ABSTRACT
BACKGROUND & AIMS: Helicobacter pylori eradication and endoscopic surveillance of gastric precancerous lesions are strategies to reduce gastric cancer (GC) risk. To our knowledge, this study is the longest prospective cohort of an H pylori eradication trial in a Hispanic population. METHODS: A total of 800 adults with precancerous lesions were randomized to anti-H pylori treatment or placebo. Gastric biopsy samples taken at baseline and 3, 6, 12, 16, and 20 years were assessed by our Correa histopathology score. A generalized linear mixed model with a participant-level random intercept was used to estimate the effect of H pylori status on the score over time. Logistic regression models were used to estimate progression by baseline diagnosis and to estimate GC risk by intestinal metaplasia (IM) subtype and anatomic location. RESULTS: Overall, 356 individuals completed 20 years of follow-up. Anti-H pylori therapy (intention-to-treat) reduced progression of the Correa score (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.38-0.93). H pylori-negative status had a beneficial effect on the score over time (P = .036). Among individuals with IM (including indefinite for dysplasia) at baseline, incidence rates per 100 person-years were 1.09 (95% CI, 0.85-1.33) for low-grade/high-grade dysplasia and 0.14 (95% CI, 0.06-0.22) for GC. Incomplete-type (vs complete-type) IM at baseline presented higher GC risk (OR, 13.4; 95% CI, 1.8-103.8). Individuals with corpus (vs antrum-restricted) IM showed an OR of 2.1 (95% CI, 0.7-6.6) for GC. CONCLUSIONS: In a high-GC-risk Hispanic population, anti-H pylori therapy had a long-term beneficial effect against histologic progression. Incomplete IM is a strong predictor of GC risk.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Gastric Mucosa/pathology , Helicobacter Infections/drug therapy , Precancerous Conditions/epidemiology , Stomach Neoplasms/prevention & control , Adult , Aged , Biopsy , Colombia/epidemiology , Disease Progression , Female , Follow-Up Studies , Gastric Mucosa/diagnostic imaging , Gastric Mucosa/microbiology , Gastroscopy/statistics & numerical data , Helicobacter Infections/microbiology , Helicobacter Infections/pathology , Helicobacter pylori/isolation & purification , Humans , Incidence , Male , Metaplasia/diagnosis , Metaplasia/epidemiology , Metaplasia/microbiology , Metaplasia/pathology , Middle Aged , Precancerous Conditions/diagnosis , Precancerous Conditions/microbiology , Precancerous Conditions/pathology , Prospective Studies , Risk Factors , Stomach Neoplasms/epidemiology , Stomach Neoplasms/microbiology , Stomach Neoplasms/pathology , Treatment OutcomeABSTRACT
INTRODUCTION: The association between a change in proteinuria over time and its impact on kidney prognosis has not been analysed in complement component 3 (C3) glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure. METHODS: This was a retrospective, multicentre observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modelling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure. RESULTS: The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13-41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (hazard ratio 0.79; 95% confidence interval 0.56-0.97; P < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up. CONCLUSIONS: The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.
Subject(s)
Glomerulonephritis, Membranoproliferative , Glomerulonephritis , Kidney Failure, Chronic , Adolescent , Adult , Complement C3/analysis , Glomerulonephritis/complications , Glomerulonephritis/epidemiology , Humans , Kidney , Kidney Failure, Chronic/complications , Proteinuria/complications , Proteinuria/etiology , Retrospective Studies , Young AdultABSTRACT
Population-based cancer registries (PBCRs) are the only means to provide reliable incidence and survival data as a basis for policy-making and resource allocations within cancer care. Yet, less than 3% and 10% of the respective populations of Central America and South America are covered by high-quality cancer registries. The Global Initiative for Cancer Registry Development provides support to improve this situation via the International Agency for Research on Cancer Regional Hub for Latin America. In this paper, we summarize activities (advocacy, technical assistance, training and research) over the last 5 years, their impact and current challenges, including the implementation of new PBCR in four countries in the region. Despite the favorable political support to cancer registration in many countries, the sustainability of cancer registration remains vulnerable. Renewed efforts are needed to improve data quality in Latin America while ensuring maximum visibility of the data collected by disseminating and promoting their use in cancer control.
