Piroxicam and intracavitary platinum-based chemotherapy for the treatment of advanced mesothelioma in pets: preliminary observations

Malignant Mesothelioma is an uncommon and very aggressive tumor that accounts for 1% of all the deaths secondary to malignancy in humans. Interestingly, this neoplasm has been occasionally described in companion animals as well. Aim of this study was the preclinical evaluation of the combination of piroxicam with platinum-based intracavitary chemotherapy in pets. Three companion animals have been treated in a three years period with this combination. Diagnosis was obtained by ultrasonographic exam of the body cavities that evidenced thickening of the mesothelium. A surgical biopsy further substantiated the diagnosis. After drainage of the malignant effusion from the affected cavity, the patients received four cycles of intracavitary CDDP at the dose of 50 mg/m2 every three weeks if dogs or four cycles of intracavitary carboplatin at the dose of 180 mg/m2 (every 3 weeks) if cats, coupled with daily administration of piroxicam at the dose of 0.3 mg/kg. The therapy was able to arrest the effusion in all patients for variable remission times: one dog is still in remission after 3 years, one dog died of progressive disease after 8 months and one cat died due to progressive neoplastic growth after six months, when the patient developed a mesothelial cuirass. The combination showed remarkable efficacy at controlling the malignant effusion secondary to MM in our patients and warrants further investigations

Apoptosis Induced by Piroxicam plus Cisplatin Combined Treatment Is Triggered by p21 in Mesothelioma

BACKGROUND: Malignant mesothelioma (MM) is a rare, highly aggressive tumor, associated to asbestos exposure. To date no chemotherapy regimen for MM has proven to be definitively curative, and new therapies for MM treatment need to be developed. We have previously shown in vivo that piroxicam/cisplatin combined treatment in MM, specifically acts on cell cycle regulation triggering apoptosis, with survival increase. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed, at molecular level, the apoptotic increase caused by piroxicam/cisplatin treatment in MM cell lines. By means of genome wide analyses, we analyzed transcriptional gene deregulation both after the single piroxicam or cisplatin and the combined treatment. Here we show that apoptotic increase following combined treatment is mediated by p21, since apoptotic increase in piroxicam/cisplatin combined treatment is abolished upon p21 silencing. CONCLUSIONS/SIGNIFICANCE: Piroxicam/cisplatin combined treatment determines an apoptosis increase in MM cells, which is dependent on the p21 expression. The results provided suggest that piroxicam/cisplatin combination might be tested in clinical settings in tumor specimens that express p21

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Prognostic value of a tissue doppler index of systodiastolic function in patients with asymptomatic heart failure

Introduction: Doppler echocardiography with early diastolic transmitral velocity (E)/early mitral annular diastolic velocity (E') ratio has been proposed as the best predictor for evaluating left ventricle (LV) filling pressure. A dimensionless index E/(E' x S') ratio (S' = systolic mitral annulus velocity) resulted in readily, reproducible, and reliable predictor of LV filling pressure. We assessed the prognostic impact of E/(E' x S') in patients with asymptomatic heart failure (HF). Materials and Methods: We calculated E/(E' x S') in 337 patients (179 male, 53%; age 54.7 +/- 13.7 years) using the average of septal and lateral mitral annular velocities. We considered a composite endpoint as follows: all-cause death, acute myocardial infarction, stroke, and HF exacerbation. Results: Baseline ejection fraction resulted 60.2 +/- 11.8%; E/(E' x S') was 1.45 +/- 0.8, with S' 7.4 +/- 2.4 cm/s and E/E' 9.5 +/- 5.4. After a 22-month median follow-up, there were 42 events: 5 deaths (12%), 3 acute myocardial infarctions (7%), 1 stroke (2%), and 33 HF hospitalizations (79%). In patients reaching the composite endpoint, E/(E' x S') resulted 2.07 +/- 1.1 versus 1.3 +/- 0.7 in event-free population (P < 0.001). In a Cox-regression analysis, adjusted for confounding clinical factors and conventional echo parameters, E/(E' x S') (P < 0.001), age (P < 0.001), and male gender (P = 0.03) resulted independent predictors of the composite endpoint. Conclusions: E/(E' x S') was an independent predictor for the future cardiac events in asymptomatic HF

Prevalence and Prognostic Impact of Metabolic Syndrome in Asymptomatic (Stage A and B Heart Failure) Patients.

BACKGROUND: Metabolic syndrome (MS) has an increased risk of cardiovascular events. Its relationship with asymptomatic left ventricular dysfunction (LVD) and prognosis has not been completely clarified. OBJECTIVES: To determine, in asymptomatic patients (Stage A, B heart failure, HF), whether MS is associated with left ventricular systolic dysfunction (LVSD) and left ventricular diastolic dysfunction and its predictive role for cardiovascular events. MATERIALS AND METHODS: We included 1920 nonconsecutive patients without symptoms of HF, with at least one cardiovascular risk factor, undergoing echocardiographic evaluation as preventive screening. We subdivided the study population according to the presence (Group 1) or absence (Group 2) of MS. The primary endpoint was a composite of cardiac death, myocardial infarction, coronary artery revascularization, stroke, and acute pulmonary edema. Secondary endpoints were hospitalization for HF and HF progression. RESULTS: Overall prevalence of MS was 13.4% (n = 262, Group 1). In Group 2 (n = 1658), the prevalence of LVSD was 12.2%, while the prevalence of LVSD was 21.8% in Group 1 (relative risk [RR] 2.01; 95% confidence interval 1.4-2.8; P < 0.001). Adjusting for age and gender, MS resulted an independent predictor of LVSD (P < 0.001). After a median follow-up of 22 months, Group 1 patients had a significantly higher incidence of primary events (P < 0.001), including cardiac death (P = 0.04), and secondary events (P < 0.001). Both primary and secondary endpoints were more frequent in patients with LVSD (P < 0.001). In multivariate survival analysis, MS (but not its specific components) and LVSD were independently associated both with primary and secondary events (P ≤ 0.003). Incremental chi-square analysis showed the presence of combined LVD added to MS, and age raised significantly the predictive value of the model for the primary endpoint (Incremental chi-square = 8.6). CONCLUSIONS: In stage A and B HF subjects, the coexistence of MS with functional or structural cardiac abnormalities, detected by echocardiography, showed a significant incremental value in predicting clinical cardiovascular events. PMID: 26866978 DOI: 10.1089/met.2015.014