Implications of Insulin-like Growth Factor 1 Receptor Activation in Lung Cancer.

Insulin-like growth factor 1 receptor (IGF1R) has been intensively investigated in many preclinical studies using cell lines and animal models, and the results have provided important knowledge to help improve the understanding of cancer biology. IGF1R is highly expressed in patients with lung cancer, and high levels of circulating insulin-like growth factor 1 (IGF1), the main ligand for IGF1R, increases the risk of developing lung malignancy in the future. Several phase I clinical trials have supported the potential use of an IGF1R-targeted strategy for cancer, including lung cancer. However, the negative results from phase III studies need further attention, especially in selecting patients with specific molecular signatures, who will gain benefits from IGF1R inhibitors with minimal side effects. This review will discuss the basic concept of IGF1R in lung cancer biology, such as epithelial-mesenchymal transition (EMT) induction and cancer stem cell (CSC) maintenance, and also the clinical implications of IGF1R for lung cancer patients, such as prognostic value and cancer therapy resistance.

Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial.

BACKGROUND: The results of FASTACT, a randomised, placebo-controlled, phase 2 study, showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. We undertook FASTACT-2, a phase 3 study in a similar patient population. METHODS: In this phase 3 trial, patients with untreated stage IIIB/IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm (stratified by disease stage, tumour histology, smoking status, and chemotherapy regimen) to receive six cycles of gemcitabine (1250 mg/m(2) on days 1 and 8, intravenously) plus platinum (carboplatin 5 × area under the curve or cisplatin 75 mg/m(2) on day 1, intravenously) with intercalated erlotinib (150 mg/day on days 15-28, orally; chemotherapy plus erlotinib) or placebo orally (chemotherapy plus placebo) every 4 weeks. With the exception of an independent group responsible for monitoring data and safety monitoring board, everyone outside the interactive internet response system company was masked to treatment allocation. Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death, and all patients in the placebo group were offered second-line erlotinib at the time of progression. The primary endpoint was PFS in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00883779. FINDINGS: From April 29, 2009, to Sept 9, 2010, 451 patients were randomly assigned to chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo (median PFS 7·6 months [95% CI 7·2-8·3], vs 6·0 months [5·6-7·1], hazard ratio [HR] 0·57 [0·47-0·69]; p<0·0001). Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months (16·3-20·8) and 15·2 months (12·7-17·5), respectively (HR 0·79 [0·64-0·99]; p=0·0420). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16·8 months [12·9-20·4] vs 6·9 months [5·3-7·6], HR 0·25 [0·16-0·39]; p<0·0001; median overall survival 31·4 months [22·2-undefined], vs 20·6 months [14·2-26·9], HR 0·48 [0·27-0·84]; p=0·0092). Serious adverse events were reported by 76 (34%) of 222 patients in the chemotherapy plus placebo group and 69 (31%) of 226 in the chemotherapy plus erlotinib group. The most common grade 3 or greater adverse events were neutropenia (65 [29%] patients and 55 [25%], respectively), thrombocytopenia (32 [14%] and 31 [14%], respectively), and anaemia (26 [12%] and 21 [9%], respectively). INTERPRETATION: Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status. FUNDING: F Hoffmann-La Roche.

Circulating miR-10b, soluble urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 as predictors of non-small cell lung cancer progression and treatment response.

BACKGROUND: Despite advances in lung cancer treatment, most lung cancers are diagnosed at an advanced stage. Expression of microRNA10b (miR-10b) and fibrinolytic activity, as reflected by soluble urokinase-type plasminogen activator receptor (suPAR) and plasminogen activator inhibitor 1 (PAI-1), are promising biomarker candidates. OBJECTIVE: To assess the expression of miR-10b, and serum levels of suPAR and PAI-1 in advanced stage non-small cell lung cancer (NSCLC) patients, and their correlation with progression, treatment response and prognosis. METHODS: The present prospective cohort and survival study was conducted at Dharmais National Cancer Hospital and included advanced stage NSCLC patients diagnosed between March 2015 and September 2016. Expression of miR-10b was quantified using qRT-PCR. Levels of suPAR and PAI-1 were assayed using ELISA. Treatment response was evaluated using the RECIST 1.1 criteria. Patients were followed up until death or at least 1 year after treatment. RESULTS: Among the 40 patients enrolled, 25 completed at least four cycles of chemotherapy and 15 patients died during treatment. Absolute miR-10b expression ⩾ 592,145 copies/µL or miR-10b fold change ⩾ 0.066 were protective for progressive disease and poor treatment response, whereas suPAR levels ⩾ 4,237 pg/mL was a risk factor for progressive disease and poor response. PAI-1 levels > 4.6 ng/mL was a protective factor for poor response. Multivariate analysis revealed suPAR as an independent risk factor for progression (ORa⁢d⁢j, 13.265; 95% confidence intervals (CI), 2.26577.701; P= 0.006) and poor response (ORa⁢d⁢j, 15.609; 95% CI, 2.221-109.704; P= 0.006), whereas PAI-1 was an independent protective factor of poor response (ORa⁢d⁢j, 0.127; 95% CI, 0.019-0.843; P= 0.033). CONCLUSIONS: Since miR-10b cannot be used as an independent risk factor for NSCLC progression and treatment response, we developed a model to predict progression using suPAR levels and treatment response using suPAR and PAI-1 levels. Further studies are needed to validate this model.

Evaluation of safety and effectiveness of remdesivir in treating COVID-19 patients after emergency use authorization study.

Background: This study aimed to determine the real-world safety and effectiveness of remdesivir in hospitalized adult COVID-19 patients with moderate-to-critical disease in Indonesia. Methods: A multicenter, retrospective cohort study was conducted at four COVID-19 referral hospitals in Jakarta. A total of 587 patients were included, of whom 243 received remdesivir within 72 h of admission. The safety endpoints were the proportions of patients with any adverse event (AE), any grade 3 AE, and AE of each system organ class. The effectiveness endpoints were ICU admission >24 h from baseline, live discharge and mortality at day 14, live discharge and mortality at day 28, and virologic conversion. Patients who received remdesivir within 72 h of admission were considered the treatment group, and those who did not were the control group. Multivariate adjustments were performed using a modified Poisson regression. Results: The study found no significant differences in safety endpoints between the two groups. However, the effectiveness endpoints showed that remdesivir was associated with a decreased risk of ICU admission >24 h from baseline (RR 0.71, 95% CI 0.52-0.96), an increased probability of live discharge at day 14 (RR 1.37, 95% CI 1.08-1.74), and an increased probability of live discharge at day 28 (RR 1.28, 95% CI 1.05-1.57). The rate of virologic conversion was not significantly different between the two groups. Conclusion: The study concludes that remdesivir is safe and effective in the treatment of moderate-to-critical COVID-19 in a real-world setting in Indonesia.

Clinical utility and diagnostic value of tumor-educated platelets in lung cancer: a systematic review and meta-analysis.

Background: The review addresses the knowledge gap concerning the diagnostic value and clinical utility of tumor-educated platelets (TEPs) in adult patients with lung cancer. Methods: We searched twelve databases: PubMed, CENTRAL, EMBASE, CINAHL, MEDLINE, Scopus, ProQuest, MedRxiv, BioRxiv, SSRN, Clinicaltrials.gov, and CNKI up to 24 March 2023, to include any diagnostic study regarding TEPs and LC. TEPs diagnostic value was evaluated from pooled sensitivity and specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the curve (AUC). QUADAS 2 was used to assess the risk of bias. Heterogeneity analysis was assessed using the receiver operating characteristic (ROC) plane, Galbraith plot, bivariate boxplot, sensitivity analysis, and meta-regression. TEPs clinical utility was evaluated from Fagan's nomogram. Results: 44 reports from 10 studies, including 7,858 events and 6,632 controls, were analyzed. The pooled sensitivity, specificity, PLR, NLR, and DOR were 0.80 (95% CI 0.79-0.80), 0.69 (95% CI 0.69-0.70), 2.92 (95% CI 2.50-3.41), 0.26 (95% CI 0.21-0.32), and 12.1 (95% CI 8.61-16.76), respectively. In addition, the AUC of the Summary ROC curve was 0.85 (95% CI: 0.81-0.88). The overall risk of bias was low. Heterogeneity may result from cancer stage, cancer control, measuring equipment, and RNA types across studies. There was no apparent publication bias (p=0.29) with significant positive (79%) and negative (22%) post-test probability, according to Deeks funnel plot asymmetry test and Fagan's nomogram. Conclusion: TEPs could be a moderately effective candidate biomarker for LC diagnosis.

Real-world clinical practice and outcomes in treating stage III non-small cell lung cancer: KINDLE-Asia subset.

Introduction: Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease requiring multimodal treatment approaches. KINDLE-Asia, as part of a real world global study, evaluated treatment patterns and associated survival outcomes in stage III NSCLC in Asia. Methods: Retrospective data from 57 centers in patients with stage III NSCLC diagnosed between January 2013 and December 2017 were analyzed. Median progression free survival (mPFS) and median overall survival (mOS) estimates with two sided 95% confidence interval (CI) were determined by applying the Kaplan-Meier survival analysis. Results: Of the total 1874 patients (median age: 63.0 years [24 to 92]) enrolled in the Asia subset, 74.8% were men, 54.7% had stage IIIA disease, 55.7% had adenocarcinoma, 34.3% had epidermal growth factor receptor mutations (EGFRm) and 50.3% had programmed death-ligand 1 (PD-L1) expression (i.e. PD-L1 ≥1%). Of the 31 treatment approaches as initial therapy, concurrent chemoradiotherapy (CRT) was the most frequent (29.3%), followed by chemotherapy (14.8%), sequential CRT (9.5%), and radiotherapy (8.5%). Targeted therapy alone was used in 81 patients of the overall population. For the Asia cohort, the mPFS and mOS were 12.8 months (95% CI, 12.2-13.7) and 42.3 months (95% CI, 38.1-46.8), respectively. Stage IIIA disease, Eastern Cooperative Oncology Group ≤1, age ≤65 years, adenocarcinoma histology and surgery/concurrent CRT as initial therapy correlated with better mOS (p < 0.05). Conclusions: The results demonstrate diverse treatment patterns and survival outcomes in the Asian region. The high prevalence of EGFRm and PD-L1 expression in stage III NSCLC in Asia suggests the need for expanding access to molecular testing for guiding treatment strategies with tyrosine kinase inhibitors and immunotherapies in this region.

Bronchoscopy Laser and Silicone Y-Stents as Emergency Airway Management in Central Airway Stenosis Due to Secondary Thyroid Carcinoma: A Case Report.

Total airway obstruction in thyroid cancer is rare and has high morbidity and mortality. Airway management in such cases is challenging, especially in cases in which thyroid masses cannot be totally resected. It is important to choose the appropriate airway treatment modality. Currently, therapeutic rigid bronchoscopy procedures and endoluminal lasers, as well as airway stent insertion, are a management modality of near-total malignant airway obstruction. We report a rigid bronchoscopy procedure combined with laser and Y-stent silicone insertion in thyroid cancer with extension infiltration, as well as compression in the trachea covering the subglottic tracheal area up to the main carina and tracheo-bronchomalacia, manifesting as acute respiratory failure.

TP53 and EGFR Mutational Status in Thymoma: A Genetic Sequencing Study.

BACKGROUND AND OBJECTIVE: Thymoma is a rare malignant tumor that usually with an indolent presentation, which was falsely assumed to be benign previously. The tumor suppressor P53 (TP53) and EGFR gene mutate most frequently in human cancers. We tried to investigate the presence of TP53 and EGFR mutations among thymoma patients referred to an Indonesian referral respiratory hospital and to discuss its potential role in thymoma management and prognosis. MATERIAL AND METHODS: Surgically resected tumor tissues were collected from thymoma patients and then underwent genomic analysis. PCR was performed on the extracted Paraffinized  DNA to amplify exon 6 of TP53 and exons 18, 19, and 21 of EGFR. The evaluation of mutational status was done using direct sequencing and sequence analysis of purified PCR products. RESULTS: Among 27 collected samples, TP53 exon 6 mutation, namely  missense mutation and nonsense mutation, was observed in two samples (7.4%). EGFR exon 18 mutation, namely E709K and nonsense mutation, was found in 2 samples (7.4%). An intronic mutation in EGFR exon 19 (3.7%) and exon 21 (3.7%) was observed in one sample. CONCLUSION: TP53 and EGFR mutations were not most frequent, so it seems that these genes are not involved in the pathogenesis of thymoma in Indonesian patients. Nevertheless, we found two samples with a significant mutation in p53 and EGFR genes, suggesting further research on thymoma prognostification and targeted therapy.

Therapeutic bronchoscopy followed by sequential radiochemotherapy in the management of life-threatening tracheal adenoid cystic carcinoma: a case report.

BACKGROUND: Adenoid cystic carcinoma of the lung is a distinctive salivary-gland-type malignant epithelial neoplasm that rarely presents as a primary tumor of the respiratory tract. Complete surgical resection remains the treatment of choice for adenoid cystic carcinoma. We present a case of large ACC tumors that caused severe central airway obstruction and were effectively treated with therapeutic bronchoscopy followed by radiotherapy and chemotherapy. CASE PRESENTATION: A 31-year-old Malay Indonesian female patient who was a nonsmoker and had no family history of cancer was admitted to the emergency ward because of worsening breathlessness accompanied by stridor since 1 week prior. Chest computed tomography revealed segmental atelectasis of the left lung; a mass on the left main bronchus, with infiltrates in segments 1, 2, and 3 of the left lung; and consolidation in the left inferior lobe, with narrowing of the main left bronchus. Lobulated masses obstructing almost the entire distal trachea up to the carina and the entire left main bronchus were found on bronchoscopy. Owing to the large tumors causing severe central airway obstruction, the medical team decided to perform central airway mass removal through rigid bronchoscopy. A neodymium-doped yttrium-aluminum-garnet laser was used first to facilitate mass shrinkage. After the laser treatment, mechanical mass removal using a rigid scope was performed. The tracheal and carinal lumens were opened to > 50% of their diameter, with the left main bronchus lumen opened only slightly. After the treatment, the patient was stable, and no stridor was found. Adjuvant intensity-modulated radiotherapy and chemotherapy were performed after the therapeutic bronchoscopy. At the end of the entire treatment, reevaluation by thoracic computed tomography scan and bronchoscopy revealed no remaining mass. CONCLUSIONS: In cases of nonresectable large adenoid cystic carcinoma tumors with life-threatening central airway obstruction, therapeutic bronchoscopy followed by sequential radiochemotherapy might achieve a complete response outcome.

Pneumocystis jirovecii colonization in bronchoalveolar lavage among naïve non-small cell lung cancer from tertiary respiratory hospital in Jakarta, Indonesia.

INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is a lung mycosis commonly found in immunocompromised patients (e.g., HIV patients); however, its role in solid cancer remains unclear. This study aims to identify Pneumocystis jirovecii colonization among naïve non-small-cell lung cancer (NSCLC) through bronchoalveolar lavage (BAL) and explore its correlation with clinical parameters. METHODOLOGY: This cross-sectional study recruited newly diagnosed naïve NSCLC patients who had not been given systemic treatments. We tested BAL from patients for P. jirovecii colonization with nested PCR targeting the mtLSU rRNA gene. Demographic and clinical characteristics were obtained from medical records, and the correlation between P. jirovecii colonization and clinicopathological data were analyzed. Kaplan-Meier analyses were done to evaluate survival. RESULTS: Among 56 newly diagnosed, naïve NSCLC patients enrolled, the prevalence of P. jirovecii colonization was 17.9% (10 subjects). There was no statistically significant difference in demographic and clinical characteristics between the P. jirovecii colonization group versus no colonization (p value > 0.05). The overall survival duration for both groups demonstrated no significant difference. CONCLUSIONS: This study demonstrated a relatively high prevalence of P. jirovecii colonization among BAL samples of naïve Indonesian NSCLC patients. Further study is needed to delineate its implications for the potential transmission source, lung cancer pathogenesis, and prognosis.

The Absence of Mutations in the Exon 2 KRAS Gene in Several Ethnic Groups in North Sumatra May Not the Main Factor for Lung Cancer.

BACKGROUND: Rat Sarcoma (RAS) protein encoded Guanosine Triphosphate (GTP-ase) activity, known as a switch of cell proliferation. The mutation of this protein alters the early stage of carcinogenesis and along with the interaction with other oncogene drivers and environmental factors affect the clinical characteristics and prognosis in cancer patients, particularly lung cancer. OBJECTIVE: This study aims to determine the Kristen Rat Sarcoma (KRAS) mutation in lung cancer patients in North Sumatera and evaluate factors that might contribute in the development of lung cancer in the absence of KRAS mutation. METHODS: This was a retrospective cohort study enrolled 44 subjects age > 18 year with the diagnosis of lung cancer. Histopathology preparation was obtained from surgery, bronchoscopy, and percutaneus needle biopsy then formed as paraffin-block. KRAS mutation was analyzed using Polymerase Chain Reaction (PCR) method with specific primer of exon 2 for evaluating the expression of RAS protein then continued with Sanger Sequencing Method at 12th and 13th codon. RESULTS: The majority of subjects were male, age > 40 years old, bataknese, heavy smoker, with Adenocarcinoma. Almost all the subjects showed the expression of exon 2 of RAS protein in PCR examinations. However, Sequencing analysis using Bioedit Software, BLASTs and Finch T showed GGT GGC as protein base 219-224 which represented 12th and 13th Codon 12 and 13. The results interpreted there was no mutations of exon 2 of KRAS in North Sumatera Population. CONCLUSION: The absence of KRAS mutation in exon 2 in several ethnics in North Sumatera populations was not the main factors of lung cancer.

Excess Risk of Lung Cancer Among Agriculture and Construction Workers in Indonesia.

Background: In Indonesia, many occupations and industries involve a variety of hazardous and toxic materials. The ILO estimates that about 21.1% of the tracheal, bronchial, and lung cancer deaths among men were attributable to workplace hazardous substances. This study investigated the relationship between occupations or workplace exposure and the risk of lung cancer in the country. The results will help determine how Indonesia can best mitigate the risk for its workers. Objectives: This case-control study utilizes the Indonesian Standard of Industrial Classification (IndSIC) 2015 with the aim of exploring the risk of lung cancer among Indonesian workers. Methods: The study included patients aged 35 years old or older receiving thoracic CT at the radiology department of Persahabatan Hospital. The cases were histological-confirmed primary lung cancers, while the controls were negative thoracic CT scan for lung cancer. The subjects' job titles and industries were classified according to IndSIC 2015 and blind to the patient's grouping as a case or control. Logistic regression was used to determine the odds ratios for lung cancer among all sections and some divisions or groups of IndSIC 2015. Findings: The mean age was 58.1 (±10.23) years for lung cancer patients and 54.5 (±10.23) years for controls. The majority of subjects (19.6%) worked in Section G (Wholesale and retail trade; repair of motor vehicles and motorcycle). After adjusting for age, gender, level of education, and smoking habit, the risk of lung cancer was nearly three-times higher (OR = 2.8, 95% CI = 1.11-7.02) in workers of Division A01 (crop, animal production, and hunting) and two-times higher (OR = 1.9, 95% CI = 1.05-3.46) in workers of Section F (construction) compared to the workers in other sections or divisions. Conclusions: The excess risk of lung cancer among certain categories of workers confirms the need for improved policy, monitoring, and control of occupational exposure for primary cancer prevention and workers' compensation purposes.