Subject(s)
Early Detection of Cancer/standards , Neoplasms/diagnosis , Registries/statistics & numerical data , Humans , Incidence , Latin America/epidemiology , Neoplasms/epidemiologyABSTRACT
RATIONALE & OBJECTIVE: A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy (C3G) proposed a prognostic histologic index (C3G-HI) that has not yet been validated. Our objective was to validate the performance of the C3G-HI in a new patient population. STUDY DESIGN: Multicenter, retrospective cohort study. SETTING & PARTICIPANTS: 111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). PREDICTORS: Demographic, clinical parameters, C3G-HI total activity score, and the C3G-HI total chronicity score. OUTCOME: Time to kidney failure. ANALYTICAL APPROACH: Intraclass correlation coefficients and κ statistic were used to summarize inter-rater reproducibility for assessment of histopathology in kidney biopsies. The nonlinear relationships of risk of kidney failure with the total activity score and total chronicity score were modeled using Cox proportional hazards analysis that incorporated cubic splines. RESULTS: The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall meanage of 35±22 (SD) years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the total activity score (intraclass correlation coefficient [ICC]=0.63) and excellent for total chronicity score (ICC=0.89). Baseline estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables. Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the total activity score and total chronicity score were added to the model, only the latter was identified as an independent predictor of kidney failure. LIMITATIONS: Only a subset of the kidney biopsies was centrally reviewed. Residual confounding. CONCLUSIONS: We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure.
Subject(s)
Complement C3/immunology , Glomerulonephritis, Membranoproliferative/pathology , Kidney Tubules/pathology , Renal Insufficiency/pathology , Adolescent , Adult , Atrophy , Child , Cohort Studies , Disease Progression , Female , Fibrosis , Glomerular Filtration Rate , Glomerulonephritis/drug therapy , Glomerulonephritis/immunology , Glomerulonephritis/metabolism , Glomerulonephritis/pathology , Glomerulonephritis, Membranoproliferative/drug therapy , Glomerulonephritis, Membranoproliferative/immunology , Glomerulonephritis, Membranoproliferative/metabolism , Humans , Immunosuppressive Agents/therapeutic use , Kidney/pathology , Male , Middle Aged , Prognosis , Proportional Hazards Models , Proteinuria , Renal Insufficiency/immunology , Renal Insufficiency/metabolism , Reproducibility of Results , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: The aims of this study are (a) to assess the psychometric quality of an instrument of acceptance of new technologies adapted from the UTAUT model, (b) to validate the UTAUT model as a valid measure to be applied in dental education, and (c) to determine which factors of the UTAUT model predict the behavioural intention of using a haptic virtual simulator (HVS). METHODS: A cross-sectional design study with a sample of 265 dentistry students was carried out. RESULTS: Using structural equation modelling, confirmatory factor analysis verified the adequacy of four-factor model, although the only factor that directly predicts behavioural intention is performance expectancy. Internal consistency coefficients of each factor ranged from 0.800 to 0.969. DISCUSSION: These findings, as well as the predictive power of performance expectancy on behaviour intention, are in line with previous evidence found in the literature. CONCLUSION: These findings suggest that the UTAUT scale has adequate reliability and construct factorial validity; therefore, UTAUT model could be a valuable approach to assess haptic virtual simulator acceptance in dental education.
Subject(s)
Education, Dental , Students, Dental , Cross-Sectional Studies , Humans , Psychometrics , Reproducibility of Results , Surveys and QuestionnairesABSTRACT
INTRODUCTION: Inflammation associated with Helicobacter pylori (H. pylori) infection is linked to the development of a gastric precancerous lesion. Helminth infections could influence the pro-inflam matory response to such infection from LTCD4+ Th1 to a less harmful LTCD4+ Th2 response. Ob jective: To characterize the polarization of the LTCD4+ Th2 immune response in co-infected pa tients with H. pylori and helminths from low-risk areas for developing gastric cancer. PATIENTS AND METHOD: We analyzed 63 patients infected by H. pylori (40 adults and 23 children). Through the Multiplex Analysis technology (xMAP), we determined the serum profiles of the interleukins asso ciated with the polarization of the immune response of LTCD4+ Th1 (IL-1Β, INF-γ, TNF-α) as well as the LTCD4+ Th2 (IL-4, IL-10, and IL-13). The ratio between helminths co-infection status in H. pylori-infected patients and the polarization of the immune response mediated by LTCD4+ Th1 and LTCD4+ Th2 was assessed using a Mixed Effects Logistic Regression Model. RESULTS: The frequency of helminths was similar between adults (15%) and children (17%). The polarization of the immu ne response was more prevalent in LTCD4+ Th1. Serum values of interleukins associated with the immune response polarization of LTCD4+ Th1 (IL-1Β, INF-γ, and TNF-α) and LTCD4+ Th2 (IL-4, IL-10, and IL-13) were independent of helminths infection status. CONCLUSION: The prevalence of in testinal parasitic infection was high and the immune response polarization was mainly LTCD4 + Th1.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Coinfection/immunology , Helicobacter Infections/immunology , Helicobacter pylori/immunology , Helminthiasis/immunology , Th1-Th2 Balance , Adolescent , Adult , Aged , Biomarkers/blood , CD4-Positive T-Lymphocytes/metabolism , Child , Child, Preschool , Coinfection/blood , Coinfection/diagnosis , Coinfection/pathology , Female , Helicobacter Infections/blood , Helicobacter Infections/diagnosis , Helicobacter Infections/pathology , Helminthiasis/blood , Helminthiasis/diagnosis , Helminthiasis/pathology , Humans , Logistic Models , Male , Middle AgedABSTRACT
