Spigot in pneumothorax cavity: A rare complication of endobronchial Watanabe spigot.

Spigot dropping is a rare but an intractable complication, because it is difficult to salvage a dropped spigot from the thoracic cavity. If the pneumothorax with a large fistula is recurrent, replacement with a larger size spigot may be recommended.

Clinical importance of long non­coding RNA LINC00460 expression in EGFR­mutant lung adenocarcinoma.

Long non­coding RNAs (lncRNAs) have been reported to be involved in the physiological and pathological processes of tumor pathogenesis, including epithelial­mesenchymal transition (EMT). However, epidermal growth factor receptor (EGFR)­tyrosine kinase inhibitor (TKI) resistance is a major challenge in the treatment of advanced and recurrent EGFR­mutant lung adenocarcinoma. An increased understanding of the underlying mechanisms would aid in the development of effective therapeutic strategies against EGFR­TKI resistance, strategies which are urgently required for clinical therapy. In this study, long non­coding RNA LINC00460 was identified as a novel marker of a poor response to EGFR­TKI and prognosis. In lung cancer cells, LINC00460 promoted EGFR­TKI resistance as a competitive decoy for miR­149­5p, thereby facilitating interleukin (IL)­6 expression and inducing EMT­like phenotypes. The knockdown or knockout of LINC00460 in gefitinib­resistant non­small cell lung cancer cells restored the response to EGFR­TKI. In addition, as compared with patients with a low LINC00460 expression in tumors, those with a high LINC00460 expression had a significantly shorter progression­free survival following gefitinib therapy, and a shorter overall survival. Therefore, LINC00460 may be a predictor of and potential therapeutic target for EGFR­TKI resistance.

New risk scoring system for predicting acute exacerbation of interstitial pneumonia after chemotherapy for lung cancer associated with interstitial pneumonia.

BACKGROUND: Fatal acute exacerbation (AE) of interstitial pneumonia (IP) sometimes occurs after chemotherapy for lung cancer. We developed and evaluated a scoring system for assessing AE risk after chemotherapy in patients with lung cancer associated with IP. METHODS: A review of medical records identified 109 patients with primary lung cancer associated with IP who had received chemotherapy at our center during the period from June 2007 through September 2017. We developed a model to score AE risk after chemotherapy in this patient group, and logistic regression was used to evaluate the model. RESULTS: The anticancer agent score was determined by using AE rates reported in past studies. The risk score was calculated with the following formula: (1 × anticancer agent score) + (3 × smoking history [>70 pack-years]) + (4 × history of steroid use) + (3 × %diffusing capacity of lung carbon monoxide [<50%]). Patients were then classified into three groups. The AE incidence rate was 12% for a risk score of 0-5, 47% for a score of 6-10, and 66.7% for a score of ≥11. The sensitivity of the scoring system was 78.6% and specificity was 67.8%. CONCLUSIONS: The present scoring system was able to identify IP patients at high risk for AE after chemotherapy for lung cancer associated with IP.

PD-L1 mRNA expression in EGFR-mutant lung adenocarcinoma.

