Tailored concept for the plastic closure of pelvic defects resulting from extralevator abdominoperineal excision (ELAPE) or pelvic exenteration.

PURPOSE: No standard exists for reconstruction after extralevator abdominoperineal excision (ELAPE) and pelvic exenteration. We propose a tailored concept with the use of bilateral gluteal V-Y advancement flaps in non-extended ELAPE and with vertical myocutaneous rectus abdominis muscle (VRAM) flaps in extended procedures. This retrospective study analyzes the feasibility of this concept. PATIENTS AND METHODS: We retrieved all consecutive patients after ELAPE or pelvic exenteration for rectal, anal, or vulva cancer with flap repair from a prospective database. Perineal wound complications were defined as the primary endpoint. Outcomes for the two different flap reconstructions were analyzed. RESULTS: From 2005 to 2021, we identified 107 patients who met the study criteria. Four patients underwent exenteration with VRAM flap repair after previous V-Y flap fashioning. Therefore, we report on 75 V-Y and 36 VRAM flaps. The V-Y group contained more rectal carcinomas, and the VRAM group exhibited more patients with recurrent cancer, more multivisceral resections, and longer operation times. Perineal wound complications occurred in 21.3% in the V-Y group and in 36.1% in the VRAM group (p = 0.097). Adjusted odds ratio for perineal wound complication was not significantly different for the two flap types. CONCLUSION: Concerning perineal wound complications, our concept yields favorable results for V-Y flap closure indicating that this less invasive approach is sufficient for non-extended ELAPE. Advantages are a shorter operation time, less donor site morbidity, and the option of a second repair. VRAM flaps were reserved for larger wounds after pelvic exenteration or vaginal repair.

Specific p38 inhibition in stimulated endothelial cells: a possible new anti-inflammatory strategy after hypothermia and rewarming.

To protect immature organ systems during corrective cardiac surgery, patients are cooled to a minimal temperature of 17 degrees C during cardiopulmonary bypass (CPB). However hypothermic CPB triggers the whole body inflammatory response and results in unwanted prolonged inflammation. The present study was designed to clarify the hypothermia and rewarming induced mechanisms and examine interventional pharmacological strategies that could prevent prolonged inflammation. Stimulated primary human umbilical vein endothelial cells (HUVECs) were exposed to a dynamic temperature protocol analogous to clinical settings. Furthermore endothelial cells were pretreated with methylprednisolone and/or tacrolimus as well as with MAPK inhibitors (SB203580, U0126 and SP600125). Cell viability, expression of IL-6 and ERK 1/2, p38 and SAPK/JNK were investigated. Stimulated endothelial cells secreted significantly higher IL-6 protein 2h after rewarming in comparison to normothermic control cells. Moreover, dynamic temperature changes lead to increased MAPK phosphorylation. Only the combined pre-treatment with MP and TAC served to inhibit the IL-6 secretion. As intracellular signalling pathway we could demonstrate that SB203580 as specific p38 inhibitor most effectively down regulated the unwanted IL-6 release after cooling and rewarming. Therefore inhibition of p38 or components of the p38 pathway could be a promising and selective antiinflammatory therapeutic target after hypothermic CPB.

Methylprednisolone and tacrolimus prevent hypothermia-induced endothelial dysfunction.

BACKGROUND: Hypothermia is used to preserve organs for transplantation and is the oldest method to protect organs during complex pediatric cardiac surgery. Loss of tissue function and tissue edema are common complications in children undergoing corrective cardiac surgery and heart transplantation. The present study was designed to examine the effects of methylprednisolone and tacrolimus on endothelial cell function and morphology after deep hypothermia and rewarming. METHODS: Human umbilical vein endothelial cells were pre-treated with methylprednisolone or tacrolimus, or both, incubated within a specially designed bioreactor or in monolayers, and then exposed to a dynamic cooling and rewarming protocol. Immunocytochemistry, time-lapse video microscopy, cell permeability and adherence assays, and Western blot analysis were performed. RESULTS: Confluent endothelial cells exposed to hypothermia displayed elongated cell shapes with intercellular gap formation, increased endothelial cell-layer permeability, and loss in adherence. Upon rewarming, however, endothelial cell integrity was restored. Opening and closing of intercellular gaps was dependent on extracellular signal-regulated kinase 1 and 2 (ERK 1/2) activation and connexin 43 expression. The combined treatment with methylprednisolone and tacrolimus inhibited these hypothermia-induced changes. CONCLUSIONS: These results suggest that methylprednisolone and tacrolimus inhibit hypothermia-induced endothelial gap formation by phosphorylated ERK 1/2 inhibition and connexin 43 stabilization. Application of combined drugs that affect multiple targets may therefore be considered as a possible new therapeutic strategy to prevent endothelial dysfunction after hypothermia and rewarming.

Hypothermia downregulates inflammation but enhances IL-6 secretion by stimulated endothelial cells.

Hypothermia is a standard method for organ protection during cardiac surgery in children. However, the mechanisms of hypothermia-induced cell protection have not yet been clearly established. Therefore, the aim of our studies was to elucidate molecular effects of clinically relevant mild and deep hypothermia on endothelial cells. The endothelium plays a pivotal role in the interaction between blood cells and actively participates in complex inflammatory events. We isolated primary human umbilical vein endothelial cells (HUVEC) and investigated cell viability, proliferation and inflammatory characteristics after TNF-alpha stimulation under mild (32 degrees C) and deep (17 degrees C) hypothermia in comparison to normothermia (37 degrees C). As a protective mechanism of endothelial cells kept under hypothermic conditions we found a significant upregulation of the antiapoptotic protein Bcl-2, resulting in the same cell viability under hypothermic conditions. Unexpectedly we demonstrated significantly higher IL-6 release after 6h of mild hypothermia. In contrast, hypothermia diminished inflammatory chemokines such as IL-8, MCP-1 and COX-2 protein expression which could lead to reduced leukocyte recruitment under hypothermia. Underlying mechanisms of this downregulation were found to be reduced ERK 1/2 phosphorylation and incomplete IkappaB-alpha degradation resulting in reduced NFkappaB-dependent proinflammatory gene expression. The upregulation of Bcl-2 protein and the higher IL-6 release after 6h of mild hypothermia are new and interesting cellular mechanisms of hypothermia in endothelial cell biology. Both factors may play a major role as cell protective mechanisms in hypothermia.