[Smoking and lung cancer]. / Palenie tytoniu a rak pluca.

In this review we presented a relation between cigarette smoking and lung cancer. We characterized molecular alterations resulting from carcinogens present in the cigarette smoke and presented the constitutive genetic profiles related to the increased risk of lung cancer. We also discussed a possible use of these profiles in the selection of high risk groups among the heavy smokers. Finally, a positive impact of quitting smoking in lung cancer patients, including those who have undergone curative resection, was presented.

Analysis of safety, risk factors and pretreatment methods during rush hymenoptera venom immunotherapy.

BACKGROUND: The safety profile of venom immunotherapy is a relevant issue. We evaluated the frequency of severe adverse events (SAE), associated risk factors, retrospective comparison of pretreatment protocols including solely H1 receptor blockers and a combination of H1 and H2 receptor blockers during rush Hymenoptera venom immunotherapy. METHODS: The study group comprised 118 patients. The treatment was initiated according to a 5-day rush protocol with the use of standardized venom allergens of either wasp or honeybee. RESULTS: During the rush induction, side effects occurred in 18 patients (15.2%), whereas SAE were present in 7 patients (5.9%). Twelve out of 18 (66.6%) developed anaphylactic reactions on the fourth day of the rush protocol, with the majority of cases at a dose of 40 or 60 microg of the venom extract (p = 0.001). The frequency of SAE was also significantly higher on the fourth day than thereafter (p = 0.0001) as well as in patients allergic to bee venom (p = 0.049). All systemic side effects were more frequent in women (p = 0.0065). However, this relation was not true when SAE were consider (p = 0.11). A higher percentage of SAE was observed in the subjects pretreated with both H1 and H2 receptor antagonists than in those pretreated with H1 blocker only (8.8 vs. 4.1%); however, the difference was not significant. CONCLUSIONS: Considerable severity of allergic adverse events requires particular attention to patients allergic to bee venom and during rush phase, especially when rapidly increasing doses are administered. Pretreatment with H2 blockers is debatable and warrants further investigation.

[Quality of life of patients with asthma which has been well and poorly controlled]. / Jakosc zycia chorych na astme dobrze i zle kontrolowana.

INTRODUCTION: The aim of the study was to assess the quality of life of patients with asthma who were well and poorly controlled. MATERIAL AND METHODS: 70 patients with diagnosed asthma, aged from 18 to 40, were included into the study between November 2005 and February 2006 at the Specialist Hospital in Chojnice and Allergy out-patient Clinic of Medical University of Gdansk. The diagnosis and stage of asthma, as well as the assessment of the control of disease was performed by the physician. Quality of life was assessed with the use of St. George Respiratory Questionnaire (SGRQ). Statistical analysis was made with the use of computer statistical program Statistica. RESULTS: According to GINA in 26 patients mild asthma was diagnosed, in 31 - moderated and in 13 - severe disease. 41 patients were assessed as well controlled and 29 - as poorly controlled. Older age and longer duration of the disease were related to severe asthma, p = 0.01 and p = 0.003, respectively. In well controlled patients overall score for SGRQ was 48.86, whereas in poorly controlled was - 74.4. There was a significant difference between the overall quality of life in well and poorly controlled patients with asthma, p = 0.0001. This difference was found in all three domains: for symptoms, activity and impact on life, p = 0.014, p = 0.035 and p = 0.003, respectively. CONCLUSIONS: Quality of life is strongly dependent on the control of symptoms in asthmatic patients.

Increased risk of non-small cell lung cancer and frequency of somatic TP53 gene mutations in Pro72 carriers of TP53 Arg72Pro polymorphism.

The aim of this study was to assess whether the TP53 Arg72Pro polymorphism is associated with an increased risk of non-small cell lung cancer (NSCLC). Additionally, in NSCLC patients, we investigated a potential association between this polymorphism and somatic TP53 gene mutations in tumour cells. The study group included 240 NSCLC patients who underwent curative pulmonary resection. The control group (576 healthy subjects) was matched for sex and cigarette smoking. TP53 Arg72Pro polymorphism was determined by denaturing high-performance liquid chromatography. Tumours from 157 NSCLC patients were analysed for mutation in TP53 exons 5-8 by single strand conformation polymorphism, followed by sequencing of samples with different band pattern. Tumours from the remaining 83 patients were subjected to a direct sequencing of TP53 exons 5-8. The proportion of Pro homo/heterozygotes versus Arg homozygotes was significantly higher in NSCLC patients (54%) than in controls (46%, p = 0.034). The crude odds ratio for NSCLC development in Pro72 allele carriers was 1.39 (95% CI: 1.03-1.88). When adjusted for sex, age and smoking status in the multivariate logistic regression model, odds ratio for NSCLC development was 1.28 (95% CI: 0.91-1.80). Somatic TP53 mutations were found in 62 out of 240 NSCLC patients (26%), more frequently in Pro carriers (31%) than in Arg homozygotes (20%, p = 0.06). These results indicate that the TP53 codon 72 Pro allele may increase the risk of NSCLC. Additionally, the correlation between Pro72 and somatic TP53 mutations suggests that Pro72 allele carriers may be predisposed to tumour development along a p53 associated form of NSCLC, a finding that warrants further investigations.

