The Impact of Vaping on Primary Spontaneous Pneumothorax Outcomes.

INTRODUCTION: Cigarette smoking is associated with primary spontaneous pneumothorax (PSP). Electronic cigarettes (E-cigarettes) are touted as a healthier alternative to cigarettes; however, the impact E-cigarette use has on PSP management is not known. The goal of this study was to determine if E-cigarette use is associated with inferior outcomes after PSP, compared to never smokers and cigarette smokers. METHODS: We conducted a retrospective cohort study of patients in a large tertiary care hospital system in an urban area who presented with PSP from September 2015 through February 2019. Primary spontaneous pneumothorax patients were identified from the institutional Society of Thoracic Surgeon (STS) database. Patients with pneumothoraces from traumatic, iatrogenic, and secondary etiologies were excluded. Baseline clinical and demographic data and outcomes including intervention(s) required, length of stay, and recurrence were evaluated. RESULTS: Identified were 71 patients with PSP. Seventeen (24%) had unverifiable smoking history. Of the remaining, 7 (13%) currently vaped, 27(50%) currently smoked cigarettes, and 20(37%) were never smokers. Mean age was 33 years; 80% male. All vapers required tube thoracostomy vs 74% of current smokers and 75% of never smokers. Vaping was associated with increased odds of recurrence compared to never smokers (OR 2.00, 95% CI 0.35,11.44). Vapers had the shortest median time to recurrence after initial hospitalization (10 d[4,18] v 20 d[5,13] cigarette smokers v 27 d[13 275] never smokers, P < .001). CONCLUSION: Vaping may complicate PSP outcomes. As vaping use increases, especially among adolescents, it is imperative that the manner of tobacco use is documented and considered when caring for patients, especially those with pulmonary problems.

Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells.

PURPOSE: Specificity protein 1 (SP1) is an oncogenic transcription factor overexpressed in various human malignancies. This study sought to examine SP1 expression in malignant pleural mesotheliomas (MPM) and ascertain the potential efficacy of targeting SP1 in these neoplasms. EXPERIMENTAL DESIGN: qRT-PCR, immunoblotting, and immunohistochemical techniques were used to evaluate SP1 expression in cultured MPM cells and MPM specimens and normal mesothelial cells/pleura. MTS, chemotaxis, soft agar, ß-galactosidase, and Apo-BrdUrd techniques were used to assess proliferation, migration, clonogenicity, senescence, and apoptosis in MPM cells following SP1 knockdown, p53 overexpression, or mithramycin treatment. Murine subcutaneous and intraperitoneal xenograft models were used to examine effects of mithramycin on MPM growth in vivo. Microarray, qRT-PCR, immunoblotting, and chromatin immunoprecipitation techniques were used to examine gene expression profiles mediated by mithramycin and combined SP1 knockdown/p53 overexpression and correlate these changes with SP1 and p53 levels within target gene promoters. RESULTS: MPM cells and tumors exhibited higher SP1 mRNA and protein levels relative to control cells/tissues. SP1 knockdown significantly inhibited proliferation, migration, and clonogenicity of MPM cells. Mithramycin depleted SP1 and activated p53, dramatically inhibiting proliferation and clonogenicity of MPM cells. Intraperitoneal mithramycin significantly inhibited growth of subcutaneous MPM xenografts and completely eradicated mesothelioma carcinomatosis in 75% of mice. Mithramycin modulated genes mediating oncogene signaling, cell-cycle regulation, senescence, and apoptosis in vitro and in vivo. The growth-inhibitory effects of mithramycin in MPM cells were recapitulated by combined SP1 knockdown/p53 overexpression. CONCLUSIONS: These findings provide preclinical rationale for phase II evaluation of mithramycin in patients with mesothelioma.

Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics.

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer.

Traumatic ventricular septal defect resulting in severe pulmonary hypertension.

Traumatic ventricular septal defect (VSD) is a widely-recognized complication of both penetrating and blunt trauma. Most cases are repaired operatively without the long-term complications of pulmonary hypertension and heart failure that are associated with unrepaired congenital VSD in the pediatric population. To our knowledge, this is the first case report of a patient with a traumatic VSD who declined surgical repair at the time of injury and subsequently developed long-term complications of pulmonary hypertension and heart failure. With nearly 20 years of follow-up, this case demonstrates that the absence of surgical treatment in asymptomatic adult patients at the time of injury can lead to long-term complications associated with VSD. This case also shows that aggressive surgical treatment in patients with severe pulmonary vascular disease and heart failure secondary to traumatic VSD can be performed safely and should be considered in cases refractory to efficacious medical interventions.

Colorectal cancer biomarkers and the potential role of cancer stem cells.

Over 50% of patients with colorectal cancer (CRC) will progress and/or develop metastases. Biomarkers capable of predicting progression, risk stratification and therapeutic benefit are needed. Cancer stem cells are thought to be responsible for tumor initiation, dissemination and treatment failure. Therefore, we hypothesized that CRC stem cell markers (CRCSC) can identify a group of patients whom are at increased risk for recurrence or progression of disease. If proven correct, these CRCSC biomarkers may herald a paradigm shift in the treatment of this deadly disease. This manuscript reviews current CRC evidence based screening modalities, patient stratification, and summarizes the current state of biomarkers and discusses the novel concept of putative CRCSC's as prognostic biomarkers.

Mithramycin represses basal and cigarette smoke-induced expression of ABCG2 and inhibits stem cell signaling in lung and esophageal cancer cells.

Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell-related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies.