Maria José Bento

Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients.

The clinical significance of ERBB2 amplification/overexpression in gastric cancer remains unclear. In this study, we evaluated the ERBB2 status in 463 gastric carcinomas using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), and compared the findings with histopathological characteristics and with disease-specific survival. ERBB2 overexpression (2+ and 3+) and amplification (ratio ERBB2/CEP17⩾2) were found in 43 (9.3%) and 38 (8.2%) gastric carcinomas, respectively. Perfect IHC/FISH correlation was found for the 19 cases scored as 0 (all negative by FISH), and also for the 25 cases scored as 3+ (all positive by FISH). One out of six carcinomas scored as 1+ and 12 out of 18 carcinomas scored as 2+ were positive by FISH. ERBB2 amplification was associated with gastric carcinomas of intestinal type (P=0.007) and with an expansive growth pattern (P=0.021). ERBB2 amplification was detected in both histological components of two mixed carcinomas, indicating a common clonal origin. A statistically significant association was found between ERBB2 amplification and worse survival in patients with expansive gastric carcinomas (P=0.011). We conclude that ERBB2 status may have clinical significance in subsets of gastric cancer patients, and that further studies are warranted to evaluate whether patients whose gastric carcinomas present ERBB2 amplification/overexpression may benefit from therapy targeting this surface receptor.

Ki-67 index enhances the prognostic accuracy of the urothelial superficial bladder carcinoma risk group classification.

Approximately 80% of bladder tumors are urothelial superficial papillary carcinomas (USPC). Despite a generally good prognosis, these tumors have a strong propensity to recur and about 1/3 of them compared to disease progression. Histological assessment of these superficial tumors is not sufficiently discriminator in predicting prognosis; therefore, we decided to evaluate the prognostic significance of p53 and Ki‐67 immunoexpression in low‐grade (GI‐II) USPC in order to predict the potential outcome of these tumors. P53 and Ki‐67 immunoexpression were studied in function of recurrence‐free and progression‐free survival in 159 primary superficial bladder tumors. A prognostic risk model based on grade, stage and multifocality was also evaluated. P53 accumulation was significantly related to tumor progression (p=0.006). High Ki‐67 index (≥18%) and multifocality were significantly related to recurrence (both p=0.0001) and progression‐free survival (both p=0.0001) and were independent prognostic factors in the multivariate analysis. The prognostic risk model based on grade, stage and multifocality was not an efficient discriminator of outcome. Adding the Ki‐67 index into the risk model, single pTa/T1‐GI Ki‐67 positive tumors, usually classified as low risk, were reclassified as of intermediate risk. After this reclassification, the risk group model identified a subgroup of pTa/T1‐G1 with a high risk of recurrence and progression. Ki‐67 index is a reliable prognostic marker in urothelial superficial bladder carcinoma and, when included into a risk profile classification of the low‐grade USPC, the accuracy of the prognostic discrimination is enhanced.

Grade is an independent prognostic factor for feline mammary carcinomas: A clinicopathological and survival analysis

Feline mammary carcinomas (FMC) are highly infiltrative tumours which show a strong tendency for local recurrence and metastasis. Histological type assessment of these tumours is not sufficiently discriminatory in predicting prognosis and in this study the prognostic significance of the Elston and Ellis method of histological grading was evaluated. Ninety-two feline mammary carcinomas from 84 cats were graded and 64 queens were included in a follow-up study. Grade was significantly related to tumour size (P=0.006), clinical stage (P=0.005), lymphovascular invasion (P<0.0001), mitotic index (P<0.0001), Ki67 index (P=0.001), overall survival (P=0.0001) and disease-free survival (P<0.0001). Cox regression analysis identified grade as an independent prognostic factor. Multivariable analysis also showed regional lymph node metastasis and lymphovascular emboli as independent prognostic factors related to overall survival and to disease-free-survival, respectively. The study demonstrated that histological grading can be used as a prognostic factor to evaluate the biological behaviour of FMC.

