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Background: The development of drug resistance and high mortality rates are the major problems observed in non-small cell lung cancer (NSCLC). Biomarkers indicating and predicting disease development towards these unfavorable directions are therefore on high demand. Many studies have demonstrated that changes in miRNAs expression may be associated with a response to treatment and disease prognosis, thus suggesting its potential biomarker value for a broad spectrum of clinical applications. The aim of the present study was to investigate the expression level of miR-181a-5p, miR-630, and its targets in NSCLC tumor tissue and plasma samples; and to analyze its association with NSCLC patient's response to treatment and disease prognosis., Methods: The study was performed in 89 paired tissue specimens and plasma samples obtained from NSCLC patients who underwent surgical treatment at the Department of Thoracic Surgery and Oncology of the National Cancer Institute. Analysis of miR-181a-5p and miR-630 expression was performed by qRT-PCR using TaqMan miRNA specific primers. Whereas BCL2, LMO3, PTEN, SNAI2, WIF1 expression levels were identified with KAPA SYBR FAST qPCR Kit. Each sample was examined in triplicate and calculated following the 2- ΔΔC t method. When the p-value was less than 0.05, the differences were considered statistically significant., Results: It was found that miR-181a-5p and miR-630 expression levels in NSCLC tissue and plasma samples were significantly decreased compared with control samples. Moreover, patients with low miR-181a-5p expression in tumor tissue and plasma had longer PFS rates than those with high miRNA expression. Decreased miR-630 expression in tumor was statistically significantly associated with better NSCLC patients' OS. In addition, the expression of miR-181a-5p, as well as miR-630 in tumor tissue, are the statistically significant variables for NSCLC patients' OS. Moreover, in NSCLC patient plasma samples circulating miR-181a-5p can be evaluated as significant independent prognostic factors for OS and PFS., Conclusions: Our findings indicate the miR-181a-5p and miR-630 expression levels have the potential to prognose and predict and therefore improve the treatment individualization and the outcome of NSCLC patients. Circulating miR-181a-5p has the potential clinical value as a non-invasive biomarker for NSCLC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Non-small cell cancer (NSCLC) has been identified with a great variation of mutations that can be surveyed during disease progression. The aim of the study was to identify and monitor lung cancer-specific mutations incidence in cell-free DNA as well as overall plasma cell-free DNA load by means of targeted next-generation sequencing. Sequencing libraries were prepared from cell-free DNA (cfDNA) isolated from 72 plasma samples of 41 patients using the Oncomine Lung cfDNA panel covering hot spot regions of 11 genes. Sequencing was performed with the Ion Torrent™ Ion S5™ system. Four genes were detected with highest mutation incidence: KRAS (43.9% of all cases), followed by ALK (36.6%), TP53 (31.7%), and PIK3CA (29.3%). Seven patients had co-occurring KRAS + TP53 (6/41, 14.6%) or KRAS + PIK3CA (7/41, 17.1%) mutations. Moreover, the mutational status of TP53 as well an overall cell-free DNA load were confirmed to be predictors of poor progression-free survival (HR = 2.5 [0.8-7.7]; p = 0.029 and HR = 2.3 [0.9-5.5]; p = 0.029, respectively) in NSCLC patients. In addition, TP53 mutation status significantly predicts shorter overall survival (HR = 3.4 [1.2-9.7]; p < 0.001). We demonstrated that TP53 mutation incidence as well as a cell-free DNA load can be used as biomarkers for NSCLC monitoring and can help to detect the disease progression prior to radiological confirmation of the status.

