RESUMO
Background: This study aimed to describe the subjective and objective results of the latissimus dorsi muscle flap and propose it as a reconstructive option for postoperative thoracic defects. Methods: A systematic search for cases with pedicle-based latissimus dorsi flaps performed after medial sternotomy was conducted, and all cases occurred between 2010 and August 2017. Preoperative, intraoperative, and postoperative factors were retrospectively analyzed and then the correlations between prognostic factors and outcomes of flap surgery were calculated. Furthermore, an evaluation of the subjective quality of life after flap surgery was performed using questionnaires. Results: A total of 25 cases were identified (8 female and 17 male patients) with the mean age of 75.28 years (range, 55-88 years). The average survival rate was 39.63 ± 23.03 months. The proportion of patients with a survival rate of 1 year was 84.00% (21 patients), and the proportion of patients with a 2-year survival rate was 80.00% (20 patients). While 24% of all patients who had latissimus dorsi flap operations experienced no complications, 64% of them developed minor complications (non-life-threatening, Clavien-Dindo grades I-IIIb) and 12% of them developed major complications (life-threatening, Clavien-Dindo grades IV-V). There was a significant correlation between the low survival rate and risk factors such as a positive history of smoking (P = .034), renal insufficiency (P = .022), metabolic syndrome (P = .004), and the presence of postoperative complications (P < .00002). No significant correlation was observed between the survival rate and obesity (P = .396), hyperlipoproteinemia (P = .684), arterial hypertonia (P = .0450), diabetes (P = .891), cardiovascular comorbidities (P = .794), the interval between sternotomy and latissimus flap surgery (P = .075), the duration of flap surgery (P = .207), sternal osteitis (P = .78), and intraoperative application of norepinephrine (P = .818). We identified metabolic syndrome (hazard ratio: 6.27), renal insufficiency (hazard ratio: 3.935), and the presence of postoperative complications (hazard ratio: 2.965) as high-risk prognostic factors. The subjective evaluations revealed positive reports from the patients with an average score of 1.86 ± 1.03 (1.0 = very good; 5.0 = poor). Conclusions: The majority of the patients with defects after median sternotomy were treated successfully with the latissimus dorsi flap. High survival rates, low rates of severe complications, and subjective scoring of improved life quality make this procedure relative safe and reliable. However, some prognostic risk factors limit the outcome, so these factors should be considered during surgical planning.
RESUMO
The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)2D3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG35-55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8+ T cells was analyzed by microarray (n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8+ T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy.