ABSTRACT
AIM: In intestinal failure, delineation of both structure and function are key to controlling symptoms and planning further intervention. We have developed a template for developing an 'anatomy at a glance' patient-specific map to aid decision making and counselling. METHOD: A core dataset was developed and used to create an editable template to demonstrate the gastrointestinal tract, its relationship to the genitourinary tract, and specific anterior abdominal wall features. This was then used to create an anatomical template, specific to each patient, and stored in the electronic patient record and imaging archive. RESULTS: We have developed a technique for integration of multi-modal information into one diagram, easily referenced by the multidisciplinary team. Radiology, endoscopy and previous operation notes can be used to fill out a core dataset, which is then transposed into a standardized template. A worked example is shown. CONCLUSION: The mapping template has been successfully integrated into practice and aided decision making at all stages of the patient's therapeutic journey. It has been found helpful in planning routes of nutrition, preoperative optimization, surgical planning, interpreting postoperative imaging and managing patient expectations.
Subject(s)
Abdominal Wall , Intestinal Failure , Abdominal Wall/surgery , Documentation , Humans , Intestine, Small , IntestinesABSTRACT
BACKGROUND: Urachal adenocarcinoma (UrAC) is a rare malignancy that can cause peritoneal metastases (PM). Analogous to other enteric malignancies, selected patients with limited PM of UrAC can be treated by cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). OBJECTIVE: The aim of this study was to address the value of diagnostic laparoscopy (DLS) and abdominal cytology (ACyt) for the detection and evaluation of the extent of PM in patients with UrAC. METHODS: A consecutive series of cN0M0 patients with UrAC who underwent DLS with or without ACyt at a tertiary referral center between 2000 and 2018 was assessed. Patients were staged with computed tomography (CT) and/or positron emission tomography (PET)/CT or bone scan. DLS was performed to rule out PM and to evaluate the extent and resectability of PM if seen on imaging. Sensitivity and specificity values were calculated for imaging, DLS, ACyt, and the combination of DLS and ACyt. RESULTS: Thirty-two patients with UrAC underwent DLS. ACyt was obtained in 19 patients. Four patients had suspicion of PM on imaging. In the 28 patients who were PM-negative on imaging, DLS and ACyt revealed PM in 6 (21%) patients, of whom 5 had macroscopically visible PM; 1 patient had positive ACyt without visible PM. Sensitivity of combined DLS/ACyt for the detection of PM was 91%, with a specificity of 100%, whereas sensitivity of imaging was 36%. DLS correctly predicted resectability in all patients. CONCLUSION: Combined DLS/ACyt proved an effective tool to detect occult PM and to evaluate the extent of PM to select UrAC patients for possible treatment with CRS/HIPEC.
Subject(s)
Adenocarcinoma , Hyperthermic Intraperitoneal Chemotherapy , Urinary Bladder Neoplasms , Adenocarcinoma/diagnosis , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Antineoplastic Agents/administration & dosage , Cytoreduction Surgical Procedures , Humans , Laparoscopy , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/pathology , Peritoneal Neoplasms/secondary , Peritoneal Neoplasms/surgery , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgeryABSTRACT
INTRODUCTION: Urachal adenocarcinoma (UrAC) is a rare malignancy arising from persistent urachal remnants, which can cause peritoneal metastases (PM). Currently, patients with this stage UrAC are considered beyond cure. Our objective is to report long-term oncological outcome after cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with PM of urachal adenocarcinoma (UrAC). MATERIALS AND METHODS: We identified 55 patients with UrAC treated at our hospital between 1994 and 2017. Patients were staged with CT, bone scintigraphy and/or PET/CT. From 2001 on, cN0M0 patients underwent staging laparoscopy. Ten patients had PM and were treated with CRS/HIPEC; 35 showed no metastases and underwent local treatment; 10 had distant metastases and received palliative chemotherapy. Disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method and log-rank tests. Postoperative complications represent a secondary outcome. RESULTS: The median follow-up was 96.8 months. Of the CRS/HIPEC patients, 5 (50%) developed a recurrence; 4 (40%) died of disease. The 2-yr and 5-yr DSS after CRS/HIPEC were 66.7% and 55.6%, respectively. DSS of the CRS/HIPEC patients did not significantly differ from DSS of patients without metastases who only underwent curative local treatment and was superior to patients with distant metastases (Pâ¯=â¯0.012). The overall complication rate after CRS/HIPEC was 60%. Major complications (Clavien 3) constituted 20%. The study is limited by its retrospective nature and the small sample size. CONCLUSION: CRS/HIPEC demonstrates satisfactory long-term oncological outcome for patients with PM of UrAC. It may be offered as a potentially curative treatment option for this group of patients.
