Objective. Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome.Methods. Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells.Results. In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with
Objective. The cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1, encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structural effect of disease-causing mutations on cryopyrin, in order to gain better understanding of the impact of disease-associated mutations on protein function.Methods. We tested for CIAS1 mutations in 22 patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome, 12 with Muckle-Wells syndrome (MWS), 18 with familial cold-induced autoinflammatory syndrome (FCAS), and 3 probands with MWS/FCAS. In a subset of mutation-negative patients, we screened for mutations in proteins that are either homologous to cryopyrin or involved in the caspase 1/interleukin-1 signaling pathway. CIAS1 and other candidate genes were sequenced, models of cryopyrin domains were constructed using structurally homologous proteins as templates, and disease-causing mutations were mapped.Results. Forty patients were mutation positive, and 7 novel mutations, V262A, C259W, L264F, V351L, F443L, F523C, and Y563N, were found in 9 patients. No mutations in any candidate genes were identified. Most mutations mapped to an inner surface of the hexameric ring in the cryopyrin model, consistent with the hypothesis that the mutations disrupt a closed form of cryopyrin, thus potentiating inflammasome assembly. Disease-causing mutations correlated with disease severity only for a subset of known mutations.Conclusion. Our modeling provides insight into potential molecular mechanisms by which cryopyrin mutations can inappropriately activate an inflammatory response. A significant number of patients who are clinically diagnosed as having cryopyrinopathies do not have identifiable disease-associated mutations.
Background Most patients with malignant peritoneal mesothelioma (MPM) present with late-stage, unresectable disease that responds poorly to systemic chemotherapy while, at the same time, effective targeted therapies are lacking. We assessed the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) in MPM. Methods We prospectively analyzed 65 patients with MPM undergoing CRS/HIPEC between 2001 and 2010. Kaplan–Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes. Results Adequate CRS was achieved in 56 patients (CC-0 = 35; CC-1 = 21), and median simplified peritoneal cancer index (SPCI) was 12. Pathologic assessment revealed predominantly epithelioid histology (81 %) and biphasic histology (8 %), while lymph node involvement was uncommon (8 %). Major postoperative morbidity (grade III/IV) occurred in 23 patients (35 %), and 60-day mortality rate was 6 %. With median follow-up of 37 months, median overall survival was 46.2 months, with 1-, 2-, and 5-year overall survival probability of 77, 57, and 39 %, respectively. Median progression-free survival was 13.9 months, with 1-, 2-, and 5-year disease failure probability of 47, 68, and 83 %, respectively. In a multivariate Cox-regression model, age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), aggressive histology (epithelioid, biphasic), and postoperative sepsis were joint significant predictors of poor survival (chi square = 42.8; p = 0.00001), while age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), and aggressive histology (epithelioid, biphasic) were joint significant predictors of disease progression (Chi square = 30.6; p = 0.00001). Conclusions Tumor histology, disease burden, and the ability to achieve adequate surgical cytoreduction are essential prognostic factors in MPM patients undergoing CRS/HIPEC.
Pre-existing anti-poxvirus immunity in cancer patients presents a severe barrier to poxvirus-mediated oncolytic virotherapy. We have explored strategies of immunosuppression (IS) and/or immune evasion for efficient delivery of an oncolytic vaccinia virus (vvDD) to tumors in the pre-immunized mice. Transient IS using immunosuppressive drugs, including tacrolimus, mycophenolate mofetil and methylprednisolone sodium succinate, have been used successfully in organ transplantation. This drug cocktail alone did not enhance viral recovery from subcutaneous tumor after systemic viral delivery. Using B cell knockout mice, we confirmed that the neutralizing antibodies played a significant role in preventing poxvirus infection. Using a MC38 peritoneal carcinomatosis (PC) model, we found that the combination of IS and tumor cells as carriers led to the most effective viral delivery, viral replication and viral spread inside the tumor mass. We found that our immunosuppressive drug cocktail facilitated recruitment of tumor-associated macrophages and conversion into an immunosuppressive M2 phenotype (IL-10hi/IL-12low) in the tumor microenvironment. A combination of IS and carrier cells led to significantly prolonged survival in the tumor model. These results demonstrated the feasibility of treating pre-vaccinated patients with peritoneal carcinomatosis using an oncolytic poxvirus and a combined immune intervention strategy.
Background The significance of tumor markers in patients with appendiceal carcinomatosis is poorly defined. We determined preoperative and postoperative tumor marker levels in patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemoperfusion (HIPEC) and examined their association with clinicopathologic features and survival. Methods A total of 176 patients undergoing attempted CRS/HIPEC for appendiceal carcinomatosis had at least 1 tumor marker measured. Marker levels were correlated with tumor characteristics and oncologic outcomes. Kaplan–Meier curves and multivariate Cox regression models were used to identify prognostic factors affecting progression and survival. Results At least 1 marker was elevated prior to CRS/ HIPEC in 70 % of patients (CEA, 54.1 %; CA19-9, 47.7 %; CA-125, 47.2 %). Among patients with elevated preoperative marker levels, normalization occurred postoperatively in 79.4 % for CEA, 92.3 % for CA19-9, and 60 % for CA-125. Absolute preoperative tumor marker levels correlated with peritoneal carcinomatosis index (PCI) (p < .0002), and the number of elevated markers was associated with PCI and progression-free survival (PFS). Elevated postoperative CEA level was associated with decreased PFS (median, 13 vs 36 months, p = .0008). On multivariate Cox regression analysis, elevated preoperative CA19-9 was associated with shorter PFS (hazard ratio [HR] 2.9, 95 % confidence interval [95 % CI] 1.5–5.3, p = .0008), whereas elevated CA-125 was associated with shorter overall survival (HR 2.6, 95 % CI 1.3–5.4, p = .01). Conclusions Most patients with appendiceal carcinomatosis will have at least 1 elevated tumor marker and will normalize following CRS/HIPEC, allowing for ongoing surveillance. CA19-9 is a promising biomarker for early progression following CRS/HIPEC, whereas CA-125 is associated with shorter survival.
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