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Introduction Tyrosine kinase inhibitors (TKIs) therapy targets at epidermal growth factor receptor (EGFR) gene mutations in non-small-cell lung cancer (NSCLC). We aimed to compare the EGFR mutation-guided target therapy versus empirical chemotherapy for first-line treatment of advanced NSCLC in the public healthcare setting of Hong Kong. Methods A Markov model was designed to simulate outcomes of a hypothetical cohort of advanced (stage IIIB/IV) NSCLC adult patients with un-tested EGFR-sensitizing mutation status. Four treatment strategies were evaluated: Empirical first-line chemotherapy with cisplatin-pemetrexed (empirical chemotherapy group), and EGFR mutation-guided use of a TKI (afatinib, erlotinib, and gefitinib). Model outcome measures were direct medical cost, progression-free survival, overall survival, and quality-adjusted life-years (QALYs). Incremental cost per QALY gained (ICER) was estimated. Sensitivity analyses were performed to examine robustness of model results. Results Empirical chemotherapy and EGFR mutation-guided gefitinib gained lower QALYs at higher costs than the erlotinib group. Comparing with EGFR mutation-guided erlotinib, the afatinib strategy gained additional QALYs with ICER (540,633 USD/QALY). In 10,000 Monte Carlo simulations for probabilistic sensitivity analysis, EGFR mutation-guided afatinib, erlotinib, gefitinib and empirical chemotherapy were preferred strategy in 0%, 98%, 0% and 2% of time at willingness-to-pay (WTP) 47,812 USD/QALY (1x gross domestic product (GDP) per capita), and in 30%, 68%, 2% and 0% of time at WTP 143,436 USD/QALY (3x GDP per capita), respectively. Conclusions EGFR mutation-guided erlotinib appears to be the cost-effective strategy from the perspective of Hong Kong public healthcare provider over a broad range of WTP.

Background The aim of this study was to evaluate the psychometric properties of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group—Neurotoxicity (FACT/GOG-Ntx) subscale in a longitudinal study of cancer patients treated with chemotherapy. Methods Patients were assessed with the FACT/GOG-Ntx subscale, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy Scale 20 (EORTC QLQ-CIPN20), National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE), and light touch test using 10 g monofilament for up to ten assessment points from baseline (prior to initiation of first chemotherapy), after the end of each cycle (up to 6 cycles, 3 weeks per cycle), and at 6, 9, and 12 months after starting chemotherapy. Psychometric analyses included internal consistency reliability, convergent validity, factorial validity, sensitivity to change and responsiveness (minimal clinically important difference, MCID). Results Cronbach’s alpha coefficients of the FACT/GOG-Ntx subscale were 0.82–0.89 across assessment points. The subscale strongly correlated with the EORTC QLQ-CIPN20 (r = 0.79–0.93) but low-to-moderately correlated with the NCI-CTCAE sensory (rs = 0.23–0.45) and motor items (rs = 0.15–0.50) as well as the monofilament test (rs = 0.23–0.47). The hypothesized 4-factor structure of the FACT/GOG-Ntx subscale was not confirmed at assessment points (χ2/df = 2.26–8.50; all P r = 0.17–0.37). The MCIDs were between 1.38 and 3.68. Conclusion The FACT/GOG-Ntx subscale has satisfactory reliability, validity, sensitivity to change and responsiveness to evaluate CIPN in cancer patients. Future research is needed to explore the factorial structure of the FACT/GOG-Ntx subscale as the published four-factor structure was not supported in this study.

Adenocarcinoma in female non-smokers is an under-explored subgroup of non-small cell lung cancer (NSCLC), in which the molecular mechanism and genetic risk factors remain unclear. We analyzed the protein profiles of plasma samples of 45 patients in this subgroup and 60 non-cancer subjects using surface-enhanced laser desorption/ionization time-of- flight mass spectrometry. Among 85 peaks of mass spectra, the differential expression analysis identified 15 markers based on False Discovery Rate control and the Discrete Wavelet Transforms further selected a cluster of 6 markers that were consistently observed at multiple scales of mass-charge ratios. This marker cluster, corresponding to 7 unique proteins, was able to distinguish the female non-smokers with adenocarcinoma from non-cancer subjects with a value of accuracy of 87.6%. We also predicted the role of competing endogenous RNAs (ceRNAs) in 3 out of these 7 proteins. Other studies reported that these ceRNAs and their targeting microRNAs, miR-206 and miR-613, were significantly associated with NSCLC. This study paves a crucial path for further investigating the genetic markers and molecular mechanism of this special NSCLC subgroup.

Author(s): Molassiotis, Alex; Cheng, Hui Lin; Leung, Kwun To; Li, Yu Chung; Wong, Kam Hung; Au, Joseph Siu Kie; Sundar, Raghav; Chan, Alexandre; Ng, Terrence Rong De; Suen, Lorna KP; Chan, Choi Wan; Yorke, Janelle; Lopez, Violeta | Abstract: BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a significant and difficult to manage side effect of neurotoxic chemotherapies.nSeveral risk factors for CIPN have been identified to date, but inconsistencies and methodological limitations exist in past research. Also, a limited number of potential risk factors has been investigated in the past.AimThe objective of this study was to assess the relative contribution of a wider range of risk factors in the development of CIPN.MethodsThis analysis used the 6-month data after starting chemotherapy from a larger prospective observational study on CIPN risk, prevalence, and quality of life. Patients were assessed at recruitment for possible CIPN risk factors, including prior history of neuropathies, current/past infectious diseases; neurotoxic medication history; personal and treatment characteristics; smoking history, alcohol use, and vegetable/fruit intake. Neuropathy was assessed at 6-months after starting chemotherapy with the neuropathy (motor/sensory) items of the NCI-CTCAE scale and the WHO criterion for neuropathy. Data on symptom burden were also collected.ResultsData were available from 255 patients from three cancer centers in Hong Kong, Singapore, and UK. The use of different scales did not always identify the same predictor variables. Key risk factors in multivariate regression models included older age (highest ORn=n1.08, pnln0.01 with the WHO scale), chemotherapy (platinum-based chemotherapy had ORn=n0.20-0.27 in developing CIPN compared to taxane-based chemotherapy), history of neuropathy (for motor CIPN only, ORn=n8.36, pnln0.01), symptom burden (ORn=n1.06, pnln0.05), number of chemotherapy cycles received (ORn=n1.19-1.24, pnln0.01), and alcohol intake (ORn=n0.32, pnln0.05). In univariate analysis, the use of statins was implicated with CIPN (pn=n0.03-0.04 with different assessments) and diabetes showed a trend (pn=n0.09) in the development of CIPN.ConclusionThis study confirmed the CIPN risk related to certain variables and identified new ones. This knowledge can assist with treatment decisions and patient education.

This is the first study to determine the minimal clinically important difference (MCID) of the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (EORTC QLQ-CIPN20), a validated instrument designed to elicit cancer patients’ experience of symptoms and functional limitations related to chemotherapy-induced peripheral neuropathy. Cancer patients receiving neurotoxic chemotherapy completed EORTC QLQ-CIPN20 and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX] at baseline, second cycle of chemotherapy (T2, n = 287), and 12 months after chemotherapy (T3, n = 191). Anchor-based approach used the validated FACT/GOG-NTX neurotoxicity (Ntx) subscale to identify optimal MCID cutoff for deterioration. Distribution-based approach used one-third standard deviation (SD), half SD, and one standard error of measurement of the total EORTC QLQ-CIPN20 score. There was a moderate correlation between the change scores of the Ntx subscale and sensory and motor subscales of QLQ-CIPN20 (T2: r = − 0.722, p

With the advent of technology, we are now at a turning point in the history of cancer management. The aim of the Hong Kong International Oncology Symposium is to bring those innovations likely to have an important impact on cancer management to the professional community. Our theme for this year’s symposium is newer immunotherapeutic approaches, functional genomics and precision medicine, advances in precision radiotherapy, including proton therapy and updates on the management of lung and urogenital cancers.

Non-small cell lung cancer (NSCLC) comprises about 84% of all lung cancers. Many treatment options are available but the survival rate is still very low due to drug resistance. It has been found that phosphoinositide-3-kinase (PI3K) affects sensitivity to tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib. Expression level of seven in absentia homolog 2 (SIAH2), an E3 ubiquitin-protein ligase, is upregulated in NSCLC and correlated with tumor grade. However, the relationship between PI3K and SIAH2 remains unclear and therefore it is not known whether they can act as treatment co-targets and theranostic dual markers for overcoming TKI resistance. It is worthy to note that PI3K and SIAH2 are potentially regulated by a common group of microRNAs in miR-30 family. Our bioinformatics analyses showed upregulated SIAH2 expression in NSCLC based on mass spectrometry data, explored its indirect interaction with PI3K and predicted their targeting microRNAs in common. We have also explored the potential role of miR-30 family in the modulation of PI3K-SIAH2 interaction in NSCLC.

Incense burning is a powerful producer of carcinogens and has been considered as a risk factor for nasopharyngeal carcinoma (NPC). We conducted a case-control study and case-only analyses to investigate the effect of incense burning and its interaction with genetic background on NPC risk among Hong Kong Chinese. Between June 2010 and December 2012, we recruited 352 incident cases of NPC and 410 controls. We collected information on lifelong practice of domestic incense burning via interviews and genotyped 80 single nucleotide polymorphisms (SNPs) in DNA repair genes. We observed an increased NPC risk associated with daily burning in women [Adjusted OR = 2.49, 95% confidence interval (CI): 1.33, 4.66] but not in men. The adjusted OR for daily burning with poor ventilation was 2.08 (95% CI: 1.02, 4.24), while that with good ventilation was 1.35 (95% CI: 0.92, 1.98). Interactions between 2 SNPs (rs2074517 and rs4771436) and incense burning were significantly associated with NPC risk and tended to have a SNP exposure-response effect. Evidence for gene-environment interactions supported the knowledge that NPC is a multi-factorial disease resulting from the joint effects of environmental exposures and inherited susceptibility.

Introduction: PIONEER (NCT01185314) was a prospective, multinational, epidemiological study of epidermal growth factor receptor (EGFR) mutations in patients from Asia with newly diagnosed advanced lung adenocarcinoma. Methods: Eligible patients (aged ≥20 years) had untreated stage IIIB/IV adenocarcinoma. The EGFR mutation status (primary end point: positive, negative, or undetermined) of tumor samples (biopsy, surgical specimen, or cytology) was determined (Scorpion amplification refractory mutation system). EGFR mutation frequency was calculated and compared between demographic and clinical subgroups. Results: Of 1482 patients from seven Asian regions, 43.4% of patients were female, median age was 60 years (range, 17–94), and 52.6% of patients were never-smokers. EGFR mutation status was evaluable in tumors from 1450 patients (97.8%) (746 [51.4%] positive; 704 [48.6%] negative). Country, sex, ethnicity, smoking status, pack-years (all p < 0.001), disease stage (p = 0.009), and histology type (p = 0.016) correlated significantly with EGFR mutation frequency. Mutation frequency was 61.1% in females, 44.0% in males; lower in patients from India (22.2%) compared with other areas (47.2%–64.2%); highest among never-smokers (60.7%); and decreased as pack-year number increased (>0–10 pack-years, 57.9%; >50 pack-years, 31.4%) (similar trend by sex). Ethnic group (p < 0.001) and pack-years (p < 0.001) had statistically significant associations with mutation frequency (multivariate analysis); sex was not significant when adjusted for smoking status. Conclusion: PIONEER is the first prospective study to confirm high EGFR mutation frequency (51.4% overall) in tumors from Asian patients with adenocarcinoma. The observed high mutation frequency in demographic/clinical subgroups compared with white populations suggests that mutation testing should be considered for all patients with stage IIIB/IV adenocarcinoma, even males and regular smokers, among Asian populations.

This study aimed to investigate the occupational risk factors for nasopharyngeal carcinoma (NPC) in Hong Kong Chinese. We conducted a case-referent study with 352 incident cases and 410 referents recruited between June 2010 and December 2012. Full occupational histories were obtained via face-to-face interviews. Unconditional logistic regressions were performed to estimate the odds ratios (ORs) for NPC associated with occupational risk factors. Workers of craft related trades and elementary occupations were at elevated NPC risk with the adjusted ORs of 2.09 [95% confidence interval (CI) 1.09, 4.01] and 2.14 (95% CI 1.04, 4.41), respectively, compared with those clerical support workers as the reference group. Occupational exposures to cotton dust, chemical fumes, and welding fumes were significantly associated with increased NPC risk after adjustment for confounders [adjusted ORs (95% CIs) 1.93 (1.13, 3.28), 13.11 (1.53, 112.17), and 9.18 (1.05, 80.35), respectively]. We also observed significant exposure–response relationship for the duration of exposure to cotton dust (P for trend = 0.0175). Those with occupational exposure to cotton dust for 15 years or more were at significantly increased risk of NPC (adjusted OR 2.08, 95% CI 1.01, 4.28). This study indicates that employment in craft related trades and elementary occupations, as well as occupational exposures to chemical fumes, welding fumes, and cotton dust may be associated with an increased risk of NPC. Further epidemiological studies remain warranted to clarify the roles of specific occupational risk factors on NPC development.

In this report, we showed that two tumor cell characteristics, namely the malignancy and drug-resistance status can be evaluated by their membrane resealing response. Specifically, membrane pores in a number of pairs of cancer and normal cell lines originated from nasopharynx, lung and intestine were introduced by nano-mechanical puncturing. Interestingly, such nanometer-sized holes in tumor cells can reseal ∼ 2-3 times faster than those in the corresponding normal cells. Furthermore, the membrane resealing time in cancer cell lines exhibiting resistance to several leading chemotherapeutic drugs was also found to be substantially shorter than that in their drug-sensitive counterparts, demonstrating the potential of using this quantity as a novel marker for future cancer diagnosis and drug resistance detection. Finally, a simple model was proposed to explain the observed resealing dynamics of cells which suggested that the distinct response exhibited by normal, tumor and drug resistant cells is likely due to the different tension levels in their lipid membranes, a conclusion that is also supported by direct cortical tension measurement., published_or_final_version

TaRceva LUng cancer Survival Treatment (TRUST) was an open-label, phase IV study of advanced non-small cell lung cancer (NSCLC). Patients failing or unsuitable for chemotherapy or radiotherapy received erlotinib 150 mg/day until progression. We examined a subpopulation of elderly patients (≥70 years) receiving first-line erlotinib (n=485) in TRUST. In this subpopulation, disease control rate (n=356 with best response data available) was 79% (vs. 69% for the overall TRUST population; p

Background Several randomized phase III studies in advanced stage non-small cell lung cancer (NSCLC) confirmed the superior response rate and progression-free survival of using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor as first-line therapy compared with chemotherapy in patients with activating EGFR mutations. Despite the need for EGFR mutation tests to guide first-line therapy in East Asian NSCLC, there are no current standard clinical and testing protocols. Methods A consensus meeting was held involving expert oncologists, pulmonologists, and pathologists to discuss the current status and variations in EGFR mutation testing of NSCLC across Asia and to recommend a standard clinical and laboratory testing approach for future use. Results Currently, EGFR mutation tests are only routinely performed in some East Asian countries and medical centers. The consensus recommendation was to perform the test in all newly diagnosed patients with advanced stage nonsquamous lung cancer and some squamous patients with clinical features associated with higher prevalence of EGFR mutations. To increase the sensitivity and specificity of the EGFR mutation tests, tissue acquisition and pretest sample evaluation are important steps in addition to standardization of the EGFR mutation test methodology. Conclusion A standardized EGFR mutation testing protocol is an essential step toward realization of personalized medicine in East Asian NSCLC treatment.

Introduction: First-line treatment with bevacizumab combined with chemotherapy has been shown to improve outcomes in patients with advanced, nonsquamous non-small cell lung cancer (NSNSCLC) in phase III clinical trials. SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a preplanned subanalysis of Asian patients enrolled in SAiL. Methods: Patients with untreated, locally advanced, metastatic or recurrent NSNSCLC received bevacizumab 7.5 or 15 mg/kg every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Eligibility criteria for SAiL permitted enrolment of a broad patient population. The primary end point was safety; secondary end points included time to disease progression and overall survival. Results: The Asian intent-to-treat population comprised 314 of the 2212 patients enrolled in the SAiL trial. In the Asian subanalysis, patients received a median of nine cycles of bevacizumab, and the median follow-up was 16.4 months. The incidence of clinically significant adverse events (grade ≥3) of special interest was relatively low in this population (15.6% overall); proteinuria (7.6%), hypertension (4.8%), and bleeding (2.5%) were the most common. A total of five adverse events related to bevacizumab were reported as grade 5. Disease control rate was 94.1%, median time to disease progression was 8.3 months, and median overall survival was 18.9 months. Conclusions: The safety and efficacy of first-line bevacizumab-based treatment in Asian patients with advanced NSNSCLC is consistent with that demonstrated in phase III studies and in the overall SAiL population. There were no new safety signals.

BACKGROUND: The anaplastic lymphoma kinase (ALK) gene is involved frequently in chromosomal translocations, resulting in fusion genes with different partners found in various lymphoproliferative conditions. It was recently reported in nonsmall cell lung cancer (NSCLC) that the fusion protein encoded by echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion gene conferred oncogenic properties. The objective of the current study was to identify other possible ALK fusion genes in NSCLC. METHODS: Immunohistochemical analysis was used to screen for aberrant ALK expression in primary NSCLC. The authors used 5′ rapid amplification of complementary DNA ends to screen for potential, novel 5′ fusion partners of ALK other than EML4-ALK. Reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization analyses were used to confirm the identity of 5′ fusion partners. The genomic breakpoint was verified using genomic sequencing. Overexpression of the novel ALK fusion gene and variants 3a and 3b of EML4-ALK was performed to assess downstream signaling and functional effects. RESULTS: The authors identified a novel gene resulting from the fusion of kinesin family member 5B (KIF5B) exon 15 to ALK exon 20 in a primary lung adenocarcinoma. Western blot analysis of clinical tumor tissues revealed the expression of a protein whose size correlated with that of the predicted KIF5B-ALK. Overexpression of KIF5B-ALK in mammalian cells led to the activation of signal transducer and activator of transcription 3 and protein kinase B and to enhanced cell proliferation, migration, and invasion. CONCLUSIONS: The discovery of the novel KIF5B-ALK variant further consolidated the role of aberrant ALK signaling in lung carcinogenesis. Cancer 2011. © 2011 American Cancer Society.

Introduction:Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor that significantly increases survival for patients with previously treated advanced non-small cell lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be particularly effective in Asian patients and may have a distinct safety profile in this population compared with non-Asian patients. We report safety and efficacy data from a subpopulation of East/South-East (E/SE) Asian patients enrolled in a global, open-label, phase IV trial of erlotinib (Tarceva Lung Cancer Survival Treatment study).Methods:Patients who had previously failed on chemotherapy or radiotherapy, or were unsuitable for these treatments, were treated with oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity.Results:Best response data were available for 1118 E/SE Asian and 4276 non-E/SE Asian patients. The overall response rates were 27% versus 10%, respectively (p < 0.0001). The disease control rates were 78% versus 66%, respectively (p < 0.0001). Survival data were available for 1242 E/SE Asian and 5338 non-E/SE Asian patients. The median progression-free survival times were 5.78 months versus 2.92 months, respectively (hazard ratio = 0.66, p < 0.0001). The median overall survival times were 14.7 months versus 6.8 months, respectively (hazard ratio = 0.57, p < 0.0001). One-year survival rates were 58.3% and 32.7%, respectively. Safety data were available for 1242 E/SE Asian patients. Seventeen percent of these patients experienced one or more erlotinib-related adverse event (AE) (other than the most frequently occurring AEs prespecified in the protocol) and 2% experienced an erlotinib-related serious AE. Dose reductions were reported for 171 (14%) patients.Conclusion:Erlotinib is an effective and well-tolerated treatment for Asian patients with advanced non-small cell lung cancer.

Background Because of the long latent period of asbestos-related mesothelioma, investigators suggest that the high incidence of this disease will continue in the coming decades. Objectives We describe the time trends of mesothelioma incidence and its relationship to historical consumption of asbestos in Hong Kong and project future trends of mesothelioma incidence. Methods We obtained local annual consumption of total asbestos for 1960–2006 (converted to kilograms per person per year). Age-standardized incidence rates (ASIRs) of mesothelioma were computed and depicted on graphs using the centered moving average method. Indirectly standardized rates were regressed on a transformation of consumption data that assumed that the latency between asbestos exposure and mesothelioma diagnosis followed a normal distribution with a mean ± SD of 42 ± 10.5 years. Results ASIRs for males started to increase substantially in 1994 and were highest in 2004; for females, ASIRs climbed in the 1980s and in the early 1990s but have fluctuated without obvious trends in recent years. The highest asbestos consumption level in Hong Kong was in 1960–1963 and then decreased sharply afterward. Using past asbestos consumption patterns, we predict that the mesothelioma incidence rate for males will peak in 2009, with the number of cases peaking in 2014, and then slowly decline in the coming decades. Conclusions Hong Kong experienced an epidemic of mesothelioma from 2000 to 2006 that corresponded with the peak of local asbestos consumption in the early 1960s assuming an average latent period of 42 years. The incidence is anticipated to decline in the coming decades but may not decrease back to the background risk level (the risk unrelated to asbestos exposure).

Background In Hong Kong, about 30% of non-small cell lung cancer patients have never smoked tobacco. Among women, 83% are never-smokers and their histological type is invariably adenocarcinoma with 70% incidence of epidermal growth factor receptor ( EGFR ) mutation. The present study focuses on the microRNA (miRNA) expression profiles of this important subset of lung cancer. Methods Paired samples collected from the lung cancer tissue and adjacent normal lung parenchyma of 10 non-smoking patients with lung adenocarcinoma were profiled by miRNA microarray. Results were validated by quantitative reverse transcription polymerase chain reaction. Transfected cell viability assays were applied to determine the effects of candidate miRNAs on lung cancer cells. Results Comparing paired lung cancer tissue with adjacent normal lung parenchyma, hsa-miR-126 ∗ , hsa-miR-145 , hsa-miR-21 , hsa-miR-182 , hsa-miR-183 and hsa-miR-210 were found to be the most differentially expressed miRNAs. Most interestingly, an obvious inhibition of cell growth was observed in the EGFR mutant lung adenocarcinoma after transfection of hsa-pre-miR-145 . Conclusions Our study is the first report to connect miR-182 to lung cancer. Our results also show that restoration of tumour suppressor hsa-miR-145 inhibits cancer cell growth in EGFR mutant lung adenocarcinoma. Further study on these specific differentially expressed miRNAs may provide important information on peculiar tumourigenetic pathways and may identify useful biomarkers.

Chinese women in Hong Kong have among the highest incidence and mortality of lung cancer in the world, in spite of a low prevalence of smoking. We carried out this population-based case-control study to evaluate the associations of previous lung disease and family cancer history with the occurrence of lung cancer among them. We selected 212 cases that were newly diagnosed with primary lung cancer, and randomly sampled 292 controls from the community, frequency matched by age group. All the cases and controls were lifetime nonsmokers. We estimated the main effects of preexisting asthma, pulmonary tuberculosis, pneumonia, chronic bronchitis, and family lung/all cancer history, using unconditional logistic regression, accounting for various potential risk factors and confounders. All of the previous lung diseases, except chronic bronchitis, were related to an elevated risk for lung cancer, and the association with asthma was significant. Those who had more than one previous lung disease tended to be at higher risk than those with only one of them. Positive family history of any cancer was associated with over 2-fold risk than negative family history. The joint effect of positive history of previous pulmonary diseases and positive family cancer history appeared to be additive, indicating the two factors acted independently. The results support an etiological link of preexisting lung disease and family cancer history to the risk of lung cancer.

No studies have specifically reported the association of lung adenocarcinoma with environmental tobacco smoke (ETS) exposure among nonsmoking males. The objective of this study was to examine the exposure-response relation between ETS exposure and lung cancer among nonsmoking males. In particular, the association with adenocarcinoma of the lung was studied. This is a population-based, case-referent study in Hong Kong during 2004-2006. A total of 132 Chinese male nonsmokers with newly diagnosed primary lung cancer and 536 nonsmoking community referents were interviewed about ETS exposures from the household and/or workplace, including ever ETS exposure, sources of exposure, number of smoking cohabitants/coworkers, and smoker-years. Univariate logistic regression analyses showed a weak association between all lung cancers and ever ETS exposure from the household and/or workplace (odds ratio (OR) = 1.11, 95% confidence interval (CI): 0.74, 1.67), but an increased risk was restricted to adenocarcinoma (OR = 1.68, 95% CI: 1.00, 2.38). After adjustment for family cancer history and other confounders, excess risk (OR = 1.62, 95% CI: 0.91, 2.88) still persisted for adenocarcinoma, although it was no longer statistically significant. Exposure-response relations for adenocarcinoma were found with increasing levels of all ETS indices when exposures from the household and workplaces were combined. The consistent exposure-response relations between ETS exposures and adenocarcinoma suggested a probable causal link, which would have to be confirmed by future larger studies.

Half of the female patients with adenocarcinoma in East Asia are never-smokers. Proteomic analysis of tumor tissue may throw important light on the pathogenesis of this interesting subgroup of lung cancer. The cancer and adjacent normal lung tissue were taken from 21 never-smoked adenocarcinoma and profiled using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Fifty-two proteins were significantly discriminatory between tumor and normal lung tissues. Ninety-three proteins were found to have high accuracy in discriminating between adenocarcinoma with or without smoking history. These proteins may yield new insights about the altered pathogenetic pathways of never-smoked lung cancers.

Reactive oxygen species (ROS) have been commonly accepted as inducers of autophagy, and autophagy in turn is activated to relieve oxidative stress. Yet, whether and how oxidative stress, generated in various human pathologies, regulates autophagy remains unknown. Here, we mechanistically studied the role of TRPM2 (transient receptor potential cation channel subfamily M member 2)-mediated Ca2+ influx in oxidative stress-mediated autophagy regulation. On the one hand, we demonstrated that oxidative stress triggered TRPM2-dependent Ca2+ influx to inhibit the induction of early autophagy, which renders cells more susceptible to death. On the other hand, oxidative stress induced autophagy (and not cell death) in the absence of the TRPM2-mediated Ca2+ influx. Moreover, in response to oxidative stress, TRPM2-mediated Ca2+ influx activated CAMK2 (calcium/calmodulin dependent protein kinase II) at levels of both phosphorylation and oxidation, and the activated CAMK2 subsequently phosphorylated BECN1/Beclin 1 on Ser295. Ser295 phosphorylation of BECN1 in turn decreased the association between BECN1 and PIK3C3/VPS34, but induced binding between BECN1 and BCL2. Clinically, acetaminophen (APAP) overdose is the most common cause of acute liver failure worldwide. We demonstrated that APAP overdose also activated ROS-TRPM2-CAMK2-BECN1 signaling to suppress autophagy, thereby causing primary hepatocytes to be more vulnerable to death. Inhibiting the TRPM2-Ca2+-CAMK2 cascade significantly mitigated APAP-induced liver injury. In summary, our data clearly demonstrate that oxidative stress activates the TRPM2-Ca2+-CAMK2 cascade to phosphorylate BECN1 resulting in autophagy inhibition.

Introduction Previous studies revealed that some indoor air pollutants and fine particle matter can interact with active smoking, enhancing lung cancer risk in smokers. Secondhand smoke (SHS), with remarkable differences from active smoking, contributes significantly to indoor air pollution and generates a considerable amount of fine particle matter, may cause a similar interaction with active smoking. Methods Information on lifetime SHS along with active smoking and other confirmed or suspected risk factors for lung cancer was collected in this case-referent study. Odds ratios and the 95% confidence intervals (95% CIs) of smoking status in different levels of SHS were evaluated. Potential multiplicative and additive interactions were explored. Results Compared with never-smokers without SHS, current smokers who were exposed to a high level of SHS demonstrated the highest odds ratio (15.13, 95% CI: 8.60, 26.65), almost doubles the effect in the current smokers without SHS. Significant additive interactions between current smoking and high level of SHS were observed for all lung cancers (synergy index = 1.80, 95% CI: 1.02, 3.24) and the squamous carcinoma subgroup. Conclusions High level of SHS exposure greatly enhanced lung cancer risk among current smokers, consistent with an additive interaction; while this interaction was predominant for the squamous carcinoma. The results provide new evidence to the rationale of promoting global smoking cessation. Implications Some indoor air pollutants can interact with active smoking, yielding a synergistic effect on inducing lung cancer. SHS, with noticeable differences from active smoking, is a major source of indoor air pollution. However, little has been known about the effect of SHS in smokers and whether there is a similar interaction between SHS and active smoking. In this study, we evaluated their separate and joint effects and indeed found a more than additive interaction between them. This finding suggests a potential problem of gathering smoking aggravating by venue restriction policies and re-advocates policy efforts on smoking cessation.

The high incidence of lung cancer among Chinese females, despite a low smoking prevalence, remains poorly explained. Cooking fume exposure during frying could be an important risk factor. We carried out a population-based case-control study in Hong Kong. Cases were Chinese female nonsmokers with newly diagnosed primary lung cancer. Controls were female nonsmokers randomly sampled from the community, frequency matched by age groups. Face-to-face interviews were conducted using a standardized questionnaire. The “total cooking dish-years,” categorized by increments of 50, was used as a surrogate of cooking fumes exposure. Multiple unconditional logistic regression was used to estimate the odds ratios (OR) for different levels of exposure after adjusting for various potential confounding factors. We interviewed 200 cases and 285 controls. The ORs of lung cancer across increasing levels of cooking dish-years were 1, 1.17, 1.92, 2.26, and 6.15. After adjusting for age and other potential confounding factors, the increasing trend of ORs with increasing exposure categories became clearer, being 1, 1.31, 4.12, 4.68, and 34. The OR of lung cancer was highest for deep-frying (2.56 per 10 dish-years) followed by that of frying (1.47), and stir-frying had the lowest OR (1.12) among the three methods. Cumulative exposure to cooking by means of any form of frying could increase the risk of lung cancer in Hong Kong nonsmoking women. Practical means to reduce exposures to cooking fumes should be given top priority in future research. (Cancer Res 2006; 66(9): 4961-7)

Background and purpose To define the dose–response relationship of nasopharyngeal carcinoma (NPC) above the conventional tumoricidal dose level of 66Gy when the basic radiotherapy (RT) course was given by the 2D Ho's technique. Patients and methods Data from all five regional cancer centers in Hong Kong were pooled for this retrospective study. All patients ( n =2426) were treated with curative-intent RT with or without chemotherapy between 1996 and 2000 with the basic RT course using the Ho's technique. The primary endpoint was local control. The prognostic significance of dose-escalation (‘boost') after 66Gy, T-stage, N-stage, use of chemotherapy, sex and age (≤40 years vs >40 years) was studied. Both univariate and multivariate analyses were performed. Results On multivariate analysis, T-stage ( P P =0.01; HR, 0.34) were the only significant factors affecting local failure for the whole study population, and for the population of patients treated by radiotherapy alone, but not for patients who also received chemotherapy. The following were independent determinants of local failure for patient groups with different T-stages treated by radiotherapy alone: use of a boost in T1/T2a disease ( P =0.01; HR, 0.33); use of a boost ( P P =0.01; HR, 1.02) in T3/T4 tumors. Among patients with T2b tumors treated by radiotherapy alone and given a boost, the use of a 20Gy-boost gave a lower local failure rate than a 10Gy-boost. There was no apparent excess mortality attributed to RT complications. Conclusions Within the context of a multi-center retrospective study, dose-escalation above 66Gy significantly improved local control for T1/T2a and T3/4 tumors when the primary RT course was based on the 2D Ho's technique without additional chemotherapy. ‘Boosting' in NPC warrants further investigation. Caution should be taken when boosting is considered because of possible increase in radiation toxicity.

Purpose To analyze the treatment results achievable for nasopharyngeal carcinoma in the modern era to identify the key failures for future improvement and to provide an updated baseline for future trials. Methods and materials The results of 2687 consecutive patients treated at all public oncology centers in Hong Kong during 1996–2000 were retrospectively analyzed. The stage distribution (by American Joint Committee on Cancer and International Union Against Cancer staging system, 1997) was 7% Stage I, 41% Stage II, 25% Stage III, and 28% Stage IVA–B. All patients were irradiated with 6-MV photons and the median total dose was 66 Gy. Only 23% of patients had additional treatment with chemotherapy. Results The 5-year local, nodal, and distant failure-free rates were 85%, 94%, and 81%, respectively; patients with local failure had significantly higher risk of nodal and distant failures. The 5-year progression-free, overall, and cancer-specific survival rates were 63%, 75%, and 80%, respectively. The presenting stage was the most important prognostic factor for all endpoints: with overall survival decreasing from 90% for Stage I to 58% for Stage IVA–B. The results achieved by the 2070 patients treated by radiotherapy alone were almost identical to that of the whole series, the distant failure-free rate among patients with locoregional control was 89% for Stage I–II and 75% for Stage III–IVB. The 860 patients (32%) staged with magnetic resonance imaging achieved significantly better results than those staged by computed tomography, the overall survival being 93% vs. 83% for Stages I–II, and 72% vs. 63% for Stages III–IVB ( p = 0.001). Conclusions Treatment results for nasopharyngeal carcinoma have substantially improved in the modern era; future trials should be based on updated baseline results. Further reduction of distant failure is important for future breakthrough, particularly for patients with advanced disease.

Background: A new strain of coronavirus (CoV) has caused an outbreak of severe acute respiratory syndrome (SARS), with 8098 individuals being infected and 774 deaths worldwide. We carried out protein chip array profiling analysis in an attempt to identify biomarkers that might be useful in monitoring the clinical course of SARS patients. Methods: We performed surface-enhanced laser desorption ionization time-of-flight mass spectrometry on 89 sera collected from 28 SARS patients, 72 sera from 51 control patients with various viral or bacterial infections, and 10 sera from apparently healthy individuals. Results: Nine significantly increased and three significantly decreased serum biomarkers were discovered in the SARS patients compared with the controls. Among these biomarkers, one (11 695 Da) was identified to be serum amyloid A (SAA) protein by peptide mapping and tandem mass spectrometric analysis. When we monitored the SAA concentrations longitudinally in 45 sera from four SARS patients, we found a good correlation of SAA concentration with the extent of pneumonia as assessed by a serial chest x-ray opacity score. Increased SAA occurred in three of four patients at the time of extensive pneumonia as indicated by high x-ray scores. Over the course of gradual recovery in two patients, as assessed clinically and radiologically, SAA concentrations gradually decreased. In the third patient, the concentrations were initially increased, but were further increased with superimposed multiple bacterial infections. SAA was not markedly increased in the fourth patient, who had low x-ray scores and whose clinical course was relatively mild. Conclusions: Protein chip array profiling analysis could be potentially useful in monitoring the severity of disease in SARS patients.

Nineteen Chinese patients with lymphoepithelioma-like carcinoma (LELC) of the lung were tested for Epstein-Barr virus (EBV) DNA in their serum samples by a quantitative polymerase chain reaction (PCR) technique. There was prospective serial monitoring of the serum in seven patients with advanced inoperable or relapsing disease. Five other patients at first diagnosis and two patients at relapse had only a single serum sample available. Serum samples were also taken from three other patients who had prior curative surgery and two patients with prolonged disease remission. Measurable levels of EBV DNA were detected in 11 of 12 patients with a pre-therapy serum sample and a clinically evident tumor. A low level of EBV DNA was also detectable in one of the two other patients whose first serum samples were obtained after some chemotherapy. There was no detectable EBV DNA in the five patients without evidence of tumor. The longitudinal serum EBV DNA profile of seven patients showed consistent correlation with response to therapy and clinical outcome. Patients with a pre-therapy serum EBV DNA >10,000 copies/mL had significantly inferior overall survival. This study suggests that circulating serum EBV DNA can be used as a tumor marker in the clinical management of patients with LELC of the lung.

Purpose: Nasopharyngeal cancer (NPC) is a common cancer in Hong Kong, and relapse can occur frequently. Using protein chip profiling analysis, we aimed to identify serum biomarkers that were useful in the diagnosis of relapse in NPC. Experimental Design: Profiling analysis was performed on 704 sera collected from 42 NPC patients, 39 lung cancer patients, 30 patients with the benign metabolic disorder thyrotoxicosis (TX), and 35 normal individuals (NM). Protein profile in each NPC patient during clinical follow up was correlated with the relapse status. Results: Profiling analysis identified two biomarkers with molecular masses of 11.6 and 11.8 kDa, which were significantly elevated in 22 of 31 (71%) and 21 of 31 (68%) NPC patients, respectively, at the time of relapse (RP) as compared with 11 patients in complete remission (CR; RP versus CR, P = 0.009), 30 TX (RP versus TX, P < 0.001), or 35 NM (RP versus NM, P < 0.001). The markers were also elevated in 16 of 39 (41%) lung cancer patients at initial diagnosis. By tryptic digestion, followed by tandem mass spectrometry fragmentation, the markers were identified as two isoforms of serum amyloid A (SAA) protein. Monitoring the patients longitudinally for SAA level both by protein chip and immunoassay showed a dramatic SAA increase, which correlated with relapse and a drastic fall correlated with response to salvage chemotherapy. Serum SAA findings were compared with those of serum Epstein-Barr virus DNA in three relapsed patients showing a similar correlation with relapse and chemo-response. Conclusions: SAA could be a useful biomarker to monitor relapse of NPC.

BACKGROUND The current study was conducted to examine the pattern and the predictive factors of distant metastases (DM) in patients with nasopharyngeal carcinoma (NPC) after primary radiotherapy treatment. METHODS Data from all five regional cancer centers in Hong Kong were collected retrospectively and pooled for the current study, which was coordinated by the Hong Kong Nasopharyngeal Carcinoma Study Group. The sample was comprised of all 2915 patients with NPC without DM at the time of presentation who were treated with radiotherapy in 1 of the 5 cancer centers during the period between January 1996 and December 2000. RESULTS DM was found to be the leading cause of NPC failure, with a 5-year actuarial rate of 14.9% in this patient cohort. Despite the poor overall survival (OS) of these patients, those with lung metastasis alone represented a distinctive group associated with a significantly better OS. International Union Against Cancer (UICC) N classification, UICC T classification, advanced age, and male gender were found to be significant and independent determinants for DM. CONCLUSIONS Long-term survival is possible in patients with distant metastatic NPC confined to the lung. An aggressive approach to treatment for this group of patients should be considered. Cancer 2004. © 2004 American Cancer Society.

Background Multiple subpopulations of cells with different phenotypes and genotypes coexist within malignant tumours. Different subpopulations seem to maintain themselves in an equilibrium position via stochastic interconversion. Such plasticity plays an important role in cancer progression, such as transition from epithelial states to mesenchymal state during metastasis, dedifferentiation of non-CSCs to CSCs and rapid transition to MDR cells during drug exposure. We attempt to explore this interconversion plasticity at both population and single cell levels to better understand the dynamics of phenotypic transition. Methods: We isolated CD90+ and CD90- cells from A549 lung adenocarcinoma cell line by flow cytometry and then characterized their phenotypic behaviors and interconversion dynamics at both population and single cells level. Single cells were cultured in 96 well plate for 13 days. Viable cells were then transferred into 6 well plate for further expansion until enough cells were collected for measurement of CD90 expression in flow cytometry. Results: A549 maintains a stable expression of CD90 (~50%) which is bimodal distributed. The sorted subpopulations eventually achieved a new equilibrium (CD90+ à 60% , CD90 - à 30%) and did not converge during the bulk cell interconversion. Individual single cell clones showed large variation of CD90 expression. The distribution of CD90 expression was significantly different between CD90+ and CD90- single cell clones, while both groups of clones achieved a similar average equilibrium as compared with the bulk cells. We noted two types of clones defined as transition clones and committed clones with differential interconversion capacities. The later one showed no sign of interconversion and was committed to the original CD90+/- expression level. Further experiments showed that the committed CD90+ cells were more mesenchymal with higher migration ability, while the committed CD90- cells were more epithelial and tumorigenic. Conclusions: Interconversion plasticity varied from cell to cell and the committed cells prohibited the return of sorted cell subpopulations returned back to the original equilibrium. Phenotypic studies of CD90+ and CD90- revealed that the interconversion between them was EMT related. Citation Format: Yuen San Chan, Edwin-Wai Kin Yu, William Weimao Wang, Chi-Chun Fong, Timothy Tak-Chun Yip, Joseph Siu-Kie Au, Mengsu Yang. Dynamic interconversion of cancer cells: single-cell analysis of population-based equilibrium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3938. doi:10.1158/1538-7445.AM2017-3938

OBJECTIVES: Previous epidemiological studies had limited power to investigate the joint effects of individual environmental risk factors and familial susceptibility to lung cancer. This study aimed to address this shortcoming. METHODS: We recruited 345 never smoking lung cancer cases and 828 community referents. We developed a collective environmental exposure index by assigning a value of 1 to subjects at high risks regarding environmental risk factors and 0 otherwise, and then summed over using weights equivalent to the excess odds ratio. Potential additive and multiplicative interactions between environmental exposure index and family cancer history were examined. RESULTS: Compared with “low environmental exposure and without family cancer history”, the odds ratio was 6.80 (95% confidence interval = 3.31–13.98) for males who had high environmental exposures but without family cancer history, whereas it increased to 30.61 (95% confidence interval = 9.38–99.87) if they also had a positive family history. The corresponding associations became weaker in never smoking females. No multiplicative interaction was observed for both genders and an additive interaction was restricted among males. CONCLUSIONS: This study developed a novel environmental exposure index that offers sufficient interest deserving further studies on the interactions between environmental exposures and familial susceptibility to lung cancer risk.

This study aimed to investigate the associations of tobacco smoking and family history of nasopharyngeal carcinoma (NPC) with the risk of NPC in Hong Kong Chinese. Between June 2010 and December 2012, we conducted a case–referent study with 352 incident cases and 410 referents in Hong Kong. We collected information on tobacco smoking and family history of NPC via face-to-face interviews. There were 174 (49.4 %) and 131 (32.0 %) ever-smokers among cases and referents, respectively. The adjusted odds ratio (OR) for NPC related to current smoking was 1.67 [95 % confidence interval (CI) 1.06, 2.61]. Exposure–response relationships were observed between years and total pack-years of smoking, and NPC risk (p = 0.001 and p = 0.018, respectively). History of NPC in first-degree relatives was associated with an increased NPC risk (adjusted OR = 4.52, 95 % CI 2.39, 8.55). The increased NPC risk associated with sibling history (adjusted OR = 6.80, 95 % CI 2.63, 17.56) was higher than that for parental history (adjusted OR = 3.04, 95 % CI 1.27, 7.25). The adjusted OR for ever-smokers with family history using never-smokers without family history as the reference was 4.54 (95 % CI 1.67, 12.34). This study verified the important roles of tobacco smoking and family history on NPC risk among Hong Kong Chinese. The provided evidence supported the knowledge that both environmental exposures and inherited susceptibility contributed to the risk of NPC.

The epidermal growth factor receptor (EGFR) signaling pathway is crucial for regulating tumorigenesis and cell survival and may be important in the development and progression of non-small cell lung cancer (NSCLC). We examined the impact of EGFR-tyrosine kinase inhibitors (TKIs) on progression-free survival (PFS) and overall survival (OS) in advanced NSCLC patients with and without EGFR mutations.Randomized trials that compared EGFR-TKIs monotherapy or combination EGFR-TKIs-chemotherapy with chemotherapy or placebo were included. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs for the EGFR mutation-positive (EGFRmut(+)) and EGFR mutation-negative (EGFRmut(-)) subgroups were calculated with the fixed-effects inverse variance weighted method. All statistical tests were two-sided.We included 23 eligible trials (13 front-line, 7 second-line, 3 maintenance; n = 14570). EGFR mutation status was known in 31% of patients. EGFR-TKIs treatment prolonged PFS in EGFRmut(+) patients, and EGFR mutation was predictive of PFS in all settings: The front-line hazard ratio for EGFRmut(+) was 0.43 (95% confidence interval [CI] = 0.38 to 0.49; P.001), and the front-line hazard ratio for EGFRmut(-) was 1.06 (95% CI = 0.94 to 1.19; P = .35; P interaction.001). The second-line hazard ratio for EGFRmut(+) was 0.34 (95% CI = 0.20 to 0.60; P.001), and the second-line hazard ratio for EGFRmut(-) was 1.23 (95% CI = 1.05 to 1.46; P = .01; P interaction.001). The maintenance hazard ratio for EGFRmut(+) was 0.15 (95% CI = 0.08 to 0.27; P.001), and the maintenance hazard ratio for EGFRmut(-) was 0.81 (95% CI = 0.68 to 0.97; P = .02; P interaction.001). EGFR-TKIs treatment had no impact on OS for EGFRmut(+) and EGFRmut(-) patients.EGFR-TKIs therapy statistically significantly delays disease progression in EGFRmut(+) patients but has no demonstrable impact on OS. EGFR mutation is a predictive biomarker of PFS benefit with EGFR-TKIs treatment in all settings. These findings support EGFR mutation assessment before initiation of treatment. EGFR-TKIs should be considered as front-line therapy in EGFRmut(+) advanced NSCLC patients.

