Atherosclerotic lesions are present even in very young individuals and therefore, risk stratification for cardiovascular (CV) disease should be implemented in childhood to promote early prevention ...strategies. In this review we critically appraise clinical, biochemical and genetic biomarkers available for pediatric clinical practice, which might be integrated to build effective algorithms to identify children at risk of future CV events. The first critical issue is to characterize in children aged 2-5 years, those CV risk factors/clinical conditions associated with dramatically accelerated atherosclerosis. Presence of clinical conditions such as obesity, diabetes mellitus, Kawasaki disease, etc., or positive family history for premature CV disease should be evaluated. Subsequently, a complete lipid profile and Lipoprotein(a) determination are recommended for children with increased baseline CV risk. Individuals with altered lipid profile could then undergo genetic testing for monogenic dyslipidemias to identify children with high CV genetic risk, who will be directed to appropriate therapeutic options. In perspective, calculation of a polygenic risk score, based on the analysis of several common single-nucleotide polymorphisms, could be integrated for better risk assessment. We here emphasize the importance of a "holistic" strategy integrating biochemical, anamnestic and genetic data to stratify CV risk in early childhood.
The purpose of this study was to provide an updated worldwide report on the methods, efficacy, and safety of catheter ablation of atrial fibrillation (AF).
A questionnaire with 46 questions was sent ...to 521 centers from 24 countries in 4 continents. Complete interviews were collected from 182 centers, of which 85 reported to have performed 20,825 catheter ablation procedures on 16,309 patients with AF between 2003 and 2006. The median number of procedures per center was 245 (range, 2 to 2715). All centers included paroxysmal AF, 85.9% also included persistent and 47.1% also included long-lasting AF. Carto-guided left atrial circumferential ablation (48.2% of patients) and Lasso-guided ostial electric disconnection (27.4%) were the most commonly used techniques. Efficacy data were analyzed with centers representing the unit of analysis. Of 16,309 patients with full disclosure of outcome data, 10 488 (median, 70.0%; interquartile range, 57.7% to 75.4%) became asymptomatic without antiarrhythmic drugs and another 2047 (10.0%; 0.5% to 17.1%) became asymptomatic in the presence of previously ineffective antiarrhythmic drugs over 18 (range, 3 to 24) months of follow-up. Success rates free of antiarrhythmic drugs and overall success rates were significantly larger in 9590 patients with paroxysmal AF (74.9% and 83.2%) than in 2800 patients with persistent AF (64.8% and 75.0%) and 1108 patients with long-lasting AF (63.1% and 72.3%) (P<0.0001). Major complications were reported in 741 patients (4.5%).
When analyzed in a large number of electrophysiology laboratories worldwide, catheter ablation of AF shows to be effective in approximately 80% of patients after 1.3 procedures per patient, with approximately 70% of them not requiring further antiarrhythmic drugs during intermediate follow-up.
Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as ...IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications.
From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features.
Besides the high mutation frequency of CDH1 in 65% of tumors, alterations in one of the three key genes of the phosphatidylinositol 3-kinase pathway, PIK3CA, PTEN, and AKT1, were present in more than one-half of the cases. HER2 and HER3 were mutated in 5.1% and 3.6% of the tumors, with most of these mutations having a proven role in activating the human epidermal growth factor receptor/ERBB pathway. Mutations in FOXA1 and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than in IDBC. The histologic diversity of ILBC was associated with specific alterations, such as enrichment for HER2 mutations in the mixed, nonclassic, and ESR1 gains in the solid subtype. Survival analyses revealed that chromosome 1q and 11p gains showed independent prognostic value in ILBC and that HER2 and AKT1 mutations were associated with increased risk of early relapse.
This study demonstrates that we can now begin to individualize the treatment of ILBC, with HER2, HER3, and AKT1 mutations representing high-prevalence therapeutic targets and FOXA1 mutations and ESR1 gains deserving urgent dedicated clinical investigation, especially in the context of endocrine treatment.
The problem of late recurrence in breast cancer has recently gained attention and was also addressed in an international workshop held in Toronto (ON, Canada), in which several aspects of the ...question were examined. This Commentary offers a few considerations, which may be useful for the ongoing investigations. A few premises are discussed: (a) clinical recurrences, especially the late ones, imply periods of tumor dormancy; (b) a structured pattern of distant metastases appearance is detectable in both early and late follow-up times; (c) the current general paradigm underlying neoplastic treatments, i.e., that killing all cancer cells is the only way to control the disease, which is strictly sprouting from the somatic mutation theory, should be re-considered. Finally, a few research approaches are suggested.
