Electrochemotherapy in the Treatment of Bone Metastases: A Phase II Trial.

INTRODUCTION: Bone metastatic disease is a major cause of pain and decreased quality of life in patients with cancer. In addition to systemic therapy and pain control with narcotic analgesics, standard local treatments include palliation with radiation therapy and surgery. However, 20-30 % of patients do not respond to conventional treatments, increasing the interest in alternative therapies. We present the results of a new minimally invasive technique in the treatment of bone metastases. METHODS: Twenty-nine patients affected by painful bone metastases were treated with electrochemotherapy (ECT) from July 2009 to July 2011; the mean age was 60 years (range 37-87); 21 patients received a previous ineffective local treatment; the appendicular skeleton was affected in 15 patients while in 14 patients other sites were involved. ECT was performed using the Cliniporator Vitae under fluoroscopy or CT guidance depending on the site of the lesion. Clinical response was assessed using VAS scale and objective tumour response was evaluated according to the MD Anderson criteria for bone metastases. RESULTS: All patients well tolerated the procedure and no intraoperative or postoperative complications were observed. At a mean follow-up of 7 months, 24 patients were available for evaluation. 84 % of the patients (20 out of 24) referred improvement of pain ≥50 % with reduction of narcotics consumption. Radiographic evaluation after 3 months in 20 evaluable patients, showed "partial response" in 1 patient, "stable disease" in 17 and "progression" in two cases. DISCUSSION: Results reported in this study demonstrated ECT to be safe and feasible in the treatment of painful bone metastases even when other previous treatments were ineffective. Pain and disease progression control was achieved in the majority of the patients with consequent improvement of quality of life. CONCLUSION: ECT should be considered a new feasible tool in the treatment of bone metastases in place or in combination with standard treatments; further developments are required to extend the use of this technique to spine metastases.

Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome.

Type 5 Bartter syndrome has been recently defined as a Bartter syndrome due to the most activating mutations of the calcium-sensing receptor (CaSR). It has been attributed to the inhibition exerted by CaSR activity on sodium transport in the thick ascending limb of the loop of Henle (TALH). Two monozygotic twin sisters (T1 and T2) with autosomal dominant hypocalcemia (ADH) due to a nonconservative activating CaSR mutation in the extracellular domain (K29E) were studied. They developed a Bartter-like syndrome characterized by a mild phenotype: hypokalemia occurred only at the age of 22 years; it was corrected with small doses of oral potassium in one twin, while the other twin needed no potassium supplements to maintain borderline levels of plasma potassium; alkalosis was absent; plasma renin and aldosterone production were not markedly activated. Furthermore, the natriuretic response to furosemide, a inhibitor of sodium reabsorption in the TALH, was conserved in both twins. The K29E mutation was previously reported as one of the most activating mutations of the CaSR gene leading to a very marked increase in CaSR sensitivity to calcium ions. These findings confirm that Bartter syndrome is typically associated with ADH provided that the underlying mutation of CaSR is able to produce a conspicuous gain of function. However, the phenotype of type 5 Bartter syndrome may manifest with variable severity, not directly related with the in vitro potency of the CaSR activating mutation.

Sodium pump alpha2 subunits control myogenic tone and blood pressure in mice.

A key question in hypertension is: How is long-term blood pressure controlled? A clue is that chronic salt retention elevates an endogenous ouabain-like compound (EOLC) and induces salt-dependent hypertension mediated by Na(+)/Ca(2)(+) exchange (NCX). The precise mechanism, however, is unresolved. Here we study blood pressure and isolated small arteries of mice with reduced expression of Na(+) pump alpha1 (alpha1(+/-)) or alpha2 (alpha2(+/-)) catalytic subunits. Both low-dose ouabain (1-100 nm; inhibits only alpha2) and high-dose ouabain (> or =1 microm; inhibits alpha1) elevate myocyte Ca(2)(+) and constrict arteries from alpha1(+/-), as well as alpha2(+/-) and wild-type mice. Nevertheless, only mice with reduced alpha2 Na(+) pump activity (alpha2(+/-)), and not alpha1 (alpha1(+/-)), have elevated blood pressure. Also, isolated, pressurized arteries from alpha2(+/-), but not alpha1(+/-), have increased myogenic tone. Ouabain antagonists (PST 2238 and canrenone) and NCX blockers (SEA0400 and KB-R7943) normalize myogenic tone in ouabain-treated arteries. Only the NCX blockers normalize the elevated myogenic tone in alpha2(+/-) arteries because this tone is ouabain independent. All four agents are known to lower blood pressure in salt-dependent and ouabain-induced hypertension. Thus, chronically reduced alpha2 activity (alpha2(+/-) or chronic ouabain) apparently regulates myogenic tone and long-term blood pressure whereas reduced alpha1 activity (alpha1(+/-)) plays no persistent role: the in vivo changes in blood pressure reflect the in vitro changes in myogenic tone. Accordingly, in salt-dependent hypertension, EOLC probably increases vascular resistance and blood pressure by reducing alpha2 Na(+) pump activity and promoting Ca(2)(+) entry via NCX in myocytes.