We aimed to examine the effect of alcohol consumption on lung cancer risk stratified by smoking, and to explore whether the impact of alcohol was modified by familial susceptibility to cancer. We recruited 1208 male lung cancer incident cases and 1069 community referents during 2004–2006 and collected their lifetime history of alcohol consumption, cigarette smoking, and family cancer history. Unconditional multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (OR). We tested multiplicative-scale interaction between exposures of interest and examined the additive-scale interaction using synergy index. A moderate association between frequent alcohol consumption and lung cancer was observed among men who had family cancer history (OR = 4.22, 95%CI: 2.46–7.23) after adjustment of smoking and other confounders, while the alcohol effect among men without family history was weak (OR = 1.24, 95%CI: 0.95–1.63) and it became no excess in the never smokers. We observed a consistent synergistic effect between alcohol drinking and family cancer history for all lung cancers and the adenocarcinoma, while there was no multiplicative-scale interaction between the exposures of interest (likelihood ratio test for interaction, p>0.05). Our study revealed a possible synergistic effect between alcohol consumption and familial susceptibility for lung cancer risk; however, this observed possible association needs to be confirmed by future larger analytic studies with more never smoking cases.

MicroRNAs (miRNAs) are emerging as important modulators in cellular pathways and they appear to play a key role in tumorigenesis. MiR-145 is downregulated in several human malignancies, including lung cancer, but the responsible molecular mechanisms remain unclear. We previously reported that restoration of hsa-miR-145 inhibits cancer cell growth in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. This study showed that hsa-miR-145 targets EGFR and nucleoside diphosphate linked moiety X-type motif 1 (NUDT1 or MTH1) in lung adenocarinoma cells. The mRNA expressions of EGFR and NUDT1 were significantly downregulated after miR-145 transfection in human lung adenocarcinoma cells. Our results demonstrated miR-145 in the negative regulation of EGFR and NUDT1 expressions at both mRNA and protein levels. Further analysis showed that miR-145 has the ability to inhibit cell proliferation on transfected lung adenocarcinoma cells over three time points (24, 48 and 72 hours). Upregulation of miR-145 appeared to be an important gene regulation mechanism for the proliferation of lung adenocarcinoma cells and it correlated strongly with the downregulation of EGFR and NUDT1. Interestingly, our study revealed that the altered proliferation in lung cancer cells is not accompanied by changes in apoptosis. Our findings provided new insight into the complex regulating pathway comprising of miR-145, EGFR, NUDT1 and other unknown factors which function in cell proliferation but not in apoptosis. Understanding miR-145's targets and its regulating pathways may lead to new therapeutic strategies for lung adenocarcinoma.

BACKGROUND Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.

Background: Lung cancer is known as the top cancer killer in most developed countries. However, there is currently no promising diagnostic or prognostic biomarker for lung cancer. This study aims to discover non-invasive differential markers in the serum of lung cancer patients, to determine the protein identity of the candidate biomarker(s), and to investigate any clinical implication of the biomarker(s) concerned. Methods: Blood specimens were collected from 154 pre-operative patients with lung cancer and 35 healthy blood donors with no evidence of lung cancer. Fractionated serum samples were processed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (MS). Candidate biomarker was identified using sodium dodecyl sulphate polyacrylamide gel electrophoresis and tryptic digestion followed by tandem MS fragmentation analysis, which was subsequently validated with immunoassay. Results: A differential protein with m/z 11.6 kDa was detected and identified as an isoform of human serum amyloid A (SAA). It was significantly increased by 1822% in lung cancer patients when compared with the healthy controls, which gave an area under the receiver operator characteristic curve of 0.88. In addition, the protein was also significantly elevated by 77% in lung cancer patients with survival

We analyzed the time trends of lung cancer by histological subtype in Hong Kong during 1991-2005, and examined how the time trends were influenced by the effects of birth cohort and calendar period of diagnosis. Cancer incidence data were obtained from Hong Kong Cancer Registry and population data from Census and Statistics Department. Age-standardized incidence rates were computed by the direct method using WHO 1966 standard population as reference. Period and cohort effects were assessed by using two separate Poisson regression models adjusting for age. From 1991 to 2005, the incidence rates in Hong Kong Chinese males decreased steadily. The decline in overall lung cancer incidence rates was limited primarily to the decrease in squamous cell carcinoma, which could be explained by the decreasing trend of cigarette smoking. Adenocarcinoma had been the most predominant histological subtype all along. The relatively horizontal trend of adenocarcinoma and the lack of cohort effect implied the important roles of gene-environment interaction and/or the use of low-tar and filter tip cigarettes. Our study suggests that different histological subtypes may represent different disease entities with perhaps some distinct risk factors. The hypotheses generated from this ecological study will need confirmation by subsequent analytic studies.

Previous studies on the serum proteome are hampered by the huge dynamic range of concentration of different protein species. The use of Equalizer Beads coupled with a combinatorial library of ligands has been shown to allow access to many low-abundance proteins or polypeptides undetectable by classical analytical methods. This study focused on never-smoked lung cancer, which is considered to be more homogeneous and distinct from smoking-related cases both clinically and biologically. Serum samples obtained from 42 never-smoked lung cancer patients (28 patients with active untreated disease and 14 patients with tumor resected) were compared with those from 30 normal control subjects using the pioneering Equalizer Beads technology followed by subsequent analysis by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Eighty-five biomarkers were significantly different between lung cancer and normal control. The application of classification algorithms based on significant biomarkers achieved good accuracy of 91.7%, 80% and 87.5% in class-prediction with respect to presence or absence of disease, subsequent development of metastasis and length of survival (longer or shorter than median) respectively. Support vector machine (SVM) performed best overall. We have proved the feasibility and convenience of using the Equalizer Beads technology to study the deep proteome of the sera of lung cancer patients in a rapid and high-throughput fashion, and which enables detection of low abundance polypeptides/proteins biomarkers. Coupling with classification algorithms, the technologies will be clinically useful for diagnosis and prediction of prognosis in lung cancer.

The gender difference in epidemiology of lung cancer has been postulated to be due to the higher susceptibility of women to risk factors especially tobacco smoking. Alternatively, such difference may also be explained by some unknown gender-specific etiological factors, which can have been masked if both the female and male prevalence of smoking are high. Hong Kong has a low female smoking prevalence rate and therefore the trend of the female incidence of lung cancer is particularly interesting because it can reflect the effects of the non-smoking related risk factors more clearly. The present study examined the trends of incidence rates for the major histologic types and smoking prevalence from 1983 to 2000 in Hong Kong with respect to gender. The prevalence of daily smokers decreased from 39.7% in 1982 to 22% in 2000 in males and from 5.6 to 3.5% in females. The time trends of the lung cancer incidence (overall or with respect to age and histology) were similar for both genders. The overall incidence decreased progressively throughout the study period, attributable to the decrease in squamous cell, small cell and large cell carcinoma. The decline occurred in all age groups but to a greater extent in the younger age groups. The incidence of adenocarcinoma increased until 1988-1990 and then stabilized. The initial increase was restricted to the older age groups. These temporal patterns suggested that the same etiological factors affected both genders to a different extent but manifested as similar changes in the direction of incidence over time. To confirm this hypothesis, further studies were needed to clarify the nature of these etiological factors for the non-smoking related lung cancer cases.

