A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma.

Background: Activation of the phosphoinisitide-3 kinase (PI3K) pathway through mutation and constitutive upregulation has been described in renal cell carcinoma (RCC), making it an attractive target for therapeutic intervention. We performed a randomized phase II study in vascular endothelial growth factor (VEGF) therapy refractory patients to determine whether MK-2206, an allosteric inhibitor of AKT, was more efficacious than the mammalian target of rapamycin inhibitor everolimus. Patients and methods: A total of 43 patients were randomized in a 2:1 distribution, with 29 patients assigned to the MK-2206 arm and 14 to the everolimus arm. Progression-free survival (PFS) was the primary endpoint. Results: The trial was closed at the first futility analysis with an observed PFS of 3.68 months in the MK-2206 arm and 5.98 months in the everolimus arm. Dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm. On the other hand, progressive disease was best response in 44.8% of MK2206 versus 14.3% of everolimus-treated patients. MK-2206 induced significantly more rash and pruritis than everolimus, and dose reduction occurred in 37.9% of MK-2206 versus 21.4% of everolimus-treated patients. Genomic analysis revealed that 57.1% of the patients in the PD group had either deleterious TP53 mutations or ATM mutations or deletions. In contrast, none of the patients in the non-PD group had TP53 or ATM defects. No predictive marker for response was observed in this small dataset. Conclusions: Dichotomous outcomes are observed when VEGF therapy refractory patients are treated with MK-2206, and MK-2206 does not demonstrate superiority to everolimus. Additionally, mutations in DNA repair genes are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC.

Hypoglycemic effect of Opuntia streptacantha Lemaire in NIDDM.

To assess the hypoglycemic effect of the nopal Opuntia streptacantha Lemaire (O. streptacantha Lem.), three groups of patients with non-insulin-dependent diabetes mellitus (NIDDM) were studied. Group one (16 patients) ingested 500 g of broiled nopal stems. Group 2 (10 patients) received only 400 ml of water as a control test. Three tests were performed on group 3 (6 patients): one with nopal, a second with water, and a third with ingestion of 500 g broiled squash. Serum glucose and insulin levels were measured at 0, 60, 120, and 180 min. After the intake of O. streptacantha Lem., serum glucose and serum insulin levels decreased significantly in groups 1 and 3, whereas no similar changes were noticed in group 2. The mean reduction of glucose reached 17.6 +/- 2.2% of basal values at 180 min in group 1 and 16.2 +/- 1.8% in group 3; the reduction of serum insulin at 180 min reached 50.2 +/- 8.0% in group 1 and 40.3 +/- 12.4% in group 3. This study shows that the stems of O. streptacantha Lem. cause a hypoglycemic effect in patients with NIDDM. The mechanism of this effect is unknown, but an increased insulin sensitivity is suggested.

The presence of LHRH-like receptors in Dunning R3327H prostate tumors.

Quantitative analyses of LH-RH-like membrane receptors were performed in five tumors from the transplantable Dunning R3372H rat prostatic adenocarcinoma. The binding of D-Trp6-LH-RH, an agonist of LH-RH, was observed in all 5 tumors. The antagonist [Ac-Dp-Cl-Phe1,2,D-Trp3,D-Lys6, D-Ala10]-LH-RH was bound to 4 tumors. The apparent equilibrium dissociation constant (Kd) for D-Trp6-LH-RH receptor was from 2.6-3.9 x 10(-10) M. The apparent equilibrium Bmax values (maximum number of binding sites) were from 17.2-86.0 fmol/mg membrane protein for D-Trp6-LH-RH receptor. The Kd for the antagonist was from 2.4-2.7 x 10(-10) M and the Bmax values were from 35.5-66.0 fmol/mg membrane protein. Similar binding studies performed in 6 normal rat prostates showed no binding capacities.

Effect of plasma volume expansion on auricular natriuretic peptide in non-dependent insulin diabetic patients with autonomic neuropathy.

The objective of this study was to determine the role of atrial natriuretic peptide (ANP) in autonomic neuropathy and to learn the effect of saline solution infusion on ANP. Twenty one subjects were distributed in three groups: 1) control group, 2) diabetic patients with autonomic neuropathy, and 3) diabetic patients without autonomic neuropathy. The levels of ANP, renin, aldosterone and cortisol were determined at baseline and 30, 60, and 75 min after saline infusion. At baseline ANP was lower in diabetic patients with autonomic neuropathy (32.9 +/- 13) than control group (34 +/- 15). ANP increased statistically significantly at 30 min after solution administration in control group (60 +/- 35, F = 4, p < 0.05), but it did not change in diabetic patients (Group II: 34.3 +/- 9.3 and Group III 34.6 +/- 10.7). Sixty and 75 min after saline infusion ANP returned to basal levels in control group, but they did not change in diabetic patients. A delayed response of renin, aldosterone and cortisol to saline solution administration was observed in diabetic patients. There was no correlation between ANP levels and alteration of autonomic tests. It is concluded that independent of autonomic neuropathy, the levels of ANP did not increase with saline infusion in diabetic patients.

