First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

TAK1 is involved in the autophagy process in retinal pigment epithelial cells.

Autophagy is an evolutionarily conserved mechanism for degrading long-lived or malfunctioning proteins and organelles, such as those resulting from oxidative stress. Several publications have demonstrated the importance of the autophagy process in the pathophysiology of dry age-related macular degeneration (AMD). Still, the mechanism underlying this process and its involvement in dry AMD are not fully characterized. Investigating the autophagy process in retinal pigment epithelial (RPE) cells, we identified transforming growth factor ß activated kinase 1 (TAK1) as a key player in the process. We found increased TAK1 phosphorylation in ARPE-19 and D407 cells treated with different inducers of autophagy, such as oxidative stress and rapamycin. Moreover, utilizing TAK1 specific inhibitor prior to oxidative stress or rapamycin treatment, we found significant reduction in LC3A/B-II expression. These results point at the involvement of TAK1 in the regulation of autophagy in RPE cells. This study suggests that aberrant activity of this kinase impairs autophagy and subsequently leads to alterations in the vitality of RPE cells. Proper activity of TAK1 may be essential for efficient autophagy, and crucial for the ability of RPE cells to respond to stress and dispose of damaged organelles, thus preventing or delaying retinal pathologies.

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

Launching the Quality Outcomes Database Tumor Registry: rationale, development, and pilot data.

OBJECTIVE: Neurosurgeons generate an enormous amount of data daily. Within these data lie rigorous, valid, and reproducible evidence. Such evidence can facilitate healthcare reform and improve quality of care. To measure the quality of care provided objectively, evaluating the safety and efficacy of clinical activities should occur in real time. Registries must be constructed and collected data analyzed with the precision akin to that of randomized clinical trials to accomplish this goal. METHODS: The Quality Outcomes Database (QOD) Tumor Registry was launched in February 2019 with 8 sites in its initial 1-year pilot phase. The Tumor Registry was proposed by the AANS/CNS Tumor Section and approved by the QOD Scientific Committee in the fall of 2018. The initial pilot phase aimed to assess the feasibility of collecting outcomes data from 8 academic practices across the United States; these outcomes included length of stay, discharge disposition, and inpatient complications. RESULTS: As of November 2019, 923 eligible patients have been entered, with the following subsets: intracranial metastasis (17.3%, n = 160), high-grade glioma (18.5%, n = 171), low-grade glioma (6%, n = 55), meningioma (20%, n = 184), pituitary tumor (14.3%, n = 132), and other intracranial tumor (24%, n = 221). CONCLUSIONS: The authors have demonstrated here, as a pilot study, the feasibility of documenting demographic, clinical, operative, and patient-reported outcome characteristics longitudinally for 6 common intracranial tumor types.

Antigen recognition: in vitro studies on the specificity of the cellular immune response.

Studies of the immunochemical specificity of antigen-induced thymidine-2-(14)C incorporation in lymph node cells obtained from animals immunized to a series of closely related alpha-DNP-oligolysines, epsilon-DNP-oligolysines, and oligolysines have shown that the sensitized cell exhibits an extraordinary degree of specificity for antigen. The sensitized cell is maximally stimulated by the homologous immunizing antigen and can discriminate among compounds which differ from one another only in the position of a dinitrophenyl group or D-lysine residue on an identical oligolysine backbone. These studies support the view that the immunogen is not degraded prior to the induction of the immune response, and that the majority of cells produced as a consequence of immunization have stereospecific antigen receptors for the DNP-oligolysine used to induce the response; a smaller and more variably sized population of cells is produced with receptors specific for the oligolysine portion of the immunizing antigen. When specifically sensitized lymph node cell cultures are stimulated in vitro by heterologous DNP-oligolysines, the oligolysine- and not the DNP-oligolysine-sensitive population of cells appears to play a crucial role in the specificity of such cross-reactions. It is concluded from these studies that the antigen receptor on the sensitized lymph node cell differs in both kind and degree from conventional antibody. The chemical nature of the receptor and the means by which this receptor reacts with antigen to initiate the biosynthetic or proliferative cellular immune response still remain undefined.

Immunochemical studies on the antigenic determinants required to elicit delayed and immediate hypersensitivity reactions.

Hartley and strain 2 guinea pigs were sensitized to chemically defined alpha-DNP(Lys)(n)-BuAm, alpha-DNP(Lys)(n)-, and (Lys)(n)-BuAm peptides and skin tested with individual members of these homologous series, related peptides and hapten-substituted proteins. The immediate skin response (Arthus) could be elicited with hapten-substituted tetra-, penta-, or hexamers, whereas both immediate and delayed skin responses could be provoked by the octamer or nonamer. The hapten is an integral part of the determinant for both immediate and delayed skin reactivity, since poly-L-lysine was unable to elicit either delayed or immediate reactions in sensitized animals. Arthus type cross-reactions occurred only when the sensitizing and test antigen shared a common haptenic determinant. In contrast to this, in this system, delayed type cross-reactions occurred only when the test antigen and the sensitizing antigen contained both a large oligo-L-lysine carrier as well as the same haptenic determinant. These observations imply that the mediation of the delayed response requires a larger determinant than is necessary to elicit the immediate response. The role of high affinity antibody as the mediator of the delayed response is discussed in terms of the size of the antigenic determinants required to elicit this response. It was found that the ability to elicit the delayed response paralleled the immunogenic capacity of these peptides, whereas the immediate response could be elicited by nonimmunogenic peptides. This finding suggests that the delayed response may require the continued biosynthesis of antibody and may be analogous to a local in vivo secondary response.

Do tubers contain function? Resection of epileptogenic foci in perirolandic cortex in children with tuberous sclerosis complex.