Subject(s)
Cytoreduction Surgical Procedures , Hyperthermia, Induced , Peritoneal Neoplasms/secondary , Peritoneal Neoplasms/therapy , Urinary Bladder Neoplasms/pathology , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Neoplasm Staging , Palliative Care , Peritoneal Neoplasms/mortality , Postoperative Complications , Survival Rate , Urinary Bladder Neoplasms/mortalityABSTRACT
BACKGROUND: Ovarian metastases of GI tumors grow rapidly and are relatively resistant to systemic chemotherapy. They may be unilateral or bilateral and macroscopic or occult. The risk of macroscopic ovarian involvement or occult involvement of macroscopically normal ovaries is unquantified. OBJECTIVE: This study aims to quantify the risks of ovarian involvement in patients with peritoneal malignancy undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. DESIGN: This was a retrospective analysis of a dedicated prospective malignancy database. SETTINGS: This study was conducted at a high-volume tertiary referral center for peritoneal malignancy. PATIENTS: Female patients with at least 1 remaining ovary, undergoing complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for appendiceal tumors or colorectal peritoneal metastases between January 2010 and March 2015 were included. OUTCOME MEASURES: Data regarding ovarian involvement was extracted from surgical and histological records. RESULTS: Two hundred fifty-eight female patients with at least 1 ovary underwent complete cytoreduction and hyperthermic intraperitoneal chemotherapy during the study period. In total, 141 of 258 (54.7%) patients had ovarian tumor involvement, and 80% with at least 1 macroscopically abnormal ovary had bilateral involvement. Of 40 patients with 1 macroscopic ovarian metastasis, microscopic involvement of the contralateral ovary was found in 18 of 40 (45.0%). Of 141 patients in whom both ovaries were macroscopically normal, 24 of 141 (17.0%) patients had microscopic ovarian involvement. LIMITATIONS: The retrospective nature limits the interpretation of these results. CONCLUSIONS: Occult malignancy was present in 17% when both ovaries looked macroscopically normal and in 45% of contralateral normal-looking ovaries if the other ovary was macroscopically involved. These results help to inform preoperative consent and intraoperative decision making in patients with advanced appendiceal and colorectal malignancy, and are of benefit in managing advanced lower GI tract malignancy.
Subject(s)
Adenocarcinoma, Mucinous/secondary , Adenocarcinoma/secondary , Appendiceal Neoplasms/pathology , Colorectal Neoplasms/pathology , Ovarian Neoplasms/secondary , Peritoneal Neoplasms/secondary , Adenocarcinoma/therapy , Adenocarcinoma, Mucinous/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Appendiceal Neoplasms/therapy , Colorectal Neoplasms/therapy , Cytoreduction Surgical Procedures , Databases, Factual , Female , Humans , Hyperthermia, Induced/methods , Infusions, Parenteral , Middle Aged , Ovarian Neoplasms/therapy , Peritoneal Neoplasms/therapy , Retrospective Studies , Tertiary Care Centers , Young AdultABSTRACT
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.
Subject(s)
Carcinogenesis/genetics , Genetic Variation , Immunity/genetics , Papillomavirus Infections/genetics , Polymorphism, Single Nucleotide , Uterine Cervical Neoplasms/genetics , Alleles , Disease Progression , Female , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Papillomaviridae/immunology , Papillomavirus Infections/complications , Papillomavirus Infections/immunology , Papillomavirus Infections/virology , Risk Factors , Uterine Cervical Neoplasms/immunologyABSTRACT
BACKGROUND: Intraperitoneal chemotherapy has an established role in the treatment of selected patients with colorectal peritoneal metastases. Oxaliplatin is highly suitable as a chemotherapeutic agent for hyperthermic intraperitoneal chemotherapy (HIPEC), but its use to date has been limited because of the morbidity caused by severe electrolyte and glycemic imbalances associated with 5% glucose as its carrier solution. This report provides an overview of the development, rationale, and application of intraperitoneal chemotherapy and the use of various drugs and carrier solutions. A novel, evidence-based protocol for bidirectional oxaliplatin-based HIPEC in a physiologic carrier solution (Dianeal PD4 dextrose 1.36%) is presented, and its impact on electrolyte and glucose levels is demonstrated. METHODS: After implementation of the new protocol, the serum electrolyte (sodium, potassium, and chloride) levels, glucose levels, and intravenous insulin requirements were intensively measured in eight consecutive cases immediately before HIPEC (T = 0), immediately after HIPEC (T = 30), 1 h after HIPEC (T = 60), and 3 h after HIPEC (T = 180). RESULTS: The median sodium levels were 140 mmol/L at T = 0, 138 mmol/L at T = 30, 140 mmol/L at T = 60, and 140 mmol/L at T = 180. The respective median potassium levels were 4.6, 4.2, 3.7, and 3.9 mmol/L, and the respective median chloride levels were 112, 111, 111, and 112 mmol/L. The respective median glucose levels were 9, 11.5, 10.7, and 8.6 mmol/L. The median insulin requirements were respectively 0.5, 1.5, 1.2, and 0 U/h. None of the patients were diabetic. CONCLUSION: Using a novel protocol for bidirectional oxaliplatin-based HIPEC in Dianeal instead of 5% glucose, the observed fluctuations in this study were minimal and not clinically relevant compared with historical values for electrolyte and glycemic changes using 5% glucose as a HIPEC carrier solution. This novel protocol leads to only minimal and clinically irrelevant electrolyte and glycemic disturbances, and its adoption as the standard protocol for oxaliplatin-based HIPEC should be considered.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/pathology , Hyperthermia, Induced , Peritoneal Neoplasms/therapy , Administration, Intravenous , Blood Glucose/metabolism , Chlorides/administration & dosage , Chlorides/blood , Cytoreduction Surgical Procedures , Dialysis Solutions/administration & dosage , Dialysis Solutions/chemistry , Evidence-Based Medicine , Female , Fluorouracil/administration & dosage , Humans , Infusions, Parenteral , Leucovorin/administration & dosage , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Peritoneal Neoplasms/secondary , Potassium/blood , Sodium/bloodABSTRACT
BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is the gold standard treatment for patients with pseudomyxoma peritonei (PMP) but involves routine bilateral salpingo-oophorectomy. Young women wishing to maintain fertility may be reluctant to pursue this. An alternative strategy in women with low-grade PMP has been explored in the form of laparoscopic evacuation of pelvic and ovarian mucin with resection of the appendiceal tumour. METHODS: Between January 2012 and January 2015, four young women (aged 28-35 years) with PMP seeking to maintain fertility underwent laparoscopy, appendicectomy and pelvic mucinous evacuation and washout. Data regarding intra-operative and histopathological findings were collected. Endpoints were fertility-related outcomes and oncological follow-up. RESULTS: Infertility was a presenting symptom in three of the four women. All four had significant pelvic mucinous disease on radiological imaging and were offered CRS and HIPEC as definitive treatment, but chose laparoscopy with appendicectomy and copious irrigation and washout of the pelvis with stripping of mucinous disease off the ovarian surfaces. Postoperative histology demonstrated a low-grade appendiceal mucinous neoplasm (LAMN) in all patients with acellular mucin or low-grade mucinous carcinoma peritonei in the peritoneal cavity. All patients successfully conceived subsequently and gave birth to healthy babies. After 12-29 months follow-up, all women are well with no radiological or laparoscopic evidence of disease recurrence. CONCLUSIONS: In patients with low-grade PMP, initial therapeutic laparoscopy can restore fertility, whilst providing short- to medium-term disease control. This modality in young women wishing to have children appears to be a feasible alternative to immediate CRS and HIPEC.
ABSTRACT
The antigen processing machinery (APM) plays an important role in immune recognition of virally infected and transformed cells. Defective expression of the APM component ERAP1 is associated with progression and poor clinical outcome in cervical carcinoma. However, the underlying mechanisms of ERAP1 protein downregulation remain to be established. We investigated ERAP1 mRNA expression levels in 14 patients with established ERAP1 protein downregulation. To further examine the possible pretranscriptional mechanisms of ERAP1 downregulation, ERAP1 DNA mutation status was analyzed alongside existing data on various single nucleotide polymorphisms. Moreover, loss of heterozygosity at various loci in the ERAP1 gene was investigated. In cases with ERAP1 protein downregulation, ERAP1 mRNA quantities were found to be significantly lower than in a cohort with normal ERAP1 protein expression (P = 0.001). Loss of heterozygosity was demonstrated to occur in up to 50% of tumors with ERAP1 downregulation. Our data indicate that ERAP1 downregulation is associated with loss of heterozygosity. These data provide the first insight into in vivo mechanisms of ERAP1 downregulation in cervical carcinoma.
