Citations

SummaryObjectiveEvaluate the seizure‐reduction response and safety of mesial temporal lobe (MTL) brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of mesial temporal lobe origin.MethodsSubjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.ResultsThere were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy‐six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow‐up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty‐nine percent of subjects experienced at least one seizure‐free period of 6 months or longer, and 15% experienced at least one seizure‐free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device‐related adverse event was soft tissue implant‐site infection (overall rate, including events categorized as device‐related, uncertain, or not device‐related: 0.03 per implant year, which is not greater than with other neurostimulation devices).SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of neocortical origin.MethodsPatients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset.ResultsThere were 126 patients with seizures of neocortical onset. The average follow‐up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty‐six percent of patients experienced at least one seizure‐free period of 6 months or longer and 14% experienced at least one seizure‐free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices.SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

SummaryThe Glivec International Patient Assistance Programme makes Glivec (Imatinib mesylate) available to Philadelphia chromosome/BCR‐ABL1 positive patients with chronic myeloid leukaemia (CML) in Lower and Middle Income Countries (LMIC). We have established a large cohort of 211 CML patients who are eligible for Imatinib, in Kathmandu, Nepal. Thirty‐one patients were lost to follow‐up. We report on 180 CML patients with a median age of 38 years (range 9–81). Of these 180 patients, 162 underwent cytogenetic testing and 110 were investigated by reverse transcription polymerase chain reaction. One hundred and thirty‐nine of the 180 patients (77·2%) had at least one optimal response. Taken together, our cohort has a 95% overall survival rate and 78% of the patients were still taking Glivec at a median time of 48·8 months (range 3–140 months). The number of patients who actually failed therapy, as defined by the LeukaemiaNet 2013 criteria, was 39 (21·7%). While our cohort has some differences with those in North America or Europe, we have shown Glivec is effective in inducing an optimal response in our patients in Nepal and that it is possible to deliver a clinical service for CML patients using tyrosine kinase inhibitors in resource‐poor settings.

60 Background: A significant number of patients with advanced cancer die in the hospital. Examination of patterns of care and palliative care (PC) involvement may identify opportunities for process of care improvements for this vulnerable population. Methods: Patients were identified using the institutional mortality review system registry (Mayo Clinic hospitals from July, 2013-June, 2014). Within this group, patients with a diagnosis of terminal malignancy were identified by chart review and ICD-9 codes. Patient demographics, clinical characteristics, and use of PC resources were characterized in the last 60 days of life. Results: There were 159 of 924 decedents identified whose primary cause of death was advanced malignancy (Table). Ninety-two patients (57%) had PC consultation during the index admission preceding death, while 31 (19%) patients had seen PC as an outpatient or inpatient prior to index admission. Lack of inpatient PC consultation at index admission was associated with hematologic malignancy (p < 0.001), full code status at death (p 0.009), shorter median time between change of code status to DNR and death (13 vs 67 hrs, p < 0.001), death in the ICU (58% vs 31%, p < 0.001), and presence of code blue (22% vs 5%, p-value = 0.003). Patients who received a PC consultation were less likely to have chemotherapy within 14 days of death (15% vs 37%, p-value = 0.001), and had a median composite aggressive end of life score (6 factor composite score based on utilization in last 30 days of life, higher score indicating more aggressive care) of 3 vs 4 (p 0.002). Conclusions: Inpatient PC consultation for cancer patients who die in the hospital is associated with less aggressive cancer care at end of life. The single-institution patient population and small sample size are the limitations of our study. [Table: see text]

A 60-year-old man presented with a 10-month history of of stereotypical spells characterized by vertigo, tinnitus, blurred vision, left hemibody numbness, and occasional syncope, precipitated by turning his head leftwards. Cerebral angiography and CT angiography of the head and neck with provocative maneuvers did not demonstrate vertebral artery narrowing. However, there was narrowing of the left internal jugular vein due to extrinsic compression from the sternocleidomastoid with leftward head rotation in the setting of hypoplasia of the right internal jugular vein. The patient underwent a cervical venogram which confirmed the finding. Manometric evaluation demonstrated a gradient of 29 mm Hg across the stenosis with the head turned leftwards compared with 1 mm Hg in the neutral position. The patient was treated with myectomies of the left sternocleidomastoid, posterior belly of the digastric, stylohyoid and omohyoid and styloid process removal. Following surgery, the patient reported complete resolution of symptoms. Repeat venography demonstrated resolution of the stenosis and pressure gradient.

Abstract Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P &lt; 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry–European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 3′ end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10−7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609–18. ©2016 AACR.

Abstract Earlier reports indicated that the role of Nf1 tumor suppressor gene in limiting sympathoadrenal cell growth during embryologic development is independent of its ability to down-modulate RAS-MAPK signaling. This finding raised the question of whether neuroblastoma pathogenesis was also accelerated by loss of a similar non-canonical function of NF1. To elucidate how loss of the NF1 tumor suppressor gene contributes to the development of high-risk neuroblastoma, we relied on a transgenic zebrafish model that overexpresses MYCN and harbors loss-of-function nf1 mutations. We show here that loss of nf1 leads to aberrant activation of RAS signaling in MYCN-induced neuroblastoma, promoting both increased tumor cell survival and rapid tumor cell proliferation. We demonstrate further that the GTPase-activating protein (GAP) activity of the (GAP)-related domain (GRD) is sufficient to suppress accelerated initiation of neuroblastoma in nf1-deficient zebrafish, even though this transgene is unable to restrict abnormal sympathoadrenal cell growth during embryologic development. Hence NF1 exhibits different activities in vivo in the normal development and tumorigenesis of the peripheral sympathetic nervous system. Our findings establish nf1-deficient zebrafish that overexpress MYCN as an ideal animal model system for investigating new strategies to improve treatment of very high risk neuroblastomas with aberrant RAS-MAPK activation. We are currently performing high-throughput in vivo drug analysis using these zebrafish with primary tumors. Citation Format: Shuning He, Marc R. Mansour, Mark W. Zimmerman, Dong Hyuk Ki, Hillary M. Layden, Koshi Akahane, Eric D. de Groh, Antonio R. Perez-Atayde, Shizhen Zhu, Jonathan A. Epstein, A Thomas Look. Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2456.