Piotr Gabryel

Susceptibility loci in lung cancer and COPD: association of IREB2 and FAM13A with pulmonary diseases.

Genome-wide association studies have identified loci at 15q25 (IREB2) and 4q22 (FAM13A), associated with lung cancer (LC) and chronic obstructive pulmonary disease (COPD). The aim of our research was to determine the association of IREB2 and FAM13A SNPs with LC and severe/very severe COPD patients. We examined IREB2 variants (rs2568494, rs2656069, rs10851906, rs13180) and FAM13A (rs1903003, rs7671167, rs2869967) among 1.141 participants (468 LC, 149 COPD, 524 smoking controls). The frequency of the minor IREB2 rs2568494 AA genotype, was higher in LC vs controls (P = 0.0081, OR = 1.682). The FAM13A rs2869967 was associated with COPD (minor CC genotype: P = 0.0007, OR = 2.414). The rs1903003, rs7671167 FAM13A variants confer a protective effect on COPD (both P < 0.002, OR < 0.405). Haplotype-based tests identified an association of the IREB2 AAAT haplotype with LC (P = 0.0021, OR = 1.513) and FAM13A TTC with COPD (P = 0.0013, OR = 1.822). Cumulative genetic risk score analyses (CGRS), derived by adding risk alleles, revealed that the risk for COPD increased with the growing number of the FAM13A risk alleles. OR (95% CI) for carriers of ≥5 risk alleles reached 2.998 (1.8 to 4.97) compared to the controls. This study confirms that the IREB2 variants contribute to an increased risk of LC, whereas FAM13A predisposes to increased susceptibility to COPD.

Video-assisted thoracic surgery pneumonectomy: the first case report in Poland.

Minimally invasive video-assisted thoracic surgery (VATS) lobectomy has proved to be equal and in some aspects superior to open lobectomy in T1 and T2 lung cancers. Indications for VATS pneumonectomy however are still not clearly defined and strictly limited. The minimally invasive VATS pneumonectomy can be undertaken in patients with centrally located tumors without extended invasion of the large pulmonary vessels, chest wall, pericardium, mediastinal structures or proximal part of the main bronchus and when sleeve resection is not feasible (T2). We present a case of a patient who underwent left VATS pneumonectomy due to left lung cancer. Based on the preoperative examinations any kind of less extensive resection than pneumonectomy was excluded. Our VATS technique consisted of three incisions: two ports and a 5-6 cm long utility incision without any kind of rib spreading. The whole of the procedure was controlled on the monitor via a thoracoscope and the technique of resection was described in detail. Total surgery time was 130 min and blood loss was 150 ml. The chest tube was removed on the 2nd post-operative day and the patient was discharged home on the 8th postoperative day. The final histopathological examination confirmed squamous cell lung cancer (T2aN0M0 stage IB). In the authors’ opinion VATS pneumonectomy should be performed only in centers with extensive experience in minimally invasive VATS lobectomy. Despite limited indications for VATS pneumonectomy, if the patients fulfill the VATS pneumonectomy inclusion criteria they may gain from all the advantages of minimally invasive techniques.

Indocyanine green fluorescence in the assessment of the quality of the pedicled intercostal muscle flap: a pilot study

