Single-stage long-segment tracheal transplantation.

Tracheal transplantation has been envisioned as a viable option for reconstruction of long-segment tracheal defects. We report the first human single-stage long-segment tracheal transplantation. Narrow-band imaging and bronchoscopic biopsies demonstrate allograft vascularization and viable epithelial lining. The recipient was immunosuppressed with Tacrolimus, Mycophenolate mofetil, and corticosteroids. Six months after transplantation, the trachea is both functional and the patient is breathing without the need of a tracheostomy or stent.

An Evidence-Based Approach to Management of Pectus Excavatum and Carinatum.

Pectus excavatum (PE) and pectus carinatum (PC) are the most common congenital chest wall anomalies. Current research suggests that PE and PC may result from overgrowth of the sternocostal cartilages. This can produce a deformation that displaces the sternum inward as in PE or outward as in PC. The etiology, clinical presentation, evaluation, and management of PE and PC are reviewed. Varied clinical presentations, cardiopulmonary effects, and psychosocial aspects are described.

Squamous cell carcinoma-related oncogene (SCCRO) neddylates Cul3 protein to selectively promote midbody localization and activity of Cul3KLHL21 protein complex during abscission.

Squamous cell carcinoma-related oncogene (SCCRO)/DCUN1D1, a component of the neddylation E3 complex, regulates the activity of the cullin-RING-ligase type of ubiquitination E3s by promoting neddylation of cullin family members. Studies have shown that SCCRO regulates proliferation in vitro and in vivo Here we show that inactivation of SCCRO results in prolonged mitotic time because of delayed and/or failed abscission. The effects of SCCRO on abscission involve its role in neddylation and localization of Cul3 to the midbody. The Cul3 adaptor KLHL21 mediates the effects of SCCRO on abscission, as it fails to localize to the midbody in SCCRO-deficient cells during abscission, and its inactivation resulted in phenotypic changes identical to SCCRO inactivation. Ubiquitination-promoted turnover of Aurora B at the midbody was deficient in SCCRO- and KLHL21-deficient cells, suggesting that it is the target of Cul3KLHL21 at the midbody. Correction of abscission delays in SCCRO-deficient cells with addition of an Aurora B inhibitor at the midbody stage suggests that Aurora B is the target of SCCRO-promoted Cul3KLHL21 activity. The activity of other Cul3-anchored complexes, including Cul3KLHL9/KLHL13, was intact in SCCRO-deficient cells, suggesting that SCCRO selectively, rather than collectively, neddylates cullins in vivo Combined, these findings support a model in which the SCCRO, substrate, and substrate adaptors cooperatively provide tight control of neddylation and cullin-RING-ligase activity in vivo.

Surgical gem: island advancement flaps for lip reconstruction.

Island advancement flaps provide specific advantages for repairing certain defects on the upper lip. We discuss the design and execution of this flap for defects on the alar sill and philtrum.

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.

Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

SCCRO (DCUN1D1) promotes nuclear translocation and assembly of the neddylation E3 complex.

SCCRO/DCUN1D1/DCN1 (squamous cell carcinoma-related oncogene/defective in cullin neddylation 1 domain containing 1/defective in cullin neddylation) serves as an accessory E3 in neddylation by binding to cullin and Ubc12 to allow efficient transfer of Nedd8. In this work we show that SCCRO has broader, pleiotropic effects that are essential for cullin neddylation in vivo. Reduced primary nuclear localization of Cul1 accompanying decreased neddylation and proliferation in SCCRO(-/-) mouse embryonic fibroblasts led us to investigate whether compartmentalization plays a regulatory role. Decreased nuclear localization, neddylation, and defective proliferation in SCCRO(-/-) mouse embryonic fibroblasts were rescued by transgenic expression of SCCRO. Expression of reciprocal SCCRO and Cul1-binding mutants confirmed the requirement for SCCRO in nuclear translocation and neddylation of cullins in vivo. Nuclear translocation of Cul1 by tagging with a nuclear localization sequence allowed neddylation independent of SCCRO, but at a lower level. We found that in the nucleus, SCCRO enhances recruitment of Ubc12 to Cul1 to promote neddylation. These findings suggest that SCCRO has an essential role in neddylation in vivo involving nuclear localization of neddylation components and recruitment and proper positioning of Ubc12.

Surgical treatment of malignant pleural mesothelioma.

Malignant Pleural Mesothelioma (MPM) remains a rare and lethal disease that is directly related to asbestos exposure in the vast majority of cases. While the total number of cases remains low compared to other malignancies, the worldwide incidence is expected to increase over the next twenty years. Currently, survival rates remain dismal and there is no standard therapy or consensus regarding treatment. However, over the last fifteen years there have been substantial improvements in the diagnosis and treatment of MPM, including easier and more accurate diagnostic techniques, improved methods of staging, more effective systemic therapy, a remarkable decrease in operative mortality, marked improvements in local control with adjuvant therapy, and perhaps most important, an emphasis on multidisciplinary care and multimodality clinical trials. Despite these advances, optimal therapy for these patients remains highly controversial and the role of surgery is actively debated. Most controversy centers on whether surgery increases survival and whether a survival benefit is best achieved with extrapleural pneumonectomy or pleurectomy/decortication within a multimodal regimen. To date, trimodality therapy that includes surgery, chemotherapy, and radiation offers the best survival advantage. It is generally accepted that the main goals of surgery, within the framework of a multimodality approach, is not only complete resection if possible, but more realistically, the resection of all macroscopic disease as an adjunct to the delivery of chemotherapy and radiation. The surgical options available to obtain this goal include extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). There are no randomized trials directly comparing EPP and P/D and the level of evidence supporting either technique remains low. Ultimately, the choice of operation depends on multiple factors including: disease stage, the patient's cardiopulmonary reserve, surgeon experience and philosophy, and the extent of planned adjuvant therapy. Yet, despite the inherent biases in most studies, the data thus far illustrates significant survival advantages with both P/D and EPP and surgeons should consider these approaches in select patients.

Tips to Avoid Complications Following Mohs Reconstruction.

To avoid complications or bad results following reconstruction of skin cancer defects, there are several factors that can be incorporated into the design and execution of repairs. These techniques not only decrease the need to correct bad results, they improve the final aesthetic and functional outcome. So although one surgeon might focus on standard corrective treatments, another might use elements of flap design and implementation that will decrease the need for such corrective procedures. We discuss 4 useful reconstructive repairs and delineate the properties of design and execution that help to ensure success and avoid bad results.

Mouse DCUN1D1 (SCCRO) is required for spermatogenetic individualization.

Squamous cell carcinoma-related oncogene (SCCRO, also known as DCUN1D1) is a component of the E3 for neddylation. As such, DCUN1D1 regulates the neddylation of cullin family members. Targeted inactivation of DCUN1D1 in mice results in male-specific infertility. Infertility in DCUN1D1-/- mice is secondary to primary defects in spermatogenesis. Time-dam experiments mapped the onset of the defect in spermatogenesis to 5.5 to 6 weeks of age, which temporally corresponds to defects in spermiogenesis. Although the first round of spermatogenesis progressed normally, the number of spermatozoa released into the seminiferous lumen and epididymis of DCUN1D1-/- mice was significantly reduced. Spermatozoa in DCUN1D1-/- mice had multiple abnormalities, including globozoospermia, macrocephaly, and multiple flagella. Many of the malformed spermatozoa in DCUN1D1-/- mice were multinucleated, with supernumerary and malpositioned centrioles, suggesting a defect in the resolution of intercellular bridges. The onset of the defect in spermatogenesis in DCUN1D1-/- mice corresponds to an increase in DCUN1D1 expression observed during normal spermatogenesis. Moreover, consistent with its known function as a component of the E3 in neddylation, the pattern of DCUN1D1 expression temporally correlates with an increase in the neddylated cullin fraction and stage-specific increases in the total ubiquitinated protein pool in wild-type mice. Levels of neddylated Cul3 were decreased in DCUN1D1-/- mice, and ubiquitinated proteins did not accumulate during the stages in which DCUN1D1 expression peaks during spermatogenesis in wild-type mice. Combined, these findings suggest that DCUN1D1-/- mice fail to release mature spermatozoa into the seminiferous lumen, possibly due to unresolved intercellular bridges. Furthermore, the effects of DCUN1D1 on spermatogenesis likely involve its regulation of cullin-RING-ligase (CRL)-type ubiquitin E3 activity during spermiogenesis through its role in promoting Cul3 neddylation. The specific CRLs required for spermiogenesis and their protein targets require identification.

The influence of insurance type on stage at presentation, treatment, and survival between Asian American and non-Hispanic White lung cancer patients.

The effect of insurance type on lung cancer diagnosis, treatment, and survival in Asian patients living in the United States is still under debate. We have analyzed this issue using the Surveillance, Epidemiology, and End Results database. There were 102,733 lung cancer patients age 18-64 years diagnosed between 2007 and 2013. Multilevel regression analysis was performed to identify the association between insurance types, stage at diagnosis, treatment modalities, and overall mortality in Asian and non-Hispanic White (NHW) patients. Clinical characteristics were significantly different between Asian and NHW patients, except for gender. Asian patients were more likely to present with advanced disease than NHW patients (ORadj  = 1.12, 95% CI = 1.06-1.19). Asian patients with non-Medicaid insurance underwent lobectomy more than NHW patients with Medicaid or uninsured; were more likely to undergo mediastinal lymph node evaluation (MLNE) (ORadj  = 1.98, 95% CI = 1.72-2.28) and cancer-directed surgery and/or radiation therapy (ORadj  = 1.41, 95% CI = 1.20-1.65). Asian patients with non-Medicaid insurance had the best overall survival. Uninsured or Medicaid-covered Asian patients were more likely to be diagnosed with advanced disease, less likely to undergo MLNE and cancer-directed treatments, and had shorter overall survival than their NHW counterpart.

Underperformance of Mediastinal Lymph Node Evaluation in Resectable Non-Small Cell Lung Cancer.

BACKGROUND: Mediastinal lymph node evaluation (MLNE) is considered to be the standard of care in curative lung cancer surgery although it is not always performed. This study identifies factors associated with patients not being evaluated (non-MLNE) in cases of resectable non-small cell lung cancer. METHODS: A retrospective observational study using the Surveillance, Epidemiology, and End Results Program database was conducted. Adult patients diagnosed with non-small cell lung cancer stage I to IIIA (2004 to 2013) were included. Multilevel logistic regression analysis was performed to identify factors that were associated with non-MLNE. RESULTS: There were 86,721 patients included in this study: 73,034 (84.2%) with MLNE and 13,687 (15.8%) without. The use of MLNE gradually increased from 82.7% in 2004 to 85.8% in 2013. In multivariable analysis, factors associated with non-MLNE included the following: age more than 75 years (adjusted odds ratio [ORadj] 1.20, 95% confidence interval [CI]: 1.13 to 1.27); black (ORadj 1.11, 95% CI: 1.32 to 1.20); Native American/Alaskan (ORadj 1.63, 95% CI: 1.15 to 2.31); uninsured (ORadj 1.28, 95% CI: 1.05 to 1.56); residing in a low-income county (ORadj 1.12, 95% CI: 1.04 to 1.21); lesion at the middle lobe (ORadj 1.42, 95% CI: 1.29 to 1.56); lower lobe (ORadj 1.06, 95% CI: 1.01 to 1.11) or main bronchus (ORadj 2.38, 95% CI: 1.93 to 2.94); stage IA (ORadj 1.24, 95% CI: 1.17 to 1.32); sublobar resection (ORadj 11.08, 95% CI: 11.30 to 12.33); and preoperative treatment (ORadj 1.21, 95% CI: 1.08 to 1.36). Non-MLNE was less likely to occur in patients with adenocarcinoma (ORadj 0.88, 95% CI: 0.83 to 0.92) and more likely in other cell types (ORadj 1.23, 95% CI: 1.15 to 1.32), compared with squamous cell carcinoma. CONCLUSIONS: Patient demographics and socioeconomic status are associated with the decision to perform MLNE. Thoracic surgeons should access these factors and perform MLNE to accurately determine tumor stage and improve survival.

Factors associated with recurrent bacterial empyema thoracis.

