Pneumonectomy with Carinal Sleeve Resection in Patients with Non-Small-Cell Lung Cancer.

BACKGROUND: Carinal sleeve resection with pneumonectomy is one of the rarest procedures in thoracic surgery, but for locally advanced central lung cancer with infiltration of the carina, it is an option to achieve complete resection. Additionally, it might be the method of choice for patients with stump insufficiency after pneumonectomy or in the cases with anastomosis dehiscence after sleeve lobectomy. The aim of this study was to evaluate the morbidity and long-term survival of patients with non-small-cell lung cancer (NSCLC) who underwent sleeve pneumonectomy, either for curative intent or as an option to treat postoperative complications. METHODS: All consecutive patients with NSCLC who underwent carinal sleeve pneumonectomy for the aforementioned indications in our department between December 2021 and September 2003 were included in this study. An analysis of demographic characteristics, perioperative variables, and long-term survival was carried out. Data were evaluated retrospectively. RESULTS: Fifty patients underwent pneumonectomy with carina sleeve resection. Thirty-one cases for curative treatment of NSCLC (primary sleeve pneumonectomy [pSP]) and 19 patients were treated because of postpneumonectomy bronchial stump insufficiency or bronchial anastomosis dehiscence (secondary sleeve pneumonectomy [sSP]). Complications occurred in 30 patients (60%) and the 90-day mortality was 18% (n = 9). Patients with pSP had an estimated overall survival of 39.6 months, compared to estimated overall survival for patients after sSP of 24.5 months (p = 0.01). The N status did not appear to affect outcomes. CONCLUSION: Carinal sleeve resection with pneumonectomy is a feasible procedure with limited morbidity and mortality. This procedure is a reasonable therapeutic option for patients with locally advanced central NSCLC after mandatory patient selection.

[Tracheobronchial Injuries]. / Tracheobronchiale Verletzungen.

Tracheobronchial injury is a rare, but potentially life-threatening condition. These injuries are associated with high morbidity and mortality, which is ascribed to underlying diseases and additional injuries. Lacerations of the airway are differentiated into iatrogenic and non-iatrogenic injuries, while the group of non-iatrogenic lesions are grouped into blunt and penetrating traumas.The exact incidence of tracheobronchial injury is unknown, because many iatrogenic injuries occur without symptoms and most patients after traumatic laceration die before inpatient treatment. All patients with suspicion of airway injury require fast and accurate management.Common signs and symptoms are dyspnoea, haemoptysis, stridor and subcutaneous emphysema.Bronchoscopy is the most important tool for diagnosis and in several cases also for initial treatment.Further management depends on the patient's clinical condition and findings of bronchoscopy and computed tomography. Surgery has been the cornerstone of therapy, but in selected patients bronchoscopic stent implantation or conservative management must be discussed.

Molecular Determinants of Human T-cell Leukemia Virus Type 1 Gag Targeting to the Plasma Membrane for Assembly.

Assembly of human T-cell leukemia virus type 1 (HTLV-1) particles is initiated by the trafficking of virally encoded Gag polyproteins to the inner leaflet of the plasma membrane (PM). Gag-PM interactions are mediated by the matrix (MA) domain, which contains a myristoyl group (myr) and a basic patch formed by lysine and arginine residues. For many retroviruses, Gag-PM interactions are mediated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]; however, previous studies suggested that HTLV-1 Gag-PM interactions and therefore virus assembly are less dependent on PI(4,5)P2. We have recently shown that PI(4,5)P2 binds directly to HTLV-1 unmyristoylated MA [myr(-)MA] and that myr(-)MA binding to membranes is significantly enhanced by inclusion of phosphatidylserine (PS) and PI(4,5)P2. Herein, we employed structural, biophysical, biochemical, mutagenesis, and cell-based assays to identify residues involved in MA-membrane interactions. Our data revealed that the lysine-rich motif (Lys47, Lys48, and Lys51) constitutes the primary PI(4,5)P2-binding site. Furthermore, we show that arginine residues 3, 7, 14 and 17 located in the unstructured N-terminus are essential for MA binding to membranes containing PS and/or PI(4,5)P2. Substitution of lysine and arginine residues severely attenuated virus-like particle production, but only the lysine residues could be clearly correlated with reduced PM binding. These results support a mechanism by which HTLV-1 Gag targeting to the PM is mediated by a trio engagement of the myr group, Arg-rich and Lys-rich motifs. These findings advance our understanding of a key step in retroviral particle assembly.