OBJECTIVES The pedicled intercostal muscle flap (IMF) is a high quality vascularized tissue commonly used to buttress the bronchial stump after pneumonectomy or bronchial anastomosis after sleeve lobectomy in order to prevent bronchopleural fistula formation. The evaluation of the viability of the muscle flap is difficult. The aim of this study was the assessment of the application of indicyanine green fluorescence for the evaluation of IMF perfusion. METHODS The study included 27 patients (10 males and 17 females), mean age 62.6 years (47-77 years). Indocyanine green fluorescence (ICG) was used for objective assessment of the IMF quality by a near-infrared camera system (Photodynamic Eye(®), Hamamatsu Photonics, Japan). The following factors that may have an impact on the quality of the IMF were assessed: age, gender, body mass index, comorbidities, IMF length and thickness and timing of the harvesting during the procedure. RESULTS The following surgical pulmonary resections with IMF harvesting were performed: 12 pneumonectomies, 2 sleeve lobectomies and 13 lobectomies. Intercostal muscle flap (IMF) was harvested before rib spreader insertion in 23 patients (85%) and at the end of the surgery in 4 patients (15%). The mean length and thickness of the harvested intercostal muscle were 19.9 ± 2.9 cm (range 13-24 cm) and 2.4 cm ± 0.7 cm (range 1.0-3.5 cm), respectively. Indocyanine green angiography showed ischaemia in the distal part of the muscle in all cases, despite the lack of obvious macroscopic signs. Median length of the ischaemic part was 4 cm (range 0.5-20 cm). The IMF length and thickness had a significant impact on the length of the ischaemic segment. In 24 patients, the ischaemic part of the muscle flap was severed. In 3 patients with the longest ischaemic segment (11, 13 and 20 cm), an alternative tissue was used to cover the bronchial stump. No major complications occurred. CONCLUSIONS Our preliminary results confirmed the simplicity and high efficacy of ICG in the assessment of intercostal muscle blood perfusion. ICG was superior to macroscopic evaluation and influenced surgical proceeding.

High costs as a slow down factor of thoracoscopic lobectomy development in Poland - an institutional experience.

Introduction Thoracoscopic (VATS) lobectomy after a decade of criticism is nowadays considered as a technically feasible, safe and oncologically proper operation. This approach has some advantages over conventional thoracotomy like: less postoperative pain, shorter hospitalization, fewer postoperative complications, better tolerance of adjuvant chemotherapy with comparable long-term survival rate. The VATS lobectomy is now generally accepted as an important alternative to open lobectomy in early-stage lung cancer. Aim In the study we analyzed all aspects of introducing video-assisted thoracoscopic surgery (VATS) lobectomy in our institution with special consideration of the costs of the procedure as a potential limiting factor of its widespread development. Material and methods The data of 212 consecutive patients with early stage lung cancer operated on during 2008-2011 were selected and analyzed. One hundred and eight patients underwent VATS lobectomy (VATS group) and 104 patients antero-lateral thoracotomy (thoracotomy group). Perioperative outcomes including operating time, blood loss during surgery, postoperative complication rate, length of hospital stay, and duration of chest tube drainage were assessed. The cost evaluation included: all direct theater costs, daily hospital costs, intensive care costs, pharmacy and disposable costs with special consideration of stapling device costs. Results The mean hospital stay after VATS lobectomy was significantly shorter than after thoracotomy, mean 7 days vs. 10 days (p < 0.0012). The complication rate and ICU admission rate were almost twice as high after thoracotomy than after VATS and were 46% vs. 23% (p < 0.0006) and 42% vs. 22% (p < 0.0027) respectively. Cost analysis showed significantly higher total costs of VATS lobectomy than after thoracotomy (median €2445 vs. €2047). Considerably higher theater costs for VATS compared to thoracotomy, median €1395 vs. €479, were caused mainly by endostapler costs, median €1069 vs. €161. Significantly higher hospital costs and ICU costs after thoracotomy did not compensate high theater costs of VATS lobectomy. Conclusions In Polish financial reality and potentially in other middle-income countries significantly higher costs of the procedure can limit widespread introduction of VATS lobectomy in clinical practice.

FAM13A as a Novel Hypoxia-Induced Gene in Non-Small Cell Lung Cancer

Several genome-wide association studies (GWASs), have identified that FAM13A and IREB2 loci are associated with lung cancer, but the mechanisms by which these genes contribute to lung diseases susceptibility, especially in hypoxia context, are unknown. Hypoxia has been identified as a major negative factor for tumor progression in clinical observation. It has been suggested, that lower oxygen tension, may modulate the IREB2 and FAM13A activity. However, the role of these genes in hypoxia response has not been explained. To precise the role of these genes in hypoxia response, we analyzed the FAM13A and IREB2 expression, in lung cancer cells in vitro and lung cancer tissue fragments cultured ex vivo. Three cell lines: non-small cell lung cancer (A549, CORL-105), human lung fibroblasts (HL) and 37 lung cancer tissue fragments were analyzed. The expression of IREB2, FAM13A and HIF1α after sustained 72 hours of hypoxia versus normal oxygen concentration were analyzed by TaqMan® Gene Expression Assays and Western Blot. The expression of FAM13A was significantly up-regulated by hypoxia in two lung cancer cell lines (A549, CORL-105, P<0.001), both at the level of protein and mRNA, and in lung cancer tissue fragments (P=0.0004). The IREB2 was down-regulated after hypoxia in A549 cancer cells (P<0.001). Conclusions: We found that FAM13A overexpression in human lung cancer cell lines overlapped with hypoxia effect on lung cancer tissues. FAM13A is strongly induced by hypoxia and may be identified as a novel hypoxia-induced gene in non-small cell lung cancer.

