Prevalence, risk factors and evolution of diabetes mellitus after treatment in primary aldosteronism. Results from the SPAIN-ALDO registry.

PURPOSE: To evaluate the prevalence, risk factors and evolution of diabetes mellitus (DM) after targeted treatment in patients with primary aldosteronism (PA). METHODS: A retrospective multicenter study of PA patients in follow-up at 27 Spanish tertiary hospitals (SPAIN-ALDO Register). RESULTS: Overall, 646 patients with PA were included. At diagnosis, 21.2% (n = 137) had DM and 67% of them had HbA1c levels < 7%. In multivariate analysis, family history of DM (OR 4.00 [1.68-9.53]), the coexistence of dyslipidemia (OR 3.57 [1.51-8.43]) and advanced age (OR 1.04 per year of increase [1.00-1.09]) were identified as independent predictive factors of DM. Diabetic patients were on beta blockers (46.7% (n = 64) vs. 27.5% (n = 140), P < 0.001) and diuretics (51.1% (n = 70) vs. 33.2% (n = 169), p < 0.001) more frequently than non-diabetics. After a median follow-up of 22 months [IQR 7.5-63.0], 6.9% of patients developed DM, with no difference between those undergoing adrenalectomy and those treated medically (HR 1.07 [0.49-2.36], p = 0.866). There was also no significant difference in the evolution of glycemic control between DM patients who underwent surgery and those medically treated (p > 0.05). CONCLUSION: DM affects about one quarter of patients with PA and the risk factors for its development are common to those of the general population. Medical and surgical treatment provides similar benefit in glycemic control in patients with PA and DM.

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome.

NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.

Deubiquitinases in cancer: new functions and therapeutic options.

Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

[Treatment of a giant serpentine type middle cerebral artery aneurysm with a high-flow bypass from the petrous internal carotid artery]. / Tratamiento de un aneurisma serpentino gigante de arteria cerebral media conbypass de alto flujo desde la arteria carótida interna petrosa.

A case report of a giant serpentine type aneurysm arising from the M1 segment of the middle cerebral artery (MCA) treated with a high-flow external saphenous vein graft from the petrous segment of the internal carotid artery is presented. The steps and challenges of this demanding surgical technique are also described. The elements to be taken into consideration in the indication, design and realization of the bypass surgery in the treatment of the MCA aneurysms are discussed.

[Olfactory groove meningiomas. Radical microsurgical treatment through the bifrontal approach]. / Meningiomas del surco olfatorio. Tratamiento microquirúrgico radical por via bifrontal.

OBJECTIVES: To describe the microsurgical technique for the radical removal of olfactory groove meningiomas through the bifrontal approach. To review the diagnostic elements to be taken into account in the selection of the surgical approach to these tumours. MATERIALS AND METHODS: A microsurgical series of 35 olfactory groove meningiomas operated on through a bifrontal craniotomy is reviewed. RESULTS: The mean tumoral volume was 85cc (4.4cm diameter). A relevant peritumoral brain edema was found in 65.7% of cases, hyperostosis in the implantation base in 80% and paranasal sinus invasion in 28.6%. A Sipmson grade 1 resection was achieved in every case. A patient died due to a postoperative pneumonia. Postoperative hospitalization time was between 3 and 20 days and at discharge all patients had a Glasgow Outcome Scale grade 4-5. The mean follow-up was 55.2 months. Two patients had postoperative transient rhinolicuorrhea and an additional patient developed hydrocephalus. An asymptomatic recurrence have been identified in a patient four years after surgery. CONCLUSIONS: In our experience the bifrontal approach allowed the radical removal of huge olfactory groove meningiomas. The microdissection of the anterior cerebral artery A2 segments is possible thanks to the arachnoidal plane between vessels and tumor. Tumoral blood flow is secured by the early approaching of the base of the tumor and preoperative embolization is not necessary. Bifrontal approach allows an aggressive treatment of the hyperostosis, bone infiltration and paranasal sinus invasion. Anterior fossa reconstruction is done using a vascularized periosteal flap.

[Treatment of intrinsic brain tumors located in motor eloquent areas. Results of a protocol based in navigation, tractography and neurophysiological monitoring of cortical and subcortical structures]. / Tratamiento de los tumores cerebrales intrínsecos de áreas motoras elocuentes. Resultados de un protocolo basado en la navegación, tractografía y monitorización neurofisiológica de estructuras corticales y subcorticales.

