Inverted Placement of Endoscopic One-Way Endobronchial Valve Combined with Gelfoam in the Closure of Bronchopleural Fistula with Empyema in a Mechanically Ventilated Patient: A Case Report.

Bronchopleural fistula (BPF) with empyema caused by severe necrotizing pulmonary infection is a complicated clinical problem that is often associated with poor general condition so surgical interventions cannot be tolerated in most cases. Here, we present the successful management of multiple BPF with empyema in a mechanically ventilated patient with aspiration lung abscess. Occlusion utilizing Gelfoam followed by endobronchial valves (EBVs) implanted inverted via bronchoscope decreased the air leaking significantly and made intrapleural irrigation for empyema achievable and safe. This is the first report of a novel way of EBV placement and the combination use with other occlusive substances in BPF with empyema in a patient on mechanical ventilation. This method may be an option for refractory BPF cases with pleural infection.

International expert consensus on diagnosis and treatment of lung cancer complicated by chronic obstructive pulmonary disease.

Background: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. Methods: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. Results: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. Conclusions: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.

Tumor mutational burden and efficacy of chemotherapy in lung cancer

Purpose TMB is one of the potent biomarkers of response to immune checkpoint blockade. The association between TMB and efficacy of chemotherapy in advanced lung cancer has not been comprehensively explored. Methods Ninety lung cancer patients receiving first-line chemotherapy with large panel next-generation sequencing data of pre-treatment tumor tissue were identified. The effect of TMB on PFS of chemotherapy were evaluated in univariate and multivariate analyses. Results The median TMB level of lung cancer patients enrolled in this study was 9.4 mutations/Mb, with TMB levels in smokers significantly higher than those in non-smokers. All patients were divided into high TMB and low TMB groups with the cutoff of the median TMB. The patients with low TMB had longer PFS of first-line chemotherapy (median PFS 9.77 vs 6.33 months, HR = 0.523, 95% CI 0.32–0.852, log-rank P = 0.009). Subgroup analysis showed that PFS of chemotherapy favored low TMB than high TMB among subgroups of male, age < 60, NSCLC, adenocarcinoma, stage IV, ECOG PS 0, driver mutation positive, TP53 wild type and patients not receiving bevacizumab. In multivariate analysis, PFS of chemotherapy remained significantly longer in low TMB group (HR = 0.554, p = 0.036). In those patients received immunotherapy upon unsatisfactory chemotherapy, PFS of immunotherapy was much longer in high TMB group (median PFS 32.88 vs 6.62 months, HR = 0.2426, 95% CI 0.06–0.977, log-rank P = 0.04). Conclusions TMB level of tumor tissue is a potent biomarker for efficacy of chemotherapy and immunotherapy in lung cancer. It may provide some clues for the decision of treatment strategy (AU)

Tumor mutational burden and efficacy of chemotherapy in lung cancer.

PURPOSE: TMB is one of the potent biomarkers of response to immune checkpoint blockade. The association between TMB and efficacy of chemotherapy in advanced lung cancer has not been comprehensively explored. METHODS: Ninety lung cancer patients receiving first-line chemotherapy with large panel next-generation sequencing data of pre-treatment tumor tissue were identified. The effect of TMB on PFS of chemotherapy were evaluated in univariate and multivariate analyses. RESULTS: The median TMB level of lung cancer patients enrolled in this study was 9.4 mutations/Mb, with TMB levels in smokers significantly higher than those in non-smokers. All patients were divided into high TMB and low TMB groups with the cutoff of the median TMB. The patients with low TMB had longer PFS of first-line chemotherapy (median PFS 9.77 vs 6.33 months, HR = 0.523, 95% CI 0.32-0.852, log-rank P = 0.009). Subgroup analysis showed that PFS of chemotherapy favored low TMB than high TMB among subgroups of male, age < 60, NSCLC, adenocarcinoma, stage IV, ECOG PS 0, driver mutation positive, TP53 wild type and patients not receiving bevacizumab. In multivariate analysis, PFS of chemotherapy remained significantly longer in low TMB group (HR = 0.554, p = 0.036). In those patients received immunotherapy upon unsatisfactory chemotherapy, PFS of immunotherapy was much longer in high TMB group (median PFS 32.88 vs 6.62 months, HR = 0.2426, 95% CI 0.06-0.977, log-rank P = 0.04). CONCLUSIONS: TMB level of tumor tissue is a potent biomarker for efficacy of chemotherapy and immunotherapy in lung cancer. It may provide some clues for the decision of treatment strategy.

Safety and Efficacy of Epitinib for EGFR-Mutant Non-Small Cell Lung Cancer With Brain Metastases: Open-Label Multicentre Dose-Expansion Phase Ib Study.

BACKGROUND: Non-small-cell lung cancer (NSCLC) had poor prognosis in patients with brain metastasis. The trial evaluated the safety and efficacy of epitinib (HMPL-813), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), for EGFR-mutant NSCLC with brain metastasis. PATIENTS AND METHODS: This open-label, dose-expansion phase Ib study (ClinicalTrials.gov: NCT02590952) was conducted at 7 Chinese centers and enrolled patients with EGFR-mutant advanced NSCLC with brain metastasis. Epitinib was administered at 120 mg or 160 mg, orally QD. The primary endpoint was safety and tolerability. RESULTS: Between April 2015 and April 2019, 72 patients were enrolled and received epitinib at 120 mg (n = 30) or 160 mg (n = 42). Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 13 (43.3%) patients in 120 mg group and 21 (50.0%) in 160 mg group. The objective response rate (ORR) was 53.6% (95% CI 33.9%-72.5%) in 120 mg group and 40.5% (25.6%-56.7%) in 160 mg group. The median duration of response in the 120 mg and 160 mg groups were 7.40 months (95% CI 3.70-7.40) and 9.10 months (6.50-12.00), respectively. The median progression-free survival were 7.40 months (95% CI 5.40-9.20) and 7.40 months (5.50-10.00), respectively. CONCLUSION: In patients with EGFR-mutant NSCLC with brain metastasis, epitinib was well tolerable with a promising efficacy. According to the comprehensive assessment on safety and efficacy, 160 mg QD could be the recommended phase 2 dose.

Expert consensus on multi-disciplinary treatment, whole-course pulmonary rehabilitation management in patients with lung cancer and chronic obstructive lung disease.

Comorbidity of lung cancer and chronic obstructive pulmonary disease (COPD) is very common. Surgical operation is the initial treatment of lung cancer. But surgery operation will aggravate the symptoms of COPD, such as shortness of breath, chest tightness. On the other side, the COPD also increase the perioperative complications. Besides, the COPD may also influence the anti-cancer treatment and long-term survival of lung cancer patients. At present, there are guidelines for pulmonary rehabilitation (PR) of COPD or lung cancer respectively, but there is no reference expert consensus on the PR of patients with lung cancer who are comorbidity of COPD. Primary care has to satisfy the patient's complex needs holistically, and single-disease guidelines are unsuitable. In view of this, we organized experts from respiratory department, thoracic surgery department, oncology department, nursing department, etc., to write the expert consensus. We discussed the contents of the expert consensus through literature review, expert correspondence, expert meeting and discussion. This expert consensus contain five parts: introduction, respiratory assessment, timing of PR, PR strategies, perioperative PR management strategies in lung cancer patients with COPD. This expert consensus focuses on patients with COPD comorbid lung cancer and undergoing surgery operation, highlighting the concept of whole process management. For clinical medical staff, this expert consensus will promote the practice of PR in and out the hospital for this specific patient; for patients, this expert consensus is helpful to better understand PR and improve the enthusiasm of participating in PR in the whole process.

Rapid discrimination between tuberculosis and sarcoidosis using next-generation sequencing.

OBJECTIVES: Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (MTB), has similar clinical, radiological, and histopathological characteristics to sarcoidosis (SA). Accurately distinguishing SA from TB remains a clinical challenge. METHODS: A total of 44 TB patients and 47 SA patients who were clinically diagnosed using chest radiography, pathological examination, routine smear microscopy, and microbial culture were enrolled in this study. The MTB genome was captured and sequenced directly from tissue specimens obtained upon operation or biopsy, and the feasibility of next-generation sequencing (NGS) for the MTB genome in the differential diagnosis of TB from SA was evaluated. RESULTS: Using a depth >10× and coverage >15% of the sequencing data, TB patients were identified via the NGS approach directly using operation or biopsy specimens without clinical pretreatment. The sensitivity, specificity, and concordance of the NGS method were 81.8% (36/44), 95.7% (45/47), and 89.0% (81/91), respectively (kappa = 0.78, 95% confidence interval 0.65-0.91; P<0.001). CONCLUSIONS: This study established an improved NGS strategy for rapidly distinguishing patients with TB from those with SA and has potential clinical benefits.

Prolonged progression-free survival and overall survival are associated with diabetes mellitus but inversely associated with levels of blood glucose in patients with lung cancer.

BACKGROUND: Previous studies have provided conflicting evidence about the increased overall survival (OS) in lung cancer patients with diabetes mellitus (DM) compared with those without DM. This study assessed progression-free survival (PFS)/OS in lung cancer patients with or without DM and tentatively analyzed the impact of blood glucose levels on PFS/OS in lung cancer patients. METHODS: Data were collected from lung cancer patients based upon admission records from January 2010 to January 2012 and follow-up records from January 2010 to January 2015 in the Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai. The data included patient sex, age, body mass index (BMI), smoking status, history of DM, level of blood glucose, pathological type, clinical stage of cancer, chemotherapy regimen, and history of anti-DM drugs. The Cox regression model and Kaplan-Meier method were used for the analysis of hazard factors and PFS/OS. For comparison of PFS/OS in lung cancer with or without DM, patients were divided into three groups: lung cancer with DM, lung cancer without DM but with elevated level of blood glucose, lung cancer without DM or elevated level of blood glucose. RESULTS: In total, the data from 200 lung cancer patients (138 males/62 females, aged 29.0 to 78.0 years, mean 60.0 ±â€Š8.6 years) were collected. For the comparison of PFS/OS in lung cancer patients with or without DM, patients were divided into three groups: lung cancer with DM (n = 31); lung cancer without DM but with elevated levels of blood glucose (n = 40); and lung cancer without both DM and elevated levels of blood glucose (n = 128), whereas 1 patient dropped out of the study. All the patients underwent complete chemotherapy and were followed up for 36.0 to 60.0 months. Kaplan-Meier survival analysis showed that lung cancer patients with DM had increased PFS and OS compared with those without DM (log-rank, P < 0.05, P < 0.01); the median PFS in lung cancer with DM was 12.0 months (95% confidence interval [CI], 4.0-16.0) vs. 6.0 months in those without DM (95% CI, 5.8-6.3); and the median OS in lung cancer patients with DM was 37.0 months (95% CI, 29.0-46.6) vs. 12.0 months in those without DM (95% CI, 10.9-13.1). For the other two groups of patients without DM, there was a trend toward a shorter PFS and OS in patients with elevated blood glucose compared with those without elevated blood glucose. Cox regression showed that PFS in lung cancer patients was favorably associated with the usage of anti-DM drugs, BMI, clinical stage of cancer, and chemotherapy regimen (all P < 0.05) but was inversely associated with the level of blood glucose (P < 0.05). CONCLUSIONS: Lung cancer patients with DM have prolonged PFS and OS compared with those without DM, and the level of blood glucose was inversely associated with PFS. The current results indicate that PFS may be a meaningful intermediate endpoint for OS and that the levels of blood glucose hopefully represent a prognostic factor in lung cancer patients.

Tumor-derived DNA from pleural effusion supernatant as a promising alternative to tumor tissue in genomic profiling of advanced lung cancer.

