Evaluation of antihypertensive medications use and survival in patients with ovarian cancer: a population-based retrospective cohort study.

BACKGROUND: Despite declining mortality in most countries and in Lithuania, ovarian cancer burden has remained high. Studies have indicated that antihypertensive medications use may help to improve ovarian cancer survival, however findings remain controversial. The aim of the study was to analyse the association between post-diagnosis antihypertensive medications intake and cancer-specific survival in ovarian cancer patients. METHODS: This retrospective cohort study included 588 ovarian cancer cases diagnosed between 2013 and 2015. Hazard ratios (HR) and corresponding 95% confidence intervals (95%CI) were estimated using multivariable Cox proportional hazards models to assess associations between antihypertensive medications and ovarian cancer-specific mortality. RESULTS: In total, 279 (47%) patients died during the follow-up; 242 (87%) of them died due to ovarian cancer. The risk of ovarian cancer death was reduced in angiotensin-converting enzyme inhibitors (ACE inhibitors) users vs. non-users (HR 0.55, 95% CI: 0.36-0.83). Subgroup analysis showed better ovarian cancer survival in higher dose ACE inhibitors users (HR 0.46, 95% CI: 0.28-0.77, p for trend 0.002); the effect was also stronger in age 51-65 years, stage I-III, surgery or chemotherapy treatment, pre-diagnosis ACE inhibitor users' and pre-diagnosis hypertension subgroups. The risk of cancer-specific death was slightly lower among calcium-channel blocker and angiotensin-receptor blocker users and higher among beta-blocker users as compared to non-users, however chance and confounding could not be ruled out. We found no association between the use of centrally and peripherally acting antiadrenergic agents and diuretics and risk of ovarian cancer-specific mortality. CONCLUSIONS: Our findings imply that post-diagnosis use of ACE inhibitors may be associated with reduced ovarian cancer-specific mortality; however, further research is needed for the comprehensive assessment.

Potential of miR-181a-5p and miR-630 as clinical biomarkers in NSCLC.

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-ΔΔCt 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.

Surveillance of cfDNA Hot Spot Mutations in NSCLC Patients during Disease Progression.

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.

Intracranial effect of osimertinib in relapsed EGFR-mutated T790M-positive and -negative non-small cell lung cancer patients: results from a phase II study.

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.

A Pilot Study of Safer Radiation Dosage to the Heart and Its Subregions.

Background and Objectives: The real impact of ionizing radiation on the heart and poorer overall survival for patients with non small cell lung cancer (NSCLC) remains unclear. This study aims to determine the safe dose constraints to the heart's subregions that could prevent patients' early non-cancerous death and improve their quality of life. Methods and Materials: A retrospective cohort study was performed containing 51 consecutive patients diagnosed with stage III NSCLC and treated using 3D, Intensity-modulated radiation therapy (IMRT), and Volumetric modulated arc therapy (VMAT) radiotherapy. For a dosimetric analysis, these structures were chosen: heart, heart base (HB), and region of great blood vessels (GBV). Dose-volume histograms (DVH) were recorded for all mentioned structures. Maximum and mean doses to the heart, HB, the muscle mass of the HB, and GBV were obtained. V10-V60 (%) parameters were calculated from the DVH. After performed statistical analysis, logistic regression models were created, and critical doses calculated. Results: The critical dose for developing a fatal endpoint for HB was 30.5 Gy, while for GBV, it was 46.3 Gy. Increasing the average dose to the HB or GBV by 1 Gy from the critical dose further increases the possibility of early death by 22.0% and 15.8%, respectively. Conclusions: We suggest that the non-canonical sub-regions of the heart (HB and GBV) should be considered during the planning stage. Additional constraints of the heart subregions should be chosen accordingly, and we propose that the mean doses to these regions be 30.5 Gy and 46.3 Gy, respectively, or less. Extrapolated DVH curves for both regions may be used during the planning stage with care.

Lung Cancer Survival in Lithuania: Changes by Histology, Age, and Sex From 2003-2007 to 2008-2012.

Lung cancer is the most common cancer-related death worldwide. The aim of this study is to describe the most recent survival rates by sex, age group, extent of disease, and histology of lung cancer in Lithuania. The study is based on the Lithuanian Cancer Registry database. The analysis included patients with primary invasive lung cancer diagnosed in 1998 to 2012 (International Classification of Diseases, Tenth Revision C33 and C34). Patients were followed up with respect to vital status until December 31, 2012. Five-year relative survival estimates were calculated using period analysis. Relative survival was calculated as the ratio of the observed survival of patients with cancer and the expected survival of the underlying general population. In our study, the overall 5-year relative survival was low but increased slightly (10.7%) from 2003-2007 to 2008-2012. Positive changes in survival were evident in both sexes, in almost all age groups and for all histological groups and disease stages. Adenocarcinoma relative survival increased from 6.7% in 2003-2007 to 12.8% in 2008-2012 and squamous cell carcinoma increased from 7.4% in 2003-2007 to 11.1% in 2008-2012. Patients with small-cell carcinoma had the worst survival (2.9% in 2003-2007 and 3.6% in 2008-2012). The majority of patients with lung cancer are diagnosed with advanced disease. The number of new cases of advanced lung cancer increased from 35.1% to 37.8%. Despite low overall survival, there were positive changes in survival in both sexes, in almost all age groups, and for all histological groups and disease stages. The survival rate of patients with lung cancer in Lithuania is similar to that in other European countries.

Prevalence of human papillomaviruses in patients with head and neck squamous cell carcinoma in Lithuania and Belarus.

Overall, head and neck sqamous cell carcinoma accounts for more than 550,000 cases annually worldwide. It is well known that human papillomavirus (HPV) is the main risk factor for cervical cancer development. As the incidence and the mortality of cervical cancer are closely related to the HPV prevalence, we hypothesized that there is the same association between HPV prevalence and head and neck squamous cell carcinoma. Therefore we performed the study aiming to compare the level of HPV infection and HPV type distribution between two groups of Lithuanian and Belarusian patients with head and neck sqamous cell carcinoma. One hundred ninety head and neck sqamous cell carcinoma patients were included in the study, 75 from Lithuania and 115 from Belarus. PCR was used for HPV detection and typing. The distribution of HPV infection among head and neck sqamous cell carcinoma patients was similar in the Lithuanian (20.0%) and Belarusian (18.3%) patient groups, however differences were found in the distribution of HPV types.

Detection of Oncogene Hotspot Mutations in Female NSCLC Tumor DNA and Cell-Free DNA.

Non-small-cell lung cancer (NSCLC) is the most prevalent type of lung cancer, with extensively characterized mutational spectra. Several biomarkers (such as EGFR, BRAF, KRAS gene mutations, etc.) have emerged as predictive and prognostic markers for NSCLC. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, prompting the search for alternatives. Cell-free DNA (cfDNA) found in plasma is emerging as a highly promising avenue or a supplementary method for assessing the efficacy of cancer treatments. This is especially valuable in instances where conventional biopsy specimens, like formalin-fixed, paraffin-embedded (FFPE), or freshly frozen tumor tissues prove inadequate for conducting molecular pathology analyses subsequent to the initial diagnostic procedures. By leveraging cfDNA from plasma, clinicians gain an additional tool to gauge the effectiveness of cancer therapies, thereby enhancing their ability to optimize tailored treatment strategies. In this study, 51 Lithuanian females with NSCLC were analyzed, with adenocarcinoma being the predominant pathology diagnosis in 40 cases (78%). Target mutations were identified in 38 out of 51 patients (74.5%) in tumor tissue samples, while in plasma samples, they were identified in only 10 patients' samples (19.6%). Even though we did not have enough voluminous plasma samples in our study, gene mutations were detected in plasma from ten women, three of whom were diagnosed with early stages of lung cancer (stages I and II). For these patients, the following mutations were detected: deletion in exon 19 of the EGFR gene and single nucleotide polymorphisms in the TP53 and MET genes. All other women were diagnosed with stages III or IV of lung cancer. This indicates that the later stages of cancer contribute more cfDNA in plasma, making extraction less complicated.

Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.

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.

Osimertinib in non-small cell lung cancer with uncommon EGFR-mutations: a post-hoc subgroup analysis with pooled data from two phase II clinical trials.

