Konstantinos Potaris

Purpose: We assessed whether preoperativemutational analyses of circulating tumor cells (CTCs) and plasma-cfDNA could be used as minimally invasive biomarkers and as complimentary tools for early prediction of relapse in early-stage non-small -cell lung cancer (NSCLC). Experimental Design: Using ddPCR assays, hotspot mutations of BRAF, KRAS, EGFR and PIK3CA were identified in plasma-cfDNA samples and size-based enriched CTCs isolated from the same blood samples of 49 early-stage NSCLC patients before surgery and in a control group of healthy blood donors (n= 22). Direct concordance of the mutational spectrum was further evaluated in 27 patient-matched plasma-cfDNA and CTC-derived DNA in comparison to tissue-derived DNA. Results: The prevalence of detectable mutations of the four tested genes was higher in CTC-derived DNA than in the corresponding plasma-cfDNA (38.8% and 24.5%, respectively).The most commonly mutated gene was PIK3CA, in both CTCs and plasma-cfDNA at baseline and at the time of relapse. Direct comparison of the mutation status of selected drug-responsive genes in CTC-derived DNA, corresponding plasma-cfDNA and paired primary FFPE tissues clearly showed the impact of heterogeneity both within a sample type, as well as between different sample components. The incidence of relapse was higher when at least one mutation was detected in CTC-derived DNA or plasma-cfDNA compared with patients in whom no mutation was detected (p =0.023). Univariate analysis showed a significantly higher risk of progression (HR: 2.716; 95% CI, 1.030–7.165; p =0.043) in patients with detectable mutations in plasma-cfDNA compared with patients with undetectable mutations, whereas the hazard ratio was higher when at least one mutation was detected in CTC-derived DNA or plasma-cfDNA (HR: 3.375; 95% CI, 1.098–10.375; p =0.034). Conclusions: Simultaneous mutational analyses of plasma-cfDNA and CTC-derived DNA provided complementary molecular information from the same blood sample and greater diversity in genomic information for cancer treatment and prognosis. The detection of specific mutations in ctDNA and CTCs in patients with early-stage NSCLC before surgery was independently associated with disease recurrence, which represents an important stratification factor for future trials.

A key unknown of the functional space in tumor immunity is whether physiologically relevant cancer antigen presentation occurs solely in draining lymph nodes versus tumors. Professional antigen presenting cells, i.e. the dendritic cells, are scarce and immature within tumors, greatly outnumbered by MHCII expressing non-hematopoietic cells, such as antigen-presenting cancer-associated fibroblasts (apCAFs). We hypothesized that after their exit from tumor-draining lymph nodes T cells depend on a second wave of antigen presentation provided in situ by structural cells. We show that dense apCAF regions in human lung tumors define hot immunological spots with increased numbers of CD4 T cells. The transcriptomic profile of human lung apCAFs aligned to that of pancreatic apCAFs across mice and humans and were both enriched for alveolar type II genes, suggesting an epithelial origin. Mechanistically, human apCAFs directly activated the TCRs of adjacent effector CD4 T cells and at the same time produced high levels of c1q, which acted on surface c1qbp on T cells to rescue them from apoptosis. Fibroblast-specific deletion of MHCII in mice impaired local MHCII immunity and accelerated tumor growth, while inducing c1qbp overexpression in adoptively transferred T cells expanded their numbers within tumors and reduced tumour burden. Collectively, our work shows that tumor T cell immunity post lymph node exit requires peripheral antigen presentation by a subset of CAFs and proposes a new conceptual framework upon which effective cancer immunotherapies can be built.