Molecular mechanisms of programmed death-ligand 1 (PD-L1) mRNA expression and roles of apoptosis and biomarkers are poorly understood in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients. Thirty-three patients with recurrent postoperative EGFR-mutant lung adenocarcinoma (exon 19 deletion in 16, L858R in 15, G719C in 2 patients) treated with gefitinib were studied. PD-L1 mRNA expression of formalin-fixed paraffin-embedded paratumoral and intratumoral tissues was quantified by PCR. Correlations of PD-L1 mRNA expression with BIM, p53 upregulated modular of apoptosis (PUMA), human epidermal growth factor receptor 2 (HER2), mesenchymal-epithelial transition (MET), EGFR, and vascular endothelial growth factor A (VEGFA) were determined. Eleven of the 33 patients (33.3%) and 14/33 patients (42.4%) expressed intratumoral and paratumoral PD-L1 mRNA, respectively. Patients with intratumoral PD-L1 mRNA expression had significantly higher BIM and lower VEGFA expression compared with paratumoral PD-L1 mRNA patients (P=0.049, P=0.009). PD-L1 mRNA expression was not associated with the expression of PUMA, HER2, EGFR and MET but was positively correlated with BIM expression (r=0.41, P=0.017) and inversely correlated with VEGFA expression (r=-0.33, P=0.043). Patients with intratumoral PD-L1 mRNA expression had significantly shorter median progression-free survival (PFS) after gefitinib therapy compared with no PD-L1 expression (255 vs. 732 days, respectively; P=0.032). Thus, PD-L1 mRNA expression in EGFR-mutant lung adenocarcinoma was associated with BIM and VEGFA mRNA expression and with shorter PFS after gefitinib therapy.

Miliary Tuberculosis that Developed after Intravesical Bacillus Calmette-Guerin Therapy.

As a treatment for superficial transitional cell carcinoma, Bacillus Calmette-Guerin (BCG) intravesical instillation can rarely cause unpredictable systemic side effects. We describe a patient admitted due to continuous pyrexia and general fatigue. He was previously treated with intravesical BCG. Laboratory data indicated a hepatic disorder, and chest computed tomography revealed extensive bilateral miliary nodules. Transbronchial lung biopsy specimens showed several small noncaseating granulomas. The diagnosis was unsolved on the basis of acid fast staining, polymerase chain reaction and microbiological cultures, so we considered the possibility of BCG side effect-induced granuloma. Two months after treatment with antituberculous agents and corticosteroids, his clinical symptoms were improved.

A feasibility study of bevacizumab and vinorelbine in patients with previously treated advanced non-squamous non-small-cell lung cancer.

The aim of this prospective study was to evaluate the efficacy and feasibility of bevacizumab combined with vinorelbine therapy in patients with previously treated non-squamous non-small-cell lung cancer (nonSq-NSCLC). Patients who had received at least one prior chemotherapy course were eligible for this study. The patients were treated with vinorelbine (25 mg/kg on days 1 and 8) and bevacizumab (15 mg/kg on day 1), which was repeated every 3 weeks until the development of progressive disease or unacceptable toxicity. Between June, 2011 and January, 2013, 15 patients were enrolled. The response and disease control rates were 26.7 and 73.3%, respectively. The median progression-free survival was 2.1 months and the median overall survival was 34.1 months. Grade 3-4 phlebitis occurred in 3 patients. Therefore, the combination of vinorelbine and bevacizumab was found to be effective in patients with previously treated nonSq-NSCLC, but physicians must be aware of the risk of phlebitis associated with this regimen.

Association of BIM Deletion Polymorphism and BIM-γ RNA Expression in NSCLC with EGFR Mutation.

AIM: This pilot study assessed the association of BIM deletion polymorphism and BIM RNA isoform in patients with EGFR-positive non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The study included 33 patients with EGFR-positive NSCLC treated with gefitinib. BIM deletion polymorphism and BIM RNA isoform (EL/L/S/γ) were determined by polymerase chain reaction (PCR). RESULTS: BIM-γ expression was significantly higher in patients with BIM deletion polymorphism than among those without BIM deletion polymorphism inside tumors (p=0.038) and around tumors (p=0.0024). Relative BIM-γ expression was significantly higher in patients with BIM deletion polymorphism than among those without BIM deletion polymorphism (p=0.0017). Patients with BIM-γ had significantly shorter progression-free survival than those without BIM-γ (median: 304 vs. 732 days; p=0.023). CONCLUSION: Expression of BIM-γ mRNA and BIM deletion polymorphism were strongly associated. BIM-γ overexpression may have a role in apoptosis related to EGFR-tyrosine kinase inhibitor.

Sorafenib treatment for patients with RET fusion-positive non-small cell lung cancer.