Pleural effusion (PE) is commonly observed in advanced lung cancer and was suggested to contain both cell-free tumor DNA and tumor cells. Molecular profiling of PE represents a minimally invasive approach of detecting tumor driver mutations for clinical decision making, especially when tumor tissues are not available. The objective of this study is to investigate the efficacy and precision of detecting gene alterations in PE samples to address the feasibility in clinical use. Methods: Sixty-three metastatic lung cancer patients with (n=30, cohort 1) or without (n=33, cohort 2) matched tumor tissues were enrolled in this study. PE and plasma samples of each patient were collected simultaneously. Supernatant and cell precipitate of PE were processed separately to extract cfDNA (PE-cfDNA) and sediment DNA (sDNA). All samples were subjected to targeted next-generation sequencing (NGS) of 416 cancer-related genes. Results: PE supernatants contain more abundant tumor DNA than PE sediments and plasma samples, suggested by higher mutant allele frequencies (MAF) and elevated mutation detection rate in PE-cfDNA (98.4% vs. 90.5% in PE sDNA vs. 87% in plasma cfDNA). In Cohort 1 with matched tumor tissue, tumor mutational burden (TMB) of PE-cfDNA was similar as tumor tissues (6.4 vs. 5.6), but significantly higher than PE sDNA (median TMB: 3.3) and plasma cfDNA (median TMB: 3.4). Ninety-three percent (27 out of 29) of tissue-determined driver mutations were detected in PE-cfDNA, including alterations in ALK, BRAF, EGFR, ERBB2, KRAS, NF1, PIK3CA, and RET, while only 62% were captured in plasma cfDNA. PE-cfDNA also has the highest detection rate of EGFR driver mutations in the full cohort (71% vs. 68% in PE sDNA vs. 59% in plasma cfDNA). Mutation detection from cytological negative and hemorrhagic PE is challenging. Comparatively, PE-cfDNA demonstrated absolute superiority than PE sDNA in such a scenario, suggesting that it is an independent source of tumor DNA and therefore less influenced by the abundance of tumor cells. Conclusion: Genomic profiling of PE-cfDNA offers an alternative, and potentially more meticulous approach in assessing tumor genomics in advanced lung cancer when tumor tissue is not available. Our data further demonstrate that in hemorrhagic or cytologically negative PE samples, PE-cfDNA has higher mutation detection sensitivity than sDNA and plasma cfDNA, and therefore is a more reliable source for genetic testing.

Calpain 2 knockdown promotes cell apoptosis and restores gefitinib sensitivity through epidermal growth factor receptor/protein kinase B/survivin signaling.

Gefitinib, an epidermal growth factor receptor (EGFR)­specific drug, is effective for ~1 year, after which resistance is inevitable. Calpain 2 (CAPN2) is known to serve a role in the drug response and resistance in certain cancer therapies. However, the full function of CAPN2, particularly in non­small cell lung cancer, has not yet been elucidated. In the present study, CAPN2 expression in gefitinib­resistant lung adenocarcinoma cells was investigated. CAPN2 function in these cells was further evaluated using gene knockdown both in vitro and in vivo. The results demonstrated that CAPN2 was strongly associated with gefitinib­resistance, and CAPN2 mRNA and protein expression levels were significantly increased in gefitinib­resistant cell lines. Furthermore, CAPN2 knockdown inhibited gefitinib­resistant cell proliferation in vitro and in vivo. CAPN2 conferred gefitinib­resistance by inhibiting cell apoptosis and arresting the cell cycle. CAPN2 knockdown also induced caspase activation and mitochondrial dysfunction, and its function in gefitinib resistance appeared to be largely mediated by EGFR/protein kinase B/survivin signaling pathway activation. These results suggest that CAPN2 is responsible for EGFR­tyrosine kinase inhibitor resistance, and CAPN2 inhibition may be used to provide therapeutic benefits in the treatment of gefitinib resistance.

Probability of cancer in high-risk patients predicted by the protein-based lung cancer biomarker panel in China: LCBP study.

BACKGROUND: The authors built a model for lung cancer diagnosis previously based on the blood biomarkers progastrin-releasing peptide (ProGRP), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and cytokeratin 19 fragment (CYFRA21-1). In the current study, they examined whether modification of the model to include relevant clinical information, risk factors, and low-dose chest computed tomography screening would improve the performance of the biomarker panel in large cohorts of Chinese adults. METHODS: The current study was a large-scale multicenter study (ClinicalTrials.gov identifier NCT01928836) performed in a Chinese population. A total of 715 participants were enrolled from 5 regional centers in Beijing, Henan, Nanjing, Shanghai, and Chongqing between October 2012 and February 2014. Serum biomarkers ProGRP, CEA, SCC, and CYFRA21-1 were analyzed on the ARCHITECT i2000SR. Relevant clinical information was collected and used to develop a patient risk model and a nodule risk model. RESULTS: The resulting patient risk model had an area under the receiver operating characteristic (ROC) curve of 0.7037 in the training data set and 0.7190 in the validation data set. The resulting nodule risk model had an area under the ROC curve of 0.9151 in the training data set and 0.5836 in the validation data set. Moreover, the nodule risk model had a relatively higher area under the ROC curve (0.9151 vs 0.8360; P = 0.001) compared with the American College of Chest Physician model in patients with lung nodules. CONCLUSIONS: Both the patient risk model and the nodule risk model, developed for the early diagnosis of lung cancer, demonstrated excellent discrimination, allowing for the stratification of patients with different levels of lung cancer risk. These new models are applicable in high-risk Chinese populations. Cancer 2018;124:262-70. © 2017 American Cancer Society.

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-ß), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-ß binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

A panel of promoter methylation markers for invasive and noninvasive early detection of NSCLC using a quantum dots-based FRET approach.

Non-small-cell lung cancer (NSCLC) leads to a significant proportion of cancer-related deaths, and early detection of NSCLC can significantly increase cancer survival rates. A promising approach has been studied to exploit DNA methylation, which is closely correlated to early cancer diagnosis. Herein, in order to realize the early detection of NSCLC, we utilized the developed quantum dots-based (QDs-based) fluorescence resonance energy transfer (FRET) nanosensor technique to analyze the promoter methylation in early stage NSCLC tissue samples and noninvasive bronchial brushing specimens. Using this method, the methylation levels can be quantitatively determined by measuring the signal amplification during FRET. A panel of three tumor suppressor genes (PCDHGB6, HOXA9 and RASSF1A) was assessed in 50 paired early stage NSCLC and their adjacent nontumorous tissue (NT) samples, and 50 early stage NSCLC bronchial brushing and normal specimens. The combined detection was able to identify not only tissue samples but noninvasive bronchial brushing specimens from control cases with a high degree of sensitivity of 92% (AUC=0.977, P<0.001) and 80% (AUC=0.907, P<0.001) respectively, indicating the versatility of promoter expression in invasive and noninvasive NSCLC samples. Therefore this approach can be used to sensitively analyze the methylation levels of cancer-related genes, which might be a potential tool for noninvasive early clinical diagnosis of cancers.

Prevention and management of lung cancer in China.

Lung cancer is the leading cause of cancer-related death worldwide. In China, the incidence of lung cancer has grown rapidly, resulting in a large social and economic burden. Several researchers have devoted their studies to lung cancer and have demonstrated that there are many risk factors for lung cancer in China, including tobacco use, environmental pollution, food, genetics, and chronic obstructive pulmonary disease. However, the lung cancer incidence is still growing rapidly in China, and there is an even higher incidence among the younger generation. One explanation may be the triple-neglect situation, in which medical policies that neglect prevention, diagnosis, and supportive care have increased patients' mortality and reduced their quality of life. Therefore, it is necessary to enhance the efficiency of prevention and early diagnosis not only by focusing more attention on treatment but also by drawing more attention to supportive care for patients with lung cancer.

Role of a serum-based biomarker panel in the early diagnosis of lung cancer for a cohort of high-risk patients.

BACKGROUND: This study applied a combined cancer biomarker panel to clinically identify small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) in a high-risk population. METHODS: The serum levels of 4 biomarkers (progastrin-releasing peptide [ProGRP], carcinoembryonic antigen [CEA], squamous cell carcinoma antigen [SCC], and cytokeratin 19 fragment [CYFRA21-1]) were determined in 153 patients with a high risk of lung cancer (12 with a new diagnosis of SCLC, 52 with NSCLC, and 89 without lung cancer). Information about diagnosis delays was collected through interviews of all participants. RESULTS: Significantly higher serum levels of ProGRP (P < .0001) were found among the SCLC patients versus the rest of the population. A receiver operating characteristic curve analysis established the cutoff values of ProGRP, CEA, SCC, and CYFRA21-1 as 300 pg/mL, 7.3 ng/mL, 3 ng/mL, and 6.5 ng/mL, respectively. The sensitivity and specificity of ProGRP in diagnosing SCLC were 75% and 100%, respectively. Among the 14 lung cancer patients with a false-negative computed tomography (CT) result, the diagnostic panel detected 8 additional cancers. CONCLUSIONS: This panel increased the diagnostic specificity for high-risk subjects (those with renal failure being excluded), and auxiliary to a CT scan, it increased the sensitivity for patients with lung cancer. These results might be applied to shorten the diagnosis delay at health care institutions in China.

Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain.

Tumor suppressor WWOX is involved in the progression of cancer and neurodegeneration. Here, we examined whether protein aggregation occurs in the brain of nondemented, middle-aged humans and whether this is associated with WWOX downregulation. We isolated an N-terminal internal deletion isoform, TPC6AΔ, derived from alternative splicing of the TRAPPC6A (TPC6A) gene transcript. TPC6AΔ proteins are present as aggregates or plaques in the extracellular matrix of the brain such as in the cortex. Filter retardation assays revealed that aggregate formation of TPC6AΔ occurs preceding Aß generation in the hippocampi of middle-aged postmortem normal humans. In a Wwox gene knockout mouse model, we showed the plaques of pT181-Tau and TPC6AΔ in the cortex and hippocampus in 3-week-old mice, suggesting a role of WWOX in limiting TPC6AΔ aggregation. To support this hypothesis, in vitro analysis revealed that TGF-ß1 induces dissociation of the ectopic complex of TPC6AΔ and WWOX in cells, and then TPC6AΔ undergoes Ser35 phosphorylation-dependent polymerization and induces caspase 3 activation and Aß production. Similarly, knockdown of WWOX by siRNA resulted in dramatic aggregation of TPC6AΔ. Together, when WWOX is downregulated, TPC6AΔ is phosphorylated at Ser35 and becomes aggregated for causing caspase activation that leads to Tau aggregation and Aß formation.

Early Detection of Lung Cancer in Serum by a Panel of MicroRNA Biomarkers.

INTRODUCTION: The objective of the study was to develop a panel of microRNAs (miRNAs) as highly sensitive and specific biomarkers for lung cancer early detection. MATERIALS AND METHODS: The study contained 2 phases: first, preliminary marker selection based on previous reports on the serum of 24 early stage lung cancer patients and 24 healthy control subjects by TaqMan probe-based real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR); and second, validation of miRNA markers on 94 early stage lung cancer, 48 stage III to IV lung cancer, and 111 healthy control serum samples. RESULTS: A total of 3 miRNAs (miR-125a-5p, miR-25, and miR-126) were selected for further analysis in this study. The combination of the 3 miRNAs could produce 0.936 area under the receiver operating characteristic curve value in distinguishing early stage lung cancer patients from control subjects with 87.5% sensitivity and 87.5% specificity, respectively. The diagnostic value of the miRNA panel in an independent set of lung cancer patients confirmed the sensitivity and specificity. CONCLUSION: The results demonstrated that the panel of miRNA biomarkers had the potential for the early detection of lung cancer.

Duodenal cryptococcus infection in an AIDS patient: retrospective clinical analysis.

