Jarosław Kużdżał

Interplay Between Heme Oxygenase-1 and miR-378 Affects Non-Small Cell Lung Carcinoma Growth, Vascularization, and Metastasis

AIMS Heme oxygenase-1 (HO-1, HMOX1) can prevent tumor initiation; while in various tumors, it has been demonstrated to promote growth, angiogenesis, and metastasis. Here, we investigated whether HMOX1 can modulate microRNAs (miRNAs) and regulate human non-small cell lung carcinoma (NSCLC) development. RESULTS Stable HMOX1 overexpression in NSCLC NCI-H292 cells up-regulated tumor-suppressive miRNAs, whereas it significantly diminished the expression of oncomirs and angiomirs. The most potently down-regulated was miR-378. HMOX1 also up-regulated p53, down-regulated angiopoietin-1 (Ang-1) and mucin-5AC (MUC5AC), reduced proliferation, migration, and diminished angiogenic potential. Carbon monoxide was a mediator of HMOX1 effects on proliferation, migration, and miR-378 expression. In contrast, stable miR-378 overexpression decreased HMOX1 and p53; while enhanced expression of MUC5AC, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and Ang-1, and consequently increased proliferation, migration, and stimulation of endothelial cells. Adenoviral delivery of HMOX1 reversed miR-378 effect on the proliferation and migration of cancer cells. In vivo, HMOX1 overexpressing tumors were smaller, less vascularized and oxygenated, and less metastatic. Overexpression of miR-378 exerted opposite effects. Accordingly, in patients with NSCLC, HMOX1 expression was lower in metastases to lymph nodes than in primary tumors. INNOVATION AND CONCLUSION In vitro and in vivo data indicate that the interplay between HMOX1 and miR-378 significantly modulates NSCLC progression and angiogenesis, suggesting miR-378 as a new therapeutic target. REBOUND TRACK: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16, 293-296, 2012) with the following serving as open reviewers: James F. George, Mahin D. Maines, Justin C. Mason, and Yasufumi Sato.

Regulation and Novel Action of Thymidine Phosphorylase in Non-Small Cell Lung Cancer: Crosstalk with Nrf2 and HO-1

Proangiogenic enzyme thymidine phosphorylase (TP) is a promising target for anticancer therapy, yet its action in non-small cell lung carcinoma (NSCLC) is not fully understood. To elucidate its role in NSCLC tumor growth, NCI-H292 lung mucoepidermoid carcinoma cells and endothelial cells were engineered to overexpress TP by viral vector transduction. NSCLC cells with altered expression of transcription factor Nrf2 or its target gene heme oxygenase-1 (HO-1) were used to study the regulation of TP and the findings from pre-clinical models were related to gene expression data from clinical NSCLC specimens. Overexpression of Nrf2 or HO-1 resulted in upregulation of TP in NCI-H292 cells, an effect mimicked by treatment with an antioxidant N-acetylcysteine and partially reversed by HO-1 knockdown. Overexpression of TP attenuated cell proliferation and migration in vitro, but simultaneously enhanced angiogenic potential of cancer cells supplemented with thymidine. The latter was also observed for SK-MES-1 squamous cell carcinoma and NCI-H460 large cell carcinoma cells. TP-overexpressing NCI-H292 tumors in vivo exhibited better oxygenation and higher expression of IL-8, IL-1β and IL-6. TP overexpression in endothelial cells augmented their angiogenic properties which was associated with enhanced generation of HO-1 and VEGF. Correlation of TP with the expression of HO-1 and inflammatory cytokines was confirmed in clinical samples of NSCLC. Altogether, the increased expression of IL-1β and IL-6 together with proangiogenic effects of TP-expressing NSCLC on endothelium can contribute to tumor growth, implying TP as a target for antiangiogenesis in NSCLC.

Iatrogenic injuries to the trachea and main bronchi

Introduction Iatrogenic tracheobronchial injuries are rare. Aim To analyse the mechanism of injury, symptoms and treatment of these patients. Material and methods Retrospective analysis of hospital records of all patients treated for main airway injuries between 1990 and 2012 was performed. Results There were 24 patients, including 21 women and 3 men. Mean time between injury and initiation of treatment was 12 hours (range: 2-48). In 16 patients the injury occurred during tracheal intubation, in 1 during rigid bronchoscopy, in 1 during rigid oesophagoscopy, in 1 during mediastinoscopy and in 5 during open surgery. Mean length of airway tear was 3.8 cm (range: 1.5-8). In 1 patient there was an injury to the cervical trachea and in the remaining 23 in the thoracic part of the airway. The treatment included repair of the membranous part of the trachea performed via right thoracotomy in 10 patients (in 1 patient additionally coverage with a pedicled intercostal muscle flap was used), a self-expanding metallic stent in 1 patient, suture of the right main bronchus and the oesophagus in 1, left upper sleeve lobectomy in 1, right upper lobectomy in 1, implantation of a silicone Y stent in 3, mini-tracheostomy in 1, and conservative treatment in 5 patients. Conclusions Intubation is the most frequent cause of iatrogenic main airway injuries. Patients with these life-threatening complications require an individualised approach and treatment in a reference centre.

Double stenting for malignant oesophago-respiratory fistula

Introduction The close anatomical relationship between the oesophagus and bronchial tree results in formation of an oesophago-respiratory fistula in a subset of patients with advanced oesophageal or lung cancer. In those patients stenting of both the oesophagus and tracheobronchial tree is a valid option of palliative treatment. Aim To determine the effectiveness, tolerance, quality of life, safety and survival after double stenting procedures. Material and methods Retrospective analysis of a prospectively collected database was performed, concerning consecutive patients with oesophago-respiratory fistulas treated with double stenting. In all patients the degree of dysphagia, respiratory function before and after the procedure, and quality of life were evaluated. Partially covered oesophageal self-expanding metallic stents (PCESEMS) were used for oesophageal stenting, and silicone Y-type or partially covered self-expanding bronchial and tracheal stents (PCASEMS) were used to restore airway patency. Results Between 2003 and 2015, 31 patients underwent double stenting due to oesophago-respiratory fistulas. Twenty-nine patients were diagnosed with oesophageal squamous cell carcinoma and 2 with bronchial carcinoma. In all patients, improvement in the general condition and quality of life was observed after airway patency restoration. Two patients required mechanical ventilation due to respiratory failure immediately after the procedure. Seven patients with oesophageal fistulas died because of bleeding in the long-term follow-up. Four patients required endoscopic re-intervention. Mean survival time was 67.1 days. Conclusions Double stenting is an effective procedure improving patients’ quality of life. However, life-threatening complications can occur.

Stenting as a palliative method in the management of advanced squamous cell carcinoma of the oesophagus and gastro-oesophageal junction

Advanced squamous cell carcinoma of the oesophagus and gastroesophageal junction usually requires palliative treatment, and the method of choice is stenting. There are several types of stents currently available, including: self-expandable metallic stents (fully or partially covered); self-expandable plastic stents; biodegradable stents. Each of the mentioned stents has its advantages and limitations, and requires a proper, patient-tailored selection. Due to the close anatomical relationship between the oesophagus and bronchial tree, some patients may require bilateral stenting. Oesophageal stenting may not only be considered as a palliative procedure, but can also be implemented to alleviate dysphagia during preoperative chemotherapy and/or radiotherapy.

Tension pneumothorax as a severe complication of endobronchial ultrasound-guided transbronchial fine needle aspiration of mediastinal lymph nodes

This article presents a case report of a patient suffering from bullous emphysema and chronic obstructive pulmonary disease, who was diagnosed with tension pneumothorax after undergoing endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Tension pneumothorax is a severe but rare complication of EBUS-TBNA. It can result from lung injury caused by the biopsy needle or, in patients suffering from bullous emphysema, from spontaneous rupture of an emphysematous bulla resulting from increased pressure in the chest cavity during cough caused by bronchofiberoscope insertion. The authors emphasize that patients should be carefully monitored after the biopsy, and, in the case of complications, provided with treatment immediately in proper hospital conditions. Patients burdened with a high risk of complications should be identified before the procedure and monitored with extreme care after its completion.

Safety and efficacy of oesophageal stenting with simultaneous percutaneous endoscopic gastrostomy as a supplementary feeding route in unresectable proximal oesophageal cancer

Introduction Proximally located oesophageal cancer poses an especially difficult problem in terms of restoration of patency and the stenting procedure. Supplementary percutaneous endoscopic gastrostomy (PEG) may be useful in these patients. Aim To assess the safety of the stenting procedure in the proximal oesophagus in patients with unresectable upper oesophageal cancer, performed simultaneously with PEG insertion. Material and methods Patients with obstructing upper oesophageal tumours were scheduled for an oesophageal stenting procedure and simultaneous PEG insertion. Degree of dysphagia, body weight loss, daily energy requirement, body mass index and performance status before and after the stenting procedure as well as complications were assessed. Results Forty-five patients aged 19–88 years were included in the study. Six of them had a fistula to the trachea and underwent stenting of the oesophagus or both the oesophagus and the airway. The technical success rate was 100%. Following the procedure all patients were able to swallow fluids and semi-liquids, and PEG was used as the primary feeding route. Body mass index increased from 20.4 to 21.1 (p = 0.0001), body weight gain improved from –10.1 to +2.0 kg and metabolic requirements improved (p = 0.0001). Also, the Karnofsky score improved significantly (56.7 vs. 65.1, p = 0.0001). Mean survival time was 133 days (range: 36–378). Conclusions Stenting of the proximal oesophagus with simultaneous PEG is a safe procedure, allowing the patients to resume oral intake of liquids whilst improving nutritional status and general performance, with an acceptable rate of complications.

Preoperative thrombocytosis in surgically treated patients with non-small cell lung cancer

Introduction Lung cancer is the most common cause of cancer‑related death. Accurate and easy‑to‑use prognostic factors are necessary. Increased platelet count might be a potential prognostic factor. Objectives We aimed to investigate the relationship between thrombocytosis and stage of lung cancer and to assess the frequency and clinical importance of thrombocytosis in this patient group. Patients and methods We retrospectively analyzed hospital records of consecutive patients with non-small cell lung cancer (NSCLC) who underwent curative‑intent pulmonary resections. Results Of 323 patients, 285 patients with NSCLC were selected (mean [SD] age, 66.55 [8.52] years; men, 63.86%). Squamous cell carcinoma was diagnosed in 130 patients (45.61%); adenocarcinoma, in 128 (44.91%); large cell carcinoma, in 16 (5.61%); and adenosquamous carcinoma, in 11 (3.86%). The prevalence of preoperative thrombocytosis in the whole sample was 10.18% (n = 29). Anemia was more common in patients with thrombocytosis compared with those without thrombocytosis (65.52% vs 30.08%; P <0.001). Thrombocytosis was found in 22.41% of patients with stage III+IV cancer and in 3.82% of those with stage I (P <0.001). Moreover, in patients with no metastases (N0, M0 according to the 7th edition of the TNM classification), thrombocytosis was more frequent in the group with stage II than in that with stage I cancer (3.85% vs 20.00%; P = 0.002). Thrombocytosis was also more frequent in patients with N2 than with N1 disease (9.76% vs 23.81%; P = 0.09). Conclusions Thrombocytosis is often observed in patients with NSCLC and is significantly associated with the higher stage of disease.

Safety and efficacy of airway stenting in patients with malignant oesophago-airway fistula

Background Close anatomical relationships between the oesophagus and the bronchial tree can lead to the formation of oesophageal fistula particularly in patients with advanced lung or oesophageal carcinoma. Stenting is a most often used treatment in such patients, but data regarding the relative value of unilateral (US) vs. double stenting (DS) are scarce. Methods Retrospective analysis of hospital records of patients with oesophageal fistula who underwent stenting between 2008 and 2016. In those in whom airway stenosis was >30%, double stenting (oesophagus and bronchial tree) was performed, whereas in those with lesser airway stenosis unilateral stenting (i.e., oesophagus only) was performed. In all patients, the degree of dysphagia, the degree of dyspnoea and the quality of life were assessed before and after the stenting. Results There were 46 patients, analysed, including 26 who underwent DS and 20 patients who underwent US. Both, DS and US resulted in significant improvement of dysphagia (2.72 vs. 1.2, P=0.0001 and 2.65 vs. 1.0, P=0.0001), dyspnoea (2.89 vs. 0.34, P=0.0001 and 1.71 vs. 0.09, P=0.0001) and performance score (53.2 vs. 66.3, P=0.0001 and 54.3 vs. 62.38, P=0.0001). Neither fistula type, nor stenting method, weight loss and gain, and BMI, had an effect on survival (P=0.34). Disease progression and recurrence of fistula requiring re-intervention occurred in 9 patients (19.5%). Conclusions Double and unilateral stenting is an effective measure to alleviate dysphagia and dyspnoea in patients treated with malignant oesophageal fistula. In those with airway stenosis of ≤30%, stenting of the oesophagus only, instead of DS, is a safe method of treatment.

Lymph node metastasis in oesophageal cancer—what we (do not) know?

Although many aspects of the treatment of oesophageal cancer remain controversial, one of them is beyond doubt: prognosis in this disease is still poor, with overall 5-year survival slightly over 10% (1). One of the most important issues determining prognosis is metastatic spread in the lymphatic system. The mechanism of this spread is poorly understood, as is the role of lymphadenectomy. Whilst there are ongoing discussions on the impact of lymph node dissection on survival, it is generally agreed that lymphadenectomy enables accurate staging and, therefore, is important for prognostic purposes. However, high quality scientific data regarding many factors related to this issue are scarce.