HLA class I loss is a significant mechanism of immune evasion by cervical carcinoma, interfering with the development of immunotherapies and cancer vaccines. We report the systematic investigation of HLA class I and antigen processing machinery component expression and association with clinical outcome. A tissue microarray containing carcinoma lesions from 109 cervical carcinoma patients was stained for HLA class I heavy chains, b 2 -microglobulin, LMP2, LMP7, LMP10, TAP1, TAP2, ERAP1, tapasin, calreticulin, calnexin and ERp57. A novel staining evaluation method was used to ensure optimal accuracy and reliability of expression data, which were correlated with known clinicopathological parameters. Partial HLA class I loss was significantly associated with decreased 5-years overall survival (61% vs. 83% for normal expression; P < 0.05) and was associated with decreased 5-years disease-free survival (DFS) (65% vs. 82% for normal expression; P = 0.05). All APM components except LMP10, calnexin and calreticulin were down-regulated in a substantial number of cases and, except ERAP1, correlated significantly with HLA class I down-regulation. LMP7, TAP1 and ERAP1 loss was significantly associated with decreased overall and (except LMP7) DFS (P < 0.05 and 0.005, respectively). ERAP1 down-regulation was an independent predictor for worse overall and DFS in multivariate analysis (HR 3.08; P < 0.05 and HR 2.84; P < 0.05, respectively). HLA class I and APM component downregulation occur frequently in cervical carcinoma, while peptide repertoire alterations due to ERAP1 loss are a major contributing factor to tumour progression and mortality.

The antigen processing machinery (APM) plays an important role in immune recognition of virally infected and transformed cells. Defective expression of several APM components is associated with progression and clinical outcome in cervical carcinoma. Genetic variation in the genes encoding APM components is known to be associated with risk of occurrence of several malignancies. However, only limited evidence exists supporting the role of single nucleotide polymorphisms (SNPs) in APM components in cervical carcinoma. We have therefore investigated the occurrence of APM component SNP genotypes and haplotypes in cervical carcinoma. Thirteen coding SNPs in the LMP2, LMP7, TAP1, TAP2, and ERAP1 genes were genotyped in 127 cervical carcinoma patients and 124 controls. Individual genotype and allele distributions were assessed by single-marker analysis. Effects of various SNP combinations were estimated by haplotype construction and subsequent haplotype interaction analysis. Significant haplotypes were modeled on disease risk. Allele distributions at the LMP7-145, TAP2-651, ERAP1-127, and ERAP1-730 loci differed significantly between cases and controls with the major allele at the LMP7 and TAP2 loci and the minor allele at both ERAP1 loci associated with increased cervical carcinoma risk. A combination of the two haplotypes spanning these loci was associated with a three-fold increased risk (OR = 3.024; P << 0.001); approximately 12% of all cervical carcinoma occurrences were attributable to this combination. Our data indicate that combined genetic variation in the TAP2, LMP7, and ERAP1 genes is associated with increased cervical carcinoma risk.

Genetic variation of the antigen processing machinery (APM) components TAP2, LMP7, and ERAP1 is related to cervical carcinoma risk, although the relation with expression and clinical outcome remains unknown. We have investigated the occurrence of APM component single nucleotide polymorphisms (SNPs) in cervical carcinoma. Twelve nonsynonymous, coding SNPs in the TAP1, TAP2, LMP2, LMP7, and ERAP1 genes were genotyped in 75 cervical carcinoma patients with known APM component and HLA class I expression levels. Individual genotype distributions were assessed for association with APM component expression, various histopathological parameters and survival. Genotype distributions at the ERAP1-56 and ERAP1-127 loci were significantly associated with overall survival (OS); haplotype construction spanning these two SNPs revealed that the combination of a major allele at ERAP1-56 and a minor allele at ERAP1-127 was significantly associated with survival, homozygosity for this haplotype being associated with decreased OS (5-year survival 50% vs. 70 and 81% for complete absence or heterozygosity for this haplotype, respectively; P = 0.021). Heterozygosity for this haplotype was an independent predictor for better OS in multivariate analysis (HR = 0.219; P = 0.014). These data indicate that genetic variation in APM component genes, particularly ERAP1, is an important contributing factor in cervical carcinogenesis, progressive tumor growth and survival. The location of the ERAP1-127 SNP in the peptidase M1 domain of the ERAP1 aminopeptidase suggests the possibility of direct functional consequences of variation at this locus.

Background:Colorectal cancer peritoneal metastasis (CPM) confers an exceptionally poor prognosis, and traditional treatment involving systemic chemotherapy (SC) is largely ineffective. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly advocated for selected patients with CPM; however, opinions are divided because of the perceived lack of evidence, high morbidity, mortality, and associated costs for this approach. As there is no clear consensus, the aim of this study was to compare outcomes following CRS+HIPEC vs SC alone for CPM using meta-analytical methodology, focusing on survival outcomes. Secondary outcomes assessed included morbidity, mortality, quality of life (QOL), and health economics (HE).Methods:An electronic literature search was conducted to identify studies comparing survival following CRS+HIPEC vs SC for CPM. The odds ratio (OR) was calculated using the Mantel–Haenszel method with corresponding 95% confidence intervals (CI) and P-values. Heterogeneity was examined using the Q-statistic and quantified with I2. The fixed-effect model (FEM) was used in the absence of significant heterogeneity. For included studies, 2- and 5-year survival was compared for CRS+HIPEC vs SC alone.Results:Four studies (three case–control, one RCT) provided comparative survival data for patients undergoing CRS+HIPEC (n=187) vs SC (n=155) for CPM. Pooled analysis demonstrated superior 2-year (OR 2.78; 95% CI 1.72–4.51; P=0.001) and 5-year (OR 4.07; 95% CI 2.17–7.64; P=0.001) survival with CRS+HIPEC compared with SC. Mortality ranged from 0 to 8%. No data were available for the assessment of QOL or HE.Conclusions:Although limited by between-study heterogeneity, the data support the assertion that in carefully selected patients, multimodal treatment of CPM with CRS+HIPEC has a highly positive prognostic impact on medium- and long-term survival compared with SC alone. There is a paucity of comparative data available on morbidity, QOL, and HE.

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The local immune response is considered a key determinant in cervical carcinogenesis after persistent infection with oncogenic, high-risk human papillomavirus (HPV) infections. Genetic variation in various immune response genes has been shown to influence risk of developing cervical cancer, as well as progression and survival among cervical cancer patients. We reviewed the literature on associations of immunogenetic single nucleotide polymorphism, allele, genotype, and haplotype distributions with risk and progression of cervical cancer. Studies on HLA and KIR gene polymorphisms were excluded due to the abundance on literature on that subject. We show that multiple genes and loci are associated with variation in risk of cervical cancer. Rather than one single gene being responsible for cervical carcinogenesis, we postulate that variations in the different immune response genes lead to subtle differences in the effectiveness of the antiviral and antitumour immune responses, ultimately leading to differences in risk of developing cervical cancer and progressive disease after HPV infection.

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Peritoneal mesothelioma (PM) is an uncommon but a serious, and often, fatal primary peritoneal tumour, with increasing incidence worldwide. Conventional systemic chemotherapy, generally based on experience with pleural mesothelioma, usually has disappointing results considering PM as a terminal condition. Patients usually present with non-specific symptoms of abdominal distension and pain making the diagnosis challenging. As PM is confined to the abdomen for all, or much, of its clinical course, a multimodality treatment combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a new standard of care, and has been reported to achieve promising survival outcomes and local disease control in selected patients with PM. This review updates the presentation, diagnosis, classification and treatment strategies for PM.