Preventing Rectourethral Fistula Recurrence With Gracilis Flap.

BACKGROUND: Rectourethral fistula (RUF) is an uncommon serious condition with various etiologies including neoplasm, radiation therapy, and surgery. Treatment for RUF remains problematic with a high recurrence rate. Although studies have suggested the recurrence rate of RUF is lower after surgical repair using a gracilis flap, outcomes have varied and the studies were small and inadequately controlled. Here, we compare outcomes of RUF repair with and without gracilis flap to evaluate its efficacy in preventing fistula recurrence and identify risk factors for recurrence. METHODS: We retrospectively reviewed patients who had undergone surgical repair for RUF between 2007 and 2018 at our institution and had at least 30 days of follow-up. Patient demographics, comorbidities, and surgical outcomes were recorded and compared for patients who had gracilis flap repair and those who did not (controls). Single variable logistic regression analysis was used to identify risk factors for recurrence. RESULTS: The gracilis group (n = 24) and control group (n = 12) had similar demographics and comorbidities. Fistula recurrence was far less frequent in the gracilis group (8% vs 50%, P = 0.009). There were no significant differences in other outcomes including length of hospitalization and surgical complications. When recurrent RUF was treated with a muscle flap (gracilis or inferior gluteus), 83% of the group had no additional fistula recurrence. In the control group, history of radiation ( P = 0.04) and urinary incontinence ( P = 0.015) were associated with fistula recurrence. CONCLUSIONS: We recommend using a gracilis flap for RUF repair given its association with lower recurrence without increased surgical complications.

Microbial signals, MyD88, and lymphotoxin drive TNF-independent intestinal epithelial tissue damage.

Anti-TNF antibodies are effective for treating patients with inflammatory bowel disease (IBD), but many patients fail to respond to anti-TNF therapy, highlighting the importance of TNF-independent disease. We previously demonstrated that acute deletion of 2 IBD susceptibility genes, A20 (Tnfaip3) and Abin-1 (Tnip1), in intestinal epithelial cells (IECs) sensitized mice to both TNF-dependent and TNF-independent death. Here we show that TNF-independent IEC death after A20 and Abin-1 deletion was rescued by germ-free derivation or deletion of MyD88, while deletion of Trif provided only partial protection. Combined deletion of Ripk3 and Casp8, which inhibits both apoptotic and necroptotic death, completely protected against death after acute deletion of A20 and Abin-1 in IECs. A20- and Abin-1-deficient IECs were sensitized to TNF-independent, TNFR1-mediated death in response to lymphotoxin α (LTα) homotrimers. Blockade of LTα in vivo reduced weight loss and improved survival when combined with partial deletion of MyD88. Biopsies of inflamed colon mucosa from patients with IBD exhibited increased LTA and IL1B expression, including a subset of patients with active colitis on anti-TNF therapy. These data show that microbial signals, MyD88, and LTα all contribute to TNF-independent intestinal injury.

A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival.

A20 (TNFAIP3) and ABIN-1 (TNIP1) are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells. Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. These data show that the disease susceptibility proteins A20 and ABIN-1 synergistically prevent intestinal inflammation by restricting IEC death and preserving tissue integrity.

A20 upregulation during treated HIV disease is associated with intestinal epithelial cell recovery and function.

TRIAL REGISTRATION: ClinicalTrials.gov Clinical Trial NCT00594880.