Clinical Effectiveness of Erlova in EGFR-Mutated Non-Small Cell Lung Cancer: An Affordable Price with Clinical Benefit.

BACKGROUND: Thyrosin kinase inhibitors (TKIs) is approved for the first line treatment of non-small cell lung cancer (NSCLC) patients with  epidermal growth factor receptor (EGFR) mutation. This study performed to assess clinical effectiveness and safety of Erlova (generic form of Erlotinib). METHODS: Somatic mutations of EGFR gene were studied in tumor tissue by polymerase chain reaction (PCR) and bi-directional sequencing in 513 chemonaive and histologically verified lung adenocarcinoma Iranian patients. Patients  with EGFR mutation received Erlova at 150 mg/day  as first line treatment. Primary endpoint was progression free survival (PFS). RESULTS: About 21% (n=109) cases had EGFR mutation. Most EGFR mutations were  occurred at exon 19. Among them, sixty nine patients treated with Erlova. Median PFS was 11.4 months and objective response rate (ORR) was about  88%. Most frequent treatment related adverse events was  skin rash. CONCLUSION: Our findings showed Erlova had remarkable effectiveness. In  mutation-positive patients with EGFR, Erlova can be used  safely instead of  other tyrosine-kinase inhibitors.

T790M and Acquired Resistance of Epidermal Growth Factor Receptor to Tyrosine Kinase Inhibitors in Patients with Lung Adenocarcinoma.

Background: Activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to tyrosine kinase inhibitors (TKIs), but responses to TKIs is not permanent and drug resistance eventually happens for almost all patients. Subsequent studies found different resistance mechanisms, among which (EGFR) T790M mutation is the most important mechanism of TKI treatment failure. Using cell-free DNA (cfDNA) is a new way for diagnosing resistance mutations in EGFR. The aim of present study is to determine cfDNA-identified recurrence mutation rate and their association with clinical outcome in lung Adenocarcinoma patients. Materials and Methods: Patients who were diagnosed with metastatic adenocarcinoma of the lung and acquired resistance to TKIs were enrolled. The incidence of T790M positivity, overall survival (OS) and median duration of TKI treatment before progression was calculated. Polymerase chain reaction (PCR) and sequencing were used to identify the T790M mutation in cfDNA. Results: The incidence of T790M mutations was higher in men, younger cases (<59 years), in patients with L858R primary mutation and never smokers although they were not significantly different (P-values= 041, 0.316, 0.316 and 0.158, respectively). There was significant longer OS in the Del19 subgroup than the L858R subgroup (p = 0.014). In multivariable analysis, significant longer OS was associated with younger age (<59 years) and primary EGFR mutation exon 19 (P-values= 0.028 and 0.050, respectively). Conclusion: T790M mutations frequency may differ by ethnicity, genetic factors and EGFR primary mutations. Detecting T790M mutations in plasma is considered as an indicator of treatment with third generation EGFR-TKIs.

Cell Free Tumoral DNA Versus Paraffin Block Epidermal Growth Factor Receptor Mutation Detection in Patients with Non-Small Cell Lung Cancer.

Increasing knowledge about the molecular profile of tumors has led to personalized treatment for achieving better outcomes in patients with nonsmall cell lung cancer (NSCLC). Currently, finding exact somatic genomic changes of tumor has gained great importance. On the other hand, crescendoing needs to actual tumor tissue at different time points during cancer treatment may produce major discomfort for NSCLC patients. Tumor genomes can be reconstructed by information obtained from circulating cell-free deoxyribonucleic acid (cfDNA) of peripheral blood. cfDNA may be represented as a suitable alternative test  for epidermal growth factor receptor (EGFR) mutation detection in these patients. This study aimed to assess validity of cfDNA in somatic EGFR mutation identification in Iranian NSCLC cases. METHODS: Somatic mutation of EGFR gene was studied in both tissue specimens and plasma. Then, mutations were detected by polymerase chain reaction(PCR) and sequencing. RESULTS: We observed a high concordance (90%) between tissue samples and cfDNA for EGFR gene mutation.  The sensitivity, accuracy, and positive precision value were 90%, 90% and 100%, respectively. A false negative rate of 10% was also demonstrated in this study. CONCLUSION: We established sensitive methods for detecting EGFR gene mutation which may be very useful in clinical practice.
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Circulating free DNA concentration as a marker of disease recurrence and metastatic potential in lung cancer.