Purpose To critically evaluate the American Joint Commission on Cancer (AJCC)/International Union Against Cancer (UICC) 1997 staging system and look back on its achievements by comparing it with the AJCC/UICC 1992 and Ho 1978 staging systems. To identify areas for additional refinement, we analyzed the prognostic heterogeneity within each stage in depth, which provided important clues for the addition or better categorization of the different defining criteria. Methods and materials We performed a retrospective review of the data from 1294 consecutive biopsy-proven nonmetastatic nasopharyngeal carcinoma patients and staged the extent of disease according to the defining criteria of the three staging systems. All patients had undergone detailed pretreatment assessment by fiberoptic endoscopy and CT. Radical-intent radiotherapy was given using the Ho technique according to our standard protocol. Results The AJCC/UICC 1997 staging system was superior to the other two staging systems, because it assigned patients to more uniform-size stage groupings and correlated better with prognosis. Parapharyngeal space involvement was not an independent predictor for survival, local control, or metastasis. On the other hand, carotid space involvement correlated with a greater likelihood of metastasis. Prognostic heterogeneity was found. Those with orbit, cranial nerve, or intracranial involvement fared worse within Stage T4; those with a maximal lymph node size >3 cm fared worse within Stage N2; and those with bilateral lymph node metastasis fared worse within Stage N3. Conclusion The prognostic accuracy of the AJCC/UICC 1997 staging system can be improved further by recategorization of the T, N, and group stage criteria.

1534 Background: The epidemiological, multicenter prospective study (NCT01185314; PIONEER) assessed EGFR mutation (M) rates in pts from Asia with newly diagnosed advanced lung adenocarcinoma (ADC). Influence of demographic and clinical factors on EGFR M rates was investigated. Methods: Pts were aged ≥20 years, with treatment naïve stage IIIB/IV lung ADC. Tumor sample (biopsy, surgical specimen, cytology) EGFR M status (primary endpoint; positive [M+], negative [M-], undetermined [MU]) was determined using Scorpion ARMS (Therascreen EGFR RGQ kit). EGFR M frequency was calculated and compared between demographic/clinical factor subgroups (chi-square/Fisher’s exact test). Factors with p50 pack years). EGFR M+ rates were 37.5% in male regular smokers (113/301), 34.8% in female regular smokers (8/23), 56.5% in male never smokers (104/184) and 62.0% in female never smokers (358/577). Ethnic group (p

OBJECTIVE: Recent studies suggested that lung adenocarcinomas in never-smokers have characteristics distinct from those in smokers. miRNAs are important modulators in cellular pathways. In this study, we investigate the expression profile of miRNAs in lung adenocarcinomas from nonsmokers and identify their target genes. Our in vitro analyses also assess the miRNA expression associated with erlotinib therapy. METHODS: Lung adenocarcinoma and adjacent normal lung parenchyma were obtained from nonsmokers. Microarray analysis was preformed and the profiling results were validated by qRT-PCR. Transfected cell viability assays were applied to determine the effects of candidate miRNAs on lung cancer cells. Systemic bioinformatic analysis was performed to investigate the potential targets of miRNA in lung cancer. The associations of miRNA and its targeted genes’ expressions were analyzed by miRNA and mRNA microarray profiling in tumor specimens from patients with lung adenocarcinoma. Expressions of miRNA and its gene targets in lung cancer cells were determined by qRT-PCR and validated by Western blot analysis. RESULTS: Comparing paired lung adenocarcinoma tissue with corresponding noncancerous tissues, miR-126*, -145, -21, -182, -183, and -210 were found to be the most differentially expressed miRNAs. An obvious inhibition of cell growth was observed in the EGFR mutant lung adenocarcinoma cells after transfection of pre-miR-145. Our study further identified EGFR and NUTD1 as potential targets of miR-145. The mRNA expressions of EGFR and NUDT1 were significantly downregulated by 60% and 50% respectively after miR-145 transfection. The enforced expression of miR-145 in three lung adenocarcinoma cell lines led to a decrease (2.5-, 5-, and 2-fold) of EGFR protein and the abolishing of NUDT1 protein expressions. In vitro analysis showed that miR-145 can gradually inhibit cell proliferation on transfected lung adenocarcinoma cells over three time points (24, 48, and 72 hours). It was also noteworthy that miR-145 expression and EGFR status correlated with sensitivity to erlotinib. The 3 cell lines treated with erlotinib showing increased expression levels of miR-145 were all mutant EGFR, but not in the 4 lung cancer cell lines with wild-type EGFR or T790M point mutation. DISCUSSION: This study has identified several miRNAs that may play a role in carcinogenesis of lung adenocarcinomas in nonsmokers. Our results also show that restoration of miR-145 inhibits cancer cell growth in EGFR mutant lung adenocarcinoma by targeting EGFR and NUDT1. We further reveal that miR-145 may reduce tumor growth by regulating EGFR in human lung adenocarcinoma but not in erlotinib-resistant cells. Our findings provide new insight into the complex regulating pathway comprising miR-145 and EGFR. Understanding this important pathway may lead to new therapeutic strategies for lung adenocarcinoma in nonsmokers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 129. doi:1538-7445.AM2012-129

OBJECTIVE: MicroRNAs (miRNAs) are emerging as important modulators in cellular pathways and appear to play a key role in tumorigenesis. MiR-145 is downregulated in several human malignancies, including lung cancer, but the responsible molecular mechanisms remain unclear. We previously reported that restoration of miR-145 inhibits cancer cell growth in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. The present study is undertaken to confirm and extend our previous findings through the identification of target genes for miR-145, and to analyze its biological functions in lung adenocarcinoma. METHODS: Systemic bioinformatic analysis was performed to investigate the potential targets of miR-145 in lung cancer, using publicly available algorithms. The associations of miR-145 and its targeted genes’ expressions were analyzed by mRNA and miRNA microarray profiling in tumor specimens from patients with lung adenocarcinoma. Expressions of miR-145 and its gene targets in human lung adenocarcinoma cells were determined using quantitative RT-PCR. Further validation was performed by Western blot analysis. RESULTS: This study showed that miR-145 targets EGFR and nucleoside diphosphate linked moiety X-type motif 1 (NUDT1 or MTH1) in lung adenocarinoma cells. A significant negative correlation was shown between expressions of miR-145 vs EGFR mRNA (r = -0.72; P = 6.3E-8) and NUDT1 mRNA (r = -0.78; P = 6.3E-8), indicating that miR-145 either directly or indirectly suppresses EGFR and NUDT1 transcriptions. The mRNA expressions of EGFR and NUDT1 were significantly downregulated by 60% and 50% after miR-145 transfection in human lung adenocarcinoma cells (P < 0.05). The enforced expression of miR-145 in three lung adenocarcinoma cell lines (NCI-H1975, HCC827, and NCI-H358) led to a decrease (2.5-, 5-, and 2-fold) of EGFR protein and the abolishing of NUDT1 protein expressions. Our results demonstrated miR-145 in the negative regulation of EGFR and NUDT1 expressions at both mRNA and protein levels. Further analysis showed that miR-145 has the ability to significantly inhibit cell proliferation on transfected lung adenocarcinoma cells over three time points (24, 48, and 72 hours). Proliferation of cells was elevated in a time-dependent fashion after transfection with pEP-miR-Null control (by 3%, 27%, and 58%). Conversely, transfection of miR-145 into the cells resulted in gradual reduction of cell viability (by 22%, 37%, and 34%). Upregulation of miR-145 appeared to be an important gene regulation mechanism for the proliferation of lung adenocarcinoma cells and it correlated strongly with the downregulation of EGFR and NUDT1. DISCUSSION: Our findings provided new insight into the complex regulating pathway comprising miR-145, EGFR, and NUDT1. Understanding miR-145's targets and its regulating pathways may lead to new therapeutic strategies for lung adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1189. doi:10.1158/1538-7445.AM2011-1189