Electrocorticographic and neurochemical findings after local cortical valproate application in patients with pharmacoresistant focal epilepsy.

Because oral pharmacological treatment of neocortical focal epilepsy is limited due to common systemic side effects and relatively low drug concentrations reached at the epileptic foci locally, application of antiepileptic agents directly onto the neocortical focus may enhance treatment tolerability and efficacy. We describe the effects of cortically applied sodium valproate (VPA) in two patients with pharmacoresistant neocortical focal epilepsy who were selected for epilepsy surgery after a circumscribed epileptic focus had been determined by invasive presurgical evaluation using subdural electrodes. Local VPA modified epileptic activity as electrocorticographically recorded from the chronic focus in both patients. In addition, VPA induced local increase of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in cortical tissue samples, whereas the excitatory glutamate was possibly decreased. In this clinical pilot study, we could show antiepileptic effects of cortically applied VPA in humans by electrocorticographic and neurochemical parameters.

Brachytherapy in soft tissue tumours: an interdisciplinary challenge!

OBJECTIVE: Interdisciplinary work including surgery and additive radiotherapy is often needed for the therapy of tumours. Beneath this, brachytherapy is an important part of the radiotherapy. It was first used over 100 years ago and is in regular use after the development of afterload technology in the early 1970s. Today it is often used in different tumour therapies, for example in soft tissue sarcoma or breast tumours, in order to decrease the risk of local recurrence. Concerning its benefits, higher doses could be used because of the localized effect with equivalent local control rate and less toxicity of treatment. Moreover, brachytherapy can also shorten the treatment time from 5-7 weeks to some days and is better reconcilable due to its localized effects, thus reducing side effects, as radiation-induced reactions, teleangiectasia and brosis. Precondition for application of brachytherapy is the need of a good soft tissue coverage and wound healing. Therefore, good interdisciplinary cooperation between plastic surgery and radiotherapy is important. After wide surgical resection reconstruction with different kind of flaps are often required, for achieving early wound healing and fast start of radiotherapy. PATIENTS AND METHOD: Between 2011 and 2017 we applied brachytherapy to 13 patients with soft tissue sarcomas and other tumours like merkel-cell-carcinoma, schwannoma, and breast cancer. The treatment consisted of tumour resection, intraoperative insertion of brachytherapy catheters and after that brachytherapy alone or in combination with external beam radiotherapy. In half of the patients a reconstruction with different flaps was required, including pedicled trapezius flap, musculus latissimus dorsi flap and radial forearm flap; in some cases nerve and tendon reconstruction for better function and faster wound healing and so faster start of postoperative brachytherapy was also needed. The mean age of the patients was 55 years (±19) and we could start brachytherapy after 3-21 days after the operation, with a mean start on day 8±5 postoperatively. Three patients received additional percutaneous radiotherapy. The patients who received only brachytherapy got a dose of 2, 5 or 3Gy twice daily, with a mean total dose of 31±3Gy. CONCLUSION: Multidisciplinary work, including surgery as the main procedure and radiotherapy additionally, is needed for a successful treatment of soft tissue tumours. Depending on the type and the stadium of tumour plastic and reconstructive surgery provides soft tissue coverage, faster wound healing and the chance for limb salvage; on the other hand, additive brachytherapy contributes to a good tumour control. Therefore, a close collaboration between the two specialties is of particular importance, in order to improve the effectiveness of the therapy and the postoperative quality of life of the patient.

Stem cells therapy: the future in the management of systemic sclerosis? A case report.

OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disorder of unknown etiology, with heterogeneous clinical manifestations and chronic and often progressive course. The diffuse cutaneous form of SSc (dcSSc) is characterized by thickening of the skin (scleroderma) and distinctive involvement of multiple internal organs. Patients with limited cutaneous SSc (lcSSc) generally have long-standing Raynaud's phenomenon before other manifestations of SSc appear. Over the last decade the Interest of adipose-derived cell therapy in regenerative medicine has increased continuously. In compare to bone marrow-derived mesenchymal stem cells (MSCs) adipose tissue-derived stem cells (ADSCs) are considered to be ideal for application in regenerative medicine. Zuk et al., introduced a multipotent, undifferentiated, self-renewing progenitor cell population isolated from adipose tissue, called processed lipoaspirate (PLA). However, subcutaneous injections of autologous adipose tissue-derived stromal vascular fraction (ADSVF), which is known to contain mesenchymal stem cells, in hands of Patients with scleroderma for enhancing their impaired hand function is still in an experimental stage, although there are already promising results of the therapy. Commonly available therapeutic options for hands of Patients with systemic sclerosis, vasodilatator drugs and physiotherapy, have many restriction and limited effects. MATERIALS AND METHOD: A 62 years old woman with scleroderma presented with progressive digital necrosis, ulceration, gangrene and impaired wound healing, despite of conventional therapy with vasodilatator drugs. Water-jet-Assisted Liposuction (Body-jet® evo, human med AG, Schwerin, Germany) of subcutaneous abdominal fat was carried out under general anesthesia by an experienced surgeon. Autologous adipose tissue-derived stromal vascular fraction (ADSVF) was harvested by in a single-use Q-graft® collector (human med AG, Schwerin, Germany). Cells were centrifuged in 400G for 5 minutes and cell pellets were aspirated carefully in a 20mL syringe filled with 0.9% NaCl. A total of ca. 2.72 million cells have been isolated. Meanwhile middle phalangeal amputation of digit 2, 3 and 4 of the left hand were performed, without closing the skin of the amputation stumps. The SVF cell suspension was injected subcutaneous into the area of metacarpophalangeal joints in both hands, as well as into the amputation stump of the left middle finger, and under a skin necrosis in the right hand. RESULTS: The therapy was good tolerated by the patient, with absence of adverse reactions. No infection was observed, despite open amputation. Three weeks after the stem cell therapy, no need to further amputation was demonstrated. The patient is still under regular clinical observation, in order to determine the long term effects of the therapy. CONCLUSION: Application of isolated adipose tissue-derived stem cells seems to be a very promising procedure in the treatment of the manifestation of systemic sclerosis. However, more clinical and experimental studies are required, in order to understand the exact mechanisms of action and standardize the therapy.

Reduction of epileptiform activity through local valproate-implants in a rat neocortical epilepsy model.

PURPOSE: Pharmacotherapy of epilepsies is limited due to low concentrations at epileptogenic foci, side effects of high systemic doses and that some potentially efficient substances do not pass the blood-brain barrier. To overcome these limitations, we tested the efficacy of local valproate (VPA)-containing polymer implants in a model of necocortical injected tetanus toxin (TeT) in the rat. METHODS: Tetanus toxin was injected intracortically and cobalt (II) chloride (CoCl2) was applied on the cortical surface. Video-electrocorticography recordings with intracortical electrodes were performed. VPA-containing polymers were implanted above the cortical focus. Antiepileptic effects were evaluated as reductions of epileptiform potentials (EPs) per hour in comparison to saline (NaCl)-containing polymer implants. RESULTS: Triple 50ng TeT injections plus CoCl2 application (20/10mg) showed consistent EPs. NaCl-implanted animals (n=6) showed a mean of 10.5EPs/h after the first week, the EP frequency increased to 53.5EPs/h after the second week. VPA-implant animals (n=5) showed a reduction in EP frequency from 71.6 to 4.8EPs/h after the second week. The EP frequency after the second week was higher in the NaCl-implanted animals than in the VPA-implanted (p=0.0303). The mean EPs/h increase in NaCl-implanted rats (+42.9EPs/h) was different (p=0.0087) from the mean EPs/h decrease in VPA-implanted rats (-66.8EPs/h). CONCLUSION: Despite former publications no clear seizures could be reproduced but it was possible to establish focal EPs, which proved to be a reliable marker for epileptic activity. Local antiepileptic therapy with VPA has shown efficacy in decreasing EP frequency.

Locally applied valproate enhances survival in rats after neocortical treatment with tetanus toxin and cobalt chloride.

PURPOSE: In neocortical epilepsies not satisfactorily responsive to systemic antiepileptic drug therapy, local application of antiepileptic agents onto the epileptic focus may enhance treatment efficacy and tolerability. We describe the effects of focally applied valproate (VPA) in a newly emerging rat model of neocortical epilepsy induced by tetanus toxin (TeT) plus cobalt chloride (CoCl2). METHODS: In rats, VPA (n = 5) or sodium chloride (NaCl) (n = 5) containing polycaprolactone (PCL) implants were applied onto the right motor cortex treated before with a triple injection of 75 ng TeT plus 15 mg CoCl2. Video-EEG monitoring was performed with intracortical depth electrodes. RESULTS: All rats randomized to the NaCl group died within one week after surgery. In contrast, the rats treated with local VPA survived significantly longer (P < 0.01). In both groups, witnessed deaths occurred in the context of seizures. At least 3/4 of the rats surviving the first postoperative day developed neocortical epilepsy with recurrent spontaneous seizures. CONCLUSIONS: The novel TeT/CoCl2 approach targets at a new model of neocortical epilepsy in rats and allows the investigation of local epilepsy therapy strategies. In this vehicle-controlled study, local application of VPA significantly enhanced survival in rats, possibly by focal antiepileptic or antiepileptogenic mechanisms.