BACKGROUND: Plasma circulating cell-free (cf) DNA is regarded as a source of tumor DNA. Based on availability of blood tissue for the purposes of early detection of cancer and patients' follow-up, several studies have evaluated concentration of cf DNA in cancer patients in association with tumor features. In the present study, we assessed concentration of cf DNA in lung cancer patients with two commercial kits (MN and QIAGEN) to find whether it can be used as a prognostic biomarker. RESULTS: Primary cf DNA concentrations as measured by QIAGEN kit was significantly higher in patients who died in the follow-up period compared with alive patients (P = 0.007). Moreover, the concentrations as measured by both methods were higher in patients who experienced recurrence in the follow-up period compared with patients without recurrence (P = 0.008 and 0.007 for MN and QIAGEN kits respectively). Significant associations were also found between cf DNA concentrations and tumor stage (P = 0.005 and 0.02 for MN and QIAGEN kits respectively). Notably, cf DNA concentration was higher in metastatic tumors compared with non-metastatic tumors in association with number of involved organs. Based on the AUC values, both kits could differentiate metastatic cancers from non-metastatic ones with accuracy of 98%. CONCLUSIONS: The current study highlights the accuracy of cf DNA concentrations for prediction of disease course in lung cancer patients.

Thymoma Recurrence and its Predisposing Factors in Iranian Population: a Single Center Study.

BACKGROUND: Thymoma is relatively rare tumor. Prognosis and patients' outcome vary across different studies. We aimed to study the predisposing factors causing tumor recurrence in thymoma patients. MATERIALS AND METHODS: A total of 43 thymoma or thymic carcinoma patients treated at the National Institute of Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital from September 2005 to January 2017 were evaluated. The primary endpoint was the progression free survival (PFS). The relation of predisposing factors to PFS was studied. RESULTS: Median age was 55 years old. The mean of follow-up duration was 22.9 months. The most prevalent pathology was thymoma unspecified. Pure red cell aplasia (n=3, 6.9%) was the most prevalent Para neoplastic syndrome. Most of the patients (n=23, 54%) were in stage III and IV Masaoka-Koga staging system. Disease progression was observed in 17 patients (39. 5%). Most recurrences occurred locally. None of demographic characteristics differed between patients who experienced disease recurrence and those who did not. After univariate and multivariate analysis, predisposing factor for disease progression was only Masaoka-Koga stage (P-value=0.015 and 0.031 respectively). CONCLUSION: In this study, among different probable predisposing factors, only Masaoka-Koga stage had significant effect on disease recurrence. Large case-control studies may be required for better evaluation of risk factors.

A Phase IV Efficacy Study of Formeta Plus Carboplatin as First-Line Treatment of Advanced Non-Squamous, Non-Small Cell Lung Cancer in Iran: An Affordable Price with Clinical Benefit

Background: This study performed to assess the efficacy and safety of Formeta (generic form of Pemetrexed) plus Carboplatin as first-line chemotherapy in advanced stage, non- squamous, non small cell lung cancer ( NSCLC) in Iran. Methods: This was a post marketing single-arm phase IV efficacy study of Formeta (manufactured by Oncomed.,Czech Republic ) and Carboplatin in chemo-naive advanced non-squamous NSCLC Iranian patients. Patients received up to six cycles of Formeta (500 mg/m2) combined with Carboplatin (area under the curve: AUC 5) every 3 weeks. The primary endpoint was the progression free survival (PFS) and secondary endpoints were safety and overall survival (OS). Results: Fifty-two patients were enrolled between June 2014 to January 2016, and 44 patients were evaluable for both safety and efficacy. Partial and complete responses were achieved in 19 (36.5 %) and 2 (3.8%) patients, respectively as well as stable disease in 8 patients (15.3 %). Median of PFS and OS were 7.9 ± 1.1 months and 12.43±0.6 months, respectively. Anemia was the most prevalent adverse events of this regimen. Grades 3 or 4 of adverse events were not observed in any patients. Non-hematologic and other grades of hematologic toxicities were generally mild, and there were no treatment-related deaths. Conclusion: The combination of Formeta and Carboplatin was effective in advanced non-squamous NSCLC and can be a suitable candidate as first-line treatment in these patient's population.

Human endogenous retrovirus env genes: Potential blood biomarkers in lung cancer.

