ABSTRACT
BACKGROUND: Protein phosphatase 2A (PP2A) is a tumour suppressor frequently inactivated in human cancer and its tyrosine-307 phosphorylation has been reported as a molecular inhibitory mechanism. METHODS: Expression of phosphorylated PP2A (p-PP2A) was evaluated in 250 metastatic colorectal cancer (CRC) patients. Chi-square, Kaplan-Meier and Cox analyses were used to determine correlations with clinical and molecular parameters and impact on clinical outcomes. RESULTS: High p-PP2A levels were found in 17.2% cases and were associated with ECOG performance status (P=0.001) and presence of synchronous metastasis at diagnosis (P=0.035). This subgroup showed substantially worse overall survival (OS) (median OS, 6.0 vs 26.2 months, P<0.001) and progression-free survival (PFS) (median PFS, 3.8 vs 13.3 months, P<0.001). The prognostic impact of p-PP2A was particularly evident in patients aged <70 years (P<0.001). Multivariate analysis revealed that p-PP2A retained its prognostic impact for OS (hazard ratio 2.7; 95% confidence interval, 1.8-4.1; P<0.001) and PFS (hazard ratio 3.0; 95% confidence interval, 1.8-5.0; P<0.001). CONCLUSIONS: Phosphorylated PP2A is an alteration that determines poor outcome in metastatic CRC and represents a novel potential therapeutic target in this disease, thus enabling to define a subgroup of patients who could benefit from future treatments based on PP2A activators.
Subject(s)
Biomarkers, Tumor/metabolism , Colorectal Neoplasms/enzymology , Liver Neoplasms/enzymology , Phosphoprotein Phosphatases/metabolism , Aged , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Humans , Kaplan-Meier Estimate , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Male , Multivariate Analysis , Phosphoproteins/metabolism , Phosphorylation , Proportional Hazards Models , Protein Phosphatase 2C , Protein Processing, Post-TranslationalABSTRACT
BACKGROUND: Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients. METHODS: Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out. RESULTS: The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10-300); for KDR 258.5 (range, 150-300); for pKDR-Y1775 10.8 (range, 0-65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10-126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49-19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25-21.05). CONCLUSIONS: Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Renal Cell/blood supply , Indoles/therapeutic use , Kidney Neoplasms/blood supply , Neovascularization, Pathologic/metabolism , Pyrroles/therapeutic use , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/pharmacology , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/secondary , Cohort Studies , Disease-Free Survival , Female , Humans , Indoles/pharmacology , Kaplan-Meier Estimate , Kidney Neoplasms/drug therapy , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Male , Microvessels/pathology , Middle Aged , Multivariate Analysis , Neovascularization, Pathologic/drug therapy , Phosphoproteins/metabolism , Proportional Hazards Models , Pyrroles/pharmacology , Sunitinib , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
A 4-month-old infant had two 3 cm x 4 cm hemangiomatous lesions on the scalp and back, present since birth, which contained peculiar white-yellowish small nodules. Histologically the lesions proved to have a hemangiomatous (capillary-type) component together with small keratin-containing epidermal cysts (milia-like) which progressively extruded their contents. The lesions also contained embryonic-like hair structures. The hemangiomas resolved spontaneously. We were unable to find any reference in the literature describing this peculiar combination of features.
Subject(s)
Hemangioma/congenital , Infant, Premature, Diseases/pathology , Scalp , Skin Neoplasms/congenital , Back , Biopsy , Hemangioma/pathology , Humans , Infant, Newborn , Infant, Premature , Male , Scalp/pathology , Skin/pathology , Skin Neoplasms/pathologyABSTRACT
Se presenta el caso de un paciente de 76 años de edad, con lesiones cutáneas ocasionadas por Fusarium solani, agente oportunista que escasamente causa infección cutánea, no que se registran antecedentes en nuestra literatura. Se destacan las características remarcables de su acción patógena y la buena respuesta terapéutica con la utilización de 200 mg diarios de ketoconazol (AU)
Subject(s)
Aged , Humans , Male , Dermatomycoses/etiology , Fusarium/pathogenicity , Ketoconazole/therapeutic use , Dermatomycoses/drug therapyABSTRACT
Se presenta el caso de un paciente de 76 años de edad, con lesiones cutáneas ocasionadas por Fusarium solani, agente oportunista que escasamente causa infección cutánea, no que se registran antecedentes en nuestra literatura. Se destacan las características remarcables de su acción patógena y la buena respuesta terapéutica con la utilización de 200 mg diarios de ketoconazol