A periplasmic cinched protein is required for siderophore secretion and virulence of Mycobacterium tuberculosis.

Iron is essential for growth of Mycobacterium tuberculosis, the causative agent of tuberculosis. To acquire iron from the host, M. tuberculosis uses the siderophores called mycobactins and carboxymycobactins. Here, we show that the rv0455c gene is essential for M. tuberculosis to grow in low-iron medium and that secretion of both mycobactins and carboxymycobactins is drastically reduced in the rv0455c deletion mutant. Both water-soluble and membrane-anchored Rv0455c are functional in siderophore secretion, supporting an intracellular role. Lack of Rv0455c results in siderophore toxicity, a phenotype observed for other siderophore secretion mutants, and severely impairs replication of M. tuberculosis in mice, demonstrating the importance of Rv0455c and siderophore secretion during disease. The crystal structure of a Rv0455c homolog reveals a novel protein fold consisting of a helical bundle with a 'cinch' formed by an essential intramolecular disulfide bond. These findings advance our understanding of the distinct M. tuberculosis siderophore secretion system.

Control of subunit stoichiometry in single-chain MspA nanopores.

Transmembrane protein channels enable fast and highly sensitive detection of single molecules. Nanopore sequencing of DNA was achieved using an engineered Mycobacterium smegmatis porin A (MspA) in combination with a motor enzyme. Due to its favorable channel geometry, the octameric MspA pore exhibits the highest current level compared with other pore proteins. To date, MspA is the only protein nanopore with a published record of DNA sequencing. While widely used in commercial devices, nanopore sequencing of DNA suffers from significant base-calling errors due to stochastic events of the complex DNA-motor-pore combination and the contribution of up to five nucleotides to the signal at each position. Different mutations in specific subunits of a pore protein offer an enormous potential to improve nucleotide resolution and sequencing accuracy. However, individual subunits of MspA and other oligomeric protein pores are randomly assembled in vivo and in vitro, preventing the efficient production of designed pores with different subunit mutations. In this study, we converted octameric MspA into a single-chain pore by connecting eight subunits using peptide linkers. Lipid bilayer experiments demonstrated that single-chain MspA formed membrane-spanning channels and discriminated all four nucleotides identical to MspA produced from monomers in DNA hairpin experiments. Single-chain constructs comprising three, five, six, and seven connected subunits assembled to functional channels, demonstrating a remarkable plasticity of MspA to different subunit stoichiometries. Thus, single-chain MspA constitutes a new milestone in the optimization of MspA as a biosensor for DNA sequencing and many other applications by enabling the production of pores with distinct subunit mutations and pore diameters.

Structural Insights into the Mechanism of Human T-cell Leukemia Virus Type 1 Gag Targeting to the Plasma Membrane for Assembly.

Retroviral Gag targeting to the plasma membrane (PM) for assembly is mediated by the N-terminal matrix (MA) domain. For many retroviruses, Gag-PM interaction is dependent on phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). However, it has been shown that for human T-cell leukemia virus type 1 (HTLV-1), Gag binding to membranes is less dependent on PI(4,5)P2 than HIV-1, suggesting that other factors may modulate Gag assembly. To elucidate the mechanism by which HTLV-1 Gag binds to the PM, we employed NMR techniques to determine the structure of unmyristoylated MA (myr(-)MA) and to characterize its interactions with lipids and liposomes. The MA structure consists of four α-helices and unstructured N- and C-termini. We show that myr(-)MA binds to PI(4,5)P2 via the polar head and that binding to inositol phosphates (IPs) is significantly enhanced by increasing the number of phosphate groups on the inositol ring, indicating that the MA-IP binding is governed by charge-charge interactions. The IP binding site was mapped to a well-defined basic patch formed by lysine and arginine residues. Using an NMR-based liposome binding assay, we show that PI(4,5)P2and phosphatidylserine enhance myr(-)MA binding in a synergistic fashion. Confocal microscopy data revealed formation of puncta on the PM of Gag expressing cells. However, G2A-Gag mutant, lacking myristoylation, is diffuse and cytoplasmic. These results suggest that although myr(-)MA binds to membranes, myristoylation appears to be key for formation of HTLV-1 Gag puncta on the PM. Altogether, these findings advance our understanding of a key mechanism in retroviral assembly.

