Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.

BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. FUNDING: Ministry of Health and Welfare of Taiwan.

Trajectory of smoking behaviour during the first 6 months after diagnosis of lung cancer: A study from Taiwan.

AIMS: To identify different classes of change pattern/ trajectory of tobacco smoking behaviour after diagnosis of lung cancer using multi-wave data and to explore factors associated with the class membership. DESIGN: This is a multi-wave observational study. METHODS: Smoking behaviour data were collected at diagnosis and then every month for 6 months from 133 newly diagnosed people with lung cancer who had recently quit smoking or continued to smoke at diagnosis. These patients were recruited from three medical centres and data were collected from May 2014 to January 2017. Smoking behaviour was assessed based on patients' self-reports on whether they smoked during the last month (yes/no) for a total of seven times. Mixture latent Markov model and logistic regression were used to analyse data. RESULTS: Two latent classes of smoking trajectory were identified among recent quitters or current smokers of people with lung cancer, namely "perseverance for abstinence" and "indecisive for abstinence." Patients who were younger age (OR = 0.95, p = 0.026), exposure to second-hand smoke (OR = 3.35, p = 0.012) and lower self-efficacy for not smoking (OR = 0.96, p = 0.011) were more likely to belong to the class of "indecisive for abstinence." CONCLUSIONS: Heterogeneous classes of smoking trajectory existed in newly diagnosed people with lung cancer. The risk factors associated with a less favourable smoking trajectory can be incorporated into tailored smoking-cessation programs for patients newly diagnosed with lung cancer. IMPACT: The dynamic trajectory of smoking behaviour had not been adequately explored among newly diagnosed people with lung cancer. Two classes of smoking trajectory and the predictors associated with the class membership were identified. These findings suggest that the diagnosis of cancer is a teachable moment for smoking cessation. Patients with younger age, lower self-efficacy of not smoking and exposure to second-hand smoke at home need special attention.

Smoking Status Among Patients With Newly Diagnosed Lung Cancer in Taiwan.

BACKGROUND: Continued smoking after receiving a diagnosis of cancer seriously affects disease prognosis and survival. The prevalence and risk factors of continued smoking among patients with newly diagnosed lung cancer are unknown in Taiwan. PURPOSE: The aims of this study were to assess the smoking status of patients with newly diagnosed lung cancer and to identify the characteristics that are associated with different smoking statuses. METHODS: Baseline data of a longitudinal study on smoking behaviors after lung cancer diagnosis were analyzed in this study. Patients were consecutively recruited from three medical centers in northern Taiwan. A structured questionnaire and medical chart reviews were used to collect data. Multinomial logistic regression analysis was used to examine the factors associated with continuing to smoke after being diagnosed with lung cancer. RESULTS: Among the 406 patients with newly diagnosed lung cancer who were recruited, 47.0% were never-smokers and 53.0% were ever-smokers. Among the second group, 38% were former smokers, 18% were recent quitters, and 44% were current smokers. Compared with former smokers, current smokers were more likely to be younger (OR = 1.05), to not exercise regularly (OR = 2.74), to currently live with smokers (OR = 2.48), and to have lower self-efficacy for refusing to smoke (OR = 0.95). Compared with recent quitters, current smokers were more likely to have lower self-efficacy for refusing to smoke. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: A significant proportion of ever-smoker lung cancer patients in Taiwan will continue to smoke after receiving their diagnosis. Variables known to modify the risk factors associated with continued smoking such as regular exercise and better refusal self-efficacy should be considered and incorporated into future smoking cessation programs for patients with lung cancer.

Glycopyrronium bromide inhibits lung inflammation and small airway remodeling induced by subchronic cigarette smoke exposure in mice.