BRCA1 and BRCA2 germline mutational spectrum and evidence for genetic anticipation in Portuguese breast/ovarian cancer families

We present the first characterisation of the mutational spectrum of the entire coding sequences and exon–intron boundaries of the BRCA1 and BRCA2 genes as well as large BRCA1 rearrangements in Portuguese families with inherited predisposition to breast/ovarian cancer. Of the 100 probands studied, pathogenic mutations were identified in 22 (24.7%) of 89 breast and/or ovarian cancer families with more than one affected member (15 in BRCA1 and seven in BRCA2), but in none of the 11 patients without family history of cancer. One (6.7%) of the BRCA1 mutations is a large deletion involving exons 11–15. Seven pathogenic point mutations are novel: 2088C>T, 2156delinsCC, and 4255_4256delCT in BRCA1 and 4608_4609delTT, 5036delA, 5583_5584insT, and 8923C>T in BRCA2. The novel 2156delinsCC was identified in three probands from different families and probably represents a founder mutation in our population. We also found a previously reported 3450_3453del4 mutation in three unrelated patients. In addition to the 22 pathogenic mutations, we identified 19 missense mutations of uncertain pathogenic significance, three of them (5241G>C in BRCA1 and IVS6+13C>T and 3731T>C in BRCA2) previously undescribed. The percentage of cases with truncating mutations in BRCA1 and BRCA2 was higher in breast/ovarian cancer (37.0%, mostly BRCA1) and male breast cancer (40%, all BRCA2) families than in families with only female breast cancer (17.5%). Interestingly, we found evidence for genetic anticipation regarding age at diagnosis of both breast and ovarian cancer in those families presenting affected members in more than one generation. These findings should be taken into consideration while planning screening and prophylactic measures in families with inherited predisposition to breast and ovarian cancer.

Incidence rates and trends of lip, oral and oro-pharyngeal cancers in Portugal

OBJECTIVES To analyse the trends and patterns of lip, oral and oro-pharyngeal cancer incidence in Portugal between 1998 and 2007. PATIENTS AND METHODS Data on lip, oral and oro-pharyngeal cancers was collected from the databases maintained at the three main Regional Cancer Registries of Portugal (1998-2007). The data were analysed by gender, age and by site. Incidence rates were age standardized by the direct method, and joinpoint regression was used to estimate trends in incidence. RESULTS During this 10-year period, a total of 9623 cases of lip, oral and oropharynx cancers were reported, 7565 (78.6%) in males and 2058 (21.4%) in females. There was an increase in the age-standardized incidence of oral cancers by 1.96% per year for both sexes grouped together and an increase of 4.34% per year for the female group. Oro-pharyngeal cancer showed an increase incidence trend of 3.49% per year for both sexes grouped together and an increase of 3.49% per year for male group among the sites analysed. Lip cancer showed a decrease in its incidence rate. CONCLUSION In view of rising trends, it is necessary to implement policies on oral cancer control by initiating campaigns on oral cancer awareness and screening and to harness political measures on tobacco and alcohol control for the Portuguese population.

Epidermal growth factor receptor immunoexpression evaluation in malignant salivary gland tumours

OBJECTIVE The aim of this study was to determine epidermal growth factor receptor (EGFR) expression in malignant salivary gland tumours and its possible relationships with clinical and morphological findings, disease course and prognosis. PATIENTS AND METHODS The study sample comprised 88 patients diagnosed and treated for primary malignant salivary gland tumours between January 1992 and December 2002. We analysed EGFR expression using immunohistochemistry on formalin-fixed, paraffin embedded surgical specimens of all patients. Statistical analysis was used to investigate possible relationships between EGFR expression and clinical findings, histological findings, disease course and patients survival. RESULTS Of all cases, 32 (36.4%) were EGFR positive. There was a statistically significant correlation between EGFR expression and histological grade. No other variable was correlated with EGFR expression including the overall and disease-free survival. Stage classification was the only parameter in multivariate analysis that was an independent predictor of low overall and disease-free survival. CONCLUSION EGFR is not a useful indicator of prognosis in malignant salivary gland tumours. However, the EGFR expression in salivary gland cancers like adenocarcinomas, undifferentiated carcinomas, mucoepidermoid carcinomas or salivary duct carcinomas suggests that these tumours may be a candidate for therapy investigation directed at EGFR.

MiR-193b promoter methylation accurately detects prostate cancer in urine sediments and miR-34b/c or miR-129-2 promoter methylation define subsets of clinically aggressive tumors