Comorbidities with non-small cell lung cancer: Is there an interdisciplinary consensus needed to qualify patients for surgical treatment?

INTRODUCTION: Radical surgical treatment is the preferred action for patients with early-stage non-small cell lung cancer (NSCLC). Qualification for surgical treatment should consider a risk associated with the effect of comorbidities on the general condition of the patient. The aim of this article was an attempt to identify the risk factors for postoperative complications in patients treated for NSCLC, with a special focus on the coexisting diseases. METHODS: A total of 400 patients with NSCLC were included in this retrospective study. The incidence of postoperative complications (including major complications according to the European Society of Thoracic Surgeons [ESTS]) was analyzed. Factors associated with high risk of postoperative complications were identified. RESULTS: Postoperative complications occurred in 151 patients (39% operated patients), including severe complications according to ESTS in 75 patients (19%). From univariate analysis, risk factors for postoperative complications were arrhythmias, pneumonectomy, and open thoracotomy. According to ESTS, for major complications, the risk factors included age ≥65 years, the presence of comorbidities, hypertension, and arrhythmias. From multivariate analysis, the risk of complications was higher in patients undergoing pneumonectomy and with cardiac arrhythmias, whereas the risk of serious complications according to ESTS was found in people ≥65 years of age and suffering from comorbidities. CONCLUSIONS: The risk of postoperative complications is affected by both surgical factors and the general health of the patient. Elderly patients with chronic disease history, hypertension, and arrhythmias have an increased risk of postoperative complications. Knowledge of these factors will identify a group of patients requiring internal consultation and optimization of preoperative treatment and postoperative follow-up.

Video-assisted-thoracoscopic surgery in left-to-right Nuss procedure for pectus excavatum for prevention of serious complications – technical aspects based on 1006 patients

Introduction Additional use of the video-assisted thoracoscopic surgery (VATS) technique in the Nuss procedure has been globally accepted for the improvement of safety of surgical treatment as well as for decreased frequency of serious intraoperative and postoperative complications. Aim To evaluate VATS in surgical treatment of patients with pectus excavatum by the left-to-right Nuss procedure for prevention of serious intra- and postoperative complications. Material and methods From 2002 to 2016, 1006 patients with pectus excavatum aged 7 to 62 years (mean: 18.6) underwent the Nuss procedure. There were 796 males and 210 females. The clinical records of all patients were analyzed retrospectively. The follow-up varied from 1 to 172 months (mean: 80.7 ±43). Results The early 30-day postoperative mortality was zero. Early thoracoscopy-dependent postoperative complications, the majority transient and non-life-threatening, occurred in 35.6% of patients. The most frequent complication was pneumothorax, diagnosed in 24.5% of patients. Two patients required repeat surgery. One patient required VATS pleurectomy due to persistent postoperative air leakage. In another patient left thoracotomy following bleeding from the pleural cavity was performed. Conclusions The use of VATS in the left-to-right Nuss procedure for pectus excavatum ensures the safety of surgical treatment and minimizes the occurrence of serious intra- and postoperative complications concerning injury of the mediastinum, lung, diaphragm or abdominal cavity.