OBJECTIVES: The role of the microsurgical management of intrinsic brain tumors is to maximize the volumetric resection of the tumoral tissue minimizing the postoperative morbidity. The purpose of our paper has been to study the benefits of an original protocol developed for the microsurgical treatment of tumors located in eloquent motor areas where the navigation and electrical stimulation of motor subcortical pathways have been implemented. MATERIALS AND METHODS: A total of 17 patients operated on for resection of cortical or subcortical tumors in motor areas were included in the series. Preoperative planning for multimodal navigation was done integrating anatomic studies, motor functional MRI (f-MRI) and subcortical pathways volumes generated by diffusion tensor imaging (DTI). Intraoperative neuromonitorization included motor mapping by direct cortical and subcortical electrical stimulation (CS and sCS) and localization of the central sulcus using cortical multipolar electrodes and the N20 wave inversion technique. The location of all cortical and subcortical stimulated points with positive motor response was stored in the navigator and correlated with the cortical or subcortical motor functional structures defined preoperatively. RESULTS: The mean tumoral volumetric resection was 89.1±14.2% of the preoperative volume, with a total resection (≥100%) in twelve patients. Preoperatively a total of 58.8% of the patients had some motor deficit, increasing 24 hours after surgery to 76.5% and decreasing to 41.1% a month later. There was a great correlation between anatomic and functional data, both cortically and subcortically. However, in six cases it was not possible to identify the central sulcus and in many cases fMRI gave contradictory information. A total of 52 cortical points submitted to CS had positive motor response, with a positive correlation of 83.7%. Also, a total of 55 subcortical points had positive motor response, being in these cases 7.3±3.1 mm the mean distance from the stimulated point to the subcortical tract. CONCLUSIONS: The integration of preoperative and intraoperative anatomic and functional studies allows a safe functional resection of the brain tumors located in eloquent areas, compared to the tumoral resection based on anatomic imaging studies. Multimodal navigation allows the integration and correlation among preoperative and intraoperative anatomic and functional data. Cortical motor functional areas are anatomically and functionally located preoperatively thanks to MRI and fMRI and subcortical motor pathways with TDI and tractography. Intraoperative confirmation is done with CS and N20 inversion wave for cortical structures and with sCS for subcortical pathways. With this protocol we achieved a mean of 90% of volumetric resection in cortical and subcortical tumors located in eloquent motor areas with an increase of neurological deficits in the immediate postoperative period that significantly decreased one month later. Ongoing studies will define the safe limits for functional resection taking into account the intraoperative brain shift. Finally, it must be demonstrated if this protocol has any benefit for patients concerning disease free or overall survival.

Induction treatment with low-dose thymoglobulin or basiliximab in renal transplants from older donors.

Transplantation of kidneys from older donors is followed by an increase in delayed graft function (DGF) and acute rejection episodes (ARE). In these circumstances, induction treatment, whether with antithymocyte globulin or with interleukin-2 receptor blockers, may delay the introduction of calcineurin inhibitors (CNI) with effective prevention of ARE. We examined the efficacy and safety of induction treatment with 2 low doses of thymoglobulin compared with 2 doses of basiliximab. A group of 27 patients were treated with thymoglobulin and another 36 with basiliximab. CNI introduction was delayed until day 3 posttransplantation. The thymoglobulin group received 2 doses of 1.25 mg/kg on alternate days and the basiliximab group 2 doses of 20 mg. A trend to a lower incidence of DGF was observed in the thymoglobulin group (33% vs 55.6%; P = .08), with lower levels of serum creatinine on days 7 (P = .02) and 14 (P = .02) posttransplantation. No patient in the thymoglobulin group experienced ARE, but 11 patients (30.6%) in the basiliximab group did (P < .001), and 5 needed rescue treatment with thymoglobulin. We found no differences in the incidence of cytomegalovirus (CMV) disease (P = .945), admission due to infections (P = .274), or neoplasia (P = .340), or differences in graft (P = .69) and patient (P = .21) survivals at 1 and 3 years. Low-dose thymoglobulin was more effective at preventing DGF and ARE in renal transplant recipients of organs from older donors, with no differences in infectious complications or graft and patient survivals.