During fiscal crisis there was a period of shortage of staplers in our hospital, which drove us to manual suturing of bronchi and pulmonary vessels during major lung resections. We present our experience during that period in comparison to a subsequent period when staplers became available again. A total of 256 lobectomies and 78 pneumonectomies using manual suturing (group A) were performed between September 2009 and September 2010, and were compared regarding surgical outcome with 248 lobectomies and 60 pneumonectomies using staplers (group B), performed between September 2011 and September 2012. Although we did not observe statistically significant differences but only a trend toward shorter operative time, for both lobectomies (P = 0.21) and pneumonectomies (P = 0.31) we actually noted savings of 41 and 47 minutes, respectively, in operative time using staplers (group B), in comparison with manual suturing (group A). We also observed a trend toward lower morbidity rates in group B patients who underwent lobectomy (10.48%) and pneumonectomy (20%) versus group A patients who underwent lobectomy (15.62%) and pneumonectomy (30.76%); we did not observe any substantial differences in the other surgical outcome variables, in patients' demographic, comorbidities, or in anatomic allocation of surgical procedures performed. The use of staplers offers safety with secure bronchial or vascular sealing, as well as reduction of operative time. Their unavailability at an interval during fiscal crisis, although it did not affect surgical outcome, revealed their usefulness and value.

BACKGROUND:Persistent air leak following pulmonary lobectomy can be very difficult to treat and results in prolonged hospitalization. We aimed to evaluate the efficacy of a new method of postoperative air leak management using intrapleurally infused ...

We aimed to consolidate our clinical observations regarding the development of pulmonary hypertension following pneumonectomy for lung cancer. Sixty-nine of 82 initially selected patients without pulmonary or cardiac comorbidities, who underwent pneumonectomy for lung cancer between October 2009 and October 2011, accomplished our protocol. Mean patient age was 60.6 years (range 44–78 years) and 10.1% were women. Postoperative complications occurred in 16 (23.2%) patients. Mortality at 1, 12, and 18 months postoperatively was 4.3%, 15.9%, and 29%, respectively. One year postoperatively, 37.9% of patients developed mild to moderate pulmonary hypertension and 3.4% had severe pulmonary hypertension. The calculated mean pulmonary artery systolic pressure at 1, 6, and 12 months postoperatively was 21.9 ± 6.6, 27.3 ± 9.3, and 34.1 ± 14 mm Hg, respectively (p < 0.001). Receiver operating characteristic curve analysis showed a cutoff point at 35.5 mm Hg for late postoperative (at 12 months) pulmonary artery systolic pressure (sensitivity 80%, specificity 82%; p < 0.001) related to suboptimal clinical outcomes (decreased performance status or death), with a detected 18-fold risk for these patients (p < 0.001). Pulmonary hypertension may occur after pneumonectomy with its known adverse effects. Patients with late postoperative pulmonary artery systolic pressure > 35.5 mm Hg are at higher risk of a suboptimal clinical outcome.

Pulmonary parenchyma-saving procedures, indicated for central tumours, seem to have better results than pneumonectomy, an alternative procedure. The purpose of this study is to report our experience at our institution with sleeve lobectomy with regard to surgical technique and outcome. We retrospectively reviewed the records of 45 patients who underwent sleeve lobectomy for non-small-cell lung cancer, with a curative intent, during the period of January 2004 and January 2008. Four of these patients underwent bronchovascular reconstructive procedures. A minor modification of the running suture technique used for bronchoplasties is described here. The study identified 40 men and five women with a median age of 64 years (range: 24-80 years). All 45 patients underwent oncological resections with negative results for malignancy bronchial resection margins. Neither bronchial nor vascular complications occurred. Complications were observed in 15% of our patients and included prolonged air leak in three, atelectasis needing daily bronchoscopy in three and respiratory failure due to pneumonia in one patient, who eventually died, accounting for a mortality rate of 2%. The follow-up period ranged from 1 to 52 months, with a median of 26 months, and it was complete for 43 (96%) of the patients. The overall 4-year survival was 57%. Sleeve lobectomy for lung cancer, although technically demanding, is associated with low morbidity and mortality and satisfactory immediate and long-term results. With increasing experience, more lung-sparing procedures should be performed in selected patients.