BACKGROUND: RET fusions were recently identified in non-small cell lung cancer (NSCLC) and are considered as a potential therapeutic target of NSCLC. Sorafenib, a multi-kinase inhibitor, has potent anti-RET activity. We conducted a study to evaluate the efficacy of sorafenib in a small number of patients with RET fusion-positive NSCLC. MATERIALS AND METHODS: Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an Eastern Cooperative Oncology Group performance status 0-2, had adequate organ function, and provided informed consent. The presence of the RET fusion gene was confirmed by a split FISH assay. The patients were treated twice daily with 400mg of sorafenib taken orally. The treatment was continued until either disease progression or unacceptable toxicity. RESULTS: From March 2012 to April 2013, three patients were enrolled. The responses to sorafenib included one patient with stable disease (SD) and two patients with progressive disease (PD). One patient took sorafenib for twelve months. The most common toxicities were palmar-plantar erythrodysesthesia syndrome, hypertension, and diarrhea. CONCLUSION: Since sorafenib did not show dramatic responses, we suggest testing other RET inhibitors for the treatment of RET fusion-positive NSCLC. This study was registered at UMIN as trial number 000007515.

Thymoma exhibiting spontaneous regression in size, pleural effusion and serum cytokeratin fragment level: A case report.

A 30-year-old man was admitted to Toho University Omori Medical Center for assessment of right chest pain and fever. Chest computed tomography (CT) revealed an anterior mediastinal tumor sized 11.0×6.0×5.0 cm, with right pleural effusion. The laboratory analysis revealed elevated white blood cell count (11,000/µl), C-reactive protein (4.1 mg/dl) and cytokeratin fragment (CYFRA; 12.7 ng/ml; normal, <2 ng/ml). The level of CYFRA in the pleural effusion was also markedly elevated (143 ng/ml). On the first day after admission (6 days after the initial CT), there was a mild regression on CT (10.0×5.5×4.4 cm; reduction rate, 26.7%), with decrease of the pleural effusion volume. A CT-guided needle biopsy was performed, but the findings were not conclusive, as most of the tissue was necrotic. Seven days later (13 days after the initial CT), a CT revealed further regression (9.5×5.4×4.2 cm; reduction rate, 34.7%) with disappearance of the pleural effusion. The patient was followed up on an outpatient basis. At 35 days after the initial CT, the tumor continued to shrink without treatment (8.0×3.6×3.0 cm; reduction rate, 73.8%) and the serum CYFRA level had decreased to 0.8 ng/ml, although it had not returned to normal levels. At 62 days after the initial CT, the patient underwent surgical resection. The resected specimen was diagnosed as thymoma (World Health Organization type B2; Masaoka classification, stage II), with prominent degeneration and necrosis. One possible cause of the spontaneous regression may be increased internal pressure, probably associated with rapid tumor growth, leading to massive necrosis with resulting chest pain, inflammatory reaction with pleural effusion and subsequent tumor regression. The serum CYFRA level may be a useful marker for the evaluation of the clinical course of thymoma with extensive necrosis.

Usefulness of nanofluidic digital PCR arrays to quantify T790M mutation in EGFR-mutant lung adenocarcinoma.

AIM: The present pilot study assessed the usefulness of nanofluidic digital polymerase chain reaction (PCR) arrays in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma after tyrosine kinase inhibitor (TKI) resistance. PATIENTS AND METHODS: We enrolled 12 patients with primary lung adenocarcinoma with sensitive EGFR mutation-confirmed T790M status by re-biopsy after TKI resistance. Nanofluidic digital PCR arrays were used to quantify T790M in genomic DNA from the pre-treatment primary site and in serum cell-free DNA (cfDNA). RESULTS: On digital PCR, quantified T790M at the pre-treatment primary site was higher in re-biopsy-positive T790M patients (n=4) than in re-biopsy-negative patients (n=8) (0.78%±0.36% vs. 0.07%±0.09%, p<0.01). T790M at the pre-treatment primary site correlated with progression-free survival (PFS) after gefitinib therapy (r=0.67, p=0.016). CONCLUSION: Use of digital PCR to quantify T790M at the primary site of EGFR-mutant lung adenocarcinoma predicted T790M emergence in re-biopsies after TKI resistance and PFS after gefitinib therapy.

Cytological findings of appendiceal mixed adenoneuroendocrine carcinoma in pleural effusion: Morphological changes evident after metastasis.

Goblet cell carcinoid (GCC) of the appendix is now regarded as a malignant tumor, and mixed adenoneuroendocrine carcinoma (MANEC) is a carcinoma progressing from GCC. We describe a man initially diagnosed with GCC of the appendix who died 4 years after diagnosis. Pleural fluid due to metastasis was noted in the terminal phase. Histological findings of the initial tumor indicated that cells with signet-ring morphology were predominant, but the cytological morphology of the fluid was more atypical, making it difficult to diagnose as metastatic GCC by cellular morphology alone. The cells in the pleural fluid were immunopositive for synaptophysin, which was compatible with GCC, but p53 and ki67 staining indicated that the metastatic tumor was more aggressive. These findings suggested a final diagnosis of poorly differentiated adenocarcinoma-type MANEC, which we define as a tumor with typical GCC characteristics and foci that cannot be distinguished from a poorly differentiated adenocarcinoma. This case, which we believe is reported here for the first time, indicates the cytological features of GCC cells may change at metastatic sites to be more atypical and aggressive as the tumor progresses, and these changes should be considered in diagnosis.

Clinical significance of BIM deletion polymorphism in non-small-cell lung cancer with epidermal growth factor receptor mutation.

BACKGROUND: Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in tumor response to treatment. To determine the clinical utility of detecting BIM deletion polymorphism in non-small-cell lung cancer positive for epidermal growth factor receptor (EGFR) mutation, we examined outcomes of patients with and without BIM alterations. METHODS: We studied 70 patients with EGFR mutation-positive non-small-cell lung cancer who were treated with an EGFR tyrosine kinase inhibitor between January 2008 and January 2013. BIM deletion was analyzed by polymerase chain reaction in 58 samples of peripheral blood and 24 formalin-fixed paraffin-embedded slides of surgical specimens (20 of lung tissue and four of brain tissue); both blood and tissue specimens were available for 12 patients. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM deletion. RESULTS: BIM deletion was present in 13 of 70 patients (18.6%). There were no significant differences between patients with and without BIM deletion in clinical characteristics, rate of response to EGFR tyrosine kinase inhibitor, or incidence of adverse events. Patients with BIM deletion had significantly shorter progression-free survival (PFS) than those without BIM deletion (median, 227 versus 533 days; p < 0.001). Multivariate Cox regression analysis showed that BIM deletion was an independent indicator of shorter PFS (hazard ratio, 3.99; 95% confidence interval, 1.864-8.547; p < 0.001). CONCLUSIONS: Polymerase chain reaction successfully detected BIM deletion in samples of peripheral blood and formalin-fixed paraffin-embedded slides of surgical specimens. BIM deletion was the most important independent prognostic factor in shorter PFS.

Detection of epidermal growth factor receptor T790M mutation in plasma DNA from patients refractory to epidermal growth factor receptor tyrosine kinase inhibitor.

A secondary epidermal growth factor receptor (EGFR) mutation, the substitution of threonine 790 with methionine (T790M), leads to acquired resistance to reversible EGFR-tyrosine kinase inhibitors (EGFR-TKIs). A non-invasive method for detecting T790M mutation would be desirable to direct patient treatment strategy. Plasma DNA samples were obtained after discontinuation of gefitinib or erlotinib in 75 patients with non-small cell lung cancer (NSCLC). T790M mutation was amplified using the SABER (single allele base extension reaction) technique and analyzed using the Sequenom MassARRAY platform. We examined the T790M mutation status in plasma samples obtained after treatment with an EGFR-TKI. The SABER assay sensitivity using mixed oligonucleotides was determined to be 0.3%. The T790M mutation was detected in 21 of the 75 plasma samples (28%). The presence of the T790M mutation was confirmed by subcloning into sequencing vectors and sequencing in 14 of the 21 samples (66.6%). In this cohort of 75 patients, the median progression-free survival (PFS) of the patients with the T790M mutation (n = 21) was not statistically different from that of the patients without the mutation (n = 54, P = 0.94). When patients under 65 years of age who had a partial response were grouped according to their plasma T790M mutation status, the PFS of the T790M-positive patients (n = 11) was significantly shorter than that of the T790M-negative patients (n = 29, P = 0.03). The SABER method is a feasible means of determining the plasma T790M mutation status and could potentially be used to monitor EGFR-TKI therapy.

[An autopsied case of giant cell myocarditis and myositis associated with invasive thymoma].

A 75-year-old man was given a diagnosis of invasive thymoma (WHO type B3, stage IVa) in 2004. He received 8 cycles of chemotherapy with doxorubicin, vincristin, cyclophosphamide and cisplatin from November 2004 to May 2005, combined thoracic radiotherapy (total dosage 60 Gy) in April 2006, and 2 cycles of chemotherapy with carboplatin and paclitaxel from July 2008 to August 2008. He was readmitted to our hospital complaining of fever and neck pain in September 2008. Laboratory data on admission revealed elevated serum levels of CRP, GOT, GPT, LDH, CK, and troponin-I with hypo gamma-globulinemia. Although he received immunoglobulin and antibiotic therapy, he suddenly died of cardiac shock on the 9th hospital day. On postmortem examination of the myocardium, the skeletal muscles of the neck and iliopsoas muscle showed inflammatory cell infiltration containing multinucleated giant cells with degeneration and necrosis of the muscle tissues. These findings were consistent with giant cell myocarditis with polymyositis. Autopsy findings suggested that sudden death was caused by giant cell myocarditis, probably associated with invasive thymoma.

Malignant pleural mesothelioma presenting as an acute surgical abdomen due to metastatic jejunal perforation.

A 52-year-old man was admitted to our hospital in June 2008 presenting abnormal tumor lesions along the left pleura on chest X-ray. The needle-biopsied specimen of the left pleura proved the biphasic type of malignant mesothelioma. However, he complained of acute abdominal pain 7 days after the diagnosis. Chest X-ray revealed free air below the right diaphragm. Emergency surgery revealed a 4-cm perforating jejunal tumor with peritonitis. Histopathology of the resected jejunum demonstrated a metastatic tumor of malignant pleural mesothelioma. This is the first reported case of malignant pleural mesothelioma presenting as an acute surgical abdomen due to jejunal metastasis with perforation.

[An autopsied case of mucinous bronchioloalveolar carcinoma associated with multiple thin-walled cavities].

A 82-year-old man was found to have mucinous bronchioloalveolar carcinoma associated with a cavity 10-cm in size in the right lower lobe, and he underwent a surgical lobectomy in April 2005 (pT2N0M0). Seven months after the surgery, chest images showed multiple metastases with thick-walled cavities in bilateral lung fields. The serial HRCT showed that thick-walled cavity lesions transformed into thin-walled cystic cavities associated with decreasing serum CEA levels. The patient's condition was good with best supportive care for 24 months from the time of recurrence. Subsequent progression of the thick-walled cavities into thin-walled cavities, was acompanied by re-elevation of serum CEA levels, and he died of respiratory failure 5 months after re-exacerbation. Macroscopic findings at autopsy showed multiple cavities in both lungs. Microscopic findings of the right lung showed desquamative mucinous bronchioloalveolar carcinoma cells lining the thick-walled cavity surface, and a single layer of tumor cells proliferating in the thin-walled cavity surface. Tumor cells with excessive mucus and necrosis were observed in the thick-walled cavities. It is suggested that thick-walled cavities were formed as a result of avascular necrosis and destruction of the pulmonary alveoli by excessive mucus, and thin-walled cavities were formed as a result of a check-valve mechanism.

[Case of pemetrexed-induced acute lung injury].

A 65-year-old man was admitted with dyspnea. Chest radiograph showed left pleural effusion and chest CT scan revealed multiple left pleural masses. The diagnosis of malignant pleural mesothelioma was made by CT-guided needle biopsy. He received the combination chemotherapy with pemetrexed and carboplatin. The day after initiating chemotherapy, he had fever and dyspnea. Chest CT scan showed diffuse ground glass opacities mainly in the right lung, suggestive of drug-induced interstitial pneumonia. Corticosteroid pulse therapy was started, but he died of respiratory failure 10 days after beginning chemotherapy. This is apparently the first reported case of pemetrexed-induced acute lung injury.

[Azithromycin-induced diffuse alveolar hemorrhage].

Azithromycin (AZM) is widely used for the treatment of respiratory infection. Macrolides are generally well tolerated and adverse reactions are extremely rare. A 78-year-old man was treated with AZM for upper respiratory infection in November 2007. He developed bloody sputum at 5 days after AZM administration. Chest X-ray and CT images revealed diffuse ground glass opacities in the bilateral lung fields. Bronchoalveolar lavage demonstrated bloody fluid. The clinical symptoms and CT image improved after the corticosteroid therapy. His past history revealed that he also developed similar clinical symptoms and radiological features after treatment with AZM for upper respiratory infection at another hospital in October 2006. At that time, his condition improved after the administration of corticosteroid under a diagnosis of interstitial lung disease of unknown etiology. Finally, we diagnosed recurrent alveolar hemorrhage caused by re-administration of AZM. This is apparently the first reported case of AZM-induced diffuse alveolar hemorrhage.

Successful treatment with pneumonectomy for pulmonary Mycobacterium abscessus infection.

We report a case of pulmonary Mycobacterium abscessus (M. abscessus) infection with destructive growth in the entire right lung. The patient was 56-year-old woman who had had pulmonary tuberculosis at the age of 40 and had been diagnosed as having pulmonary Mycobacterium abscessus infection 4 years prior to admission at our hospital. Although various antibiotics were administered, persistent fever, hemoptysis and weight loss developed. After undergoing a right pneumonectomy, her clinical symptoms improved dramatically and sputum excretions of M. abscessus ceased. No relapse of the disease has been observed in the 2 years since surgery. Pneumonectomy was very effective for refractory M. abscessus infection that destroyed the right lung.

[Efficacy of fluoro-2-deoxyglucose positron emission tomography imaging in response evaluation of patients with small cell lung cancer (pilot study)].

The purpose of this study was to assess the feasibility of PET/CT in response evaluation of patients with small cell lung cancer (SCLC). Among the 25 patients with primary small cell lung cancer who had been treated from August 2004 through to May 2008, we compared the response evaluation between conventional CT and fluoro-2-deoxyglucose positron emission tomography (FDG-PET), [CMR (Complete Metabolic Response), PMR (Partial Metabolic Response), SMD (Stable Metabolic Disease), PMD (Progressive Metabolic Disease)] before and after the treatment. Response assessment was discordant in 2 out of 25 cases (8%) after the first cycle of chemotherapy and in 3 out of 19 cases (16%) after the fourth cycle of chemotherapy. Two discordant cases after the first cycle of chemotherapy were PR and SD respectively by CT but both were found to be PMD by PET. Two out of three discordant cases after the fourth cycle of chemotherapy were PR by CT but both found to be CMR by PET. These results suggest that FDG-PET is useful for response assessment of early diagnosis of recurrence and prognostic outlook in small cell lung cancer, however further cases need to be collected.