[The treatment of colonic and ovarian cancer with radioactive monoclonal antibodies against the CA l9-9 and CA 125 antigens]. / Tratamiento de cáncer de colon y ovario con anticuerpos monoclonales radiactivos contra antígenos Ca 19-9 y Ca 125.

The age of monoclonal antibodies arose with the papers by Köhler and Milstein in 1975. By means of a fusion between a neoplastic cell with one which produced a specific antibody they obtained a hybrid or clonal cell. Five years later, Nadler et al issued the first report of a patient with lymphoma treated with monoclonal antibodies. After the first announcement, diverse research centers have reported the clinical results obtained in various neoplasias treated with radioactive monoclonal antibodies directed against antigens associated with neoplasias, as well as non-specific tumoral antigens, including lymphomas, melanomas and cancers of the colon, ovary and breast.

The effect of two sequential doses of Opuntia streptacantha upon glycemia.

To find out if a second dose of O. streptacantha may enhance its hypoglycemic effect, three tests were performed in fasting condition to 8 type II diabetic subjects and 6 healthy individuals. The tests were as follows: A. 500 g of broiled stems of O. streptacantha were given orally initially and two hours later. B. Only the initial dose. C. Control test with water. Serum glucose and C peptide were measured every two hours from 0 to 6 hours. In diabetic patients a significant (P < 0.01 vs control) decrease of serum glucose reaching from 41 to 46% less than initial value, was noticed in tests A and B, without differences between them. C peptide did not change. In healthy subjects serum glucose and C peptide did not significantly differ between tests. A second dose of O. streptacantha, two hours after the first one, did not improve its hypoglycemic activity.

[The effect of acute hyperinsulinemia on arterial pressure in healthy individuals]. / Effecto de la hiperinsulinemia aguda en la tensión arterial de individuos sanos.

To assess if induced hyperinsulinemia enhances blood pressure (BP), three tests were performed to nine healthy volunteers as follows: A. After an oral dextrose load (75 g), 250 ml of 0.9% NaCl plus 25 g dextrose were infused in three hours. B. The same procedure, plus 15 U of regular insulin in the intravenous solution. C. (control) The same procedure but without insulin and dextrose. Pulse and BP were measured every 15 minutes, serum glucose and insulin were determined hourly. Hyperinsulinemia from 2 to 7-fold the basal value was induced in the test A, and from 7 to 30-fold in the test B (P less than 0.01). BP did not rise with hyperinsulinemia, but a slight and nonsignificant decrease of mean BP and higher heart rate (P less than 0.05) were noticed at the third hour in the test B. Acute hyperinsulinemia do not cause high BP. A cause-effect relationship between hyperinsulinemia and hypertension is still unproved.

Influence of nopal intake upon fasting glycemia in type II diabetics and healthy subjects.

To assess if the acute hypoglycemic effect of nopal which occurs in diabetic patients also appears in healthy individuals, 500 g of nopal stems (O. streptacantha Lem.) were given orally to 14 healthy volunteers and to 14 patients with NIDDM. Serum glucose and insulin levels were measured at 0, 60, 120 and 180 minutes after nopal ingestion. A control test was performed with the intake of 400 ml of water. The intake of nopal by the NIDDM group was followed by a significant reduction of serum glucose and insulin concentration reaching 40.8 + 4.6 mg/dl (n = 14) (mean+SEM) and 7.8 + 1.5 uU/ml (n = 7) less than basal value, respectively, at 180 minutes. (P less than 0.001 vs control test). No significant changes were noticed in the healthy group as compared with the control test (P greater than 0.05). Acute hypoglycemic effect of nopal was observed in patients with NIDDM but not in healthy subjects, thus the mechanisms of this effect differs from current hypoglycemic agents.

Polarization observations with the Cosmic Background Imager.

Polarization observations of the cosmic microwave background with the Cosmic Background Imager from September 2002 to May 2004 provide a significant detection of the E-mode polarization and reveal an angular power spectrum of polarized emission showing peaks and valleys that are shifted in phase by half a cycle relative to those of the total intensity spectrum. This key agreement between the phase of the observed polarization spectrum and that predicted on the basis of the total intensity spectrum provides support for the standard model of cosmology, in which dark matter and dark energy are the dominant constituents, the geometry is close to flat, and primordial density fluctuations are predominantly adiabatic with a matter power spectrum commensurate with inflationary cosmological models.