Emiliano Aroasio

Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly

Toxicity of adjuvant mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant mitotane treatment and correlate the findings with mitotane concentrations. Seventeen consecutive patients who were treated with mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma mitotane was measured by an in-house HPLC assay. All the patients reached mitotane concentrations >14 mg/l and none of them discontinued definitively mitotane for toxicity; 14 patients maintained consistently elevated mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy.

Effects of Serum Testosterone Levels After 6 Months of Androgen Deprivation Therapy on the Outcome of Patients With Prostate Cancer

BACKGROUND Controversy exists about whether testosterone serum levels at a cutoff point of < 50 ng/dL during luteinizing hormone-releasing hormone analogue (LHRHA) treatment are related to the outcome of patients with prostate cancer. We assessed the relationship between serum testosterone levels after 6 months of LHRHA therapy and disease outcome in a consecutive series of patients with prostate cancer. PATIENTS AND METHODS Serum testosterone levels were measured prospectively in a cohort of patients given LHRHA for 6 months. End points were time to progression (TTP) and overall survival (OS). RESULTS The study population was 153 patients: 54 with metastatic disease and 99 with biochemical failure. In multivariate analysis, adjustment for age, baseline serum prostatic specific antigen (PSA) levels, Gleason score, and disease stage, testosterone levels < 50 ng/dL failed to be associated with TTP and OS. A cutoff of < 20 ng/dL was associated with a nonsignificant lower risk of progression (adjusted hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.30-1.15; P = .12) and a significant lower risk of death (adjusted HR, 0.19; 95% CI, 0.04-0.76; P = .02). Only 25 patients attained serum testosterone levels < 20 ng/dL. Using a receiver operating characteristic curve (ROC), we found that a testosterone value of 30 ng/dL offered the best overall sensitivity and specificity for prediction of death. Serum testosterone levels < 30 ng/mL were associated with a significantly lower risk of death (adjusted HR, 0.45; 95% CI, 0.22-0.94; P = .034. CONCLUSIONS Serum testosterone levels lower than the currently adopted cutoff of 50 ng/dL have a prognostic role in patients with prostate cancer receiving LHRHA and are a promising surrogate parameter of LHRHA efficacy.

Tailoring dialysis and resuming low-protein diets may favor chronic dialysis discontinuation: report on three cases.

Renal function recovery (RFR), defined as the discontinuation of dialysis after 3 months of replacement therapy, is reported in about 1% of chronic dialysis patients. The role of personalized, intensive dialysis schedules and of resuming low‐protein diets has not been studied to date. This report describes three patients with RFR who were recently treated at a new dialysis unit set up to offer intensive hemodialysis. All three patients were females, aged 73, 75, and 78 years. Kidney disease included vascular‐cholesterol emboli, diabetic nephropathy and vascular and dysmetabolic disease. At time of RFR, the patients had been dialysis‐dependent from 3 months to 1 year. Dialysis was started with different schedules and was progressively discontinued with a “decremental” policy, progressively decreasing number and duration of the sessions. A moderately restricted low‐protein diet (proteins 0.6 g/kg/day) was started immediately after dialysis discontinuation. The most recent update showed that two patients are well off dialysis for 5 and 6 months; the diabetic patient died (sudden death) 3 months after dialysis discontinuation. Within the limits of small numbers, our case series may suggest a role for personalized dialysis treatments and for including low‐protein diets in the therapy, in enhancing long‐term RFR in elderly dialysis patients.

Chronic dialysis discontinuation: a systematic narrative review of the literature in the new millennium

Introduction and aims Renal function recovery (RFR), defined as the discontinuation of dialysis after 3 months of replacement therapy, is an uncommon occurrence. At a time when the “too early” start of dialysis is in discussion, a systematic review of the literature for cases in which patients recovered renal function after starting dialysis with chronic indications, including single cases and large series, may lead to attention being focused on this interesting issue. Methods The search strategy was built in Medline on Pubmed, in EMBASE and in the Cochrane Collaboration (August 2013) combining Mesh, Emtree and free terms: dialysis or hemodialysis, kidney function, renal function and recovery (publication date 2000-2013). The following tasks were performed in duplicate: titles and abstracts were manually screened, the data were extracted: title, author, objective, year, journal, period of study, multi-center, country, type of study. Results The systematic review retrieved 1 894 titles; 58 full papers were retrieved and the final selection included 24 papers: 11 case series or Registry data (4 from ANZdata) and 13 case reports. In spite of the high heterogeneity of the studies, overall they suggest that RFR occurs in about 1% of patients, without differences between PD and HD. RFR appears to be more frequent in elderly patients with renal vascular disease (up to 10% RFR in cholesterol emboli or scleroderma), but is reported in all types of primary and secondary kidney diseases. Conclusions RFR is a clinical event that should be looked for, particularly in elderly patients with vascular comorbidity.

An exploratory analysis of the association between levels of hormones implied in steroid biosynthesis and activity of abiraterone in patients with metastatic castration-resistant prostate cancer.

BACKGROUND Abiraterone acetate, approved for patients with metastatic castration-resistant prostate cancer (mCRPC), blocks androgen byosinthesis. We aimed to describe changes determined by abiraterone in hormones implied in steroid biosynthesis, exploring association between hormonal levels and drug activity. METHODS Patients with mCRPC, receiving standard abiraterone + prednisone after docetaxel failure, were studied. We determined serum levels of progesterone, 17OH-progesterone, cortisol, ACTH, DHEA-sulphate, androstenedione, testosterone, sex hormone-binding globulin, aldosterone, plasma renin activity, and cholesterol, baseline and every 12 weeks. For each hormone, association with treatment activity was tested 1) comparing baseline values in responders vs. non-responders; 2) comparing progression-free survival (PFS) of patients with baseline low vs. high values; 3) comparing values after 12 weeks in responders vs. non-responders. RESULTS Forty-nine patients were analyzed; 26 patients (53.1%) experienced PSA response. Baseline values of all hormones were not statistically different between responders and non-responders. For all hormones, PFS difference of patients with low vs. high baseline values was not statistically significant. Several hormones showed significant and sustained changes vs. baseline, but all significant changes were similar between responders and non-responders. CONCLUSIONS This analysis does not suggest a significant association between baseline hormonal values, or changes induced by abiraterone, and treatment activity.

Calcium-phosphate and parathyroid intradialytic profiles: A potential aid for tailoring the dialysate calcium content of patients on different hemodialysis schedules

Severe hyperparathyroidism is a challenge on hemodialysis. The definition of dialysate calcium (Ca) is a pending issue with renewed importance in cases of individualized dialysis schedules and of portable home dialysis machines with low‐flow dialysate. Direct measurement of calcium mass transfer is complex and is imprecisely reflected by differences in start‐to‐end of dialysis Ca levels. The study was performed in a dialysis unit dedicated to home hemodialysis and to critical patients with wide use of daily and tailored schedules. The Ca‐phosphate (P)‐parathyroid hormone (PTH) profile includes creatinine, urea, total and ionized Ca, albumin, sodium, potassium, P, PTH levels at start, mid, and end of dialysis. “Severe” secondary hyperparathyroidism was defined as PTH > 300 pg/mL for ≥3 months. Four schedules were tested: conventional dialysis (polysulfone dialyzer 1.8–2.1 m2), with dialysate Ca 1.5 or 1.75 mmol/L, NxStage (Ca 1.5 mmol/L), and NxStage plus intradialytic Ca infusion. Dosages of vitamin D, calcium, phosphate binders, and Ca mimetic agents were adjusted monthly. Eighty Ca‐P‐PTH profiles were collected in 12 patients. Serum phosphate was efficiently reduced by all techniques. No differences in start‐to‐end PTH and Ca levels on dialysis were observed in patients with PTH levels < 300 pg/mL. Conversely, Ca levels in “severe” secondary hyperparathyroid patients significantly increased and PTH decreased during dialysis on all schedules except on Nxstage (P < 0.05). Our data support the need for tailored dialysate Ca content, even on “low‐flow” daily home dialysis, in “severe” secondary hyperparathyroid patients in order to increase the therapeutic potentials of the new dialysis techniques.

Revisiting nephrocalcinosis: A single-centre perspective. A northern Italian experience.

Nephrocalcinosis is a clinical‐pathological entity characterized by the deposition of calcium salts within the kidney parenchyma. Both the protean presentation and multiple causes may explain the lack of data regarding its prevalence. The aim of this study is to report the prevalence and main clinical features of nephrocalcinosis diagnosed in a newly opened nephrology outpatient unit.

Revisiting nephrocalcinosis: A single‐center perspective

Nephrocalcinosis is a clinical‐pathological entity characterized by the deposition of calcium salts within the kidney parenchyma. Both the protean presentation and multiple causes may explain the lack of data regarding its prevalence. The aim of this study is to report the prevalence and main clinical features of nephrocalcinosis diagnosed in a newly opened nephrology outpatient unit.

MP40-08 ROLE OF NEUTROPHIL GELATINASE-ASSOCIATED LIPOCAIN IN THE DETECTION OF KIDNEY INJURY FOLLOWING CLAMPLESS AND CLAMPED LAPAROSCOPIC PARTIAL NEPHRECTOMY

flow (ERPF) and regional Tc-MAG3 uptake to evaluate the benefit of AO clamping on postoperative renal function. METHODS: We included 58 patients who underwent laparoscopic partial nephrectomy for non-hilar exophytic renal tumors in this study. Arteryevein (AV) clamping was used for 26 of these patients, while arteryeonly (AO) clamping was used for 32. All patients had a functional contralateral kidney. We assessed effective renal plasma flow (ERPF) by Technetium-mercaptoacetyltriglycine (Tc-MAG3) renal scintigraphy preoperatively and at 1 week and 6 months postoperatively. In addition, we analyzed Tc-MAG3 uptake regionally in the surgically non-affected areas (Fig. 1). RESULTS: Mean tumor diameters were 3.0 cm in the AV group and 2.8 cm in the AO group. Warm ischemic time was significantly shorter in the AV group than the AO group (26.3 vs. 30.7 min, respectively, p 1⁄4 0.007). There were no differences in the estimated glomerular filtration rates or ERPF of the operated kidney between groups preoperatively or 1 week or 6 months postoperatively. The decrease in regional Tc-MAG3 uptake of the operated kidney at 1 week was correlated with warm ischemic time in both groups, being stronger in the AV group (p < 0.001) than in the AO group (p 1⁄4 0.027). This decrease was significantly less in the AO group when the ischemic time was 25 min (88.1% vs 102.5%, p 1⁄4 0.001). CONCLUSIONS: Ischemic renal damage during laparoscopic partial nephrectomy was lessened by applying AO clamping particularly in cases with prolonged ischemic time.