Carinal sleeve resection: last exit for bronchial insufficiency-a 17-year, single-centre experience.

OBJECTIVES: Bronchopleural fistula after pneumonectomy and dehiscence of an anastomosis after sleeve lobectomy are severe complications. Several established therapeutic options are available. Conservative treatment is recommended for a small fistula without pleural infection. In patients with a bronchopleural fistula and subsequent pleural empyema, surgical management is the mainstay. Overall, the associated morbidity and mortality are high. Carinal sleeve resection is the last resort for patients with a short stump after pneumonectomy or anastomotic dehiscence after sleeve resection near the carina. METHODS: All patients with bronchopleural fistula after pneumonectomy or sleeve resection who underwent secondary carinal sleeve resection between 2003 and 2019 in our institution were evaluated retrospectively. Patients with anastomotic dehiscence after sleeve lobectomy underwent a completion pneumonectomy. The surgical approach was an anterolateral thoracotomy; the anastomosis was covered with muscle flap, pericardial fat or omentum majus. In case of empyema, povidone-iodine-soaked towels were introduced into the cavity and changed at least twice. RESULTS: A total of 17 patients with an initial sleeve lobectomy in 12 patients and pneumonectomy in 5 patients were treated with carinal sleeve resection in our department. Morbidity was 64.7% and 30-day survival was 82.4% (n = 14). A total of 70.6% of the patients survived 90 days (n = 12). Median hospitalization was 17 days and the median stay in the intensive care unit was 12 days. CONCLUSIONS: Carinal sleeve resection is a feasible option in patients with a post-pneumonectomy fistula or anastomotic insufficiency following sleeve lobectomy in the absence of alternative therapeutic strategies. Nevertheless, postoperative morbidity is high, including prolonged intensive care unit stay.

Thoracoscopic sleeve segmentectomy for bipulmonal non-small-cell lung cancer with curative approach.

A patient with simultaneous bilateral non-small-cell lung cancer underwent a thoracoscopic sleeve segmentectomy on the right side to avoid lobectomy in curative approach. The patient also had a second, left-sided tumour requiring at least a left-sided sleeve upper lobectomy for complete resection. In anticipation of the second pulmonary resection in a patient whose lung function was already impaired by the first operation, we opted for a thoracoscopic approach with fast recovery. The left-sided operation was performed 60 days after the right-sided sleeve segmentectomy without any complications.

[Failure of Endo-VAC or Stenting Therapy after Oesophageal Anastomotic Insufficiency - How to Avoid Oesophagectomy]. / Interdisziplinäres Management bei Anastomoseninsuffizienz nach Ösophagusresektion zur Vermeidung der Ösophagektomie.

INTRODUCTION: Oesophageal anastomotic leak after oesophagectomy is a severe complication and associated with a high mortality rate. Initial treatment is conservative and includes stent implantation or endo-VAC therapy. This study describes a combined treatment strategy of endoscopic and surgical management after failure of conservative management. MATERIALS AND METHODS: All patients were included who had been treated after oesophagectomy with gastric conduit reconstruction in our department of thoracic surgery between May 2008 and December 2016. Clinical data was evaluated from a prospectively acquired database. We surgically managed these patients with a combination of oesophageal stent implantation, transmural stent fixation with absorbable suture, stent coverage with muscle flap, radical debridement of mediastinal and pleural empyema and discontinuous pleural space irrigation, when conservative management failed. We evaluated the factors influencing mortality rate after surgical treatment of anastomotic insufficiency repair. RESULTS: 18 patients were introduced to our department after external failure of conservative therapy. 15 patients were introduced < 20 days after conservative therapy and three cases after > 20 days of conservative therapy. All patients presented with right sided pleural empyema, pneumonia, mediastinitis and sepsis. Three cases were accompanied by bilateral pleural empyema. Definitive successful surgical reconstruction occurred in 100%. The 90-day mortality rate was 20% (three patients), who died because of multi-organ failure. CONCLUSION: Oesophageal anastomotic leak after oesophagectomy can be managed successfully by the combined treatment strategy of endoscopic and surgical procedures following failure of conservative treatment. The only factor influencing mortality seems to be a prolonged conservative therapy of more than 20 days.

Does less surgical trauma result in better outcome in management of iatrogenic tracheobronchial laceration?