Background: Osimertinib is standard of care for EGFR-mutated non-small cell lung cancer (NSCLC) patients. The efficacy of the drug in patients with mutations other than the common deletion in exon 19 and L858R in exon 21 is largely unknown. Methods: We identified patients with uncommon EGFR-mutations from two prospective clinical phase II, single-arm studies for previously treated patients and untreated patients, respectively, and pooled data for this analysis. All patients received treatment with osimertinib 80 mg daily until radiological progression or death. The primary endpoint of both trials was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS) and intracranial efficacy as key secondary endpoints. Circulating tumour DNA (ctDNA) was analysed before and two weeks after treatment initiation in the first line cohort. Results: Of 299 enrolled patients in the two trials, 21 patients with uncommon mutations were identified; 12 patients had a single mutation (G719X or L861Q), one patient had L861Q and an exon 20 insertion, and 8 patients had compound mutations with G719X and either L861Q or S768I. Three of the 10 pretreated patients had the T790M resistance mutation. ORR was 47.6% and disease control rate (DCR) 85.7%. The median duration of response (DoR) was 7.9 months. Among 11 patients treated with osimertinib in first line, ORR was 63.6% vs. 30.0% of 10 previously treated patients. The median PFS was 5.5 months in both groups. Patients with G719X-compound mutations had a higher response rate (62.5% vs. 38.5%), a longer median PFS (13.7 vs. 3.5 months) and median OS (29.3 vs. 7.5 months) than patients with other mutations. Most first line treated patients (81.8%) displayed a reduction in ctDNA after two weeks of treatment. Conclusions: Osimertinib demonstrates activity in patients with uncommon EGFR-mutations, and especially for G719X-compound mutations.

Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.

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.

The Impact of the COVID-19 Pandemic on Cancer Patient's Management-Lithuanian Cancer Center Experience.

The pandemic spread of the COVID-19 virus significantly affected daily life, but the highest pressure was piled on the health care system. Our aim was to evaluate an impact of COVID-19 pandemic management measures on cancer services at the National Cancer Institute (NCI) of Lithuania. We assessed the time period from 1 February 2020 to 31 December 2020 and compared it to the same period of 2019. Data for our analysis were extracted from the NCI Hospital Information System (HIS) and the National Health Insurance Fund (NHIF). Contingency table analysis and ANOVA were performed. The COVID-19 pandemic negatively affected the cancer services provided by NCI. Reductions in diagnostic radiology (-16%) and endoscopy (-29%) procedures were accompanied by a decreased number of patients with ongoing medical (-30%), radiation (-6%) or surgical (-10%) treatment. The changes in the number of newly diagnosed cancer patients were dependent on tumor type and disease stage, showing a rise in advanced disease at diagnosis already during the early period of the first lockdown. The extent of out-patient consultations (-14%) and disease follow-up visits (-16%) was also affected by the pandemic, and only referrals to psychological/psychiatric counselling were increased. Additionally, the COVID-19 pandemic had an impact on the structure of cancer services by fostering the application of modified systemic anticancer therapy or hypofractionated radiotherapy. The most dramatic drop occurred in the number of patients participating in cancer prevention programs; the loss was 25% for colon cancer and 62% for breast cancer screening. Marked restriction in access to preventive cancer screening and overall reduction of the whole spectrum of cancer services may negatively affect cancer survival measures in the nearest future.

A Cohort Study of Exposure to Antihyperglycemic Therapy and Survival in Patients with Lung Cancer.

We evaluated the effect of antihyperglycemic therapy on the survival of patients with lung cancer (LC). The analysis included patients with LC and concomitant type 2 diabetes. 15,929 patients were classified into five groups: metformin users, insulin users, metformin and insulin users, sulphonylurea users and non-diabetic group. A multivariate analysis showed that exposure to either metformin or to insulin was associated with a lower risk of LC-specific mortality, and this approached statistical significance (HR 0.82, 95% CI 0.72-92 for metformin and HR 0.65, 95% CI 0.44-95 for insulin). When deaths from all causes were considered, only metformin exposure was associated with a significantly lower risk of death (HR 0.82, 95% CI 0.73-0.92). Users of sulphonylurea were at a higher risk of LC-specific and overall mortality (HRs 1.19, 95% CI 0.99-1.43 and 1.22, 95% CI 1.03-1.45). Our study shows a positive effect of metformin on the survival of patients with LC. Moreover, our results show that exposure to insulin was associated with a lower risk of LC-specific mortality, but not with deaths from all causes. The study results suggested that users of sulphonylurea may be at a higher risk of LC-specific and overall mortality.

Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study).

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).

Spontaneous pneumothorax as a first sign of pulmonary carcinoma.

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.

[Treatment outcome of locally advanced stage IIIA/B lung cancer]. / Vietiskai isplitusio IIIA/B stadijos plauciu vezio gydymo rezultatai.

