clinicaltrials.gov Identifier: NCT00311636.

A new renal function test was developed based upon the pharmacologic effects of furosemide to quantify separately the rates of electrolyte and water reabsorption by different segments of the human nephron in vivo. Since furosemide impairs active NaCl transport to Henle's loop and the attendant hypertonicity of the interstitium, osmotic water reabsorption from collecting ducts decreases and the unreabsorbed volume is lost into the urine, causing a rise in flow rate. This volume is computed from the difference in urine flow rate during furosemide with respect to that previously measured during maximal water diuresis alone. Starting from this value, an appropriate set of equations allows the separate calculation of Na reabsorption by the loop of Henle and by the distal tubule. Studies to validate this hypothesis were performed by clearance techniques during maximal water diuresis in 58 normal controls, in 19 patients with liver cirrhosis and ascites, and in 11 patients with chronic renal failure. Measurements were performed before and after the intravenous administration of 50 mg furosemide. The quantitative measurements of segmental solute reabsorption in normal subjects were consistent with results obtained by different methods in man and experimental animals, fully validating this new method. In addition, the data allowed to establish that distal reabsorption is depressed because of reduced proximal delivery in cirrhosis, as a result of impaired transport along Henle's loop in chronic renal disease, while permeability of collecting ducts to water was normal in both conditions. Though still approximate, this new furosemide test represents a considerable improvement over current methods for measuring segmental transport by the human nephron.

Breast cancer is the most common malignancy in women, with an incidence that varies between 40 and 90 per 100 000 (standardized rate) worldwide. Breast cancer is the most frequent female tumour in Italy, representing about 25% of all female tumours as reported in Italian registries (Zanetti et al, 1997).A positive family history is known to be a high risk factor for developing the disease: 5-10% of all breast cancers arise in individuals carrying a germline mutation and are usually considered hereditary forms (Claus et al, 1991). Two major breast cancersusceptibility genes, BRCA1 and BRCA2, have been cloned (Miki et al, 1994;Wooster et al, 1995) and both are thought to account for 30-60% of hereditary breast cancer (Serova et al, 1997;Szabo et al, 1997;Vehmanen et al, 1997aVehmanen et al, , 1997b. However, large-scale mutation analyses conducted in several populations suggest the existence of additional breast cancer-susceptibility gene(s). BRCA1 mutations are responsible for the majority of familial breast cancer associated with ovarian carcinoma, for about 50% of cases with breast cancer alone and for very few male breast cancer cases (Easton et al, 1993;Stratton et al, 1994;Narod et al, 1995). It has been estimated that women carrying a germline mutation in BRCA1 have a risk ranging from 80 to 90% for developing breast cancer and from 44 to 63% for developing ovarian cancer (Easton et al, 1993(Easton et al, , 1995Ford et al, 1994; Miki et al, 1994;Wooster et al, 1994). BRCA2 mutations account for a similar proportion of inherited breast cancer and are frequently associated with male breast cancer (Wooster et al, 1995). Breast cancer risk in females carrying BRCA2 mutations is calculated to be similar to that conferred by BRCA1 mutations (Easton et al, 1993Ford et al, 1994; Miki et al, 1994;Wooster et al, 1994). BRCA1 and particularly BRCA2 families are often affected by other tumours such as prostate, liver, pancreas, lung, stomach and colorectum (Wooster et al, 1995;Gudmundsson et al, 1996;Phelan et al, 1996;Thorlacius et al, 1996;Vehmanen et al, 1997b;Tonin et al, 1998). Except for higher incidences of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 of BRCA2 (the so-called ovarian cancer cluster region [OCCR]; Gayther et al, 1997), no other significant association between genotype and phenotype was described. BRCA1 and BRCA2 mutations are for the most part frame-shifts due to small deletions leading to premature translation termination (Wooster et al, 1995;Phelan et al, 1996;Tavtigian et al, 1996;Gayther et al, 1997).Some of these mutations are prevalent in genetically homogeneous populations as a consequence of a founder effect. A single BRCA2 mutation accounts for the majority of hereditary breast cancer in Iceland Thorlacius et al, 1996) and for 40% of male breast cancer cases , whereas three different founder mutations (185delAG and 5382insC in BRCA1, and 6174delT in BRCA2) have a high frequency in Ashkenazi Jews (Roa et al, 1996). Although at different rates, BRCA1 and BRCA2 f...

No abstract

Identification of such features should address BC patients and their families to genetic counseling and BRCA1/2 mutational analysis. In addition, this is the first report of a detailed BRCA1/2 mutation screening in Sardinia, having immediate implications for the clinical management of BC families.