This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.

IMPORTANCE Nerve growth factor (NGF) is an endogenous neurotrophic factor that prevents the death and augments the functional state of cholinergic neurons of the basal forebrain, a cell population that undergoes extensive degeneration in Alzheimer disease (AD).OBJECTIVE To determine whether stereotactically guided intracerebral injections of adeno-associated viral vector (serotype 2)-nerve growth factor (AAV2-NGF) are well tolerated and exhibit preliminary evidence of impact on cognitive decline in mild to moderate AD-associated dementia. DESIGN, SETTING, AND PARTICIPANTSIn a multicenter phase 2 trial, 49 participants with mild to moderate AD were randomly assigned in a 1:1 ratio to receive stereotactically guided intracerebral injections of AAV2-NGF or sham surgery. Participants were enrolled between November 2009 and December 2012. Analyses began in February 2015. The study was conducted at 10 US academic medical centers. Eligibility required a diagnosis of mild to moderate dementia due to AD and individuals aged 55 to 80 years. A total of 39 participants did not pass screening; the most common reason was Mini-Mental State Examination scores below cutoff. Analyses were intention-to-treat.INTERVENTIONS Stereotactically guided intracerebral injections of AAV2-NGF into the nucleus basalis of Meynert of each hemisphere or sham surgery. MAIN OUTCOMES AND MEASURESChange from baseline on the Alzheimer Disease Assessment Scale-cognitive subscale at month 24. RESULTS Among 49 participants, 21 (43%) were women, 42 (86%) self-identified as white, and the mean (SD) age was 68 (6.4) years. AAV2-NGF was safe and well-tolerated through 24 months. No significant difference was noted between the treatment group and placebo on the primary outcome measure, the Alzheimer Disease Assessment Scale-cognitive subscale (mean [SD] score, 14.52 [4.66] vs 9.11 [4.65], P = .17). CONCLUSIONS AND RELEVANCEThis multicenter randomized clinical trial demonstrated the feasibility of sham-surgery-controlled stereotactic gene delivery studies in patients with AD. AAV2-NGF delivery was well-tolerated but did not affect clinical outcomes or selected AD biomarkers. Pathological confirmation of accurate gene targeting is needed. TRIAL REGISTRATION clinicaltrials.gov Identifier NCT00876863

Recording neural activity during neurosurgical interventions is an invaluable tool for both improving patient outcomes and advancing our understanding of neural mechanisms and organization. However, increasing clinical electrodes' signal-to-noise and spatial specificity requires overcoming substantial physical barriers due to the compromised metal electrochemical interface properties. The electrochemical properties of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) based interfaces surpass those of current clinical electrocorticography electrodes. Here, robust fabrication process of PEDOT:PSS microelectrode arrays is demonstrated for safe and high fidelity intraoperative monitoring of human brain. PEDOT:PSS microelectrodes measure significant differential neural modulation under various clinically relevant conditions. This study reports the first evoked (stimulus-locked) cognitive activity with changes in amplitude across pial surface distances as small as 400 µm, potentially enabling basic neurophysiology studies at the scale of neural micro-circuitry.

Colloidal quantum dots (QDs) are widely studied due to their promising optoelectronic properties. This study explores the application of specially designed and synthesized “giant” core/shell CdSe/(CdS)x QDs with variable CdS shell thickness, while keeping the core size at 1.65 nm, as a highly efficient and stable light harvester for QD sensitized solar cells (QDSCs). The comparative study demonstrates that the photovoltaic performance of QDSCs can be significantly enhanced by optimizing the CdS shell thickness. The highest photoconversion efficiency (PCE) of 3.01% is obtained at optimum CdS shell thickness ≈1.96 nm. To further improve the PCE and fully highlight the effect of core/shell QDs interface engineering, a CdSexS1−x interfacial alloyed layer is introduced between CdSe core and CdS shell. The resulting alloyed CdSe/(CdSexS1−x)5/(CdS)1 core/shell QD‐based QDSCs yield a maximum PCE of 6.86%, thanks to favorable stepwise electronic band alignment and improved electron transfer rate with the incorporation of CdSexS1−x interfacial layer with respect to CdSe/(CdS)6 core/shell. In addition, QDSCs based on “giant” core/CdS‐shell or alloyed core/shell QDs exhibit excellent long‐term stability with respect to bare CdSe‐based QDSCs. The giant core/shell QDs interface engineering methodology offers a new path to improve PCE and the long‐term stability of liquid junction QDSCs.

Adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) offers the possibility of a new treatment for patients with malignant glial tumors. In a clinical trial, the effectiveness of a 5-day treatment cycle of direct intratumoral administration of both LAK cells and IL-2 via a reservoir/catheter system in patients with recurrent malignant gliomas was studied. Ten patients were entered into the study, nine of whom were treated with 15 cycles of LAK cells (0.9 to 21.0 x 10(9) cells) and IL-2 (49 to 450 x 10(3) U/kg). The 10th patient in the study was not treated because of the onset of severe neurological deficits prior to beginning immunotherapy. Of the nine patients treated, one had a partial tumor response to immunotherapy as documented by computerized tomography. Neurological side effects occurred in all patients undergoing treatment and were related to increases in cerebral edema that appeared to be mediated by the immunotherapy. This report demonstrates the present limitations of regional adoptive immunotherapy with LAK cells and IL-2 in the treatment of human glial tumors.

IMPORTANCE Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment.OBJECTIVE To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset.

The authors studied complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases (LM). One hundred twenty consecutive patients with LM (71 females and 49 males) ranging in age from 10 to 72 years (median 42 years) were treated with involved-field radiotherapy and intraventricular chemotherapy using an Ommaya reservoir and intraventricular catheter system. The diagnosis of LM was determined by a combination of clinical presentation (114 patients); cerebrospinal fluid cytological studies (100); or neuroradiographic studies (42). Systemic tumor histological findings included breast (34 patients); non-Hodgkin's lymphoma (22); melanoma (16); primitive neuroectodermal tumors including medulloblastoma (10); glial neoplasms, leukemia, small cell lung, nonsmall cell lung, and colon (six each); prostate and kidney (three each); and gastric cancers (two). Sixteen patients, all with non-Hodgkin's lymphoma, also had acquired immune deficiency syndrome. Patients received one to four (median two) chemotherapeutic drugs and underwent a total of 1110 cycles of intraventricular chemotherapy (median 10). Intraventricular chemotherapy administration and diagnostic Ommaya reservoir punctures totaled 4400, with a median of 46 per patient. Complications included aseptic/chemical meningitis (52 patients); myelosuppression due to intraventricular chemotherapy (21); catheter-related infections (nine); unidirectional catheter obstruction (six); intraventricular catheter malpositioning (two); Ommaya reservoir exposure (two); leukoencephalopathy (two); and chemotherapy-related myelopathy (one). There were no treatment-related deaths; however, seven patients (6%) required additional surgery for either catheter repositioning (two) or reservoir removal (five). Seven patients with catheter-related infections were treated successfully with intraventricular and systemic antibiotic drugs, thereby preserving the Ommaya system. The authors conclude that Ommaya reservoirs are convenient and pharmacologically rational systems for administering intraventricular chemotherapy. Overall, serious complications requiring surgery are infrequent (6%) and most often secondary to catheter infections, Ommaya reservoir exposure, or initial catheter malpositioning. In the majority of instances, catheter infections may be managed medically, as may the most common complications of intraventricular chemotherapy including aseptic meningitis (43% of patients) and myelosuppression (18%).

Previous reports showed that the loss of DNA sequences on the short arm of chromosome 3 (3p) is consistently found in sporadic renal cell carcinomas. To evaluate the significance of this genetic change, we looked for the loss of 3p alleles in hereditary renal cell carcinomas and other tumors from patients with von Hippel-Lindau disease. Specific loss of alleles from chromosome 3p was detected with polymorphic DNA markers in 11 renal cell carcinomas, one pheochromocytoma, two spinal hemangioblastomas and one cerebellar hemangioblastoma from von Hippel-Lindau patients. Multiple renal cell carcinomas in individuals with von Hippel-Lindau disease showed loss of the same chromosome 3p alleles, which demonstrated that the same chromosome was deleted in each tumor. Analysis of haplotypes indicated that the loss of chromosome 3p alleles was from the chromosome bearing the balancing, wild-type allele of the VHL gene. These results are consistent with the concept that the VHL gene is a recessive oncogene. Renal cell carcinoma, pheochromocytoma, and spinal and cerebellar hemangioblastomas develop in predisposed family members when somatic mutational events lead to loss of chromosome 3p sequences bearing the wild-type allele of the VHL gene.