Lung cancer, the leading cause of cancer mortality, needs urgent development of newly qualified diagnostic and therapeutic biomarkers. Recently, Human Endogenous Retroviruses (HERVs) have been introduced for cancer diagnosis. In this case-control study, we have collected blood samples from 60 lung cancer patients and 20 healthy controls. Quantitative gene expression analysis of various HERV env genes, including HERV-R, HERV-H, HERV-K, and HERV-P was performed by real-time PCR. Results indicate that expression of all four HERV env mRNAs is significantly increased in the blood of lung cancer patients than healthy controls (P-values<0.01). Furthermore, we have observed a positive and significant pairwise correlation between the expressions of four HERV env genes. The level of HERV env transcript in the blood of adenocarcinoma patients was generally much higher than squamous cell carcinoma (SCC) and small-cell lung cancer (SCLC) patients. Also, the expression of three HERV P, HERV H, and HERV K in the blood of lung cancer patients could significantly differentiate between adenocarcinoma and other types of lung cancer. In conclusion, these four HERV families could be considered as promising non-invasive blood-based biomarkers for prognosis, early detection, and monitoring of lung cancer.

Correlation of Minichromosome Maintenance Protein 6 Expression Rate and Clinical Outcome in Patients With Hodgkin's Lymphoma.

Minichromosome maintenance complex component 6 (MCM-6) is one of the six proteins of the MCM family, which are involved in the initiation of DNA replication, represents a marker of proliferating cells. The goal of this study was to evaluate the prognostic relevance of the neoplastic cell proliferation rate in patients with Hodgkin's lymphoma (HL). We evaluated the formalin-fixed paraffin-embedded lymph node biopsy specimens from 55 patients by using monoclonal antibody against MCM-6 and compared these findings with clinical data and treatment outcome. Median of MCM-6 expression was 85% (range: 35%-99%). In multivariate analysis, MCM-6 expression, B symptoms, and age were not statistically significant predictor for relapse in contrary to response (P=.001) and stage of disease (P=.048). Patients with lower MCM-6 expression rates showed higher relapse rate and lower disease-free survival (DFS). Meanwhile, patients with MCM-6 expression less than 85% showed shorter DFS (P=.031). We hypothesize that in group of patients with lower MCM-6 expression rate, a larger proportion of proliferating malignant cells are arrested in the very early phase of mitosis, in comparison to the group of patients with higher MCM-6 expression, and this could imply a shorter and probably higher relapse rate in the former group.

Analysis of Cisplatin-Induced Ototoxicity Risk Factors in Iranian Patients with Solid Tumors: a Cohort, Prospective and Single Institute Study

Background: Cisplatin has been associated with irreversible hearing damage. Up to now, there is no therapeutic intervention showing benefit in preventing Cisplatin-induced ototoxicity. The aim of this study was to determine risk factors contributing to hearing impairment after cisplatin administration in Iranian patients. Methods: Hearing thresholds of 124 patients before and after cisplatin administration were assessed with reference to pure-tone audiometry averages at several frequencies from 2006 to 2010. Mean values were calculated at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Hearing impairment was assessed with the Münster score. Results: The mean age at diagnosis and the median cumulative Cisplatin dose were 47.3 years and 453.8 milligrams, respectively. Bilateral hearing loss, mostly of grade 1, and tinnitus were detected in 26% and 3.2% of patients. Logistic regression analysis showed that a high cumulative dose of cisplatin was the most important risk factor for developing hearing damage (P=0.034). The most significant changes in the status of the auditory system and the most severe threshold shift from base line (35 dB) were observed at a frequency of 8 kHz. Also, patients who received higher individual doses of Cisplatin showed significantly more tinnitus (P=0.002). Conclusions: The results are testament to benefits of routine audiometric monitoring program during cisplatin-based chemotherapy. Further research should be performed to understand other risk factors, such as genetic predictors of Cisplatin-induced ototoxicity.

Prospective Randomized Phase II Parallel Study of Vinorelbine Maintenance Therapy versus Best Supportive Care in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Maintenance strategy has been used to improve survival in non-small cell lung cancer (NSCLC). We investigated whether switch maintenance therapy with vinorelbine improved progression free survival (PFS) after first-line chemotherapy with gemcitabine plus carboplatin. MATERIALS AND METHODS: In this single blind, parallel, phase 2, randomized trial, patients with NSCLC pathology, age >18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-2, and advanced stage (IIIB and IV) were treated with up to 6 cycles of gemcitabine 1250 mg/m2 (day 1 and 8) plus carboplatin AUC 5 (day 1) every 3 weeks. Patients who did not show progression after first-line chemotherapy were randomly assigned to receive switch maintenance with vinorelbine (25 mg/m2, day 1, 15) or the best supportive care until disease progression. RESULTS: A total of 100 patients were registered, of whom 34 had a non-progressive response to first-line chemotherapy and randomly received maintenance vinorelbine (n=19) or best supportive care (n=15). The hazard ratio of PFS in the vinorelbine group relative to the best supportive care group was 1.097 (95% confidence interval = 0.479-2.510; P-value =0.827). There was no significant difference between the overall survival for the two groups (P=0.068). CONCLUSION: Switch maintenance strategies are beneficial, but defining the right candidates for treatment is a problem. Moreover, the trial designs do not always reflect the real-world considerations. Switch maintenance therapy with vinorelbine, though had tolerable toxicity, did not improve PFS in patients with NSCLC. Therefore, other agents should be considered in this setting.

Clinicopathological Characteristics of Iranian Patients with Lung Cancer: a Single Institute Experience.

BACKGROUND: Lung cancer has long been a leading cause of cancer related death in both women and men worldwide. The focus of this study was to review clinicopathological features of Iranian patients diagnosed with lung cancer. MATERIALS AND METHODS: Clinicopathological data of 1353 primary lung cancer patients diagnosed during 17 years (1997-2014) in the "National Institute of Tuberculosis and Lung Disease" (NRITLD), Tehran, Iran, were retrospectively reviewed. RESULTS: The median age of patients was 60 (mean: 58.95 years, range: 16- 99) and adenocarcinoma was the most prevalent pathology (45.2%). Male/female ratio was 3.22 and 57.2% of patients were smokers (men 70.3%, women 15%). The majority (85.3%) were referred in advanced stages (stage IIIB and IV). CONCLUSIONS: Although some of our findings are in concordance with other studies in lung cancer there are some discrepancies particularly in terms of smoking status and median age of Iranian patients. Further clinical and epidemiological studies are warranted to elucidate etiologic and factors other than smoking contributing to development of lung cancer, such as environmental exposures or genetic predisposition.

Bilateral Lymphoblastic Lymphoma of Breast Mimicking Inflammatory Breast Cancer: A Case Report and Review of Literature.

We report a 45 year-old woman who had bilateral breast masses with extradural involvement. Pathologic report revealed malignant high-grade lymphoblastic lymphoma. Systemic chemotherapy was performed but 3 months later, lesions indicating relapse in bone and breast re-appeared. She received salvage chemotherapy, but 4 months after that she was expired.

Human epidermal growth factor receptor 2 and estrogen receptor status in respect to tumor characteristics in non-metastatic breast cancer.

BACKGROUND: The expressions of estrogen receptor (ER) and cell surface receptor, Tyrosine Kinase Human Epidermal Growth Factor Receptor 2 (HER 2), have emerged as the most important molecular biomarkers determining the breast cancer prognosis. In this study, interactions between ER and HER2 were assessed to determine if they modulate tumor characteristics. MATERIALS AND METHODS: Tissue samples from 120 patients with early stage breast cancer receiving adjuvant chemotherapy were reviewed to evaluate ER and HER2 status quantified by immunohistochemistry and fluorescence in situ hybridization, and the correlation of ER and HER2 with patient characteristics and tumor pathology was studied. RESULTS: A total of 37(30.8%) and 80(66.6%) out of 120 samples were HER2 (3+ by immunohistochemistry or positive by fluorescent in situ hybridization) and ER positive (by immunohistochemistry), respectively. ER-negative tumors were significantly more likely to be HER-2 positive than were ER-positive tumors (21.25%; odds ratio, 0.270; 95% CI, 0.119 to 0.612; P = 0.002). ER positivity was associated with <2 cm tumor size and higher histological grade (P = 0.007 and 0.019, respectively). No significant correlation was seen between the co-expression of HER2 and ER and tumor characteristics. CONCLUSION: HER2 positive tumors were less common compared to ER positive tumors in early stage breast cancer Iranian patients. Also, higher histological grade among ER negative tumors showed higher aggressiveness of the tumor. Future studies are needed to evaluate the effect of receptor status on prognosis.