Malignant hypertension is listed among the causes of secondary thrombotic microangiopathy, but pathogenic mutations in complement genes have been reported in patients with hypertension-induced thrombotic microangiopathy. Here we investigated the frequency and severity of hypertension in 55 patients with primary atypical hemolytic uremic syndrome (aHUS). A genetic analysis was performed in all patients, and funduscopic examination was performed in all the patients with Grades 2 and 3 hypertension. A cohort of 110 patients with malignant hypertension caused by diseases other than aHUS served as control. Thirty-six patients with aHUS presented Grade 2 or Grade 3 hypertension and funduscopic examination showed malignant hypertension in 19. Genetic abnormalities in complement were found in 19 patients (37% among patients with malignant hypertension). Plasmapheresis was performed in 46 patients and 26 received eculizumab. Renal and hematological responses were significantly lower after plasmapheresis (24%) than after eculizumab (81%). Renal survival was significantly higher in patients treated with eculizumab (85% at one, three and five years) compared to patients who did not receive this treatment (54%, 46% and 41%), respectively. Response to eculizumab was independent of hypertension severity and the presence of complement genetic abnormalities. Among patients with malignant hypertension caused by other diseases the prevalence of thrombotic microangiopathy was very low (5%). Thus, severe and malignant hypertension are common among patients with aHUS and eculizumab treatment leads to a higher renal survival when compared to plasmapheresis. However, thrombotic microangiopathy is uncommon among patients presenting with malignant hypertension caused by diseases other than aHUS.
Subject(s)
Atypical Hemolytic Uremic Syndrome/complications , Complement System Proteins/genetics , Hypertension, Malignant/epidemiology , Severity of Illness Index , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Atypical Hemolytic Uremic Syndrome/genetics , Atypical Hemolytic Uremic Syndrome/therapy , Complement Inactivating Agents/therapeutic use , Female , Humans , Hypertension, Malignant/diagnosis , Hypertension, Malignant/genetics , Hypertension, Malignant/therapy , Incidence , Male , Middle Aged , Plasmapheresis , Retrospective Studies , Young AdultABSTRACT
OBJECTIVE: To evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions. DESIGN: 795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1-6). The score difference between baseline and 16 years was modelled by generalised linear models. RESULTS: Individuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with H. pylori. The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p<0.001). CONCLUSIONS: Long-term exposure to H. pylori infection was associated with progression of precancerous lesions. Individuals infected with H. pylori with these lesions may benefit from eradication, particularly those with atrophic gastritis without IM. Incomplete-type IM may be a useful marker for the identification of individuals at higher risk for cancer.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Helicobacter Infections/drug therapy , Helicobacter Infections/pathology , Precancerous Conditions/microbiology , Precancerous Conditions/pathology , Stomach Neoplasms/microbiology , Adult , Aged , Disease Progression , Drug Administration Schedule , Female , Follow-Up Studies , Helicobacter Infections/complications , Helicobacter pylori , Humans , Male , Metaplasia , Middle Aged , Risk Factors , Stomach Neoplasms/pathologyABSTRACT
Helicobacter pylori is the principal cause of gastric cancer, the second leading cause of cancer mortality worldwide. However, H. pylori prevalence generally does not predict cancer incidence. To determine whether coevolution between host and pathogen influences disease risk, we examined the association between the severity of gastric lesions and patterns of genomic variation in matched human and H. pylori samples. Patients were recruited from two geographically distinct Colombian populations with significantly different incidences of gastric cancer, but virtually identical prevalence of H. pylori infection. All H. pylori isolates contained the genetic signatures of multiple ancestries, with an ancestral African cluster predominating in a low-risk, coastal population and a European cluster in a high-risk, mountain population. The human ancestry of the biopsied individuals also varied with geography, with mostly African ancestry in the coastal region (58%), and mostly Amerindian ancestry in the mountain region (67%). The interaction between the host and pathogen ancestries completely accounted for the difference in the severity of gastric lesions in the two regions of Colombia. In particular, African H. pylori ancestry was relatively benign in humans of African ancestry but was deleterious in individuals with substantial Amerindian ancestry. Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population.
Subject(s)
Disease Susceptibility , Evolution, Molecular , Helicobacter Infections/microbiology , Helicobacter pylori/genetics , Stomach Diseases/microbiology , Adult , Aged , Helicobacter Infections/complications , Humans , Middle AgedABSTRACT
Gastric cancer incidence varies considerably among populations, even those with comparable rates of Helicobacter pylori infection. To test the hypothesis that genetic variation plays a role in gastric disease, we assessed the relationship between genotypes and gastric histopathology in a Colombian study population, using a genotyping array of immune-related single nucleotide polymorphisms (SNPs). Two synonymous SNPs (rs6061243 and rs6587239) were associated with progression of premalignant gastric lesions in a dominant-effects model after correction for multiple comparisons (p = 2.63E-07 and p = 7.97E-07, respectively); effect sizes were ß = -0.863 and ß = -0.815, respectively, where ß is an estimate of effect on histopathology scores, which ranged from 1 (normal) to 5 (dysplasia). In our replication cohort, a second Colombian population, both SNPs were associated with histopathology when additively modeled (ß = -0.256, 95 % CI = -0.47, -0.039; and ß = -0.239, 95 % CI = -0.45, -0.024), and rs6587239 was significantly associated in a dominant-effects model (ß = -0.330, 95 % CI = -0.66, 0.00). Because promoter methylation of GATA5 has previously been associated with gastric cancer, we also tested for the association of methylation status with more advanced histopathology scores in our samples and found a significant relationship (p = 0.001). A multivariate regression model revealed that the effects of both the promoter methylation and the exonic SNPs in GATA5 were independent. A SNP-by-methylation interaction term was also significant. This interaction between GATA5 variants and GATA5 promoter methylation indicates that the association of either factor with gastric disease progression is modified by the other.
Subject(s)
DNA Methylation/genetics , Epigenomics , GATA5 Transcription Factor/genetics , Helicobacter Infections/genetics , Stomach Neoplasms/genetics , Adult , Female , Genetic Association Studies , Genotype , Helicobacter Infections/microbiology , Helicobacter Infections/pathology , Helicobacter pylori/pathogenicity , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Risk Factors , Stomach Neoplasms/microbiology , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America. METHODS: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed. RESULTS: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated. CONCLUSIONS: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.
Subject(s)
Breast Neoplasms/therapy , Carcinoma, Ductal, Breast/therapy , Neoplasm Recurrence, Local , Patient Selection , Radiotherapy/statistics & numerical data , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Canada , Carcinoma, Ductal, Breast/secondary , Disease-Free Survival , Female , Humans , Intraoperative Care , Lymphatic Metastasis , Mastectomy, Segmental/adverse effects , Middle Aged , Neoplasm Staging , Neoplasm, Residual , Radiotherapy/methods , Radiotherapy Dosage , Registries , Retrospective Studies , Sentinel Lymph Node/pathology , Tumor Burden , United StatesABSTRACT
BACKGROUND: Treatment abandonment (TxA) is a primary cause of therapy failure in children with cancer in low-/middle-income countries. We explored the absence of social support network (SSN), among other predictive factors, and TxA in children with cancer in Cali, Colombia. PROCEDURE: In this prospective cohort study, we included children diagnosed with cancer at a public university hospital. A social worker and a psychologist administered semistructured questionnaires to patients' caregivers. We extracted information from the questionnaires about social, economic, and psychological conditions of the patients' families. Outcomes were death, relapse, and TxA. Failure either to start or to continue the planned course of curative treatment for 4 weeks or more was defined as TxA. We identified events with Cali's childhood cancer outcomes surveillance system (VIGICANCER). We adjusted the hazard ratios (HRs) for potential confounders using multivariate Cox regression analyses. RESULTS: Among 188 patients diagnosed from January 2011 to June 2013, 99 interviews were conducted. Median age was 5 years old (range: 0.3, 14.9), 53% were male, 17% were of Colombian-Indian ethnicity, and 68% lived in rural areas. The 2-year cumulative incidence of TxA was 21% (95% confidence interval [CI]: 13, 35) and the annual proportion was 14%. The adjusted HR for the absence of SSN was 4.9 (95% CI: 1.6, 15.3). CONCLUSIONS: We found a strong association between the absence of SSN and TxA that was independent of other covariates, including surrogate measures of wealth. Our findings highlight the imperative understanding of social ties and support surrounding children's families for planning strategies to prevent TxA.