The effects of long-acting muscarinic receptor antagonists (LAMAs) have not been evaluated in a model with simultaneous lung inflammation and small airway remodeling induced by cigarette smoke (CS). We exposed the mice to CS for four weeks with daily treatment with a LAMA (glycopyrronium bromide, NVA237) or its vehicle. Human bronchial epithelial cells (PBECs) and lung fibroblasts were exposed to CS extract (CSE) or acetylcholine with or without NVA237 treatment. We found that NVA237, but not its vehicle, suppressed elevations in inflammatory score, epithelial thickness, and peribronchial collagen deposition in CS-exposed mice. NVA237 alleviated CS-induced increased levels of chemokines, inflammatory cells, and total protein in the bronchoalveolar lavage fluid. NVA237 suppressed acetylcholine- or CSE-induced elevations in IL-8 production in PBECs and elevations in proliferation and collagen production in lung fibroblasts. These phenomena were also prevented by a p44/42 MAPK inhibitor. In conclusion, NVA237 exerted a potent suppressive effect on lung inflammation and small airway remodeling induced by subchronic CS exposure.

Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma.

Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild-type counterparts expressing all isoforms (fs120, fs164, fs188, or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 vs. fs188/WT); fs120 cells also produced more lung colonies than fs188 cells when injected intravenously. Metastasis from subcutaneous fs120 tumors was more sensitive than fs188 to treatment with the anti-VEGFA antibody B20-4.1.1. Despite elevated plasma levels of VEGFA in fs120 tumor-bearing mice and a dependence on VEGF receptor 1 activity for metastasis to the lung, B20-4.1.1 did not affect survival in the lung on intravenous injection. B20-4.1.1 inhibited subcutaneous tumor growth and decreased vascular density in both fs120 and fs188 tumors. However, migration of fs120, but not fs188 cells, in vitro was inhibited by B20-4.1.1. The greater survival of fs120 cells in the lung was associated with VEGFR1-dependent accumulation of CD11b-positive myeloid cells and higher expression of the VEGFR1 ligand, PlGF2, by the fs120 cells in vitro and in the plasma and lungs of fs120 tumor-bearing mice. We conclude that soluble VEGFA isoform expression increases fibrosarcoma metastasis through multiple mechanisms that vary in their sensitivity to anti-VEGF/VEGFR inhibition, with VEGFA-targeted therapy suppressing metastasis through effects on the primary tumor rather than the metastatic site. Cancer Res; 77(10); 2633-46. ©2017 AACR.

Brain metastasis features and association with tumor epidermal growth factor receptor mutation in patients with adenocarcinoma of the lung.

AIM: Epidermal growth factor receptor (EGFR) mutations are frequent in pulmonary adenocarcinoma patients. The association between tumor EGFR mutation and characteristics of brain metastasis (BM) is still unclear. METHODS: We retrospectively reviewed pulmonary adenocarcinoma patients with and without BMs, and characteristics of BM to analyze the association between tumor EGFR mutation and characteristics of BM. RESULTS: Of 374 cases, 239 had EGFR mutations; 69 had BM at initial diagnosis, and 82 with BMs after treatment. All eligible patients received EGFR-tyrosine kinase inhibitors treatment. Older patients (≥70 years old) were less likely to have BMs than younger patients (25.8% vs 48%, P < 0.001). Patients with higher N stage had higher proportion of BMs (P = 0.006). Patients with exon 19 deletion were more likely to have BMs than those without EGFR mutation (48.1% vs 34.1%, P = 0.021). Patients with exon 19 deletion didn't have significantly higher chance of BMs at initial diagnosis but had higher chance to develop BM after treatment than those without EGFR mutation (35.6% vs 21.2%, P = 0.019). Patients with exon 19 deletion survived longer than those without EGFR mutation (1-year survival rate 95.8% vs 78.7%, P = 0.003). Thus, longer survival may lead to higher proportion of BM occurrence in patients with exon 19 deletion than those without EGFR mutation. CONCLUSIONS: In pulmonary adenocarcinoma, there is no significant difference in frequency of BMs at initial diagnosis between patients with EGFR mutation and wild type. However, after treatment, patients with EGFR mutations are significantly more likely to develop BM.

The Efficacy of Traditional Chinese Herbal Medicine in the Treatment of EGFR Mutated Stage IV Pulmonary Adenocarcinoma Patients Who Received First-Line EGFR-TKI Treatment.

BACKGROUND: Chinese herbal medicine (CHM) has been used for thousands of year in Eastern countries. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard treatment in stage IV pulmonary adenocarcinoma patients who had tumor EGFR mutations. This study was to find the efficacy of CHM on lung cancer treatment. MATERIALS AND METHODS: We retrospectively reviewed chart records of our stage IV EGFR-mutated pulmonary adenocarcinoma patients who received first-line EGFR-TKI treatment from January 2010 to September 2014. RESULTS: Total, 527 patients were studied. Among them, 34 patients received CHM treatment, including 24 patients who received CHM treatment from the beginning of first-line EGFR-TKI treatment and 10 patients who started to receive CHM treatment after their disease had progressed to EGFR-TKI treatment. Median progression-free survival (PFS) of first-line EGFR-TKI treatment was numerically better in patients who also received CHM than those who did not (12.1 months vs 10.5 months, P = .7668). Overall survival of those 24 patient who received CHM treatment together with EGFR-TKI was 30.63 months (95% CI = 11.7 to not reached), compared to 23.67 months in the remaining patients (95% CI = 21.37-26; hazard ratio = 0.75; P = .399). No increase of CHM-related toxicities was found during CHM treatment, compared with EGFR-TKI treatment alone ( P > .05). CONCLUSION: Alternative CHM treatment during first-line EGFR-TKI treatment did no harm to the patients and PFS and overall survival was numerically better, although not significant, than those patients who did not receive CHM treatment.

Induced Pluripotent Stem Cell-conditioned Medium Suppressed Melanoma Tumorigenicity Through the Enhancement of Natural-Killer Cellular Immunity.

Induced pluripotent stem cells (iPSCs) can secrete cytokines that are involved in T-cell development and affect cytotoxic activity. To assess the effect of iPSC-conditioned medium on tumorigenicity, we retrieved splenocytes from B6 mice and cocultured them with or without irradiated B16 melanoma cells, mouse interleukin-2 (mIL-2), or iPSC-conditioned medium. Splenocyte cytotoxicity assays against B16 melanoma cells [as cytotoxic T lymphocyte (CTL) activity] and P815 cells [as natural killer (NK) activity] were performed. IL-10 and interferon-γ concentrations were measured. An in vivo subcutaneous B16 melanoma growth model was performed in B6 mice and treated with iPSC-conditioned medium. The lymphocyte subpopulation depletion test was performed to determine effectors against B16 melanoma cells. We found that unstimulated splenocytes had little cytotoxic activity. Without tumor cells, mIL-2 could augment iPSC-conditioned medium-treated CTL and NK activities (P<0.01). With irradiated tumor cells, mIL-2 treatment of splenocytes could not enhance CTL or NK activity, but iPSC-conditioned medium could enhance CTL and NK activity (P<0.001). Irradiated tumor cells induced mice splenocytes to secrete more IL-10, similar to mIL-2 treatment, but not iPSC-conditioned medium treatment. mIL-2 had better efficacy than conditioned medium in inducing splenocyte interferon-γ production. The CTL and NK cell depletion test showed that the immunostimulating effect of iPSC-conditioned medium on splenocytes was through the enhancement of NK cellular activity (P<0.05). The subcutaneous melanoma growth model showed that B16-bearing mice treated with an iPSC-conditioned medium intraperitoneal injection had a decreased tumor growth rate (P<0.01). Our study suggests that iPSC-conditioned medium had a protective effect against tumor-induced immunosuppression through the enhancement of host NK cellular activity.

Adjuvant Therapy for Thymic Carcinoma--A Decade of Experience in a Taiwan National Teaching Hospital.

BACKGROUND: Thymic carcinomas are rare tumors for which surgical resection is the first treatment of choice. The role of adjuvant treatment after surgery is unknown because of limited available data. The present study evaluated the efficacy of post-surgery adjuvant chemotherapy or radiotherapy in patients with thymic carcinoma. METHODS: To evaluate the role of adjuvant therapy in patients with thymic carcinoma, we retrospectively reviewed the records of patients with thymic carcinoma who were diagnosed and treated between 2004 and 2014. RESULTS: Among 78 patients with thymic carcinoma, 30 patients received surgical resection. Progression-free survival (PFS) and overall survival (OS) were significantly longer among these patients than among patients who received other treatments (PFS: 88.4 months vs 9.1 months, p<0.001; OS: 134.9 months vs 60.9 months; p = 0.003). Patients with stage III thymic carcinoma who received surgery had a longer OS than patients who did not receive surgery (70.1 months vs 23.9 months; p = 0.017, n = 11). Among 47 patients with stage IV carcinoma, 12 patients who received an extended thymothymectomy had a longer PFS than 35 patients who did not receive surgery (18.9 months vs 8.7 months; p = 0.029). Among 30 patients (with stage I- IV carcinoma) who received primary lesion surgery, 19 patients received an R0 resection and 9 patients of the 19 patients received adjuvant radiotherapy. These patients had longer PFS (50.3 months) than 2 patients who received adjuvant chemotherapy (5.9 months) or 4 patients who received concurrent chemoradiotherapy (7.5 months) after surgery (p = 0.003). CONCLUSIONS: Surgical resection should be considered for patients with thymic carcinoma, even for patients with locally advanced or stage IV carcinoma. Adjuvant radiotherapy resulted in a better PFS after R0 resection.

A prospective study of the use of circulating markers as predictors for epidermal growth factor receptor-tyrosine kinase inhibitor treatment in pulmonary adenocarcinoma.

BACKGROUND: The use of liquid tissue, such as circulating cells, to predict treatment response is attracting more attention. OBJECTIVE: The aim of this study was to evaluate association between circulating markers and treatment response. METHODS: One hundred and twelve advanced pulmonary adenocarcinoma patients who were going to receive epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were included. Tumor tissue and plasma specimens were collected before treatment and analyzed for EGFR mutation and plasma IL-6 and IL-8. Pre-treatment peripheral blood CD146+/CD3- cells (as circulating endothelial cells, CECs), CD34+/CD45- cells (as endothelial progenitor cells, EPCs), and CD133+ cells (as cancer stem cells, CSCs) were measured with flow cytometry. RESULTS: The progression-free survival (PFS) was significantly longer in patients with low CEC, low EPC, and low CSC counts than in those with high cell counts (p < 0.001, 0.041, and 0.001, respectively). Multivariate analysis showed that mutant plasma EGFR (pEGFR) was a poor prognostic factor in EGFR-mutated patients (p = 0.048), and there was a tendency for EGFR mutation-negative patients with high IL-6 level to have worse overall survival (p = 0.051). CONCLUSIONS: CECs, EPCs, CSCs, and mutant pEGFR are useful predictive biomarkers of EGFR-TKI treatment efficacy. IL-6 may predict prognosis in advanced lung cancer.

Efficacy of chemotherapy in epidermal growth factor receptor (EGFR) mutated metastatic pulmonary adenocarcinoma patients who had acquired resistance to first-line EGFR tyrosine kinase inhibitor (TKI).

INTRODUCTION: Salvage chemotherapy is frequently used when tumour epidermal growth factor receptor (EGFR) mutated patients experience disease progression with first-line EGFR-tyrosine kinase inhibitor (TKI) treatment. However, the efficacy of salvage chemotherapy is still unknown. METHODS: We retrospectively reviewed the chart records of our pulmonary adenocarcinoma patients between 2010 and 2013. RESULTS: Five hundred and six of the 1240 stage IV adenocarcinoma patients had an EGFR mutation and 338 received first-line EGFR-TKI treatment. In all, 169 patients in this group received salvage chemotherapy after failure of EGFR-TKI, and 102 patients were eligible for this study. The chemotherapy response rate of these 102 patients was 24.5%, with a median progression-free survival (PFS) of 4.5?months, and median survival time was 14.6?months. Patients who received pemetrexed-based chemotherapy had longer PFS and overall survival (OS), although the extent was statistically insignificant. Progression-free survival and OS were longer for patients who received combination chemotherapy than single-agent chemotherapy. CONCLUSIONS: Pemetrexed-based combination chemotherapy is preferred before a more efficient treatment strategy is found.

Erlotinib Salvage Therapy in Pulmonary Adenocarcinoma Patients With Disease Progression After Previous EGFR-TKI Treatment.

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with promising efficacy in treating pulmonary adenocarcinoma. Treatment choices are few when patients with pulmonary adenocarcinoma have failed both EGFR-TKI and chemotherapy. The purpose of this study was to demonstrate the efficacy of erlotinib as salvage treatment for these nonresponsive patients. METHODS: We retrospectively reviewed the chart records of our stage IV pulmonary adenocarcinoma patients who were diagnosed and treated between July 2004 and June 2013. Clinical data, including type of response to treatment, time to disease progression, duration between the end of first-line EGFR-TKI treatment and starting erlotinib treatment, and overall survival time, were collected. RESULTS: A total of 98 patients were enrolled, and all had been treated with EGFR-TKI, either as a first-line therapy or following platinum-based chemotherapy; of them, 60 patients had a response to initial EGFR-TKI treatment. All received erlotinib as salvage treatment after their disease had progressed following EGFR-TKI treatment. Ninety-three (93.3%) patients had also received previous platinum-based chemotherapy. The median progression-free survival with erlotinib as salvage treatment for patients with and without a response to front-line EGFR-TKI was 4.9 and 3.4 months (P=0.869), respectively. The progression-free survival with erlotinib treatment in the sensitizing EGFR mutation group was 4.3 months, and in the EGFR wild-type group it was 2.6 months (P=0.22). CONCLUSIONS: In pulmonary adenocarcinoma patients who had been heavily treated, erlotinib could still be a choice, regardless of the EGFR mutation status, or whether the patients had responded to previous EGFR-TKI treatment.

Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Treatment and Salvage Chemotherapy in EGFR-Mutated Elderly Pulmonary Adenocarcinoma Patients.

BACKGROUND: Lung cancer is frequently a disease of elderly patients. However, these patients are often treated less actively owing to a higher comorbidity rate and poor performance status. The efficacy of different treatments in elderly patients with epidermal growth factor receptor (EGFR)-mutated lung cancer is still unknown. MATERIALS AND METHODS: We retrospectively reviewed the records of our pulmonary adenocarcinoma patients treated between 2010 and 2013. Data on patient age, type of tumor EGFR mutation, response to first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, type of salvage chemotherapy, and efficacy of EGFR-TKI and salvage chemotherapy were collected. RESULTS: In all, 473 of 1,230 stage IV adenocarcinoma patients had an EGFR mutation, and 330 of them received first-line TKI treatment. Of the 330 patients, 160 were ≥70 years old (elderly group) and 170 were <70 years old (younger group). The response rate and progression-free survival (PFS) with first-line TKI treatment were not significantly different. The elderly group had shorter median survival. A total of 107 patients received salvage chemotherapy after first-line EGFR-TKI treatment: 45 in the elderly group and 62 in the younger group. Their response rate and PFS were not significantly different; however, the younger group had longer median survival. Additional subgroup analysis showed that younger patients who received platinum-based chemotherapy or combination chemotherapy had better median survival than did the elderly patients. The PFS was longer among younger patients receiving a platinum-based regimen than that among the elderly patients. CONCLUSION: Elderly patients with disease progression after first-line EGFR-TKI treatment can receive chemotherapy and have a response rate similar to that of younger patients. IMPLICATIONS FOR PRACTICE: The aim of the present study was to investigate the efficacy of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients and the outcomes of subsequent salvage chemotherapy after disease progression. The most important finding was that elderly patients with disease progression after first-line EGFR-TKI treatment can receive salvage chemotherapy and have a response rate similar to that of younger patients who received salvage chemotherapy.

Amyloidosis and the risk of cancer: a nationwide population-based study.

BACKGROUND: The association between amyloidosis and cancer remains unclear. PARTICIPANTS AND METHODS: Using the Taiwan National Health Insurance Research Database we conducted a population-based cohort study. Patients newly diagnosed with amyloidosis between 1997 and 2009 were enrolled. Patients with antecedent cancer were excluded. Standardized incidence ratios (SIR) of cancers were calculated for the study cohort and compared with cancer incidence among the general population. We used a multivariate Cox regression model to evaluate the predictors of cancer development for patients with amyloidosis. RESULTS: The study included 1,693 subjects with median follow-up of 5.63 years. A total of 68 patients developed cancer. The incidence of kidney cancer (SIR 3.42; 95 % CI 1.11-7.97; p = 0.034) and hematologic malignancies (SIR 3.88; 95 % CI 1.86-7.14; p < 0.001) were significantly higher for patients with amyloidosis. CONCLUSION: This is currently the largest study to evaluate cancer risk among patients with amyloidosis. The results indicate that amyloidosis may be associated with an increased risk of kidney cancer and hematologic malignancies.

A phase I multicenter study of antroquinonol in patients with metastatic non-small-cell lung cancer who have received at least two prior systemic treatment regimens, including one platinum-based chemotherapy regimen.

Antroquinonol is isolated from Antrodia camphorata, a camphor tree mushroom, and is a valuable traditional Chinese herbal medicine that exhibits pharmacological activities against several diseases, including cancer. This first-in-human phase I study of antroquinonol included patients with metastatic non-small-cell lung cancer who had received at least two prior systemic treatment regimens. An open-label, dose escalation, pharmacokinetic (PK) study was conducted to determine the maximum tolerable dose (MTD), dose-limiting toxicities (DLTs), and safety/tolerability and preliminary efficacy profiles of antroquinonol. The patients received escalating doses of once-daily antroquinonol in 4-week cycles (up to 3 cycles). The escalated doses were 50-600 mg. PKs were evaluated on day 1 and 28 of cycle 1. Between January, 2011 and October, 2012, 13 patients with metastatic adenocarcinoma were enrolled. No DLTs occurred in any patient at any dose level. Tmax was observed between 1.00 and 3.70 h under single-dose conditions, and at 1.92-4.05 h under multiple-dose conditions. The mean elimination half-life ranged between 1.30 and 4.33 h, independent of the treatment dose. Antroquinonol at all dose levels had a mild toxicity profile, with no reported treatment-related mortality. The most common treatment-related adverse events were diarrhea, vomiting and nausea. The best tumor response was stable disease in 3 patients. In conclusion, antroquinonol at all dose levels, administered daily for 4 weeks, was generally safe and well tolerated, without DLTs. The recommended dose level for a phase II study is ≥600 mg daily.

The association between tumor epidermal growth factor receptor (EGFR) mutation and multiple primary malignancies in patients with adenocarcinoma of the lungs.

OBJECTIVES: An increased incidence of multiple primary malignancies has been found in recent decades. However, the nature of the association between the epidermal growth factor receptor (EGFR) mutation status and multiple primary malignancies in patients with adenocarcinoma of the lungs is not clearly understood at this time. METHODS: We retrospectively reviewed the data of our patients with adenocarcinoma of the lungs, and evaluated the association between the tumor EGFR mutation status and multiple primary malignancies. RESULTS: From December 2008 to November 2011, 655 pulmonary adenocarcinoma patients with tumor EGFR mutation data were available for analysis. Of them, 359 had EGFR mutations (including 336 classic EGFR mutations), 63 had double primary malignancies, and 7 had triple primary malignancies. Patients with classic EGFR mutations had a higher incidence of multiple primary malignancies than those without (P=0.042). Multiple primary malignancies occurred more frequently in patients with exon 19 mutations (including insertions, point mutations, or deletions) or exon 19 deletions than in patients without (P=0.037 and 0.032, respectively). Patients with any EGFR mutations or classic EGFR mutations survived longer than those who did not (P<0.001 and <0.001, respectively). Patients with multiple primary malignancies survived for a longer period than those without (P=0.006). CONCLUSIONS: Multiple primary malignancies occurred more frequently in patients with classic EGFR mutations, especially those with exon 19 deletions.

Gender disparities in latent tuberculosis infection in high-risk individuals: a cross-sectional study.

Male predominance in active tuberculosis (TB) is widely-reported globally. Gender inequalities in socio-cultural status are frequently regarded as contributing factors for disparities in sex in active TB. The disparities of sex in the prevalence of latent TB infection (LTBI) are less frequently investigated and deserve clarification. In this cross-sectional study conducted in a TB endemic area, we enrolled patients at high-risk for LTBI and progression from LTBI to active TB from 2011 to 2012. Diagnosis of LTBI was made by QuantiFERON-TB Gold In-Tube (QFT-GIT). Differences in sex in terms of prevalence of LTBI and clinical predictors for LTBI were investigated. Associations among age, smoking status, and sex disparities in LTBI were also analyzed. A total of 1018 high-risk individuals with definite QFT-GIT results were included for analysis, including 534 males and 484 females. The proportion of LTBI was significantly higher in males than in females (32.6% vs. 25.2%, p = 0.010). Differences in the proportion of LTBI between sexes were most prominent in older patients (age ≥ 55 years). In multivariate analysis, independent clinical factors associated with LTBI were age (p = 0.014), smoking (p = 0.048), and fibro-calcified lesions on chest radiogram (p = 0.009). Male sex was not an independent factor for LTBI (p = 0.88). When stratifying patients according to the smoking status, the proportion of LTBI remained comparable between sexes among smokers and non-smokers. In conclusion, although the proportion of LTBI is higher in men, there is no significant disparity in terms of sex in LTBI among high-risk individuals after adjusting for age, smoking status, and other clinical factors.

Number of liver metastatic nodules affects treatment options for pulmonary adenocarcinoma patients with liver metastases.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), the development of liver metastasis (LM) is a poor prognostic factor. Whether systemic treatment combined with local treatment for LM has benefit for NSCLC patients with LM is unknown. METHODS: We retrospectively reviewed and analyzed the clinical data and tumor epidermal growth factor receptor (EGFR) mutation status of 673 pulmonary adenocarcinoma patients, including 85 patients who developed LM at any time point in the course of the disease. Radiofrequency ablation (RFA) with real-time ultrasonographic guidance was used for local treatment of LM in these patients, if appropriate. RESULTS: Patients with an EGFR mutation were more prone to having synchronous LM than patients with EGFR wild-type (50.0% vs. 23.5%, P=0.019). Fifty-six patients (65.9%) had ≦5 LM nodules. The median overall survival (OS) of patients with ≦5 LM nodules was 7.6 months compared with 2.9 months for those with multiple nodules (P<0.001). The independent prognostic factors after LM were performance status, EGFR mutation, synchronous LM and LM numbers. The independent prognostic factors for patients with ≦5 LM nodules were performance status, EGFR mutation, LM concomitant with adrenal metastasis and having received RFA. Patients who received RFA treatment (n=6) had longer OS after LM than those without RFA treatment (n=42) (23.1 vs. 7.9 months, P=0.035). CONCLUSIONS: We recommend that patients with a better performance status and ≦5 LM nodules be considered for systemic treatment combined with RFA when LM develops.

Latent TB infection in newly diagnosed lung cancer patients - A multicenter prospective observational study.

OBJECTIVES: Lung cancer and tuberculosis (TB) share common risk factors and are associated with high morbidity and mortality. Coexistence of lung cancer and TB were reported in previous studies, with uncertain pathogenesis. The association between lung cancer and latent TB infection (LTBI) remains to be explored. METHODS: Newly diagnosed, treatment-naïve lung cancer patients were prospectively enrolled from four referral medical centers in Taiwan. The presence of LTBI was determined by QuantiFERON-TB Gold In-Tube (QFT-GIT). Demographic characteristics and cancer-related factors associated with LTBI were investigated. The survival status was also analyzed according to the status of LTBI. RESULTS: A total of 340 lung cancer patients were enrolled, including 96 (28.2%) LTBI, 214 (62.9%) non-LTBI, and 30 (8.8%) QFT-GIT results-indeterminate cases. Non-adenocarcinoma cases had higher proportion of LTBI than those of adenocarcinoma, especially in patients with younger age. In multivariate analysis, COPD (OR 2.41, 95% CI 1.25-4.64), fibrocalcified lesions on chest radiogram (OR 2.73, 95% CI 1.45-5.11), and main tumor located in typical TB areas (OR 2.02, 95% CI 1.15-3.55) were independent clinical predictors for LTBI. Kaplan-Meier survival analysis demonstrated patients with indeterminate QFT-GIT results had significantly higher 1-year all-cause mortality than those with LTBI (p<0.001) and non-LTBI (p=0.003). In multivariate analysis, independent predictors for 1-year all-cause mortality included BMI<18.5 (HR 2.09, 95% CI 1.06-4.14, p=0.033), advanced stage of lung cancer (RR 7.76, 95% CI 1.90-31.78, p=0.004), and indeterminate QFT-GIT results (RR 2.40, 95% CI 1.27-4.54, p=0.007). CONCLUSIONS: More than one-quarter of newly diagnosed lung cancer patients in Taiwan have LTBI. The independent predictors for LTBI include COPD, fibrocalcified lesions on chest radiogram, and main tumor located in typical TB areas. The survival rate is comparable between LTBI and non-LTBI cases. However, indeterminate QFT-GIT result was an independent predictor for all-cause mortality in lung cancer patients.

Serum estradiol levels predict survival and acute kidney injury in patients with septic shock--a prospective study.

Sex hormones have diverse immunomodulatory effects that may be involved in the pathogenesis of sepsis. However, the roles of serum sex hormones in predicting outcomes and the severity of organ dysfunction, especially acute kidney injury (AKI), in septic shock patients remains controversial. We prospectively enrolled 107 clinically diagnosed pneumonia-related septic shock patients and serum sex hormone levels were measured on the day of shock onset. The aim of the present study was to investigate the predictive values of serum sex hormones levels for 28-day mortality and organs dysfunction, especially AKI. Compared with survivors, serum levels of progesterone (p<0.001) and estradiol (p<0.001) were significantly elevated in non-survivors. In multivariate Cox regression analysis, serum level of estradiol >40 pg/mL (p = 0.047) and APACHE II score ≥25 (p = <0.001) were found to be independent predictors of day 28 mortality. Inclusion of estradiol levels further enhanced the ability of APACHE II scores to predict survival in patients with high mortality risk. A serum level of estradiol >40 pg/mL was also an independent predictor of concomitant AKI (p = 0.002) and correlated well with severity of renal dysfunction using RIFLE classification. Elevated serum estradiol levels also predicted the development of new AKI within 28 days of shock onset (p = 0.013). In conclusion, serum estradiol levels appear to have value in predicting 28-day mortality in septic shock patients. Increased serum estradiol levels are associated with higher severity of concomitant AKI and predict development of new AKI.