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.

[Malignant pleural diseases: diagnosis and treatment]. / Piktybiniu pleuros ligu diagnostika ir gydymas.

OBJECTIVE: To evaluate efficacy of diagnostic procedures, results of surgery, and complications in malignant pleural diseases. MATERIAL AND METHODS: From 1999 to 2006, 169 patients underwent treatment in the Department of Thoracic Surgery and Oncology, Institute of Oncology, Vilnius University. Patients were divided into two groups: group I, patients with primary pleural malignant diseases (93 patients, 55.0%), and group II, secondary pleural tumors (76 patients, 45%). Of the 76 patients, 40 patients (52.6%) were diagnosed with metastatic pleural tumors and 36 patients (47.4%) with tumors invading parietal pleura. We used noninvasive and invasive methods for diagnosis. Noninvasive methods included chest x-ray, chest computed tomography, magnetic resonance imaging, chest ultrasound, positron emission tomography/computed tomography (performed in Germany), and invasive methods included puncture of pleural effusions, transthoracic pleural puncture, drainage, pleural biopsy and video-assisted thoracoscopic pleural biopsy, pleural resection, and ultrasound-guided needle biopsy of the pleura. The following procedures were performed in group I: pleurectomy in 15 patients (16.1%), pleural pneumonectomy in 42 patients (45.2%), pleural decortication in 12 patients (12.9%), extended pleuropneumonectomy with diaphragm and pericardium resections and plastic surgery in 14 patients (15.0%), pleurectomy with costal resections in 10 patients (10.1%). Procedures performed in group II included video-assisted thoracoscopic pleurectomy in 15 patients (19.7%), pleural biopsy in 10 patients (13.2%), pleurectomy in 15 patients (19.7%), pleural drainage and fenestration in 5 patients (6.5%), lung and pleura resection in 12 patients (15.8%), chest wall and pleura resection in 10 patients (13.2%), diaphragm and pleura resections in 9 patients (11.8%). RESULTS: Early stage primary pleural tumors were found in 24 patients (25.8%). Metastatic pleural disease was found in 32 patients with early primary tumors (80.0%). In all 36 patients (100.0%) with chest wall tumors, disease of advanced stage was determined. Main surgical complications of the group I were observed in 26 patients (27.9%). Six patients (6.5%) died after surgery. In group II, 23 patients (30.2%) had postoperative complications; 3 patients (3.9%) died. CONCLUSIONS: In noninvasive methods, the highest sensitivity was achieved for chest computed tomography and magnetic resonance imaging (97%); the specificity of chest magnetic resonance imaging was 100%, and the specificity chest computed tomography and magnetic resonance imaging--98%. The accuracy of chest x-ray plus computed tomography was 98%. In invasive methods, accuracies of pleural biopsy, video-assisted thoracoscopic pleural biopsy, and pleurectomy were 100%, 90%, and 100%, respectively. In case of primary pleural tumors, the main surgery was extended pleuropulmonectomy (45.2%) with or without mediastinal resection. Mortality rate was 6.5%. In case of metastatic pleural disease, the main surgery was video-assisted thoracoscopic pleurectomy (19.7%). Mortality was rate 5%. In cases of pleural invasion by other thoracic malignancies, the main surgeries were chest wall and pleural resection (13.2%) and lung and pleural resection (15.8%). Mortality rate was 2.8%. After 169 operations due to malignant pleural diseases, the rate of postoperative complications ranged from 1.3% to 7.8%.

Sternal resection of a solitary renal cell carcinoma metastasis: a case report and a literature review.

BACKGROUND: Renal cell carcinoma (RCC) may be metastatic, although solitary sternal metastasis of RCC is a rare medical condition. Here we report an unusual case of a 63-year-old male with a solitary sternal metastasis as an initial presentation of clear-cell renal cell carcinoma. MATERIALS AND METHODS: A 63-year-old male presented with a small sternal mass. Chest computer tomography (CT) and a biopsy from the sternal tumour were performed. Histopathological examination revealed the diagnosis of renal clear cell carcinoma metastasis to the sternal bone. On the basis of a subsequently performed abdominal CT the patient was confirmed with a suspicion of a left renal lower pole tumour. Treatment with sunitinib was initiated. Due to the limited response and a growing sternal mass, the patient was admitted to the National Cancer Institute after two cycles of sunitinib therapy. Open left partial nephrectomy was performed followed by the resection of the sternal metastasis two months later. The chest wall was reconstructed with polypropylene mesh combined with transversal rectus abdominis musculocutaneous flap. RESULTS: The postoperative course after the partial nephrectomy was uneventful. The postoperative course of metastasectomy complicated with the right pneumothorax which was successfully treated by insertion of a chest tube. Bleeding from the upper digestive tract also occurred on the seventh postoperative day but was successfully controlled by haemostasis with three 20 ml endoscopic injections of 1:10,000 solution of epinephrine. The patient had been followed up after the surgery for 30 months with biannual chest and abdominal CT scans that showed neither local nor distant recurrence of the disease. CONCLUSIONS: Radical surgical treatment of a solitary renal clear cell carcinoma metastasis may offer the best cancer-specific outcomes and improve the quality of life in some patients.

Individual and combined effect of TP53, MDM2, MDM4, MTHFR, CCR5, and CASP8 gene polymorphisms in lung cancer.

Lung cancer (LC) is the second common and with the highest mortality oncological disease. Specific biomarkers for its diagnostics, treatment, and prognosis are still under the investigations. Aim of our study was to evaluate the relationship between the polymorphisms of TP53 pathway genes TP53, MDM2, MDM4, the polymorphisms of HPV-associated genes MTHFR, CASP8, CCR5, and HPV infection with survival of LC patients. SNPs were genotyped using PCR-RFLP. qRT-PCR was used to detect, identify, and quantify HPV. No statistically significant differences were detected between individual SNPs and patient survival with stage I-IV LC. Cluster analysis of SNPs in genes MDM4 A/A, CCR5 wt/Δ32, MTHFR C/T, MDM2 T/T showed possible association with the worse survival. Patients who were diagnosed with C/T polymorphic variant of gene MTHFR tend not to survive stage III-IV LC (P = .12). There is a tendency between MDM2 gene T/T variant and worse survival of patients diagnosed with late stage LC (P = .11). HPV infection is very rear among LC patients (3 of 92). Overall, there is a link, although statistically insignificant, between specific SNPs and LC patient survival frequency and time, meanwhile the combination of specific SNPs showed a statistically significant measure. In conclusion, we determined statistically significant (P = .04) link between the poor survival of LC patients after surgery and the combination of polymorphic variants C/T of the MTHFR and T/T of the MDM2 genes, whereas individually these SNPs do not show significant relationship with the survival of patients after surgery.

Lung cancer in patients with tuberculosis.

BACKGROUND: Coexistent lung cancer and pulmonary tuberculosis is an urgent problem of thoracic surgery presenting a challenging task for diagnosis and surgical treatment. MATERIALS AND METHODS: From 1990 to 2005, 2218 patients with lung cancer underwent surgical treatment in Department of Thoracic Surgery and Oncology, Institute of Oncology, Vilnius University. In 46 (2.1%) patients coexistence of lung cancer and tuberculosis was found. Central lung cancer was diagnosed in 37 (80.4%) and peripheral--in 9 (19.6%) patients. Epidermoid cancer was diagnosed in 24 (52.2%) patients, adenocarcinoma--in 10 (21.7%) and adenoepidermoid carcinoma--in 12 (26.1%) patients. Stage I cancer was diagnosed in 12 (26.1%), stage II--in 11 (23.9%), and stage IIIA--in 23 (50%) patients. RESULTS: Pneumonectomy was performed in 18 (39.2%), lobectomy in 10 (21.7%), bilobectomy in 10 (21.7%), segmentectomy in 8 (17.4%) patients. Postoperative surgical complications were observed in 9 (19.5%) patients, non-surgical complications occurred in 19 patients (41.3%). Six patients (13.04%) died. Combined treatment was applied to 23 (50%) patients. CONCLUSION: Coexistence of tuberculosis and lung cancer in thoracic surgery is fairly rare. This combination was diagnosed only in 46 cases (2.1%) out of 2218 operated lung cancer patients. Epidermoid carcinoma and stage IIIA disease was diagnosed in 50% of patients. Postoperative surgical complications occurred in 9 patients (19.5%) with lung cancer and tuberculosis. Six patients (13%) died in postoperative period. Surgery is the method of choice in treatment of combination of tuberculosis and lung cancer. Median survival of these patients was 28 +/- 2 months.