BACKGROUND: Empyema thoracis (ET) is one of the common thoracic diseases frequently found in developing countries. In the past, only a few studies have analyzed recurrent ET, and none had clearly identified the prognostic factors for recurrence. The aim of this study is to identify the prognostic factors of recurrent ET in Northern Thailand. METHODS: A retrospective cohort study was conducted. All patients diagnosed with Stage II and III ET at Maharaj Nakorn Chiang Mai Hospital (a tertiary-care hospital in northern Thailand) between January 1, 2007 and November 31, 2012 were enrolled in this study. All clinical data were extracted from the medical recording system. The primary outcome was recurrent disease. Multivariable Cox's proportion hazard model was used to identify the independent prognostic factors for recurrence. RESULTS: There were 382 patients enrolled in this study, and 34 patients (8.9%) had recurrent disease. The most common gram-positive and gram-negative pathogens found were Staphylococcus aureus and Acinetobacter baumannii, respectively. Three independent prognostic factors for recurrent disease were nonsepsis status prior to the surgery [hazard ratio (HR) = 12.3; 95% confidence interval (CI), 4.25-35.43], nonperforming decortication (HR = 5.4; 95% CI, 1.82-15.92), and persistent pleural spaces (HR = 4.1; 95% CI, 1.93-8.68). CONCLUSIONS: Clinical characteristics, surgical procedure, and persistent pleural spaces were independent prognostic factors for ET recurrence in this study. Decortication and early thoracoplasty in patients who had persistent pleural space should be considered. Large cohort studies are warranted to support these findings.

Laparoscopic Repair of an Intrapericardial Diaphragmatic Hernia After Convergent Maze Procedure.

The convergent maze procedure (CMP) is a new minimally invasive technique for the surgical treatment of atrial fibrillation (AF). Recently, multiple groups have published excellent results and few adverse events with CMP. However, we now report the second case of an intrapericardial diaphragmatic hernia with small bowel obstruction that resulted from CMP. This adverse event was managed successfully by laparoscopic repair of the hernia and the use of a polytetrafluoroethylene mesh closure with hepatic buttress, achieving an excellent result. With the expanding use of CMP for the treatment of AF, awareness of this adverse event and its appropriate management are increasingly important.

Comparison of Conservative Treatment and Thymectomy on Myasthenia Gravis Outcome.

BACKGROUND: A systematic review of the literature was performed to compare long-term outcomes of thymectomy and medical treatment for generalized myasthenia gravis (MG). METHODS: A Medline search through June 2015 resulted in 71 studies, 27 of which were selected (10,140 patients: 5,275 thymectomies, 4,865 medication). RESULTS: The pooled proportion of remission with thymectomy was 0.31 (95% CI, 0.25-0.37), with conservative treatment it was 0.15 (95% CI, 0.12-0.18). The odds ratio (OR) of remission with thymectomy in comparison with medication alone was 2.44 (95% CI, 1.91-3.12) overall and according to medication type and remission definitions. CONCLUSIONS: Thymectomy is superior to conservative treatment with solely medication on remission in MG.

Thymectomy for Myasthenia Gravis: Complete Stable Remission and Associated Prognostic Factors in Over 1000 Cases.

The efficacy of thymectomy and the optimal surgical technique in the treatment of myasthenia gravis (MG) remain controversial. Long-term outcomes are lacking and remission rates are based on small populations. We reviewed our institutional experience of thymectomy for MG focusing on long-term outcomes, complete stable remission (CSR), improvement of symptoms, after transcervical, transsternal, thoracotomy, and VATS thymectomy. A retrospective review of a prospectively maintained database of 3017 patients from 1941-2013 with MG was performed. Patients who underwent thymectomy with follow-up data including age at the time of surgery, sex, date of onset of symptoms, date of surgery, Osserman classification before and after surgery, surgical technique, date of remission, and status at last follow-up were included in the analysis. CSR and prognostic factors were analyzed by crude rate, Kaplan-Meier estimate, chi-squared test, Wilcoxon test, and a Cox proportional model. Overall, 1002 thymectomy patients with complete data were analyzed, and 35.5% (n = 355) derived benefit from surgery. Crude rate CSR was 19% (n = 191) and an additional 16% (n = 164) symptomatically improved requiring less medication after thymectomy. Also, 58% (n = 580) were stable after resection, and 6.7% (n = 67) developed progressive disease. Kaplan-Meier estimates of CSR were 27.7%, 36.7%, and 47.3% at 10, 25, and 40 years, respectively. On multivariate analysis, transsternal technique, thymoma, and preoperative Osserman classification were significantly associated with failure to achieve CSR. Thymectomy provides long-term CSR in 47.3% of patients with long-term follow-up. Patients with MG should be offered thymectomy when possible.