Subject(s)
Caregivers/economics , Child, Abandoned , Neoplasms , Social Support , Surveys and Questionnaires , Adolescent , Adult , Child , Child, Preschool , Colombia , Female , Hospitals, Public , Hospitals, Teaching , Humans , Infant , Male , Neoplasms/economics , Neoplasms/psychology , Neoplasms/therapy , Prospective StudiesABSTRACT
Helicobacter pylori incites a futile inflammatory response, which is the key feature of its immunopathogenesis. This leads to the ability of this bacterial pathogen to survive in the stomach and cause peptic ulcers and gastric cancer. Myeloid cells recruited to the gastric mucosa during H. pylori infection have been directly implicated in the modulation of host defense against the bacterium and gastric inflammation. Heme oxygenase-1 (HO-1) is an inducible enzyme that exhibits anti-inflammatory functions. Our aim was to analyze the induction and role of HO-1 in macrophages during H. pylori infection. We now show that phosphorylation of the H. pylori virulence factor cytotoxin-associated gene A (CagA) in macrophages results in expression of hmox-1, the gene encoding HO-1, through p38/NF (erythroid-derived 2)-like 2 signaling. Blocking phagocytosis prevented CagA phosphorylation and HO-1 induction. The expression of HO-1 was also increased in gastric mononuclear cells of human patients and macrophages of mice infected with cagA(+) H. pylori strains. Genetic ablation of hmox-1 in H. pylori-infected mice increased histologic gastritis, which was associated with enhanced M1/Th1/Th17 responses, decreased regulatory macrophage (Mreg) response, and reduced H. pylori colonization. Gastric macrophages of H. pylori-infected mice and macrophages infected in vitro with this bacterium showed an M1/Mreg mixed polarization type; deletion of hmox-1 or inhibition of HO-1 in macrophages caused an increased M1 and a decrease of Mreg phenotype. These data highlight a mechanism by which H. pylori impairs the immune response and favors its own survival via activation of macrophage HO-1.
Subject(s)
Antigens, Bacterial/immunology , Bacterial Proteins/immunology , Helicobacter Infections/immunology , Helicobacter pylori/immunology , Heme Oxygenase-1/immunology , Macrophages/immunology , Membrane Proteins/immunology , Animals , Antigens, Bacterial/genetics , Bacterial Proteins/genetics , Cell Line , Enzyme Inhibitors/pharmacology , Gastric Mucosa/cytology , Gastric Mucosa/immunology , Gastric Mucosa/microbiology , Gastritis/immunology , Gastritis/microbiology , Helicobacter Infections/microbiology , Helicobacter pylori/pathogenicity , Heme Oxygenase-1/antagonists & inhibitors , Heme Oxygenase-1/biosynthesis , Heme Oxygenase-1/genetics , Humans , Imidazoles/pharmacology , Inflammation/immunology , Interleukin-10/biosynthesis , MAP Kinase Signaling System/immunology , Macrophages/enzymology , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/biosynthesis , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-E2-Related Factor 2/immunology , Nitric Oxide Synthase Type II/biosynthesis , Phagocytosis/immunology , Phosphorylation/immunology , Pyridines/pharmacology , Signal Transduction/immunology , Stomach/microbiology , Stomach/pathology , Th1 Cells/immunology , Th17 Cells/immunology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/immunologyABSTRACT
BACKGROUND & AIMS: The gastric cancer-causing pathogen Helicobacter pylori up-regulates spermine oxidase (SMOX) in gastric epithelial cells, causing oxidative stress-induced apoptosis and DNA damage. A subpopulation of SMOX(high) cells are resistant to apoptosis, despite their high levels of DNA damage. Because epidermal growth factor receptor (EGFR) activation can regulate apoptosis, we determined its role in SMOX-mediated effects. METHODS: SMOX, apoptosis, and DNA damage were measured in gastric epithelial cells from H. pylori-infected Egfr(wa5) mice (which have attenuated EGFR activity), Egfr wild-type mice, or in infected cells incubated with EGFR inhibitors or deficient in EGFR. A phosphoproteomic analysis was performed. Two independent tissue microarrays containing each stage of disease, from gastritis to carcinoma, and gastric biopsy specimens from Colombian