BackgroundContemporary challenges of prostate cancer (PCa) include overdiagnosis and overtreatment, entailing the need for novel clinical tools to improve risk stratification and therapy selection. PCa diagnosis and prognostication might be perfected using epigenetic biomarkers, among which aberrant DNA methylation of microRNA promoters has not been systematically explored. Herein, we identified aberrantly methylated microRNAs promoters in PCa and assessed its diagnostic and prognostic biomarker potential.MethodsUsing HumanMethylation450 BeadChip-based analysis differentially methylated CpGs in microRNA promoters were identified. Promoter methylation of six microRNAs (miR-34b/c, miR-129-2, miR-152, miR-193b, miR-663a and miR-1258) was analyzed by qMSP in three sets (180 prostatectomies, 95 urine sediments and 74 prostate biopsies). Biomarkers’ diagnostic (validity estimates) and prognostic [disease-free (DFS) and disease-specific survival (DSS)] performance was assessed.ResultsSignificantly higher promoter methylation levels in PCa were confirmed for six candidate microRNAs. Except for miR-152, all displayed AUC values higher than 0.90, with miR-1258 and miR-193b disclosing the best performance (AUC = 0.99 and AUC = 0.96, respectively). In urine samples, miR-193b showed the best performance (91.6% sensitivity, 95.7% specificity, AUC = 0.96). Moreover, higher miR-129-2 independently predicted for shorter DSS and miR−34b/c methylation levels independently predicted for shorter DFS and DSS.ConclusionsQuantitative miR-193b, miR-129-2 and miR-34b/c promoter methylation might be clinically useful PCa biomarkers for non-invasive detection/diagnosis and prognostication, both in tissue and urine samples.

Identification of Two Novel HOXB13 Germline Mutations in Portuguese Prostate Cancer Patients

The HOXB13 germline variant G84E (rs138213197) was recently described in men of European descent, with the highest prevalence in Northern Europe. The G84E mutation has not been found in patients of African or Asian ancestry, which may carry other HOXB13 variants, indicating allelic heterogeneity depending on the population. In order to gain insight into the full scope of coding HOXB13 mutations in Portuguese prostate cancer patients, we decided to sequence the entire coding region of the HOXB13 gene in 462 early-onset or familial/hereditary cases. Additionally, we searched for somatic HOXB13 mutations in 178 prostate carcinomas to evaluate their prevalence in prostate carcinogenesis. Three different patients were found to carry in their germline DNA two novel missense variants, which were not identified in 132 control subjects. Both variants are predicted to be deleterious by different in silico tools. No somatic mutations were found. These findings further support the hypothesis that different rare HOXB13 mutations may be found in different ethnic groups. Detection of mutations predisposing to prostate cancer may require re-sequencing rather than genotyping, as appropriate to the population under investigation.

Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations

Objective Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. Design Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003–2016 were analysed. Age-standardised resection rates for overall and stage I–II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. Results A total of 153 698 records were analysed. In population-based registries in 2012–2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I–II tumours, with great international variations. During 2003–2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I–II tumours: 0.05–0.18 and 0.01–0.06 across countries) and increasing age (ORs for patients 70–79 and ≥80 versus those <60 years: 0.37–0.63 and 0.03–0.16 across countries). Patients with advanced-stage tumours (stage III–IV: 63.8%–81.2%) and at older ages (≥70 years: 52.6%–59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. Conclusion Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.

Health-related behaviours in the EpiPorto study: cancer survivors versus participants with no cancer history.

Cancer survivors are at an increased risk of a second primary cancer, partly due to unhealthy behaviours. In a cohort of adults (recruitment: 1999–2003; follow-up – linkage with population-based cancer registry: up to 2009) we compared the baseline exposure to smoking, alcohol and dietary intake and physical activity between: cancer survivors (CS) – cancer diagnosis before baseline (n=53); no cancer (NC) participants – without cancer diagnosis at baseline or during follow-up (n=2261); latent cancer (LC) participants – without cancer diagnosis at baseline but diagnosed during follow-up (n=139). Age-, sex- and education-adjusted prevalences and means were computed, as applicable. The prevalence of current smoking was nearly 20% among CS and NC (approximately four cigarettes per day) and 30% in LC (seven cigarettes per day). LC had the highest average alcohol intake (25.5 g/day) and NC the lowest (17.0 g/day). The proportion of participants reporting sports practice was higher for CS (50%) than for NC or LC (approximately 33%). CS and NC had higher fruit/vegetable consumption than LC (4.2 and 4.4 vs. 3.8 servings per day). In a composite index on health behaviours (including smoking, physical activity and alcohol and fruit/vegetable intake) the highest and lowest scores were 1.74 for NC and 1.52 for LC respectively, whereas CS scored 1.63. The exposure to each risk factor appeared comparable in CS and NC, whereas LC tended to have unhealthier behaviours. This may be partially explained by the acquisition of healthier habits by CS after diagnosis, but there still remains scope for improvement, as revealed by the low scores observed for the joint exposure to the main risk factors.