Subject(s)
Aminopeptidases/genetics , Down-Regulation/genetics , Uterine Cervical Neoplasms/genetics , Aminopeptidases/metabolism , Female , Gene Expression Regulation, Neoplastic , Genotype , Humans , Loss of Heterozygosity , Microsatellite Instability , Middle Aged , Minor Histocompatibility Antigens , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is currently considered the standard of care for pseudomyxoma peritonei, mesothelioma and peritoneal metastases (PM) from colorectal cancer. CRS + HIPEC has also been suggested as a potential treatment option in PM of the much rarer small bowel cancer. Therefore, the current study was undertaken to investigate the results of CRS + HIPEC in all HIPEC centers in The Netherlands. METHODS: From the 4 tertiary referral centers for peritoneal surface malignancies in The Netherlands, data from all patients with peritoneally metastasized small bowel carcinoma intended to undergo CRS and HIPEC were collected between January 2005 and July 2014. Primary tumor characteristics, operative details, and survival outcomes were collected. RESULTS: Sixteen of 19 patients (84.2%) who underwent explorative laparotomy underwent CRS + HIPEC. Of these patients, 81.3% were female, and primary tumors were mainly located in the ileum (50%). A complete macroscopic resection was achieved in 93.8%. Serious adverse events requiring re-intervention occurred in 25%, and no in-hospital mortality was observed. Recurrent disease was observed in 50% of patients and median survival after CRS and HIPEC was 31 months. CONCLUSION: In a select group of patients in whom a complete macroscopic resection can be achieved, survival rates comparable with those in colorectal PM are attainable with acceptable morbidity. The role of adjuvant chemotherapy needs further research.
Subject(s)
Adenocarcinoma/secondary , Chemotherapy, Cancer, Regional Perfusion/methods , Cytoreduction Surgical Procedures/methods , Neoplasm Recurrence, Local/mortality , Peritoneal Neoplasms/secondary , Peritoneal Neoplasms/therapy , Adenocarcinoma/surgery , Adult , Aged , Chemotherapy, Cancer, Regional Perfusion/mortality , Combined Modality Therapy , Cytoreduction Surgical Procedures/mortality , Databases, Factual , Disease-Free Survival , Female , Humans , Hypothermia, Induced , Intestinal Neoplasms/pathology , Intestinal Neoplasms/surgery , Intestine, Small/pathology , Intestine, Small/surgery , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Netherlands , Peritoneal Neoplasms/mortality , Prognosis , Retrospective Studies , Risk Assessment , Survival Analysis , Tertiary Care Centers , Treatment OutcomeABSTRACT
Genetic variation of antigen-processing machinery (APM) components has been shown to be associated with cervical carcinoma risk and outcome in a genetically homogeneous Dutch population. However, the role of APM component single nucleotide polymorphisms (SNPs) in genetically heterogeneous populations with different distributions of human papillomavirus (HPV) subtypes remains unclear. Eleven non-synonymous, coding SNPs in the TAP1, TAP2, LMP2, LMP7 and ERAP1 genes were genotyped in cervical carcinoma patients and healthy controls from two distinct Indonesian populations (Balinese and Javanese). Individual genotype and allele distributions were investigated using single-marker analysis, and combined SNP effects were assessed by haplotype construction and haplotype interaction analysis. Allele distribution patterns in Bali and Java differed in relation to cervical carcinoma risk, with four ERAP1 SNPs and one TAP2 SNP in the Javanese population showing significant association with cervical carcinoma risk, while in the Balinese population, only one TAP2 SNP showed this association. Multimarker analysis demonstrated that in the Javanese patients, one specific haplotype, consisting of the ERAP1-575 locus on chromosome 5 and the TAP2-379 and TAP2-651 loci on chromosome 6, was significantly associated with cervical carcinoma risk (global P = 0.008); no significant haplotype associations were found in the Balinese population. These data indicate not only that genetic variation in APM component genes is associated with cervical carcinoma risk in Indonesia but also that the patterns of association differ depending on background genetic composition and possibly on differences in HPV type distribution.
Subject(s)
Antigen Presentation/genetics , Carcinoma/genetics , Genetics, Population , Uterine Cervical Neoplasms/genetics , Alleles , Antigen Presentation/immunology , Carcinoma/immunology , Carcinoma/pathology , Female , Genetic Predisposition to Disease , Genetic Variation , Haplotypes , Humans , Indonesia , Polymorphism, Single Nucleotide , Risk Factors , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/pathologyABSTRACT
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.
Subject(s)
Aminopeptidases/genetics , Polymorphism, Single Nucleotide , Uterine Cervical Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Female , Gene Expression , Humans , Kaplan-Meier Estimate , Middle Aged , Minor Histocompatibility Antigens , Multivariate Analysis , Prognosis , Proportional Hazards Models , Risk , Uterine Cervical Neoplasms/diagnosisABSTRACT
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, beta(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 down-regulation occur frequently in cervical carcinoma, while peptide repertoire alterations due to ERAP1 loss are a major contributing factor to tumour progression and mortality.
Subject(s)
Antigen Presentation/immunology , Histocompatibility Antigens Class I/metabolism , Uterine Cervical Neoplasms/pathology , ATP Binding Cassette Transporter, Subfamily B, Member 2 , ATP-Binding Cassette Transporters/metabolism , Adult , Aged , Aged, 80 and over , Aminopeptidases/metabolism , Disease-Free Survival , Down-Regulation , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Minor Histocompatibility Antigens , Prognosis , Tissue Array Analysis , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/mortalityABSTRACT
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.