Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition.

The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.

Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer.

Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as overexpressed in several cancers and shown to contribute to proliferation, migration and invasion of cancer cells. We have previously demonstrated that myoferlin regulates epidermal growth factor receptor activity in breast cancer. In the current study, we report a consistent overexpression of myoferlin in triple-negative breast cancer cells (TNBC) over cells originating from other breast cancer subtypes. Using a combination of proteomics, metabolomics and electron microscopy, we demonstrate that myoferlin depletion results in marked alteration of endosomal system and metabolism. Mechanistically, myoferlin depletion caused impaired vesicle traffic that led to a misbalance of saturated/unsaturated fatty acids. This provoked mitochondrial dysfunction in TNBC cells. As a consequence of the major metabolic stress, TNBC cells rapidly triggered AMP activated protein kinase-mediated metabolic reprogramming to glycolysis. This reduced their ability to balance between oxidative phosphorylation and glycolysis, rendering TNBC cells metabolically inflexible, and more sensitive to metabolic drug targeting in vitro. In line with this, our in vivo findings demonstrated a significantly reduced capacity of myoferlin-deficient TNBC cells to metastasise to lungs. The significance of this observation was further supported by clinical data, showing that TNBC patients whose tumors overexpress myoferlin have worst distant metastasis-free and overall survivals. This novel insight into myoferlin function establishes an important link between vesicle traffic, cancer metabolism and progression, offering new diagnostic and therapeutic concepts to develop treatments for TNBC patients.

HDAC7 inhibition resets STAT3 tumorigenic activity in human glioblastoma independently of EGFR and PTEN: new opportunities for selected targeted therapies.

To date, the mutational status of EGFR and PTEN has been shown as relevant for favoring pro- or anti-tumor functions of STAT3 in human glioblastoma multiforme (GBM). We have screened genomic data from 154 patients and have identified a strong positive correlation between STAT3 and HDAC7 expression. In the current work we show the existence of a subpopulation of patients overexpressing HDAC7 and STAT3 that has particularly poor clinical outcome. Surprisingly, the somatic mutation rate of both STAT3 and HDAC7 was insignificant in GBM comparing with EGFR, PTEN or TP53. Depletion of HDAC7 in a range of GBM cells induced the expression of tyrosine kinase JAK1 and the tumor suppressor AKAP12. Both proteins synergistically sustained the activity of STAT3 by inducing its phosphorylation (JAK1) and protein expression (AKAP12). In absence of HDAC7, activated STAT3 was responsible for significant imbalance of secreted pro-/anti-angiogenic factors. This inhibited the migration and sprouting of endothelial cells in paracrine fashion in vitro as well as angiogenesis in vivo. In a murine model of GBM, induced HDAC7-silencing decreased the tumor burden by threefold. The current data show for the first time that silencing HDAC7 can reset the tumor suppressor activity of STAT3, independently of the EGFR/PTEN/TP53 background of the GBM. This effect could be exploited to overcome tumor heterogeneity and provide a new rationale behind the development of specific HDAC7 inhibitors for clinical use.

Performance of ePTFE-covered endograft in patients with occlusive disease of the superficial femoral artery: a three-year clinical follow-up study.

AIM: Feasibility of ePTFE-covered endoprosthesis for treatment of atherosclerotic stenosis or occlusions of the SFA. This was a prospective follow-up study on intention-to-treat basis. ePTFE-covered endoprosthesis were used. METHODS: From November 2001 to December 2006, 96 patients were treated for invalidating claudication, critical ischemia or gangrene. ABI and ischemia severity score according to Rutherford were defined. Morphology of the lesions was classified according to the Trans-Atlantic InterSociety Consensus. Clinical outcome was investigated by ABI, Duplex-ultrasound, and luminal diameter measurements inside grafts. Follow-up visits were conducted at six weeks and six months, and yearly thereafter. RESULTS: Significant clinical improvement was achieved in all patients. ABI increased to normal, and did not fall during three-year follow-up. Kaplan-Meier estimates for primary patency were 76% (N.=77), 70% (N.=56) and 67.7% (N.=40), and for secondary patency 86.9% (N.=85), 82.2 (N.=63) and 79.8% (N.=45) at 1, 2, and 3 years. Intraluminal graft diameters did not decrease significantly during follow-up. Graft occlusion was seen in 21/96 endografts; 20 patients underwent additional PTAs, only three patients had intragraft stenosis. Occluded grafts did not show reduction of luminal diameters on follow-up examinations before occlusion. CONCLUSION: ePTFE-covered endografts have excellent properties for treatment of SFA stenosis or occlusions. There was no intimal hyperplasia inside endografts, and graft occlusion occurred due to progression of atherosclerotic disease outside the graft.

