Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth.

The paracaspase MALT1 plays an essential role in activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) downstream of B cell and TLR pathway genes mutated in these tumors. Although MALT1 is considered a compelling therapeutic target, the development of tractable and specific MALT1 protease inhibitors has thus far been elusive. Here, we developed a target engagement assay that provides a quantitative readout for specific MALT1-inhibitory effects in living cells. This enabled a structure-guided medicinal chemistry effort culminating in the discovery of pharmacologically tractable, irreversible substrate-mimetic compounds that bind the MALT1 active site. We confirmed that MALT1 targeting with compound 3 is effective at suppressing ABC DLBCL cells in vitro and in vivo. We show that a reduction in serum IL-10 levels exquisitely correlates with the drug pharmacokinetics and degree of MALT1 inhibition in vitro and in vivo and could constitute a useful pharmacodynamic biomarker to evaluate these compounds in clinical trials. Compound 3 revealed insights into the biology of MALT1 in ABC DLBCL, such as the role of MALT1 in driving JAK/STAT signaling and suppressing the type I IFN response and MHC class II expression, suggesting that MALT1 inhibition could prime lymphomas for immune recognition by cytotoxic immune cells.

Perianal Crohn's disease: predictive factors and genotype-phenotype correlations.

AIM: To investigate genotype-phenotype correlations in patients with perianal Crohn's disease (PCD) in order to determine which factors predispose to development of perianal disease in Crohn's patients. METHODS: Seven-hundred and ninety-five Caucasian individuals (317 CD patients and 478 controls without inflammatory bowel disease, IBD) were prospectively enrolled into a clinical/genetic database. Demographic and clinical data, as well as peripheral blood leukocyte DNA were obtained from all patients. The following were evaluated: three NOD2/CARD15 polymorphisms: R702W, G908R, and 1007insC; five IL-23r risk alleles: rs1004819, rs10489629, rs2201841, rs11465804, and rs11209026; a well-characterized single-nucleotide polymorphism (SNP) on the IBD5 risk haplotype (OCTN1) and two peripheral tag SNPs (IGR2060 and IGR3096). RESULTS: PCD occurred in 147 (46%) of CD patients. There was no significant difference in the age at disease diagnosis between non-PCD and PCD patients (33 vs. 29 years, respectively). PCD patients were more likely to have disease located in the colon and ileocolic regions (79 PCD vs. 57% non-PCD; n = 116 vs. n = 96; p < 0.001), whereas patients with non-PCD were more likely to have Crohn's within the terminal ileum and upper gastrointestinal tract (43% non-PCD vs. 21% PCD; n = 73 vs. n = 31; p < 0.05). Thirty-four percent of patients with PCD required a permanent ileostomy (n = 50) compared to only 4% of non-PCD patients (n = 6; p < 0.05). Mutations in CARD15/NOD2 and IL-23r were risk factors for CD overall; however, in contrast to prior reports, in this patient population, OCTN1 and IGR variations within the IBD5 haplotype were not significant predictors of PCD. CONCLUSION: Colon/ileocolic CD location appears to be a significant predictor of perianal manifestations of CD. Patients with PCD are more likely to require permanent fecal diversion. We did not identify any genetic variations or combination of clinical findings and genetic variations within the CARD15/NOD2, IL-23r, and OCTN1 genes or IGR that were predictive of PCD.

Abdominal wall component release is a sensible choice for patients requiring complicated closure of abdominal defects.

BACKGROUND: Abdominal wall component release (AWCR) is an operation that frequently restores the abdominal wall integrity in both sick and anatomically complex patients. The patients reported herein are different from the widely reported but somewhat less complex trauma patient, such as following damage control laparotomy. AWCR has acceptable postoperative outcomes in terms of infection, hernia, and fistula rates. METHODS: We describe the application of AWCR in 63 consecutive patients, in whom only 11 (17%) had complementary prosthesis use. Unlike many previous reports of AWCR in trauma patients, 47 (75%) of these patients had permanent stomas. These patients had undergone a total of 103 prior abdominal operations (mean 1.7 operations, range 0-7); 29 patients had cancer (46%), 11 of which were recurrent, and 16 patients (22%) had serious complications of prior surgery. Interestingly, 20 patients (32%) had both prior abdominal operations and underlying cancer. RESULTS: In a median follow-up of 32 months (range 16-120 months), only 15 patients (5 of whom had a stoma) developed recurrent abdominal wall hernias with 5 of those being peristomal. No correlation was found between prior abdominal operations, intestinal stomas, and contamination source at time of surgery with recurrence of hernia (p > 0.05). The 41 patients (86%) with an intact abdominal wall (free of recurrent hernia) had a median follow-up of 27 months (range 13-117 months). Twelve patients (19%) had a source of abdominal/abdominal wall contamination present at the time of AWCR. Only 1 of the 11 patients in whom complementary prosthesis was used developed infection. Other infectious complications were noted in 12 patients (19%), including fistula in 1 patient who required reoperation. CONCLUSIONS: AWCR offers acceptable results in very high-risk patients with tolerable postoperative infection rates.