Asbestos-Related Lung Cancer: A Hospital-Based Case-Control Study in Indonesia.

Indonesia has limited data on asbestos-related diseases despite abundant use. This study investigated the risk of occupational asbestos exposure for lung cancer development, utilizing a hospital-based case-control study. Subjects were patients who received a thoracic CT scan at Persahabatan Hospital, Jakarta. The cases had primary lung cancer confirmed by histology, the controls were negative for lung cancer. The cumulative occupational asbestos exposure was calculated by multiplying the exposure intensity by the years of exposure. The exposure intensity was obtained by adopting the weighted arithmetic mean value of asbestos exposure from a job-exposure matrix developed in Korea. The primary data analysis was based on logistic regression. The study included 696 subjects, with 336 cases and 360 controls. The chance of lung cancer for subjects exposed to asbestos was doubled (OR = 2.04, 95% CI = 1.21-3.42) compared with unexposed, and subjects with a cumulative asbestos exposure of 10 fiber-years or more even showed an OR of 3.08 (95% CI = 1.01-9.46). The OR of the combined effect between smoking and asbestos was 8.7 (95% CI = 1.71-44.39); the interaction was consistent with an additive and multiplicative risk model. Asbestos exposure is associated with a higher chance of lung cancer. Improved policies are needed to protect the population from asbestos hazards.

Evaluation of PCR-HRM, RFLP, and direct sequencing as simple and cost-effective methods to detect common EGFR mutations in plasma cell-free DNA of non-small cell lung cancer patients.

BACKGROUND: Lung cancer patients with mutations in epidermal growth factor receptor (EGFR) gene are treated with tyrosine kinase inhibitor (TKI). AIMS: We aimed to evaluate polymerase chain reaction (PCR)-high-resolution melting (HRM), restriction fragment length polymorphism (RFLP), and direct sequencing (DS) to detect EGFR mutations in cell-free DNA (cfDNA) before and after TKI treatment in real-world settings of a developing country. METHODS: Paired cytology and plasma samples were collected from 116 treatment-naïve lung cancer patients. DNA from both plasma and cytology specimens was isolated and analyzed using PCR-HRM (to detect exon 19 insertion/deletion), RFLP (to genotypes L858R and L861Q), and DS (to detect uncommon mutations G719A, G719C, or G719S [G719Xaa] in exon 18 and T790M and insertion mutations in exon 20). RESULTS: EGFR genotypes were obtained in all 116 (100%) cfDNA and 110/116 (94.82%) of cytological specimens of treatment-naïve patient (baseline samples). EGFR-activating mutations were detected in 46/110 (40.6%) plasma samples, and 69/110 (63.2%) mutations were found in routine cytology samples. Using cytological EGFR genotypes as reference, we found that sensitivity and specificity of baseline plasma EGFR testing varied from 9.1% to 39.39% and 83.12% to 96.55%, respectively. In particular, the sensitivity and specificity of this assay in detecting baseline T790M mutations in exon 20 were 30% and 89.58%, respectively. Three months after TKI treatment, plasma T790M and insertion exon 20 mutations appeared in 5.4% and 2.7% patients, respectively. CONCLUSIONS: Despite low sensitivity, combined DS, RFLP, and PCR-HRM was able to detect EGFR mutations in plasma cfDNA with high specificity. Moreover, TKI resistance exon 20 insertions mutation was detected as early as 3 months post TKI treatment.

Impact of smoking on frequency and spectrum of K-RAS and EGFR mutations in treatment naive Indonesian lung cancer patients.

