapy regimen, a liver biopsy revealed a diagnosis of recurrence with a T790M mutation. After an 82-day course of osimertinib therapy, the patient developed osimertinib-induced interstitial lung disease (ILD). Osimertinib was discontinued, and oral prednisolone was started. The ILD quickly improved, but liver metastases progressed and osimertinib was restarted concurrently with prednisolone. The patient showed neither disease progression nor a recurrence of ILD at 5 months. In situations in which no alternative treatment is available, osimertinib rechallenge should thus be considered as an alternative treatment.

Spontaneous Regression of Epithelioid Angiosarcoma in a Young Woman.

A 20-year-old Japanese woman with a history of pulmonary atresia was referred to our hospital after the detection of an abnormal mass in the right lung and mediastinal lymphadenopathy. A cytological specimen obtained by transbronchial brushing indicated that the pathological diagnosis was non-small cell lung cancer. During the follow-up period, the tumor spontaneously regressed. At four months after the diagnosis, she experienced sudden bleeding from the small intestine. The histological characteristics of the small intestine tumor were compatible with the cytological characteristics of the lung tumor. Detailed immunohistochemical analyses led to a final diagnosis of epithelial angiosarcoma of the small intestine, which might have formed metastatic lesions in the lung.

Amphiregulin as a Novel Resistance Factor for Amrubicin in Lung Cancer Cells.

BACKGROUND/AIM: Amrubicin (AMR) has shown promising activity for lung cancer. However, little is known about the mechanism underlying resistance to this agent. The aim of this study was to elucidate the mechanism underlying resistance to AMR. MATERIALS AND METHODS: We first developed amrubicinol (AMR-OH)-resistant cell lines (H520/R and DMS53/R) by exposing lung cancer cell lines (H520 and DMS53) to increasing concentrations of AMR-OH and performed functional analysis by using these cell lines. RESULTS: Transcriptome analyses showed that amphiregulin (AREG) was the most highly up-regulated gene in both AMR-OH-resistant cell lines compared to parent cells. Conditioned medium from DMS53/R cells reduced the sensitivity to AMR-OH in DMS53 cells. In contrast, DMS53/R cells transfected with siRNA directed against AREG recovered their sensitivity to AMR-OH. An additional administration of cetuximab with amrubicinol also restored the sensitivity to AMR-OH. CONCLUSION: Amphiregulin plays an important role in resistance to AMR-OH.

Administration of JTE013 abrogates experimental asthma by regulating proinflammatory cytokine production from bronchial epithelial cells.

BACKGROUND: Sphingosine-1-phosphate (S1P) is a bioactive phospholipid that acts as a signal transducer by binding to S1P receptors (S1PR) 1 to 5. The S1P/S1PRs pathway has been associated with remodeling and allergic inflammation in asthma, but the expression pattern of S1PR and its effects on non-immune cells have not been completely clarified. The aim of this study was to examine the contribution of the signaling of S1P and S1PRs expressed in airway epithelial cells (ECs) to asthma responses in mice. METHODS: Bronchial asthma was experimentally induced in BALB/c mice by ovalbumin (OVA) sensitization followed by an OVA inhalation challenge. The effects of S1PR antagonists on the development of asthma were analyzed 24 h after the OVA challenge. RESULTS: Immunohistological analysis revealed S1PR1-3 expression on mouse airway ECs. Quantitative real-time polymerase chain reaction demonstrated that S1P greatly stimulated the induction of CCL3 and TIMP2 mRNA in human airway ECs, i.e., BEAS-2B cells, in a dose-dependent manner. Pretreatment with the S1PR2 antagonist JTE013 inhibited the CCL3 gene expression in BEAS-2B cells. Immunohistological analysis also showed that the expression level of CCL3 was attenuated by JTE013 in asthmatic mice. Furthermore, JTE013 as well as anti-CCL3 antibody attenuated allergic responses. Intratracheal administration of JTE013 also attenuated eosinophilic reactions in bronchoalveolar lavage fluids. S1P induced transcription factor NFκB activation, while JTE013 greatly reduced the NFκB activation. CONCLUSIONS: JTE013 attenuated allergic airway reactions by regulating CCL3 production from bronchial ECs. The intratracheal administration of JTE013 may be a promising therapeutic strategy for bronchial asthma.

Diagnostic utility of additional conventional techniques after endobronchial ultrasonography guidance during transbronchial biopsy.

BACKGROUND AND OBJECTIVE: Endobronchial ultrasonography with a guide sheath transbronchial biopsy (EBUS-GS TBB) has been used to diagnose peripheral pulmonary lesions (PPLs). In this study, we evaluated the diagnostic utility of conventional TBB after EBUS-GS TBB. METHODS: A retrospective analysis of patients who underwent conventional TBB after EBUS-GS TBB for PPL between August 1, 2012 and December 31, 2014. We performed multivariate analysis to examine the association of various clinical factors, including EBUS probe distance and sample size area, with diagnostic yield. RESULTS: Of 88 eligible patients, 57 (65%) were successfully diagnosed by EBUS-GS TBB. In 31 patients not diagnosed by EBUS-GS TBB, 15 (48%) were successfully diagnosed by additional conventional TBB. Ground glass opacity (GGO) was a significant factor associated with the diagnostic yield of additional conventional TBB following EBUS-GS TBB. Multivariate analysis and receiver operator curves revealed that distance between the PPL and the EBUS probe of less than 2.55 mm favored the utility of conventional TBB. CONCLUSION: Additional conventional TBB after EBUS-GS TBB could be a useful procedure for the diagnosis of ground glass opacity PPLs and in cases of a distance of less than 2.55 mm between the EBUS probe and the lesion.

A multi-institutional study of clinicopathological features and molecular epidemiology of epidermal growth factor receptor mutations in lung cancer patients living with human immunodeficiency virus infection.

PURPOSE: Lung cancer has become a crucial problem among individuals living with the human immunodeficiency virus (HIV) and causes high mortality in Western countries. Japan has an increasing number of newly infected HIV patients, and lung cancer is becoming a theme in this population. However, clinical factors of this particular population in East Asian are unclear given the identification of ethnic differences in lung cancer in the general population. METHODS: From 1986 to 2013, a retrospective nationwide study involving Japanese patients living with HIV and diagnosed with lung cancer was undertaken. RESULTS: Forty-three lung cancer patients with HIV were identified (median age, 60.0 years; males, 97.7%; early-stage cancer, 37.2%; metastatic cancer, 34.9%), 41 (95.3%) of whom developed lung cancer in the antiretroviral era. The median CD4-positive T-cell count was 326 cells/µL. Adenocarcinoma was the most frequent histology (55.8%), followed by squamous cell carcinoma (27.9%). Epidermal growth factor receptor (EGFR) status was examined in 14 patients; five (35.7%) had EGFR mutations. The median overall survival time was 25.1 months for all stages and 7.9 months for advanced-stage cancer. Using univariate analysis, the only favorable prognostic factor for overall survival was cancer stage (p = 0.02). CONCLUSIONS: The incidence of lung cancer among HIV patients in Japan has been increasing in the past decade. The present Japanese cohort showed similar EGFR mutation status similar to that of general population. The ethnic differences known in the general population were seen even in the population living with HIV, implying distinct clinical characteristics and outcomes from those reported in Western countries.