Surgical strategy in patients with secondary and tertiary hyperparathyroidism. A bi-institutional series.

BACKGROUND: Although total parathyroidectomy with forearm autotransplantation is a widely accepted treatment for patients with secondary/tertiary hyperparathyroidism (HPT) some debate persists about the optimal surgical strategy. In particular, the question what to do when less than four parathyroid glands can be found during surgery has yet to be resolved. The aim of this retrospective study was to review the outcome of total parathyroidectomy with autotransplantation and to assess the proper procedure (to autotransplant or not) when finding less than 4 glands after extensive surgical exploration. METHODS: Between 1995 and 2005, parathyroidectomy was performed in 74 patients in two affiliated centers. In this case-control study both clinical and biochemical outcomes of a total or subtotal parathyroidectomy were compared. The parathyroid hormone (PTH), serum calcium concentration, phosphate and alkaline phosphatase levels were monitored preoperatively, 1 and 12 months postoperatively. RESULTS: Sixty five patients underwent a total parathyroidectomy and nine patients underwent a subtotal parathyroidectomy. Persistent HPT was seen in nine patients (12%). Recurrent HPT was seen in eight patients (11%). There were no significant differences between the group with > or = 4 glands excised and the group with three glands excised regarding serum PTH levels after 12 months and the number of patients with a hypo- or hyperparathyroidism (persistent or recurrent). Procedure related morbidity was minimal. CONCLUSIONS: Total parathyroidectomy with forearm autotransplantation is safe and effective for patients with secondary/tertiary hyperparathyroidism. In case of not finding a fourth gland after extensive surgical exploration, our general advice is to proceed as planned with the autotransplantation.

Prospective randomized study of carotid endarterectomy with Fluoropassiv thin wall carotid patch versus venous patch.

INTRODUCTION: The practice of carotid endarterectomy (CEA) with patch angioplasty is more effective compared to primary closure. However, the type of patch material remains a controversy. The Fluoropassiv thin wall carotid patch is a polyester patch with an interpenetrating, nanometer-scale, solvent-applied surface modification, based on a biocompatible fluoropolymer. The present pilot study is the first clinical trial evaluating results of CEA with Fluoropassiv versus venous patch. MATERIALS/METHODS: Eighty-seven patients were randomized to 42 Fluoropassiv patching and 45 venous patching. Patients were observed by a vascular surgeon and a neurologist and scanned using duplex ultrasound with a follow-up of 2 years. No patients were lost to follow-up. Restenosis was defined as a Peak Systolic Velocity ratio >2.6, lumen reduction >50%. RESULTS: Perioperative stroke rate was 2.4% in the Fluoropassiv group and 8.9% in the venous group (p=0.02; 1 regressive, 4 non-regressive strokes). Multivariate analysis showed that bilateral carotid stenosis and stroke as indication for CEA were related to perioperative stroke. There was no link between perioperative stroke and patch type after correction for these factors. Patch type had no influence on operation time, clamp time, cranial nerve damage, hypertension, hematoma, infections, time to discharge, or early thromboembolic events. There were no significant differences between the Fluoropassiv and the venous group for cumulative mortality (respectively 4.4 vs 4.8%), patch occlusion (4.8 vs 2.2%), or stroke rate during 2 year follow-up (2.2 vs 2.4%). CONCLUSION: This first clinical study with the Fluoropassiv thin wall carotid patch showed no enhanced thrombogenicity compared to a venous patch. The Fluoropassiv patch is not related to a higher rate of postoperative bleeding events either.

Interscalenic approach to the cervico-brachial plexus.

The concept of a closed peri-neurovascular space surrounding the cervicobrachial plexus, introduced by A. Winnie, allows the blockade of the cervical and brachial plexuses by means of a single puncture technique. The single puncture has positive advantages: 1. The rapidity of the blockade; 2. The simplicity of the blockade; 3. Comfort for the patient. The landmarks are easy to make. As with epidural blockade, the injection level and the volume of local anesthetic determine the quality and extent of the block. The traditional indication is surgery of the shoulder and of the supraclavicular area. A new indication seems to be the implantation of a cardiac pacemaker. Complications often quoted in literature are Horner syndrome-a minor complication-and blockade of the ascending branches of the recurrent laryngeal nerve and of the phrenic nerve. The risk of a pneumothorax is almost nil.