BACKGROUND: Iatrogenic tracheobronchial injury is a rare, but severe complication of endotracheal intubation. Risk factors are emergency intubation, percutaneous dilatational tracheostomy and intubation with double lumen tube. Regarding these procedures, underlying patients often suffer from severe comorbidities. The aim of this study was to evaluate the results of a standardized treatment algorithm in a referral center with focus on the surgical approach. METHODS: Sixty-four patients with iatrogenic tracheal lesion were treated in our department by standardized management adopted to clinical findings between 2003 and 2019. Patients with superficial laceration were treated conservatively. In the case of transmural injury of the tracheal wall and necessity of mechanical ventilation, patients underwent surgery. We decided on a cervical surgical approach for lesions limited to the trachea. In case of involvement of a main bronchus we performed thoracotomy. Data were evaluated retrospectively. RESULTS: In 19 patients the tracheal lesion occurred in elective intubation and in 17 patients during emergency intubation. In 23 cases a tracheal tear occurred during percutaneous dilatational tracheostomy and in three patients at replacement of a tracheostomy tube. Two patients received laceration during bronchoscopy. Twenty-nine patients underwent surgery with cervical approach and 14 underwent thoracotomy. There was no difference in the mortality of these groups. Treatment of tracheal tear was successful in 62 individuals. Nine patients died of multi organ dysfunction syndrome (MODS), two of them during surgery. CONCLUSIONS: Iatrogenic tracheal laceration is a life-threatening complication and the mortality after tracheal injury is high, even in a specialized thoracic unit. Conservative management in patients with superficial tracheal lesion is a feasible procedure. In case of complete laceration of tracheal wall, surgical therapy is recommendable, whereby several approaches of surgical management seem to be equivalent.

Role of BK polyomavirus (BKV) and Torque teno virus (TTV) in liver transplant recipients with renal impairment.

PURPOSE: Renal impairment is a common complication after liver transplantation (LT). While BK polyomavirus (BKV) has been linked to renal failure in kidney transplant recipients, Torque teno virus (TTV) is a surrogate marker for immunosuppression that does not have a clear association with any human disease. The impact of BKV and TTV on renal impairment after LT is unknown. METHODOLOGY: In this retrospective study, urine and serum samples from 136 liver transplant recipients were screened for BKV and TTV by quantitative PCR. In addition, serum was screened for BKV-specific antibodies and the VP1 typing region was sequenced for BKV genotyping. All parameters were correlated with clinical data.Results/Key findings. BK viruria was detected up to 21 years after transplantation in 16.9 % of cases. BK viraemia was detected in 8.7 % of patients with BK viruria up to 4 years after LT. BKV-specific antibodies were detected in 93.6 % of all LT recipients and correlated with BKV viral load in urine. There was no correlation between renal impairment and the detection of BK DNA in urine (OR 0.983). TTV DNA was detected in 84.6 % of serum samples and in 66.6 % of urine samples. The TTV viral load in serum correlated with the BKV viral load but had no impact on renal impairment. CONCLUSION: Our data indicate that the detection of BKV and TTV is not a risk factor for renal impairment after LT. A correlation of TTV and BKV viral load seems to be an indicator for the immune status of the host.

Initial management of primary spontaneous pneumothorax with video-assisted thoracoscopic surgery: a 10-year experience.

OBJECTIVES: First-line conservative treatment of primary spontaneous pneumothorax (PSP) may be challenged by recurrence rates and complications associated with different treatment options. The aim of this study was to evaluate the use of a standardized surgical treatment as 'first-line' treatment. METHODS: In a 10-year period, 185 patients with PSP were treated with a standardized video-assisted thoracic surgery (VATS) approach including wedge resection and parietal pleurectomy. Data were evaluated retrospectively. All patients with a first event of PSP were included in the study. In addition, follow-up was done by a questionnaire. RESULTS: Mean follow-up period was 70.8 months (±33.5 months). Sub-pleural emphysematous changes were found in every histopathological specimen. In addition, 70.8% had fibrosis of visceral pleura. Recurrence occurred in 4 patients (2.2%). Ten-year freedom from recurrence was 96.2%. Procedure-related morbidity rate was 7.6%. Approximately 85.7% of patients were satisfied with the procedure and the cosmetic result. Three patients died during follow-up (1.6%). CONCLUSIONS: Treatment of first episode of PSP by VATS is a safe procedure, with a very low rate of recurrence and a high patient satisfaction. This management of first episode of PSP is based on the underlying pathology. We recommend the use of VATS as the treatment of first choice for patients with PSP.