Long-term results of surgical treatment of non-small cell lung cancer in patients over 75 years of age

Introduction Patients over 75 years of age, who, in addition, often have already exceeded the average life expectancy, in the Polish population on average 77.4 years, are the subject of discussion concerning the most appropriate choice of treatment. Aim To analyse the long-term results in elderly patients over 75 years of age with lung cancer who underwent curative pulmonary resection. Material and methods 166 patients aged from 75 to 85 (mean: 77.4 ±2.3) operated on for non-small cell lung cancer (NSCLC) were included in this study. There were 128 (77%) men and 38 (23%) women. Results Lobectomy, including bilobectomy, was performed in 122 (74%) patients, pneumonectomy in 8 (5%) patients, and wedge resections or segmentectomy in the remaining 36 patients. Squamous or adenocarcinoma was diagnosed in 46% and 42% of cases respectively. Clinical stage I A was diagnosed in 36 (22%) patients, I B in 51 (31%), IIA in 30 (18%), IIB in 19 (11%) and IIIA in 30 (18%) of our cases. The early 30-day postoperative mortality was 5% whilst postoperative morbidity occurred in 47% of cases. The five-year survival rate was 30%. In statistical analysis, the TNM classification (p = 0.0490), the number of postoperative complications (p = 0.0001) and obstructive atelectasis requiring repeat bronchofibroscopic aspirations (p = 0.0137) in the early postoperative period most negatively influenced the long-term survival in the whole study group. Conclusions Surgical resections for lung cancer in patients over 75 years of age are characterised by a relatively good long-term prognosis. Careful and strictly detailed preoperative selection, particularly of patients with pulmonary comorbidities and the earliest possible diagnosis of a lung tumour, can reduce the occurrence of these postoperative complications in elderly patients, which negatively influence long-term results.

Klotho expression and nodal involvement as predictive factors for large cell lung carcinoma

Introduction Klotho has been recently described as a carcinogenesis suppressor. Large cell neuroendocrine lung carcinoma (LCNEC) is a rare, highly malignant neoplasm. In the light of increasing incidence of neuroendocrine tumours, biomarkers predicting survival are needed. We consider that Klotho might be one. Material and methods We analysed records of all patients diagnosed with LCNEC, atypical carcinoid and typical carcinoid operated on in our institution between 2007 and 2015. Initially, we found 134 cases. Forty-six specimens were unattainable and thus excluded from research. All patients diagnosed with LCNEC according to the WHO classification were included in the study. Immunohistochemical staining for Klotho was performed. We retrospectively reviewed patient charts and analysed multiple variables. Results Positive staining for Klotho was present in 36 tissue specimens, while 12 patients were Klotho-negative. Survival length was significantly higher in Klotho-positive cases (p = 0.024), while advanced nodal status (N1 and N2) represented a marker of poor outcome (p = 0.011). In multivariate analysis, both Klotho presence (p = 0.015; HR = 0.37; 95% CI: 0.17–0.86) and nodal involvement (p = 0.007; HR = 3.04; 95% CI: 1.37–6.82) were independent prognostic factors. Tumour vessel invasion and visceral pleura infiltration were not associated with worse treatment results. Klotho presence predicted a favourable prognosis in these groups (p = 0.018; p = 0.007). Conclusions Our results suggest that Klotho might be a positive factor for predicting survival in LCNEC and nodal involvement a negative one. Thus, these two markers may assist in the selection of subjects with unfavourable prognosis and to personalise therapy regimens.

Clinical significance of nestin and its association with survival in neuroendocrine lung tumours

Nestin is considered to be a cancer stem cell marker. Nestin expression in neuroendocrine tumours might be useful to predict prognosis and facilitate treatment planning. 88 patients with neuroendocrine lung tumours operated in the Department of Thoracic Surgery from 2007 to 2015 were included into the study. Immunohistochemical staining for nestin was performed. Clinicopathological and survival data were retrospectively analyzed. Nestin expression was detected in 15 (17%) specimens. Multivariate analysis showed that lymph node metastases (p = 0.0001; hazard ratio (HR) = 3.93; confidence interval (CI) 95%: 1.96-7.87), nestin expression (p = 0.034; HR = 2.30; CI 95%: 1.06-4.99) and patients age (p = 0.024; HR = 1.04; CI 95%: 1.00-1.09) were independent negative prognostic factors. Nestin expression was significantly higher in large cell neuroendocrine carcinoma when compared with carcinoids (p = 0.001). Collected data support the thesis that nestin can be regarded as a biomarker in patients with neuroendocrine lung tumours.