and Honduran cohorts were analyzed by immunohistochemistry. RESULTS: SMOX expression and DNA damage were decreased, and apoptosis increased in H. pylori-infected Egfr(wa5) mice. H. pylori-infected cells with deletion or inhibition of EGFR had reduced levels of SMOX, DNA damage, and DNA damage(high) apoptosis(low) cells. Phosphoproteomic analysis showed increased EGFR and erythroblastic leukemia-associated viral oncogene B (ERBB)2 signaling. Immunoblot analysis showed the presence of a phosphorylated (p)EGFR-ERBB2 heterodimer and pERBB2; knockdown of ErbB2 facilitated apoptosis of DNA damage(high) apoptosis(low) cells. SMOX was increased in all stages of gastric disease, peaking in tissues with intestinal metaplasia, whereas pEGFR, pEGFR-ERBB2, and pERBB2 were increased predominantly in tissues showing gastritis or atrophic gastritis. Principal component analysis separated gastritis tissues from patients with cancer vs those without cancer. pEGFR, pEGFR-ERBB2, pERBB2, and SMOX were increased in gastric samples from patients whose disease progressed to intestinal metaplasia or dysplasia, compared with patients whose disease did not progress. CONCLUSIONS: In an analysis of gastric tissues from mice and patients, we identified a molecular signature (based on levels of pEGFR, pERBB2, and SMOX) for the initiation of gastric carcinogenesis.
Subject(s)
DNA Damage , Epithelial Cells/enzymology , ErbB Receptors/metabolism , Gastric Mucosa/enzymology , Helicobacter Infections/enzymology , Helicobacter pylori/metabolism , Receptor, ErbB-2/metabolism , Animals , Apoptosis , Cell Line , Cell Survival , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Coculture Techniques , Colombia , Disease Progression , Enzyme Activation , Epithelial Cells/microbiology , Epithelial Cells/pathology , ErbB Receptors/deficiency , ErbB Receptors/genetics , Gastric Mucosa/microbiology , Gastric Mucosa/pathology , Gastritis/enzymology , Gastritis/microbiology , Gastritis/pathology , Helicobacter Infections/genetics , Helicobacter Infections/microbiology , Helicobacter Infections/pathology , Helicobacter pylori/pathogenicity , Honduras , Humans , Metaplasia , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Phosphorylation , Precancerous Conditions/enzymology , Precancerous Conditions/microbiology , Precancerous Conditions/pathology , Principal Component Analysis , Protein Multimerization , Receptor, ErbB-2/genetics , Signal Transduction , Stomach Neoplasms/enzymology , Stomach Neoplasms/microbiology , Stomach Neoplasms/pathology , Tennessee , Polyamine OxidaseABSTRACT
Contribution over time of human papillomavirus (HPV) types in human cancers has been poorly documented. Such data is fundamental to measure current HPV vaccines impact in the years to come. We estimated the HPV type-specific distribution in a large international series of invasive cervical cancer (ICC) over 70 years prior to vaccination. Paraffin embedded ICC cases diagnosed between 1940 and 2007 were retrieved from eleven countries in Central-South America, Asia and Europe. Included countries reported to have low-medium cervical cancer screening uptake. Information on age at and year of diagnosis was collected from medical records. After histological confirmation, HPV DNA detection was performed by SPF-10/DEIA/LiPA25 (version1). Logistic regression models were used for estimating the adjusted relative contributions (RC) of HPV16 and of HPV18 over time. Among 4,771 HPV DNA positive ICC cases, HPV16 and HPV18 were the two most common HPVs in all the decades with no statistically significant variations of their adjusted-RC from 1940-59 to 2000-07 (HPV16-from 61.5 to 62.1%, and HPV18-from 6.9 to 7.2%). As well, the RC of other HPV types did not varied over time. In the stratified analysis by histology, HPV16 adjusted-RC significantly increased across decades in adenocarcinomas. Regarding age, cases associated to either HPV16, 18 or 45 were younger than those with other HPV types in all the evaluated decades. The observed stability on the HPV type distribution predicts a high and stable impact of HPV vaccination in reducing the cervical cancer burden in future vaccinated generations.