Introduction: Osimertinib is effective for relapsed T790M-positive patients with brain metastases. The high brain permeability suggests that also such patients without T790M could benefit. Therefore, we evaluated the effect of osimertinib on brain metastases in both T790M-positive and -negative patients., Methods: The TREM-study was an investigator-initiated phase II, single-arm, multi-institutional clinical trial conducted in Northern Europe. Patients with resistance to prior EGFR-TKIs received osimertinib until radiological progression, unacceptable toxicity or death. Baseline brain scans were performed in patients with known or suspected brain metastases and repeated every 8-12 weeks. We assessed intracranial efficacy in patients with baseline brain metastases., Results: Brain metastases were detected in 48/199 patients at baseline. Of these, 63% were T790M-positive, 27% -negative and 10% had unknown T790M-status. The majority (73%) of the patients had received prior whole brain radiotherapy and additionally 8% had received stereotactic radiosurgery (SRS). Brain scans were available for review for 42 patients. The intracranial progression free survival was 39.7 versus 3.5 months for T790M + and T790M- patients, respectively ( p  < 0.001). The overall intracranial disease control rate (iDCR) was 81%, and for T790M + and T790M- patients the DCR was 89% versus 55%, respectively. The estimated risk of CNS progression was 0.8% at 6 months and 6% at 12 months for T790M-positive patients, and 14% and 17% at 6 and 12 months, respectively, for the T790M-negative., Conclusion: This subgroup analysis confirms CNS efficacy of osimertinib in patients with the T790M resistance mutation, while other treatment options should be considered for EGFR-TKI relapsed T790M-negative patients with brain metastases.

Objectives: In non-small cell lung cancer patients with acquired resistance to first- or second-generation EGFR-TKIs, osimertinib is approved in the presence of the T790 M resistance mutation. We assessed the efficacy of osimertinib in both T790M-positive and T790M-negative patients., Materials and Methods: The TREM-study is an investigator-initiated, multi-centre, single-arm, phase 2 clinical trial conducted in five Northern European countries. Patients with progression on at least one previous EGFR-TKI were assigned to treatment with 80 mg of osimertinib daily until radiological progression or death. Patients were included regardless of the presence of T790 M. The primary endpoint was objective response rate (ORR)., Results: Of 199 included patients, 120 (60 %) were T790M-positive, 52 (26 %) were T790M-negative and 27 (14 %) had unknown T790M-status. 24 % had brain metastases and 15 % had an ECOG performance status of 2. Overall ORR was 48 % (95 % CI, 41 %-55 %), 60 % (51 %-69 %) for T790M-positive patients and 28 % (15 %-41 %) for T790M-negative patients, p < 0.001. ORR for patients with co-occurring del19 vs L858R was 61 % vs 32 %, p = 0.001. Duration of response was similar between the T790M-positive and -negative groups (11.8 vs 10.7 months, p = 0.229). Overall median progression-free survival (PFS) was 8.9 months (95 % CI, 7.4-10.5), and 10.8 vs 5.1 months for T790M-positive vs -negative patients (HR 0.62, p = 0.007). Median overall survival (OS) was 17.9 months (95 % CI, 14.4-21.3). For T790M-positive vs -negative median OS was 22.5 vs 13.4 months, (HR 0.55, p = 0.002)., Conclusions: This study confirms the efficacy of osimertinib for T790M-positive patients. There was also clinically significant activity of osimertinib in a proportion of T790M-negative patients., Clinical Trial Registration: This trial is registered with ClinicalTrials.gov (NCT02504346)., Competing Interests: Declaration of Competing Interest IJZE, ÅH, SE and SC have nothing to disclose. AM has received grants from AstraZeneca. KHH has received honoraria for lectures or advisory boards for Takeda, Roche, MSD, AstraZeneca, Pierre Fabre and BMS. JK has received honoraria for lectures or advisory boards from AstraZeneca, BMS, Boehringer-Ingelheim, MSD and Roche. BHG has received honoraria for lectures and advisory boards for AstraZeneca. OTB has received grants from Roche and Pfizer., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Matrix metalloproteinases (MMPs) are implicated in cancer cells invasion and metastasis processes and have been investigated as potential cancer biomarkers. In this study MMP-9 gene expression and MMP-9 -1562 C/T polymorphism in breast and non-small cell lung cancer patients' blood and tumor samples and its correlation with clinicopathological parameters were investigated., Material/methods: MMP-9 gene expression was assessed by reverse transcription - polymerase chain reaction method in 108 cancer patients' blood and tumor samples. MMP-9 -1562 C/T polymorphism was determined by the polymerase chain reaction - based restriction fragment length polymorphism method., Results: Significant relationship of MMP-9 gene expression and tumor differentiation grade was found only between groups with G1 and G3 breast tumors. Low survival rates were identified among positive MMP-9 expression in blood and ductal carcinoma of the breast (p=0.01) and negative progesterone receptor reaction (p=0.04). Significant differences in the distribution among genotypes were found between groups with stage I and stages III/IV (p=0.005) as well as between groups with lymph node status N0 and N1 (p<0.001). Breast cancer patients with tumor differentiation grade G3 and identified CC variant had a longer survival time (p=0.014). Shorter survival time was found among positive MMP-9 expression in tumor and stage I non-small cell lung cancer patients with negative lymph node (p=0.012) and squamous cell carcinoma (p=0.019)., Conclusions: Expression of MMP-9 in blood and tumor together indicates worse prognosis for breast cancer patients.