We assessed the inter-method bias of total (tPSA) and free (fPSA) prostate-specific antigen (PSA) immunoassays to establish if tPSA-based risk thresholds for advanced prostate cancer (PCa), obtained ...from one method (Roche) can be converted into the corresponding concentrations assayed by other methods. Then we evaluated the impact of the bias of tPSA and fPSA on the estimation of the %f/tPSA ratio and performed a re-calibration of the proposed thresholds for the %f/tPSA ratio according to the assay used.
tPSA and fPSA were measured in 135 and 137 serum samples, respectively by Abbott Alinity i, Beckman Access Dxl, Roche Cobas e801, and Siemens Atellica IM analytical platforms. Scatterplots, Bland-Altman diagrams, Passing-Bablok (PB) were used to inspect and estimate the systematic and proportional bias between the methods. The linear equations with confidence intervals of the parameter estimates were used to transform the tPSA risk thresholds for advanced PCa into the corresponding concentrations measurable by the other analytical methods. To construct a correction coefficient for converting the %f/tPSA ratio from one method to the other, PB and non-parametric boostrapping were used.
The inter-method bias is not constant but strictly linear allowing the conversion of PSA results obtained from Roche into the other assays, which underestimate tPSA vs. Roche. Siemens and Abbott vs. Roche and Beckman assays, being characterized by a positive and a negative proportional bias for tPSA and fPSA measurements, tend to overestimate the %f/tPSA ratio.
There is a consistent risk to miss advanced PCa, if appropriate conversion factors are not applied.
Trop-2 is a calcium signal transducer that drives tumor growth. Anti-Trop-2 antibodies with selective reactivity versus Trop-2 maturation stages allowed to identify two different pools of Trop-2, one ...localized in the cell membrane and one in the cytoplasm. Of note, membrane-localized/functional Trop-2 was found to be differentially associated with determinants of tumor aggressiveness and distinct breast cancer subgroups. These findings candidated Trop-2 states to having an impact on cancer progression. We tested this model in breast cancer. A large, consecutive human breast cancer case series (702 cases; 8 years median follow-up) was analyzed by immunohistochemistry with anti-Trop-2 antibodies with selective reactivity for cytoplasmic-retained versus functional, membrane-associated Trop-2. We show that membrane localization of Trop-2 is an unfavorable prognostic factor for overall survival (1+ versus 0 for all deaths: hazard ratio, 1.63; P = 0.04), whereas intracellular Trop-2 has a favorable impact on prognosis, with an adjusted hazard ratio for all deaths of 0.48 (high versus low; P = 0.003). A corresponding impact of intracellular Trop-2 was found on disease relapse (high versus low: hazard ratio, 0.51; P = 0.004). Altogether, we demonstrate that the Trop-2 activation states are critical determinants of tumor progression and are powerful indicators of breast cancer patients survival.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as analgesics in primary cancer surgery. Retrospective studies suggest that NSAIDs could reduce breast cancer ...recurrences. Because NSAIDs also act on biological mechanisms present in patients with increased adiposity, we aimed at assessing whether the intra-operative administration of ketorolac or diclofenac would be associated with a reduction of recurrence in patients with elevated body mass index (BMI).
We considered two institutional retrospective series of 827 and 1007 patients evaluating the administration of ketorolac (n = 529 with, n = 298 without) or diclofenac (n = 787 with, n = 220 without). The BMI subgroups were defined as less than 25 kg/m2 (lean) and 25 or more kg/m2 (overweight and obese). Cumulative incidence estimation of distant metastases as well as Fine-Gray and Dixon-Simon models was used. These analyses were adjusted for clinico-pathological variables. All statistical tests were two-sided.
The administration of ketorolac was statistically significantly associated with decreased incidence of distant recurrences (adjusted hazard ratio aHR= 0.59, 95% confidence interval CI = 0.37 to 0.96, P = .03). In particular, the association was evident in the high-body mass index (BMI) group of patients (aHR = 0.55, 95% CI = 0.31 to 0.96, P = .04). The administration of diclofenac was not statistically significantly associated with decreased incidence of distant recurrences, either in the global population or in the BMI subgroups.
These results show that the intra-operative administration of ketorolac, but not diclofenac, is statistically significantly associated with a reduction of distant recurrences in patients with increased BMI. Altogether, this study points to a potentially important repositioning of ketorolac in the intra-operative treatment of patients with elevated BMI that, if prospectively validated, might be as impactful as and cheaper than adjuvant systemic anticancer therapies.
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