Purpose: To evaluate the outcomes of video-thoracoscopic and open surgical management of patients with thoracic empyema. Methods: We studied 122 patients retrospectively who underwent surgery for thoracic empyema in our hospital between January, 1999 and January, 2005. Patients' medical records, surgical procedures, and outcomes were reviewed. The study identified 97 affected men and 25 affected women with a mean age of 54 years (range 16–78 years). The empyema was parapneumonic in 95 patients (78%). Results: Forty-four patients who had stage II empyema underwent video-assisted thoracic surgery (VATS). The procedure was converted to thoracotomy in 13 patients (29.5%); the morbidity and mortality rates of VATS were 13% and 0, respectively. Seventy-eight patients had stage III empyema and, along with those 13 who were converted, underwent thoracotomy for decortication. The associated morbidity rate was 12%, and the mortality rate was 6.6%. Thoracotomy was considered successful in 90 of 91 patients (99%); one patient needed a reoperative thoracotomy for an organ space/surgical site infection with pus in the pleural cavity. Conclusions: Many treatment modalities are available for thoracic empyema, depending on the results of appropriate clinical and laboratory investigations. In fibrinopurulent empyema, VATS debridement is safe and effective, with minimal morbidity and no deaths. Lung decortication via thoracotomy is the only option for organized empyema and is associated with a substantial mortality rate.

The aim of this study was to evaluate the experience of our institution with the use of video-assisted thoracic surgery (VATS) in chest trauma. Between January 1999 and September 2004, 25,213 patients presented with chest trauma to the emergency room, and 2304 were admitted to our service. Twenty-three hemodynamically stable patients (1%) underwent VATS. They were 19 men and 4 women with an average age of 42 years (range, 19–67 years). Indications included post-traumatic hemothorax in 11 patients, and post-traumatic empyema in 3, treated after 24 h of trauma. Indications for exploratory VATS in the acute phase included suspected diaphragmatic injury in 3 patients, persistent pneumothorax in 2, continued hemorrhage in 2 and removal of intrathoracic foreign body in 2. There was no mortality and complications occurred in 3 patients (13%). Management of hemodynamically stable thoracic injuries by using VATS provides diagnostic accuracy and therapeutic efficacy. It can be successfully applied in the trauma setting and surgeons should gain experience with its use.

The purpose of this study was to test the performance of an albumin-glutaraldehyde tissue adhesive, BioGlue(r) Surgical Adhesive (BioGlue) in the sealing of air leaks from pulmonary parenchyma and bronchopleural fistulas. Between March 2000 and November 2001 BioGlue was applied in 38 randomly selected patients, who underwent 39 operations. The mean age was 51.4 years (range 19 to 75 years). A median of 5 cc of BioGlue was used per patient (range 5 to 20 cc). The operations included 36 thoracotomies, 2 video-assisted thoracoscopies and one rigid bronchoscopy. The duration of air leak ranged from 0 to 2 days with a median of 1 day. The duration of total (air and fluid) chest tube drainage ranged from 1 to 12 days with a median of 3 days. Complications were observed in 3 patients (8%) and included atelectasis in one and residual space in 2. Three patients died because of preexisting respiratory failure unrelated to BioGlue application. Hospitalization ranged from 4 to 16 days with a median of 6 days and was prolonged in some patients because of their primary disease (empyema, bronchopleural fistula, etc.). The use of BioGlue proved to be safe and effective in the sealing of lung lacerations and in preventing air leakage from suture or staple lines in emphysematous lungs. It was also successful in sealing bronchopleural fistulas when applied either intra-bronchially through the rigid bronchoscope or during thoracotomy.

The purpose of this study was to evaluate the effectiveness of an albumin-glutaraldehyde tissue adhesive (BioGlue Surgical Adhesive) in preventing air leaks after bullectomy. Between January 1999 and June 2002, BioGlue was applied over the staple or suture lines of 21 consecutive patients who underwent resection of bullae for persistent or recurrent pneumothorax. An age- and sex-matched control group of 19 bullectomy patients from our center was used for comparison. Air leak duration was significantly reduced in the BioGlue group (mean, 0.42 days; range, 0-2 days), compared with the control group (mean, 3.68 days; range, 2-11 days; P < .001). Chest tube drainage time was reduced to a mean of 2.33 days (range, 2-4 days) in the BioGlue group, compared with a mean of 5.42 days (range, 3-12 days) in the control group (P < .05). Morbidity and hospital stay length were slightly lower in the BioGlue group. There was no mortality or BioGlue-related complication in this patient cohort. The use of BioGlue as a surgical lung sealant significantly decreased the duration of postoperative air leaks and the time to chest tube removal. Use of BioGlue facilitates the postoperative course following bullectomy.