Background: Erlotinib, docetaxel, and pemetrexed are approved for the second-line treatment of non-small-cell lung cancer (NSCLC), but no head-to-head data from large clinical trials are available. We undertook the Tarceva In Treatment of Advanced NSCLC (TITAN) study to assess the efficacy and tolerability of second-line erlotinib versus chemotherapy in patients with refractory NSCLC., Methods: TITAN was an international, randomised multicentre, open-label, phase 3 study that was done at 77 sites in 24 countries. Chemotherapy-naive patients with locally advanced, recurrent, or metastatic NSCLC received up to four cycles of first-line platinum doublet chemotherapy, after which patients with disease progression during or immediately after chemotherapy were offered enrolment into TITAN. Enrolled patients were randomly assigned (1:1) by a minimisation method to ensure balanced stratification, to receive erlotinib 150 mg/day or chemotherapy (standard docetaxel or pemetrexed regimens, at the treating investigators' discretion), until unacceptable toxicity, disease progression, or death. Patients were stratified by disease stage, Eastern Cooperative Oncology Group performance status, smoking history, and region of residence. The primary endpoint was overall survival in the intention-to-treat population. TITAN was halted prematurely because of slow recruitment. This study is registered with ClinicalTrials.gov, number NCT00556322., Findings: Between April 10, 2006, and Feb 24, 2010, 2590 chemotherapy-naive patients were treated with first-line platinum doublet chemotherapy, of whom 424 had disease progression and were enrolled into TITAN. 203 patients were randomly assigned to receive erlotinib and 221 were assigned to receive chemotherapy. Median follow-up was 27·9 months (IQR 11·0-36·0) in the erlotinib group and 24·8 months (12·1-41·6) in the chemotherapy group. Median overall survival was 5·3 months (95% CI 4·0-6·0) with erlotinib and 5·5 months (4·4-7·1) with chemotherapy (hazard ratio [HR] 0·96, 95% CI 0·78-1·19; log-rank p=0·73). The adverse-event profile of each group was in line with previous studies. Rash (98/196 [50%] in the erlotinib group vs 10/213 [5%] in the chemotherapy group for all grades; nine [5%] vs none for grade 3 or 4) and diarrhoea (36 [18%] vs four [2%] for all grades; five [3%] vs none for grade 3 or 4) were the most common treatment-related adverse events with erlotinib, whereas alopecia (none vs 23 [11%] for all grades; none vs one [<1%] for grade 3/4) was the most common treatment-related adverse event with chemotherapy., Interpretation: No significant differences in efficacy were noted between patients treated with erlotinib and those treated with docetaxel or pemetrexed. Since the toxicity profiles of erlotinib and chemotherapy differ, second-line treatment decisions should take into account patient preference and specific toxicity risk profiles., Funding: F Hoffmann-La Roche., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: First-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) is usually limited to four to six cycles. Maintenance therapy can delay progression and prolong survival. The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib has proven efficacy and tolerability in second-line NSCLC. We designed the phase 3, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study to assess use of erlotinib as maintenance therapy in patients with non-progressive disease following first-line platinum-doublet chemotherapy., Methods: Between December, 2005, and May, 2008, 1949 patients were included in the run-in phase (four cycles of platinum-based chemotherapy). At the end of the run-in phase, 889 patients who did not have progressive disease were entered into the main study, and were randomly allocated using a 1:1 adaptive randomisation method through a third-party interactive voice response system to receive erlotinib (150 mg/day; n=438) or placebo (n=451) until progression or unacceptable toxicity. Patients were stratified by EGFR immunohistochemistry status, stage, Eastern Cooperative Oncology Group performance status, chemotherapy regimen, smoking history, and region. Co-primary endpoints were progression-free survival (PFS) in all analysable patients irrespective of EGFR status, and PFS in patients whose tumours had EGFR protein overexpression, as determined by immunohistochemistry. This study is registered with www.ClinicalTrials.gov, number NCT00556712., Findings: 884 patients were analysable for PFS; 437 in the erlotinib group and 447 in the placebo group. After a median follow-up of 11.4 months for the erlotinib group and 11.5 months for the placebo group, median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group (HR 0.71, 95% CI 0.62-0.82; p<0.0001). PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib (n=307) compared with EGFR-positive patients given placebo (n=311; median PFS 12.3 weeks in the erlotinib group vs 11.1 weeks in the placebo group; HR 0.69, 0.58-0.82; p<0.0001). The most common grade 3 or higher adverse events were rash (37 [9%] of 443 patients in the erlotinib group vs none of 445 in the placebo group) and diarrhoea (seven [2%] of 443 patients vs none of 445). Serious adverse events were reported in 47 patients (11%) on erlotinib compared with 34 patients (8%) on placebo. The most common serious adverse event was pneumonia (seven cases [2%] with erlotinib and four [<1%] with placebo)., Interpretation: Maintenance therapy with erlotinib for patients with NSCLC is well tolerated and significantly prolongs PFS compared with placebo. First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy., Funding: F Hoffmann-La Roche Ltd., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Spontaneous pneumothorax (SP) is a rare manifestation of lung cancer. The mechanisms by which pneumothorax occurs in lung cancer is not clear, resulting in different views being expressed., Case Presentation: Here we present a case in which pneumothorax occurred as a first manifestation of lung cancer. The chest x-ray of a 68 year old man revealed a right partial pneumothorax. VATS was then performed: the visceral pleura lying over segment S3 was destroyed and air leaks were found in this section. Pathologic examination of the biopsy specimen revealed non-small cell carcinoma. Thoracoscopic talc pleurodesis was performed., Conclusion: Spontaneous pneumothorax in association with lung cancer is rarely seen. Pneumothorax can be the first sign of lung cancer. The most common possibility for SP complicating lung cancer is the tumor necrosis mechanism or, in separate cases, rupture of the emphysematous bullae. Lung cancer should always be considered as a possible cause of SP in elderly patients or in heavy smokers.

