Vladimir Neychev

The basal ganglia and cerebellum interact in the expression of dystonic movement

Dystonia is a neurological disorder characterized by excessive involuntary muscle contractions that lead to twisting movements or abnormal posturing. Traditional views place responsibility for dystonia with dysfunction of basal ganglia circuits, yet recent evidence has pointed towards cerebellar circuits as well. In the current studies we used two strategies to explore the hypothesis that the expression of dystonic movements depends on influences from a motor network that includes both the basal ganglia and cerebellum. The first strategy was to evaluate the consequences of subthreshold lesions of the striatum in two different animal models where dystonic movements are thought to originate from abnormal cerebellar function. The second strategy employed microdialysis to search for changes in striatal dopamine release in these two animal models where the cerebellum has been already implicated. One of the animal models involved tottering mice, which exhibit paroxysmal dystonia due to an inherited defect affecting calcium channels. In keeping with prior results implicating the cerebellum in this model, surgical removal of the cerebellum eliminated their dystonic attacks. In contrast, subclinical lesions of the striatum with either 6-hydroxydopamine (6OHDA) or quinolinic acid (QA) exaggerated their dystonic attacks. Microdialysis of the striatum revealed dystonic attacks in tottering mice to be associated with a significant reduction in extracellular striatal dopamine. The other animal model involved the induction of dystonia via pharmacological excitation of the cerebellar cortex by local application of kainic acid in normal mice. In this model the site of stimulation determines the origin of dystonia in the cerebellum. However, subclinical striatal lesions with either 6OHDA or QA again exaggerated their generalized dystonia. When dystonic movements were triggered by pharmacological stimulation of the cerebellum, microdialysis revealed significant reductions in striatal dopamine release. These results demonstrate important functional relationships between cerebellar and basal ganglia circuits in two different animal models of dystonia. They suggest that expression of dystonic movements depends on influences from both basal ganglia and cerebellum in both models. These results support the hypothesis that dystonia may result from disruption of a motor network involving both the basal ganglia and cerebellum, rather than isolated dysfunction of only one motor system.

Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites

PURPOSE Gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) are increasing in incidence, and accurate staging is important for selecting the appropriate treatment. (68)Ga-DOTATATE imaging is a promising approach for detecting GEPNETs and could help in selecting optimal therapeutic strategies. The aim of this study was to prospectively determine the clinical utility of (68)Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) in detecting unknown primary and metastatic GEPNETs. PATIENTS AND METHODS One hundred thirty-one patients were enrolled in a prospective study of patients undergoing (68)Ga-DOTATATE PET/CT, (111)In-pentetreotide single-photon emission computed tomography (SPECT)/CT and multiphasic CT scan, and/or magnetic resonance imaging in a blinded fashion with comprehensive biochemical testing. The primary outcome measure was the detection of lesions by each imaging study. RESULTS (68)Ga-DOTATATE PET/CT imaging detected 95.1% of lesions (95% CI, 92.4% to 96.8%) with an average maximum standardized uptake value of 65.4 ± 47 (range, 6.9 to 244), anatomic imaging detected 45.3% of lesions (95% CI, 37.9% to 52.9%), and (111)In-pentetreotide SPECT/CT detected 30.9% of lesions (95% CI, 25.0% to 37.5%), with a significant difference between imaging modalities (P < .001). In four of 14 patients (28.6%), (68)Ga-DOTATATE PET/CT found a previously unknown primary tumor, and detected primary GEPNET, lymph node, and distant metastases correctly in 72 of 113 lesions (63.7%) when compared with histopathology, with 22.1% and 38.9% detected by using (111)In-pentetreotide SPECT/CT and anatomic imaging, respectively. On the basis of findings with (68)Ga-DOTATATE PET/CT, 43 of 131 patients (32.8%) had a change in management recommendation. In patients with carcinoid symptoms but negative biochemical testing, (68)Ga-DOTATATE PET/CT detected lesions in 65.2% of patients, 40% of which were detected neither by anatomic imaging nor by (111)In-pentetreotide SPECT/CT. CONCLUSION (68)Ga-DOTATATE PET/CT imaging provides important information for accurate staging of GEPNETs and selection of appropriate treatment interventions even in the absence of biochemical evidence of disease in symptomatic patients.