[Thymectomy in myasthenia gravis]. / Znaczenie usuniecia grasicy u chorych na myasthenia gravis.

OBJECTIVES AND METHODS: To evaluate the results of thymectomy in myasthenia gravis we performed retrospective analysis of 82 consecutive patients in the mean age of 39 +/- 15 treated between 1991 and 2001. All patients underwent extended thymectomy by median sternotomy. Follow-up was assessed in 74 of 81(91.4%) patients, in the mean age of 39 +/- 15, discharged from the Department. RESULTS: Fifty three (71.6%) patients had symptoms of myasthenia gravis for less than 2 years. According to Osserman's classification 8 (10.8%) patients were assessed as class I, 32 (43.2%) as IIA 26 (35.2%) as IIB and 8 (10.8%) as IIC. In the postoperative period 8 (10.8%) patients had respiratory insufficiency, 5 (6.8%) were reoperated for bleeding. One patient died (1.4%) due to bilateral pneumonia and pulmonary insufficiency. After thymectomy the improvement of patient's clinical status was observed in 46 patients (86.4%) and complete remission was in 13 patients (17.6%). Prompt improvement after thymectomy (p = 0.008) and short duration of symptoms (p = 0.036) are positive predictive factors. Patients in class I had significantly better prognosis concerning complete remission (p = 0.036). Age, gender, histology of the thymus, and type of the thymoma had no influence on long time follow up. CONCLUSIONS: Extended thymectomy is a safe procedure leading to the improvement in majority of patients treated for myasthenia gravis.

[Analysis of prognostic value of TP53 gene mutations in non-small cell lung cancer]. / Analiza rokowniczego znaczenia mutacji genu TP53 u chorych na niedrobnokomórkowego raka pluca.

The aim of this study was to assess the frequency and prognostic value of TP53 gene somatic mutations in non-small cell lung cancer. The study group included 240 NSCLC patients who underwent pulmonary resection at the Department of Thoracic Surgery, Medical University of Gdansk. Tumour samples were evaluated for the presence of TP53 gene mutations in exons 5-8. In 157 cases SSCP method was used as a screening followed by sequencing of positive samples. In the remaining 83 patients mutations were analysed by direct sequencing. A total of 76 mutations (32%) were found, of those a missense type was dominant (67%), followed by silent and null type mutations (14% and 10%, respectively). There was no correlation between mutations and clinical characteristics, including age, sex, histological subtype, differentiation, tumour size, lymph node metastases, pTNM stage and smoking status. A multivariate Cox analysis demonstrated that tumour differentiation and pTNM stage were independent prognostic factors, whereas TP53 gene mutations were not. The results of this study indicate that TP53 gene mutations in NSCLC patients are not correlated with clinical characteristics and have no impact on survival.

The influence of blood transfusion on survival in operated non-small cell lung cancer patients.

BACKGROUND: It has been postulated that allogeneic transfusions have immunosuppressive effects that can promote tumor growth and metastasis formation. Despite the variety of publications on this controversial topic, the influence of blood transfusion on survival is not yet clearly identified. The impact of autologous blood transfusion on survival has only occasionally been analyzed in cancer patients. OBJECTIVE: To determine the effect of perioperative allogeneic and autologous blood transfusions on survival in non-small cell lung cancer patients treated with curative pulmonary resection. METHODS: Of 493 consecutive patients, 185 (37.5%) received allogeneic blood products and 145 (29.4%) received autologous blood products, whereas 163 patients (33.1%) received no blood products. Survival analysis included univariate log-rank test and multivariate Cox regression model. RESULTS: Three-year survival probabilities in allogeneic, autologous, and nontransfused groups were 40%, 48%, and 61%, respectively, and the estimated 5-year survival probabilities were 34%, 38%, and 48%, respectively. In the univariate analysis there was a reduced survival in allogeneic versus nontransfused group (P <.01). In the multivariate analysis stage (P <.01), initial hemoglobin level (P =.01) and sedimentation rate (P =.03) remained significant factors, whereas the type of blood transfusion (allogeneic versus autologous) was no longer significant. There was no significant impact of transfusion in the multivariate analysis when patients in stage III or patients who underwent pneumonectomy were excluded. CONCLUSION: Neither allogeneic nor autologous blood transfusion has independent, adverse survival impact in non-small cell lung cancer patients treated with radical pulmonary resection.

MDM2 gene amplification: a new independent factor of adverse prognosis in non-small cell lung cancer (NSCLC).

The prognostic impact of MDM2 amplification in non-small cell lung cancer (NSCLC) remains unknown. In this study, we investigated the occurrence of MDM2 amplification in surgically treated NSCLC patients. Molecular data were correlated with clinicopathological factors and evaluated for their prognostic value. The study group included 116 NSCLC patients who underwent pulmonary resection between 1996 and 1999. MDM2 amplification was assessed by real-time PCR using hybridization probe format on a LightCycler (Roche). The calculated ratio was a MDM2 value normalized to the amplification of the housekeeping gene phenylalaninhydroxylase (PAH). Survival curves were drawn according to the Kaplan-Meier method and compared with the use of the log-rank test. Multivariate analysis was based on Cox regression analysis. MDM2 amplification was found in 24 patients (21%). There was no relationship between MDM2 amplification and clinicopathological factors, such as sex, age and stage of disease, pT, pN, histology and tumor differentiation. Median disease-free survival (DFS) in patients with and without MDM2 amplification was 3 and 31 months, and 5-year DFS 24 and 33%, respectively (log-rank, P = 0.02). Likewise, median overall survival (OS) in patients with and without MDM2 amplification was 9 and 33 months, respectively, and 5-year OS 24 and 39%, respectively (log-rank, P = 0.01). The strong prognostic relevance of MDM2 amplification for both DFS and OS was confirmed in multivariate analysis (P < 0.01 for both comparisons). Our results suggest that MDM2 gene amplification analysis provides additional prognostic information in surgically treated NSCLC patients.

[P53 and P16 gene mutations in non-small cell lung cancer]. / Mutacje genów p53 i p16 w niedrobnokomórkowym raku pluca.

The aim of this study was to assess prospectively the occurrence of p53 and p16 mutations (considered separately and together) in NSCLC in terms of their clinical and prognostic relevance. Study group included 87 patients who underwent pulmonary resection for cure. p53 and p16 mutations were found in 22 (25%) and 14 (16%) cases, respectively. In eight patients (9%) both mutations were present, and the tendency for their common occurrence was significant (p = 0.02). There was no relation between mutation and clinical characteristics. Median survival in the entire group was 17 months and the 3-year survival probability--41%. There was no correlation between the occurrence of any mutation (considered separately or together) and survival. These results indicate that p53 and p16 gene mutations tend to occur together in NSCLC, however these alterations seem not to have noteworthy clinical and prognostic significance.

[Serum anti-P53 antibodies (AB-anti-P53) in patients with advanced non-small cell lung cancer (NSCLC)]. / Wystepowanie przeciwcial przeciw bialku p53 w surowicy chorych na zaawansowanego niedrobnokomórkowego raka pluca. Doniesienie wstepne.

The aim of the study was to assess the frequency of serum Ab-anti-p53 in 39 patients with advanced NSCLC and to evaluate the predictive value of the test. Antibodies were present in 10 (25.6%) of patients. There was no correlation between Ab-anti-p53 and clinical characteristics including age, gender, and histological type of tumor. In 17 patients response to chemotherapy (CT) was obtained (in one patient--complete, and in 16--partial response). The percentage of patients responding to CT in group with and without serum antibodies did not differ significantly (33% and 48%, respectively; p = 0.48). The results of the study indicate that serum Ab-anti-p53 are relatively often present in advanced NSCLC patients, however the clinical value of this test needs further evaluation.

Insulin-like growth factor receptor 1 (IGF1R) gene copy number is associated with survival in operable non-small-cell lung cancer: a comparison between IGF1R fluorescent in situ hybridization, protein expression, and mRNA expression.

PURPOSE: The purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non-small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis. PATIENTS AND METHODS: One hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181). RESULTS: IGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis. CONCLUSION: IGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.

BRCA1: a novel prognostic factor in resected non-small-cell lung cancer.

BACKGROUND: Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). METHODOLOGY AND PRINCIPAL FINDINGS: We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). CONCLUSIONS: Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated.

P53 and K-ras mutations are frequent events in microscopically negative surgical margins from patients with nonsmall cell lung carcinoma.

BACKGROUND: The objective of the current study was to determine whether tumor cells harboring P53 and K-ras mutations could be detected in histopathologically tumor-free surgical margins in patients with nonsmall cell lung carcinoma who underwent complete pulmonary resection. METHODS: In 118 consecutive patients, DNA obtained from primary tumors and from surgical margins was extracted for molecular analysis. A fragment of P53 gene encompassing exons 5-8 and codon 12 of the K-ras gene were amplified with the polymerase chain reaction technique and were assayed for the presence of mutations. RESULTS: P53 and K-ras mutations were found in 30% and 39% of primary tumors, respectively, and in 11 (9%) and 22 (18%) apparently tumor-free surgical margins, respectively. At least 1 of those mutations was found in surgical margins in 29 patients (25%), and both mutations were found in 2 patients (1.7%). P53 mutations in surgical margins accompanied mutations in primary tumors in 9 of 35 patients (26%), and K-ras mutations accompanied mutations in primary tumors in 20 of 46 patients (44%). Among patients with either mutation in primary tumors, the incidence of at least 1 mutation in surgical margins was 43% (28 of 65 patients). In four patients, mutations (two K-ras mutations and two P53 mutations) were found in surgical margins despite the absence of the corresponding mutations in primary tumors. The presence of mutations in primary tumors and in surgical margins was not related significantly to clinical characteristics or to patient outcomes. CONCLUSIONS: P53 and K-ras mutations are frequent events in surgical margins determined to be tumor free on light microscopy. The clinical relevance of these findings remains to be established.