Subject(s)
Human papillomavirus 16/genetics , Human papillomavirus 18/genetics , Neoplasm Invasiveness/genetics , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/pathology , Adult , Aged , Asia , Central America , DNA, Viral/genetics , DNA, Viral/isolation & purification , Early Detection of Cancer , Europe , Female , Human papillomavirus 16/classification , Human papillomavirus 16/pathogenicity , Human papillomavirus 18/classification , Human papillomavirus 18/pathogenicity , Humans , Logistic Models , Middle Aged , Neoplasm Invasiveness/pathology , Paraffin Embedding , Retrospective Studies , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/virologyABSTRACT
OBJECTIVE: To describe the incidence, mortality, time trends and prognostic factors for cervical cancer in Cali, Colombia, and to review the molecular epidemiological evidence showing that HPV is the major and necessary cause of cervical cancer and the implications of this discovery for primary and secondary prevention. MATERIALS AND METHODS: Incidence rates of cervical cancer during a 45-year period (1962-2007) were estimated based on the population-based cancer registry of Cali and the mortality statistics from the Municipal Health Secretariat of Cali. Prognostic factors were estimated based on relative survival. Review of the molecular epidemiological evidence linking HPV to cervical cancer was focused on the studies carried out in Cali and in other countries. RESULTS: Incidence rates of squamous cell carcinoma (SCC) declined from 120.4 per 100 000 in 1962-1966 to 25.7 in 2003-2007 while those of adenocarcinoma increased from 4.2 to 5.8. Mortality rates for cervical cancer declined from 18.5 in 1984-1988 to 7.0 per 100 000 in 2009-2011. Survival was lower in women over 65 years of age and in clinical stages 3-4. Review of the molecular epidemiological evidence showed that certain types of HPV are the central and necessary cause of cervical cancer. CONCLUSIONS: A decline in the incidence and mortality of SCC and an increase in the incidence of adenocarcinoma during a 45-year period was documented in Cali, Colombia.
Subject(s)
Uterine Cervical Neoplasms/epidemiology , Adenocarcinoma/epidemiology , Adenocarcinoma/virology , Adult , Age Distribution , Aged , Carcinoma, Squamous Cell/epidemiology , Carcinoma, Squamous Cell/virology , Case-Control Studies , Colombia/epidemiology , Female , Humans , Incidence , Middle Aged , Morbidity/trends , Mortality/trends , Papillomaviridae/pathogenicity , Papillomavirus Infections/epidemiology , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines , Registries , Uterine Cervical Neoplasms/prevention & control , Uterine Cervical Neoplasms/virology , Young AdultABSTRACT
OBJECTIVE: To describe the behavior of breast cancer (BC)during the 1962-2012 period from information provided by the Cali Cancer Registry and the Municipal Health Secretariat of Cali. MATERIALS AND METHODS: The incidence trend (1962-2007) and mortality trend (1984-2012) for breast cancer was studied and relative survival (RS)(1995-2004) was estimated. Age-standardized incidence and mortality rates to the world population (ASIR(w)/ASMR(w)) were expressed per 100000 persons-year. Their temporal trend was examined with the annual percent of change (APC), and the Cox model was used to analyze the variables that influenced the survival of women with breast cancer. RESULTS: The risk of breast cancer significantly increased in Cali through the 1962-2007 period, with an APC =1.7(95%CI:1.4-2.0). The ASIR(w) of BC increased from 27.1 in 1962 to 48.0 in 2007 and currently there are more than 500 cases reported annually. The mortality for BC has remained stable since 1984; in the 2009-2012 period, the ASMR(w) was 14.2. The 5-year RS was 69% (95%CI:66-71) from 2000-2004 and 62% (95%CI:59-65) from 1995-1999. The risk of death (HR) from BC was greater in persons from lower socioeconomic strata (SES) than from higher SES, HR=1.9(95%CI:1.3-2.9) and in those older than 70 years vs. <50, HR=1.6(95%CI:1.1-2.2). CONCLUSION: Mortality remained stable while incidence increased and survival improved, which may be associated with better detection and advances in treatment.
Subject(s)
Breast Neoplasms/epidemiology , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Colombia/epidemiology , Female , Fertility , Humans , Incidence , Middle Aged , Morbidity/trends , Mortality/trends , Obesity/epidemiology , Registries , Retrospective Studies , Risk Factors , Socioeconomic Factors , Survival Analysis , Young AdultABSTRACT
OBJECTIVE: To study the colorectal cancer (CRC) behavior in Cali, Colombia, during the 1963-2012 period using data from the Population-based Cancer Registry of Cali and the Municipal Health Secretariat of Cali. MATERIALS AND METHODS: An ecological time series analysis to study the CRC incidence (1962-2007) and mortality (1984-2012) rate trends; and a survival analysis of CRC cases registered in Cali between 1995 and 2004 were conducted. The age-standardized temporal trend of incidence (I-ASR) and mortality (M-ASR) rates were studied using an annual percent change (APC). The 5-year relative survival was estimated and a multivariate analysis was performed using the Cox proportional hazard regression model. RESULTS: During the 1962-2007 period, CRC TTIR increased in men and women living in Cali [APC= 2.6 (95% CI 2.2-3.0) and APC= 2.2% (95% CI 1.8-2.7), respectively]. In the 1984-2012 period, the TTMR remained stable in women but increased in men in all age groups [APC= 1.8 (95% CI 0.8-2.8)]. The 5-year relative survival was independent of sex and increased from 29.7% in 1995-1999 to 39.8% in 2000-2004. The risk of dying from CRC was higher in people of lower socio-economic status (SES) vs higher SES [HR= 2.1 (95% CI: 1.7-2.6)], among people older than 70 years of age vs younger than 50 years [HR= 2.4 (95% CI: 1.9-2.9)], and for the 1995-1999 period vs 2000-2004 period [HR= 1.5 (95% CI 1.3-1.7)]. CONCLUSION: CRC is beginning to take a prominent place among the most important cancers in Cali, Colombia.
Subject(s)
Colorectal Neoplasms/epidemiology , Adult , Aged , Aged, 80 and over , Colombia/epidemiology , Female , Humans , Incidence , Male , Middle Aged , Morbidity/trends , Mortality/trends , Proportional Hazards Models , Registries , Socioeconomic Factors , Survival AnalysisABSTRACT
OBJECTIVE: To describe the time trends of the incidence and mortality rates of oral cancer (OC) in Cali, Colombia between 1962-2007. MATERIALS AND METHODS: Age-standardized (Segi's world population) incidence (ASIR) and mortality (ASMR) rates for oral cancer were estimated using data from the Population-based Cancer Registry of Cali, Colombia and from the database of the Municipal Secretary of Public Health (MSPH) respectively. Annual percentage change (APC) was used to measure the changes in rates over time. RESULTS: 1637 new cases of oral cancer were registered in the CPCR and the mean age upon diagnosis was 60 years. The ASIR decreased from 1962-2007 in men APC= 1.3 (IC95%:-2.0; -0.6) and women APC= -1.0 (IC95%: -1.7; -0.4).The ASMR decreased from 1984-2001 only in men, APC=2.8 (IC95%: -4.1; -1.5). CONCLUSIONS: There was a significant decrease in the incidence and mortality rates for OC in Cali, Colombia. The type of tumor associated to these changes was the squamous cell carcinoma.
Subject(s)
Mouth Neoplasms/epidemiology , Adult , Aged , Colombia/epidemiology , Female , Humans , Incidence , Male , Middle Aged , Morbidity/trends , Mortality/trends , Pharyngeal Neoplasms/epidemiology , Registries , Survival AnalysisABSTRACT
OBJECTIVE: To analyze the trend in prostate cancer survival, incidence and mortality rates in Cali, Colombia from 1962 to 2011. MATERIALS AND METHODS: Based on the Cancer Registry of Cali, Colombia and the mortality registry of the City's Public Health Secretary, incidence, mortality age-standardized rates and relative survival were calculated during 1962-2011. RESULTS: Prostate cancer incidence rates increased sharply between 1986 and 2002 (APC: 6.21%) and then leveled off. Mortality diminished in 1997 in men older than 70 years-old while in men aged 50-69 years declined since 1981. The 5-year-relative-survival was 69.8% (CI95% 67.5-72.0) and it was significantly associated with age, quinquennial period of diagnosis and socioeconomic strata. CONCLUSION: The increase in incidence rates of prostate cancer in time coincides with the implementation of the PSA in Cali. There is evidence of improvement in prostate cancer survival, and decreased prostate cancer mortality.