Unusual presentation and treatment of spontaneous celiac artery dissection

The management options of an isolated celiac artery dissection include medical, open surgical, and endovascular techniques. Which strategy is chosen depends on the severity of the dissection, collateral circulation to the liver, the patients hemodynamic status, and the surgeons expertise. We describe an unusual case of celiac artery dissection involving splenic and hepatic arteries complicated by hemorrhage. The patient was successfully treated by coil embolization of the splenic and gastric branches. Hepatic arterial blood flow was preserved with a stent graft extending from the origin of the gastroduodenal artery to the orifice of the celiac artery.

A phase II trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin.

Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that has antiproliferative effects on several types of cancer, including thyroid cancer. In addition, VA has been reported to upregulate the sodium‐iodine symporter in thyroid cancer cells and increases radioiodine uptake in preclinical studies. The aim of this study was to assess the antiproliferative effects of VA and to evaluate if VA can increase the radioiodine uptake in patients with advanced, radioiodine‐negative thyroid cancer.

Phase I trial of systemic intravenous infusion of interleukin-13-Pseudomonas exotoxin in patients with metastatic adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare but lethal malignancy without effective current therapy for metastatic disease. IL‐13‐PE is a recombinant cytotoxin consisting of human interleukin‐13 (IL‐13) and a truncated form of Pseudomonas exotoxin A (PE). The main objectives of this Phase I dose‐escalation trial were to assess the maximum‐tolerated dose (MTD), safety, and pharmacokinetics (PK) of IL‐13‐PE in patients with metastatic ACC. Eligible patients had confirmed IL‐13 receptor alpha 2 (IL‐13Rα2) expressions in their tumors. IL‐13‐PE at dose of 1–2 μg/kg was administered intravenously (IV) on day 1, 3, and 5 in a 4‐week cycle. Six patients received 1 μg/kg and two patients received 2 μg/kg of IL‐13‐PE. Dose‐limiting toxicity was observed at 2 μg/kg, at which patients exhibited thrombocytopenia and renal insufficiency without requiring dialysis. PK analysis demonstrated that at MTD, the mean maximum serum concentration (Cmax) of IL‐13‐PE was 21.0 ng/mL, and the terminal half‐life of IL‐13‐PE was 30–39 min. Two (25%) of the eight patients had baseline neutralizing antibodies against PE. Three (75%) of the remaining four tested patients developed neutralizing antibodies against IL‐13‐PE within 14–28 days of initial treatment. Of the five patients treated at MTD and assessed for response, one patient had stable disease for 5.5 months before disease progression; the others progressed within 1–2 months. In conclusion, systemic IV administration of IL‐13‐PE is safe at 1 μg/kg. All tested patients developed high levels of neutralizing antibodies during IL‐13‐PE treatment. Use of strategies for immunodepletion before IL‐13‐PE treatment should be considered in future trials.

Mutation-targeted therapy with sunitinib or everolimus in patients with advanced low-grade or intermediate- grade neuroendocrine tumours of the gastrointestinal tract and pancreas with or without cytoreductive surgery: protocol for a phase II clinical trial

Introduction Finding the optimal management strategy for patients with advanced, metastatic neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas is a work in progress. Sunitinib and everolimus are currently approved for the treatment of progressive, unresectable, locally advanced or metastatic low-grade or intermediate-grade pancreatic NETs. However, mutation-targeted therapy with sunitinib or everolimus has not been studied in this patient population. Methods and analysis This prospective, open-label phase II clinical trial was designed to determine if mutation-targeting therapy with sunitinib or everolimus for patients with advanced low-grade or intermediate-grade NETs is more effective than historically expected results with progression-free survival (PFS) as the primary end point. Patients ≥18 years of age with progressive, low-grade or intermediate-grade locally advanced or metastatic NETs are eligible for this study. Patients will undergo tumour biopsy (if they are not a surgical candidate) for tumour genotyping. Patients will be assigned to sunitininb or everolimus based on somatic/germline mutations profile. Patients who have disease progression on either sunitinib or everolimus will crossover to the other drug. Treatment will continue until disease progression, unacceptable toxicity, or consent to withdrawal. Using the proposed criteria, 44 patients will be accrued within each treatment group during a 48-month period (a total of 88 patients for the 2 treatments), and followed for up to an additional 12 months (a total of 60 months from entry of the first patient) to achieve 80% power in order to test whether there is an improvement in PFS compared to historically expected results, with a 0.10 α level one-sided significance test. Ethics and dissemination The study protocol was approved by the institutional review board of the National Cancer Institute (NCI-IRB Number 15C0040; iRIS Reference Number 339636). The results will be published in a peer-reviewed journal and shared with the worldwide medical community. Trial registration number NCT02315625.

Endovascular Hypogastric Artery Preservation During Endovascular Aneurysm Repair: A Review of Current Techniques and Devices

Despite the improvement in endovascular techniques, one aspect of aneurysmal disease that continues to be challenging is the management of aortoiliac aneurysms. Sacrificing the hypogastric artery (HGA) for effective treatment is not without sequelae, which may include buttocks claudication, colonic ischemia, spinal cord ischemia, as well as buttock and scrotal necrosis. This should be taken into consideration particularly in patients with previous intervention or potential additional future interventions. This review describes the current endovascular techniques for preservation of HGA perfusion.

Detection of insulinoma using 68 Gallium-DOTATATE PET/CT: a case report

Insulinomas are the most common cause of endogenous hyperinsulinemic hypoglycemia in non-diabetic adults. They are most often benign, small and difficult to localize with current imaging techniques. This is of high importance, as complete surgical resection is the only curative treatment. Anatomic imaging, (111)In-pentetreotide scan and (68)Gallium-DOTATATE positron emission tomography/computed tomography (PET/CT) were compared in a patient with insulinoma. (68)Gallium-DOTATATE PET/CT and selective arterial calcium stimulation localized the insulinoma. At surgery, a tumor in the anterior aspect of the pancreatic body was found which confirmed the preoperative localization, and a 2.1 cm tumor was enucleated, World Health Organization (WHO) grade I insulinoma. The patient remains euglycemic and free of symptoms at last follow up. In conclusion, (68)Gallium-DOTATATE PET/CT imaging may be a useful adjunct localizing study for insulinomas. It is a non-invasive preoperative localization study that could guide surgical exploration for successful therapy.

Minimizing Shear and Compressive Stress During Pancreaticojejunostomy: Rationale of a New Technical Modification

The failure of the pancreaticojejunal anastomosis remains an important and potentially lethal postoperative complication after pancreaticoduodenectomy. During the pancreaticojejunostomy, creation of compressive and shear forces during suture placement and knot tying may cause deformation of and cutting through the fragile pancreatic parenchyma. We sought to understand the mechanics of needle-pancreas interaction and make adjustments to our pancreaticojejunostomy technique so that the creation of shear and compressive stress could be minimized. We provide a detailed description, a mathematical model, and analysis of the outcomes of our new technical modifications.

Management Options for Advanced Low or Intermediate Grade Gastroenteropancreatic Neuroendocrine Tumors: Review of Recent Literature

Our understanding of the biology, genetics, and natural history of neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas has improved considerably in the last several decades and the spectrum of available therapeutic options is rapidly expanding. The management of patients with metastatic low or intermediate grade NETs has been revolutionized by the development of new treatment strategies such as molecular targeting therapies with everolimus and sunitinib, somatostatin analogs, tryptophan hydroxylase inhibitors, and peptide receptor radionuclide therapy that can be used alone or as a multimodal approach with or without surgery. To further define and clarify the utility, appropriateness, and the sequence of the growing list of available therapies for this patient population will require more high level evidence; however, data from well-designed randomized phase III clinical trials is rapidly accumulating that will further stimulate development of new management strategies. It is therefore important to thoroughly review emerging evidence and report major findings in frequent updates, which will expand our knowledge and contribute to a better understanding, characterization, and management of advanced NETs.