Bartosz Kubisa

Accelerated treatment of postpneumonectomy empyema : a binational long-term study

OBJECTIVE Postpneumonectomy empyema remains a clinical challenge. We proposed an accelerated therapy without an open chest window 5 years ago. This concept was evaluated on a larger scale in 2 centers in 2 different countries. METHODS Between July 1995 and October 2005, 75 consecutive patients with postpneumonectomy empyema were treated in Szczecin, Poland (n = 35), and Zurich, Switzerland (n = 40). The therapy consisted of repeated open surgical debridement of the pleural cavity after achievement of general anesthesia, a negative pressure wound therapy of the temporarily closed chest cavity filled with povidone-iodine-soaked towels, and continuous suction and systemic antimicrobial therapy. If present, bronchopleural fistulae were closed and reinforced either with a muscle flap or the omentum. Finally, the pleural space was filled with an antibiotic solution and definitively closed. RESULTS Of 75 patients (63 men; median age, 59 years; age range, 19-82 years), postpneumonectomy empyema was present on the right in 46 patients (32 with bronchopleural fistula) and in 29 patients (12 with bronchopleural fistula) on the left. Median time between pneumonectomy and postpneumonectomy empyema was 131 days (range, 7-7200 days). Bronchopleural fistulae have been closed and additionally reinforced by means of different methods (omentum, 18; muscle, 11; pericardial fat, 5; azygos vein, 1). The chest was definitively closed within 8 days in 94.6% of patients. The median hospitalization time was 18 days (range, 9-134 days). Postpneumonectomy empyema was successfully treated in 97.3% of patients, including 10 (13%) patients who needed a second treatment cycle. Three (4%) patients died within 90 days. The median follow-up time was 29.5 moths (range, 3-107 months). CONCLUSIONS Treatment of postpneumonectomy empyema with the accelerated treatment is effective and safe. Our results are superior compared with those in reported series using a (temporary) chest fenestration. Patients appreciate the physical integrity of the chest.

Additional pulmonary resections after pneumonectomy: actual long-term survival and functional results

OBJECTIVE Pulmonary resections after pneumonectomy due to metastases or metachronous non-small cell lung cancer (NSCLC) are rare because of the high potential risk of the second procedure and uncertain long-term results. On the basis of our series (largest in Europe) we tried to assess the long-term survival of patients treated in stage IV NSCLC. METHODS Retrospective analysis was carried out on 18 patients treated at our department by pneumonectomy followed by additional resection in the years 1981-2002 (15 males and 3 females, 44-69 years, mean 57). Eleven pneumonectomies were performed on the right side and seven on the left. Twelve squamous cell carcinomas and six adenocarcinomas were diagnosed. All patients were staged postoperatively as IIB-IIIA (four were N2). Their WHO status ranged between 0 and 1. The second surgical procedure (16 wedge resections, 2 chest wall resections) was performed 4-106 months later (mean 26). The patients staged N2 were radiated postoperatively. RESULTS There were no early postoperative deaths. The morbidity rate after second surgery was comparable to that observed after ordinary wedge resection. Histology of the lesions removed during the second operation was the same as after pneumonectomy in all patients. The pulmonary function tests (PFT) results worsened significantly but still reached 56-63% of the predicted values. Sixteen resected tumors of the remaining lung were staged T1 (<3cm), 2 - T3 (<3cm but infiltration of the parietal pleura on an area of 2-4cm(2)). Three patients revealed N2 disease (they were all N0 after pneumonectomy). All patients were considered M1 after second surgery. WHO status after the second procedure remained the same in 8 patients (44%) and worsened in 10 patients (56%). The survival rates were as follows: 11 patients survived 2 years (61%) while 8 patients survived 5 years (44%). The majority of patients died due to lung cancer (70%) but all the rest (30%) due to circulatory or respiratory insufficiency. There was a significant difference (p<0.05) in 5-year survival for N0-N1 vs N2 status (63% vs 14% - 1 patient) and also regarding the time interval between surgeries: less than 12 months vs more than 12 months (0% vs 63%). CONCLUSIONS Pulmonary resections performed after pneumonectomy due to NSCLC are rare procedures but with an acceptable perioperative risk. The second procedure should be limited to wedge resection. The prognosis is poor for patients with N2 status and for those treated by second surgery earlier than 12 months after the first procedure.

Lung cancer in situs inversus totalis (SIT) - literature review

We present 21 studies of cases of lung cancer in patients with situs inversus totalis (SIT) published worldwide. The first case was described in 1952. Thirteen patients were from Japan, 4 from Eastern Europe, including 2 Polish cases from the authors` center (Department of Thoracic Surgery, Pomeranian Medical University in Szczecin, Poland), 2 from Western Asia, 1 from the U.S. and 1 from Australia. Male patients (20/21) as well as left-sided lung cancer cases (14/21) and squamous cell carcinoma cases (8/21) dominated in the entire group. Thirteen patients underwent surgical treatment. There were 10 left-sided and 3 right-sided surgical interventions with uneventful intra- and postoperative course. Explorative thoracotomy was performed in one case only on the right side. Upper lobectomy was performed in 5 cases, pneumonectomy in 3 cases, lower bilobectomy and middle lobectomy in one case and lower lobectomy in two cases. Surgery was performed through thoracotomy in 10 cases, VATS-assisted approach in two cases and sternotomy in one case. Descriptions of the surgical anatomy confirmed mirror image of the anatomy in all cases and were consistent with the preoperative CT images. Preoperative diagnosis was discussed including the role of 3-D reconstruction of CT for improving perioperative safety in this group of patients. In conclusion, lung cancer/SIT cases despite inversed but regular anatomy can be operated on radically as cases with normal anatomy with preservation of intraoperative security level.

Non-viral gene delivery to atelectatic and ventilated lungs.

BACKGROUND Three different nonviral vectors and naked DNA were evaluated for in vivo transfer of plasmid DNA to rat lungs through airways in either atelectatic or ventilated lungs. METHODS The F344 rats underwent instillation of 300 microg DNA (pCIluc, luciferase) to the left lung. Naked DNA, linear polyethylenimine, branched polyethylenimine, and lipid GL-67 (in either atelectatic or ventilated lungs) were assessed (n = 5 per group). After 24 hours, left lung PaO2 (mm Hg) and luciferase activity (RLU/mg) were measured. The median (range) was given, and the analysis of variance was applied, followed by the planned comparison on log-transformed data. RESULTS In atelectatic lungs, lipid GL-67 was best (927 [330 to 4112] RLU/mg; p < 0.001 versus other groups of atelectatic lung; p < 0.001 versus all other groups), but highest luciferase activity in all groups was measured in ventilated lungs using linear polyethylenimine (1,240 [922 to 2519] RLU/mg; p < 0.001 versus other groups of ventilated lung; p < 0.001 versus all other groups). In comparison with naked DNA, all nonviral vector systems significantly impaired PaO2 24 hours after airway transfection (p < 0.001; naked DNA versus all other groups). Regardless of transfection technique, PaO2 was worst in lungs transfected by linear polyethylenimine. CONCLUSIONS Highest transfection was achieved with GL-67 in atelectatic lungs and with linear polyethylenimine in ventilated lungs. All gene delivery systems impaired gas exchange of the transduced lung in comparison with naked DNA.

The impact of the sequence of pulmonary vessel ligation during anatomic resection for lung cancer on long-term survival - a prospective randomized trial

PURPOSE The aim of this prospective randomized trial was to assess the influence of the sequence of pulmonary vessel ligation, during anatomic resection, on long term survival in patients with NSCLC. MATERIAL/METHODS This prospective randomized study included 385 patients treated surgically with lobectomy or pneumonectomy and standard lymphadenectomy between 1999 and 2003. Patients were randomly assigned to either primary ligation of the pulmonary artery or arteries (group A - 215 patients) or of the pulmonary vein or veins (group V - 170 patients). Patients were excluded if the sequence of vessel ligation was affected by technical difficulties or anatomic limitations. Univariate and multivariate analyses included: the sequence of vessel ligation, age, gender, tumor histology, stage (TNM), and cause of death (cancer related or non-cancer related). RESULTS Median follow-up was 63 months. The groups were comparable regarding gender, histology, type of resection, and T, N, and overall stage. Overall, 5-year survival reached 50% in group A and 54% in group V (p = 0.82) and did not differ significantly in cancer related and non-cancer related deaths (p = 0.67 and p = 0.26, respectively). Univariate analysis identified higher T and N factors, advanced stage, pneumonectomy, male sex, and older age as negative prognostic factors. Multivariate analysis demonstrated that age, T3-4 disease, and nodal involvement were associated with inferior survival. CONCLUSIONS The sequence of pulmonary vessel ligation during anatomic resection for non-small cell lung cancer does not significantly affect long-term survival.

1,25-Dihydroxycholecalciferol with low-calcium diet reduces acute rejection in rat lung allotransplantation.

OBJECTIVES The effect of 1,25-dihydroxycholecalciferol (calcitriol, vitamin D3) with a low-calcium diet on the acute lung allograft rejection in a rat unilateral left lung transplantation model was evaluated. METHODS Three transplantation groups were studied (n = 5, male Brown-Norway to Fischer F344, 235 ± 15 g body weight): calcitriol and low-calcium diet, low-calcium diet and normal diet. Calcitriol (4 μg/kg/day) was injected intraperitoneally for 5 days, starting from the day of transplantation. In addition, two non-transplantation groups were compared: (n = 3, Brown-Norway) to measure the level of cytokines, and Fischer F344 receiving calcitriol and a low-calcium diet to measure the serum calcium level. The recipients of transplantation were killed on Day 5 post-transplant. The contralateral right main bronchus and the pulmonary artery were occluded for 5 min and blood was drawn for the blood gas analysis, and the grafts were assessed for histology (International Society for Heart and Lung Transplantation 1996/rank scale). Lung levels of interleukin (IL)-2, IL-6, IL-12 and tumour necrosis factor-α (TNF-α) were assessed within the calcitriol and low-calcium diet, low-calcium diet and Brown-Norway groups. The serum calcium level was assessed in the Fischer F344 group. An analysis of variance with Tukeys post hoc test was used to compare the arterial blood oxygen pressure and the lung cytokine expression between groups. A non-parametric Kruskal-Wallis test followed by the Siegel and Castellan post hoc test was used to assess the differences between the groups according to the lung graft rejection grading. Students paired t-test was used to compare the serum calcium level. RESULTS The arterial PaO(2) was significantly higher in the calcitriol and the low-calcium diet groups when compared with low-calcium diet or normal diet groups (356 ± 72 mmHg; P < 0.05 vs other groups). The arterial and bronchial rejection observed in calcitriol and low-calcium diet group was significantly milder than in the low-calcium diet or normal diet groups (A1-2, B1-2; P < 0.05 vs other groups). IL-2 and IL-6 levels were significantly higher in low-calcium diet vs calcitriol and low-calcium diet and Brown-Norway groups. IL-12 and TNF-α did not differ among the groups. There was no significant difference in serum calcium level before and after the treatment in the Fischer F344 group. CONCLUSIONS Calcitriol with a low-calcium diet treatment improves lung function, reduces lung allograft acute rejection, decreases IL-2 and IL-6 allograft expression and does not change the serum calcium level significantly.

Strong additive effect of 1,25-dihydroxycholecalciferol and cyclosporine A but not tacrolimus in rat lung allotransplantation

OBJECTIVES 1,25-Dihydroxycholecalciferol (calcitriol, vitamin D3) has immunosuppressive properties. This study evaluates the effect of calcitriol in combination with either cyclosporine A or tacrolimus on acute lung allograft rejection in a rat model of unilateral left lung allotransplantation. METHODS Unilateral left lung transplantation was performed in male rats (Brown-Norway to Fischer F344, 200-250 g body weight). For immunosuppression, the following subtherapeutic doses were used: calcitriol 0.5 microg/kg/day, cyclosporine A 2.5 mg/kg/day i.p., and tacrolimus 40 microg/kg i.m. Five groups (n = 5) were analyzed: cyclosporine A; cyclosporine A and calcitriol; calcitriol; tacrolimus and calcitriol; and tacrolimus. The injections were performed for 5 days starting from the day of transplantation. Recipients were sacrificed on day 5 post-transplant. The contralateral right main bronchus and pulmonary artery were occluded for 5 min and blood was drawn for blood gas analysis. The grafts were excised, fixed in formaline and embedded in paraffin. Histological evaluation was done in blinded fashion (ISHLT 1999/rank scale). The mean and standard error of the mean (PaO2) or the median and range (rejection grading) are given. ANOVA followed by planned comparison for the PaO2 and Kruskal-Wallis ANOVA for rejection grading were applied, p < 0.05 considered significant. RESULTS Arterial PaO2 on day 5 was very low in animals treated with subtherapeutic dosages of either cyclosporine A (48 +/- 10 mmHg), calcitriol (51 +/- 3) or tacrolimus (86 +/- 22). Combined treatment with cyclosporine A and calcitriol revealed a significant improvement (248 +/- 78; p < 0.05 vs. other groups), whereas the combination of tacrolimus with calcitriol did not reveal any benefit (65 +/- 9). Rejection grading with these subtherapeutic doses did not show any significant difference between groups. CONCLUSIONS Our data indicate that cyclosporine A, but not tacrolimus, has a strong additive effect with calcitriol on acute rat lung allograft rejection.

Pneumopericardium as a non-small-cell lung carcinoma complication

Below we present a case of a young man with symptoms of progressive weakness, fever, cough, rapid decrease in body weight and the presence of a tumor in the left axillary region. The chest radiography and echocardiography revealed gas bubbles in the pericardium. The more detailed diagnostics and computed tomography of the chest showed an infiltration of the left lung cavity and a fistula among the bronchus, pleural and pericardial cavities. Further diagnostics demonstrated that the pneumopericardium (diagnosed by means of chest radiograph and echocardiography) was a complication of a primary non-small-cell lung carcinoma.

Safety and Immunogenicity of the PRAME Cancer Immunotherapeutic in Patients with Resected Non–Small Cell Lung Cancer: A Phase I Dose Escalation Study

Introduction: Adjuvant platinum‐based chemotherapy is standard treatment for surgically resected stage II to IIIA NSCLC, but the relapse rate is high. The preferentially expressed antigen of melanoma (PRAME) tumor antigen is expressed in two‐thirds of NSCLC and offers an attractive target for antigen‐specific immunization. A phase I dose escalation study assessed the safety and immunogenicity of a PRAME immunotherapeutic consisting of recombinant PRAME plus proprietary immunostimulant AS15 in patients with surgically resected NSCLC (NCT01159964). Methods: Patients with PRAME‐positive resected stage IB to IIIA NSCLC were enrolled in three consecutive cohorts to receive up to 13 injections of PRAME immunotherapeutic (recombinant PRAME protein dose of 20 &mgr;g, 100 &mgr;g, or 500 &mgr;g, with a fixed dose of AS15). Adverse events, predefined dose‐limiting toxicity, and the anti‐PRAME humoral response (measured by enzyme‐linked immunosorbent assay) were coprimary end points. Anti‐PRAME cellular responses were assessed. Results: A total of 60 patients were treated (18 received 20 &mgr;g of PRAME, 18 received 100 &mgr;g of PRAME, and 24 received 500 &mgr;g of PRAME). No dose‐limiting toxicity was reported. Adverse events considered by the investigator to be causally related to treatment were grade 1 or 2, and most were injection site reactions or fever. All patients had detectable anti‐PRAME antibodies after four immunizations. The percentages of patients with PRAME‐specific CD4‐positive T cells were higher at the dose of 500 &mgr;g compared with lower doses. No predefined CD8‐positive T‐cell responses were detected. Conclusion: The PRAME immunotherapeutic had an acceptable safety profile. All patients had anti‐PRAME humoral responses that were not dose related, and 80% of those treated at the highest dose showed a cellular immune response. The dose of 500 &mgr;g was selected. However, further development was stopped after negative results with a similar immunotherapeutic in patients with NSCLC.

Primary pulmonary mucosa-associated lymphoid tissue lymphoma: a case report

Primary pulmonary lymphoma accounts only 0,5% of all primary lung neoplasms. Mucosa-associated lymphoid tissue (MALT) lymphoma is a low grade B-cell extranodal lymphoma. It is a quite infrequent entity, however it constitutes from 72% to 90% of all pulmonary lung lymphomas. Long-term stimulation of bronchus-associated lymphoid tissue by antigens, smoking, inflammatory disorders or autoimmune diseases are thought to be leading to the development of MALT lymphoma. We present the case of primary pulmonary mucosa-associated lymphoid tissue lymphoma. A 76-year-old man with a history of heavy smoking (22.5 pack years) was admitted to the hospital for a further diagnostics of an abnormal finding in the right lung visualized on the chest X-ray. The diagnostic process, including imagining studies did not reveal the etiology of a lesion in the right lung. The patient was qualified for surgical diagnostics. The histological finding confirmed extranodal marginal low-grade B-cell lymphoma of mucosa -associated lymphoid tissue.