Objective: To determine survival of patients with stage IIIA/B non-small cell lung cancer considering disease stage and treatment methods., Material and Methods: A total of 304 patients with non-small cell lung cancer were treated at the Department of Thoracic Surgery and Oncology, Institute of Oncology, Vilnius University, in 2000-2004. Stage IIIA (T3N1-2M0) cancer was diagnosed for 193 (63.5%) patients and stage IIIB (T4N0-1M0) cancer was diagnosed for 111 (36.5%) patients. There were 277 (91.1%) males and 27 (8.9%) females. According to morphology, there were 219 (72%) patients with squamous cell lung cancer, 80 (26.3%) with adenocarcinoma, and 5 (1.7%) patients with large cell carcinoma. Surgery was performed in 145 patients: 84 (57.9%) patients underwent lung resection (T3-4N0-1M0), 51 (35.2%) patients - thoracotomy, and 10 (6.7%) patients - other palliative thoracic procedures (mediastinotomy, pleurectomy, mediastinoscopy). Forty-eight (30.2%) patients were treated with radiation therapy with total doses of >40 Gy and 58 (36.5%) patients were treated with radiation therapy with total doses of <40 Gy. Fifty-four (33.9%) patients were treated with Gemzar and cisplatin and 19 (11.9%) patients were treated with etoposide and cisplatin., Results: Overall median and mean survival was 7.8 months (95% CI, 6.8 to 8.8) and 9.9 months (95% CI, 9.0 to 10.9), respectively. The median and mean survival of patients with stage IIIA cancer was 8.3 months and 10.4 months, respectively, and that of patients with stage IIIB cancer - 6.4 months and 9.0 months, respectively (P < or =0.05). The median survival of the patients with stage IIIA cancer who received a combination of operation, chemotherapy, and radiation therapy with a total dose of >40 Gy was 14.4 months (mean, 14.7 months), and the median survival of those who received operation, chemotherapy, and radiation therapy with a total dose of < or =40 Gy was 9.7 months (mean, 14.1 months); the median survival of the patients who underwent surgery alone was 4.9 months (mean, 6.7 months) (P=0.004 and P=0.007), respectively. There was a significant difference in the median survival comparing the patients with stage IIIB cancer who underwent surgery alone and those who received a combination of radiation therapy and chemotherapy (median survival of 5.0 months [mean, 8.1 months] versus 16.8 months [mean, 17.6 months], respectively; P < or =0.05)., Conclusions: Disease stage had an influence on the survival of patients with non-small cell lung cancer: patients with stage IIIA (T3N0-1M0) cancer without metastases to mediastinal lymph nodes (N factor) survived longer than patients with stage IIIB (T4N1-2M0) cancer, where not only N factor had an impact but T factor as well. Better treatment outcomes, i.e. longer survival, can be achieved when a combination of three treatment types - surgery, chemotherapy, and radiation therapy - is applied to patients with stage IIIA or IIIB non-small cell lung cancer. The patients with stage IIIA disease who received surgery and radiation therapy (total dose, >40 Gy), and combinations of surgery, chemotherapy, and radiation therapy and second-line chemotherapy showed a significantly longer survival than those who received surgery alone.

Unlabelled: The aim of the study was: to evaluate efficacy of postoperative chemotherapy and chemoradiotherapy in patients with NSCLC (N2) disease and to point out time to tumor progression and reccurence, as well as to patients survival. Study was performed as a part of International Adjuvant Lung Cancer Treatment (IALT) protocol. In 1999-2000, 110 patients patients with NSCLC with metastases to N1 and N2 regions entered the trial. Patients were randomized for investigonal group: postoperative chemotherapy 31 patients (48.4%), and chemoradiotherapy 34 patients (53.1%). These patients were compared to 45 patients who underwent only surgery (control group). Patients in the first group according to stages were: II A st. 30 patients (46.1%), IIB - 6 patients. (9.2%), IIIA st. 29 patients (44.6%). Morphology: squamos cell 44 patients (67.6%) and adeno 16 patients (24.6%)., Operations: lobectomy - 20 patients (30.7%), bilobectomy - 6 patients (9.2%), pleuropneumonectomy 13 patients (20%), combined pneumonectomy 13 patients (20%), pneumonectomy 12 patients (18.4%). Chemotherapy started within 60 days after operation. Radiation started in 10 days after last cycle of chemotherapy., Results: Postoperatively 42.8% patients had reccurences after pneumonectomy. In surgery group 26.6% patients had reccurences in 3-year period. Medial survival in adjuvant group was 21.3 months. In surgery group three-year survival was in 19.7% of patients, chemoradiation group - 42.4%, and chemotherapy group - 37.2%., Conclusions: Postoperative adjuvant therapy remains unsolved and controversal problem. Neither chemotherapy, nor chemoradiotherapy has real impact on survival: 3-year survival in surgery group was observed in 19.7%, in chemoradiation - 42.2%, and in chemotherapy group in 37.2% of patients. Efficacy of postoperative treatment depends on radical removal of lymphodes, tumor morphology and postoperative complications.