Background: Indonesia has the highest cigarette consumption in the world. We explored the clinical impact of smoking on the prevalence of EGFR and K-RAS mutations and survival in this prospective study. Methods: 143 treatment naive lung cancer patients were recruited from Persahabatan Hospital, a national tertiary hospital. DNA from cytological specimens had been extracted and genotyped for both EGFR and K-RAS mutations using a combination of PCR high resolution melting, restriction fragment length polymorphism (RFLP) and direct DNA sequencing. Results: EGFR mutation frequency in never smokers (NS) and ever smokers (ES) were 75% and 56% (p = 0.0401), respectively. In this cohort, the overall K-RAS mutation rate was 7%. Neither gender nor smoking history were associated with K-RAS mutation significantly. However, K-RAS transversion mutations were more common in male ES than transition mutations. Smoking history did not affect EGFR and K-RAS mutation frequencies in women. Concurrent EGFR/K-RAS mutation rate was 2.8% (4 of 143 patients). Four out of 91 EGFR mutation positive patients (4.4%) had simultaneous K-RAS mutation. Conclusions: In region where cigarette consumption is prevalent, smoking history affected frequencies of EGFR and K-RAS mutations, mainly in males.

Efficacy of gefitinib and radiotherapy combination in Indonesian patients with lung adenocarcinoma.

INTRODUCTION: Combinations of gefitinib and radiotherapy have been observed to have synergistic and anti-proliferative effects on lung cancer in vitro. In the clinical setting, patients who presented with respiratory difficulties such as superior vena cava syndrome (SVCS), radiotherapy should be given immediately to address the emergency while waiting for the results of epidermal growth factor receptor (EGFR) mutation test. However, there has been no study that described the role of radio-therapy in Indonesian patients with EGFR-mutant lung adenocarcinoma. METHODS: This preliminary study aimed to evaluate the efficacy and toxicities of gefitinib and radiotherapy combination in lung adenocarcinoma patients in Persahabatan National Respiratory Referral Hospital, Jakarta, Indonesia. Subjects were consecutively recruited between January 2013 and December 2016. RESULTS: Thirty-one lung adenocarcinoma with EGFR mutations were enrolled. Most of them were male (51.61%) with a median age of 54.5 years old (range 38-70 years old). EGFR mutation characteristics were on exon 21 L858R point mutation (61.30%), exon 21 L861Q point mutation (16.12%) and exon 19 deletion (22.58%). Radiotherapy was given at doses between 30-60 Gy. Among these subjects, median progression-free survival (PFS) was 185 days (95%CI; 123.69 - 246.30), 1-year survival rate (1-yr) was 45.2%, and median overall survival (OS) was 300 days (95%CI; 130.94 - 469.06). There were no grade 3/4 hematological and nonhematological toxicities recorded. The most frequent grade 1 and 2 non-hematological toxicities were skin rash, diarrhea, and paronychia that might be related to tyrosine kinase inhibitor (TKI). CONCLUSION: The combination of TKI with radiation may be considered in EGFR-mutant lung adenocarcinoma subjects.

Genetic Polymorphism of CYP2A6 and Its Relationship with Nicotine Metabolism in Male Bataknese Smokers Suffered from Lung Cancer in Indonesia.

BACKGROUND: Cytochrome P450 2A6 (CYP2A6) is known as an enzyme which is responsible for the metabolism of chemical compounds. AIM: This study aimed to analyse the relationship between CYP2A6 gene polymorphism with nicotine metabolism rates and lung cancer incidence among smokers of Batak ethnic group in Indonesia. METHODS: This study was a case-control study involving 140 research subjects through a purposive sampling technique from three hospitals in Medan, Indonesia. An examination of nicotine metabolism rates was conducted for all subjects using the 3HC/cotinine ratio parameter with LC-MS/MS technique. The examination of the CYP2A6 gene was performed with PCR-RFLP. Data were analysed with Conditional Logistic Regression test using Epi Info 7.0 software. RESULTS: The allele frequencies of CYP2A6*1A, CYP2A6*1B, and CYP2A6*4A found were 44.3%, 48.9%, and 6.8%, respectively. The *1B allele showed the highest metabolism rate. It is found that slow metabolizer individuals were 5.49 times more likely to develop lung cancer (P = 0.01, 95%CI 1.2-24.8). CONCLUSION: Among the Bataknese smokers studied, the CYP2A6*1B allele was found to be the most common allele and showed the highest rate of nicotine metabolism. However, the results show the insignificant relationship among CYP2A6 genetic polymorphism, nicotine metabolism, and lung cancer incidence.