Comparing docetaxel plus Cisplatin with Paclitaxel plus Carboplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer: a single institute study.

The backbone of treatment in advanced non-small cell lung cancer is platinum-based doublet chemotherapy. We intended to compare the effectiveness of two commonly used regimens in real world practice. This single institute, parallel comparative post marketing study included 100 patients with chemo-naïve advanced (stage IIIB, IV) non-small cell lung cancer and Eastern Cooperative Oncology Group performance status of 0 to 2. They were randomly assigned by stratified blocks to receive Docetaxel/Cisplatin (DC, n=50) on day 1 or Paclitaxel/Carboplatin AUC 5 (PC, n=50) on day 1, every 3 weeks for up to six cycles. Primary end point was progression free survival (PFS); secondary end points were objective response rate, overall survival (OS) and toxicity. The administered dosage could be modified according to clinician's discretion for each individual patient. PFS was similar between DC and PC arms (4.5 ± 0.3 v 4.6 ± 1.8 months, respectively; HR= 1.337; 95% CI: 0.874 to 2.046, P = 0.181). Although median overall survival for DC arm was longer (17.2 ± 4.4 m) than PC arm (10.6 ± 0.7 m) but was not statistically significant (P = 0.300). The 1-year survival rates were in favor of DC arm (53.1% v 37.9%). Objective response rates were similar in both groups. In our study, hematologic toxicity and neuropathy were more frequent in DC and PC arms, respectively. In our study two commonly used regimens of DC and PC showed statistically similar outcomes in terms of PFS and OS, albeit numerically results of OS and 1-year survival were in favor of DC arm.

Two thymus-related autoimmune disorders: a case report and review of the literature.

Thymoma is the most common tumor in the anterior mediastinum. A 56-year-old man presented unremitting and periodic chronic diarrhea of 9 weeks duration, and clinical examination revealed a huge nonhomogeneous mass lesion in the right lung and leukocytosis. He was treated with CHOP regimen (cyclophosphamide 1,200 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.5 mg/m(2), and prednisolone 75 mg/m(2) × 5 days) based on lung mass computed tomography-guided biopsy, but he was reevaluated because neither symptom improved. Surprisingly, celiac disease was documented with increased titer of immunoglobulin antibodies to gliadin and tissue transglutaminase. Lung mass rebiopsy and thymectomy demonstrated thymoma. After surgery, the patient showed aplastic anemia that responded well to cyclosporine. At 2-year follow-up, the patient's hematologic status and diarrhea were completely recovered and no symptom and/or sign of thymoma recurrence was seen.

Overexpression of HER2/neu as a Prognostic Value in Iranian Women With Early Stage Breast Cancer; A Single Institute Study.

BACKGROUND: Patients with early stage breast cancer with same treatment strategy can have markedly different outcomes. Human epidermal growth factor receptor 2 (HER2/nue) gene amplification or the subsequent overexpression of protein has been proved to be associated with patient's outcome and response to anthracyclins-based regimens. OBJECTIVES: This study assessed prognostic value of HER2/nue marker in patients with early stage breast cancer who received adjuvant chemotherapy with anthracyclins-based regimens. MATERIALS AND METHODS: Fifty tissue samples from patients with primary breast cancer of moderate risk receiving sequential adjuvant chemotherapy with anthracyclins-based regimens were assessed to evaluate HER2/nue gene status (quantified by Immunohistochemistry and fluorescence in situ hybridization) retrospectively. Besides, correlation of HER2/neu with patients' characteristics and outcome was studied. RESULTS: HER2/neu amplification was identified in 19 (38%) of 50 patients. No significant difference regarding HER2/neu status was seen in clinic pathological characteristics of patients. Although Progression Free Survival (PFS) was shorter in HER2 overexpressed group, but uni/multivariate analysis adjusted for HER2 overexpression, nodal involvement, hormone receptor status, age and tumor size revealed no significant predictive and/or prognostic value for HER2 regarding PFS. CONCLUSIONS: This study on a limited number of patients treated with adjutant anthracyclins-based regimens, revealed that HER2/neu is not a unique strong predictor for outcome, thus according to combination of HER2/neu status and other clinical factors, it is necessary to distinguish patients at high risk of recurrence.