Cryptococcal infection primarily affects the lung or the central nervous system and rare cases have been reported involving the gastrointestinal tract. However, among patients with HIV/AIDS, the gastrointestinal involvement is increasing. According to the PubMed search results, there were seven cases reported involving duodenal cryptococcosis combined with AIDS in five reports. Here, we report the case of a patient found to have AIDS combined with duodenal, pulmonary, and subsequent neurological cryptococcal infection simultaneously. The duodenal cryptococcosis was diagnosed on the basis of PET/computed tomography, which showed intense captation of glucose metabolism in duodenum (maximum standardized uptake value 16.53); a positive serum cryptococcal latex agglutination test; and upper gastrointestinal endoscopy-guided duodenal biopsy that confirmed Cryptococcus neoformans yeast. The patient's HIV screen test was positive. Because of refusal of lumbar puncture and the difficulty of performing transbronchial lung biopsy, the pulmonary and neurological involvements were the only clinical diagnoses. This case indicates that when cryptococcosis exists in a rare location, AIDS should be considered and when cryptococcosis occurs in the HIV-infected patient, disseminated disease is more common.

[Therapeutic efficacy and safety of chemotherapy subsequent EGFR-TKI in advanced non-small cell lung cancer patients with EGFR-TKI acquired resistance].

OBJECTIVE: To explore the therapeutic efficacy and safety of chemotherapy subsequent epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in advanced non-small cell lung cancer (NSCLC) patients with EGFR-TKI acquired resistance. METHODS: The clinical features of 36 advanced NSCLC patients with EGFR-TKI acquired resistance from Affiliated Zhongshan Hospital, Fudan University between May 2006 and April 2014 were retrospectively reviewed. Twenty-seven of them received chemotherapy subsequent EGFR-TKI and another 9 chemotherapy alone. The short-term response, progression-free survival and side effects of two groups were compared. RESULTS: The objective response rates of chemotherapy subsequent EGFR-TKI and chemotherapy alone groups were 7.4% and 0 (P = 0.557), disease control rates 81.5% and 44.4% (P = 0.046) and median progression-free survival 3.3 and 2.5 months, respectively (P = 0.587). No significant differences existed in the rates of side effects between two groups (P > 0.05). CONCLUSIONS: The disease control rates of chemotherapy subsequent EGFR-TKI group are higher than chemotherapy alone group, but there is no survival benefit. And the side effects of subsequent therapy are tolerable.

The use of mutation-specific antibodies in predicting the effect of EGFR-TKIs in patients with non-small-cell lung cancer.

PURPOSE: We aimed to quantify the epidermal growth factor receptor (EGFR) mutation in tumors and to analyze its prediction of EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients. METHODS: We examined EGFR mutation status in 124 lung cancer samples by direct sequencing and amplification refractory mutation system. Among them, 41 were appropriate to quantify the expression of mutant EGFR proteins using immunohistochemistry (IHC) with mutation-specific antibodies. The quantification was determined by both the staining intensity and the proportion of stained tumor cells. RESULTS: The median progression-free survival (PFS) in patients with a high score for mutant EGFR expression was 18.0 months (95 % CI 16.0-20.0), which was significantly longer than that in patients with a low score (8.0 months; 95 % CI 2.6-13.4; P = 0.048). Such significant association with patients' PFS was also apparent in the proportion of stained tumor cells (median, 19.0 vs. 8.0 months; P = 0.019), but not in the staining intensity (P = 0.787). Among the 41 specimens, 32 were detected EGFR mutation positive by both direct sequencing and ARMS, referring to a relatively high abundance of mutation, and 26 (81.3 %) of them gained a high expression score of mutant proteins as well. Six samples with mutation negative by direct sequencing but positive by ARMS, which showed a low abundance, and 5 (83.3 %) of them also revealed a low expression score. The EGFR mutation quantitative analysis using mutation-specific IHC was moderately consistent with that by molecular-based assays (P = 0.001, kappa value 0.50). CONCLUSIONS: Our results suggest that immunohistochemical analysis with mutation-specific antibodies is a promising approach for quantifying EGFR mutations, and may predict the effect of EGFR-TKI treatment for EGFR mutation-positive NSCLC.