The Role of CYP2A6 Genetic Polymorphism in Nicotine Dependence and Tobacco Consumption among Bataknese Male Smokers.

AIM: This research aimed to analyse the relationship between CYP2A6 gene polymorphism with nicotine dependence and its relation to the number of cigarette consumption among Bataknese smokers. METHOD: This study was a cross-sectional study involving 140 research subjects in Medan, Indonesia. RESULTS: Nicotine dependence rates were found to be significantly associated with the number of cigarette consumption expressed in the Brinkman Index. CONCLUSION: The *1A wild-type alleles have a greater risk of high-very high dependence rate compared to the other variants.

Uncommon EGFR mutations in cytological specimens of 1,874 newly diagnosed Indonesian lung cancer patients.

PURPOSE: We aimed to evaluate the distribution of individual epidermal growth factor receptor (EGFR) mutation subtypes found in routine cytological specimens. PATIENTS AND METHODS: A retrospective audit was performed on EGFR testing results of 1,874 consecutive cytological samples of newly diagnosed or treatment-naïve Indonesian lung cancer patients (years 2015-2016). Testing was performed by ISO15189 accredited central laboratory. RESULTS: Overall test failure rate was 5.1%, with the highest failure (7.1%) observed in pleural effusion and lowest (1.6%) in needle aspiration samples. EGFR mutation frequency was 44.4%. Tyrosine kinase inhibitor (TKI)-sensitive common EGFR mutations (ins/dels exon 19, L858R) and uncommon mutations (G719X, T790M, L861Q) contributed 57.1% and 29%, respectively. Approximately 13.9% of mutation-positive patients carried a mixture of common and uncommon mutations. Women had higher EGFR mutation rate (52.9%) vs men (39.1%; p<0.05). In contrast, uncommon mutations conferring either TKI responsive (G719X, L861Q) or TKI resistance (T790M, exon 20 insertions) were consistently more frequent in men than in women (67.3% vs 32.7% or 69.4% vs 30.6%; p<0.05). Up to 10% EGFR mutation-positive patients had baseline single mutation T790M, exon 20 insertion, or in coexistence with TKI-sensitive mutations. Up to 9% patients had complex or multiple EGFR mutations, whereby 48.7% patients harbored TKI-resistant mutations. One patient presented third-generation TKI-resistant mutation L792F simultaneously with T790M. CONCLUSION: Routine diagnostic cytological techniques yielded similar success rate to detect EGFR mutations. Uncommon EGFR mutations were frequent events in Indonesian lung cancer patients.

Adenocarcinoma of the lung with positive epidermal growth factor receptor mutation in pregnancy.

Lung cancer during pregnancy is a rare condition. We report a case of 28-year-old nonsmoker female, who was admitted to our hospital with massive left pleural effusion in the 21st week of gestation. Chest radiograph showed total left hemithorax opacity with contralateral mediastinal deviation. Pleural biopsy and cytological examination of pleural fluid revealed adenocarcinoma invasion with positive epidermal growth factor receptor mutation status. Cesarean section was performed at 32 weeks of pregnancy, and targeted therapy was given to this patient after delivery. Computed tomography of the thorax showed a mass lesion in the left hemithorax with liver metastases. Unfortunately, the patient died 10 days after delivery.