PURPOSE: Surgical resection of single, dominant, epileptogenic lesions in patients with tuberous sclerosis complex (TSC) is now accepted as an effective therapy. However, patients with symptomatic tubers in eloquent cortex are sometimes not offered surgery because of the concern for postoperative neurologic morbidity. In this study, we examine our results in children undergoing surgery for resection of tubers and associated seizure foci in rolandic and perirolandic cortex. METHODS: Between 1998 and 2008, 52 pediatric patients (mean age 4 years) with TSC underwent epilepsy surgery at the NYU Comprehensive Epilepsy Center. Fifteen of these patients underwent multistage surgery for invasive mapping of seizure foci and surrounding functional cortex followed by resection of tubers/seizure foci in or near rolandic cortex. Data were retrospectively collected and neurologic outcomes were tabulated. RESULTS: Postoperatively, four patients (27%) had either new hemiparesis or worsening of a preexisting hemiparesis. However, all patients were back to their neurologic baselines at 3-month follow-up, yielding no permanent postoperative deficits. The modified Engel outcome was class I in nine patients (60%), class II in three patients (20%), class III in two patients (13%), and class IV in one patient (7%) after 40 months mean follow-up. DISCUSSION: Surgical resection of tubers and associated epileptogenic foci in rolandic and perirolandic cortex in children with TSC is feasible, with low neurologic morbidity, and yields good seizure control. These results suggest that tubers and perituberal epileptogenic foci can be safely resected even in eloquent regions because of reorganization of functional cortex or because these lesions contain no neurologic function.

Organized Hematoma of the Sphenoid Sinus With Acute Blindness: Insight Into Pathogenesis of Disease.

Sinonasal organized hematomas (OHs) are rare lesions that primarily localize to the maxillary sinus. The rate of growth of these masses has not been described in the literature. We present a case of a 59-year-old gentleman with polyostotic fibrous dysplasia who presented with acute loss of vision in the left eye from an expanding OH of the sphenoid sinusitis. After expanded endonasal, transpterygoid approach and debulking, patient experienced significant vision improvement. Close follow-up imaging preoperatively allowed radiologic documentation of the rate of OH growth and this is presented in detail.

Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions.

Most striatal and cortical interneurons arise from the basal telencephalon, later segregating to their respective targets. Here, we show that migrating cortical interneurons avoid entering the striatum because of a chemorepulsive signal composed at least in part of semaphorin 3A and semaphorin 3F. Migrating interneurons expressing neuropilins, receptors for semaphorins, are directed to the cortex; those lacking them go to the striatum. Loss of neuropilin function increases the number of interneurons that migrate into the striatum. These observations reveal a mechanism by which neuropilins mediate sorting of distinct neuronal populations into different brain structures, and provide evidence that, in addition to guiding axons, these receptors also control neuronal migration in the central nervous system.

Refractory epilepsy in tuberous sclerosis: vagus nerve stimulation with or without subsequent resective surgery.

OBJECTIVE: The goal of the work described here was to assess the efficacy and safety of vagus nerve stimulation in a cohort of patients with tuberous sclerosis complex with refractory epilepsy. Furthermore, we examined the impact of vagus nerve stimulation failure on the ultimate outcome following subsequent intracranial epilepsy surgery. METHODS: A retrospective review was performed on 19 patients with refractory epilepsy and TSC who underwent vagus nerve stimulator (VNS) implantation. There were 11 (58%) females and 8 (42%) males aged 2 to 44 years when the VNS was implanted (mean: 14.7+/-12 years). Twelve patients underwent primary VNS implantation after having failed a mean of 7.1 antiepileptic drugs. Two patients (17%) had generalized epilepsy, one had a single seizure focus, three (25%) had multifocal epilepsy, and six (50%) had multifocal and generalized epilepsy. Seven patients were referred for device removal and evaluation for intracranial procedures. One patient in the primary implantation group was lost to follow-up and excluded from outcome analysis. RESULTS: All implantations and removals were performed without permanent complications. The duration of treatment for primary VNS implants varied from 8.5 months to 9.6 years (mean: 4.9 years). Mean seizure frequency significantly improved following VNS implantation (mean reduction: 72%, P<0.002). Two patients had Engel Class I (18%), one had Class II (9%), seven had Class III (64%), and one had Class IV (9%) outcome. Three patients with poor response to vagus nerve stimulation therapy at our center underwent resection of one or more seizure foci (Engel Class I, two patients; Engel Class III, one patient). Seven patients referred to our center for VNS removal and craniotomy underwent seizure focus resection (6) or corpus callosotomy (1) (Engel Class II: 2, Engel III: 2; Engel IV: 3). In total, 8 of 10 (80%) patients experienced improved seizure control following intracranial surgery (mean reduction: 65%, range: 0-100%, P<0.05). CONCLUSIONS: VNS is a safe and effective treatment option for medically refractory epilepsy in patients with tuberous sclerosis complex. Nine of 11 patients (82%) experienced at least a 67% reduction in seizure burden. Lack of response to vagus nerve stimulation does not preclude subsequent improvement in seizure burden with intracranial epilepsy surgery.

Plexin-A3 mediates semaphorin signaling and regulates the development of hippocampal axonal projections.

Plexins are receptors implicated in mediating signaling by semaphorins, a family of axonal chemorepellents. The role of specific plexins in mediating semaphorin function in vivo has not, however, yet been examined in vertebrates. Here, we show that plexin-A3 is the most ubiquitously expressed plexin family member within regions of the developing mammalian nervous system known to contain semaphorin-responsive neurons. Using a chimeric receptor construct, we provide evidence that plexin-A3 can transduce a repulsive signal in growth cones in vitro. Analysis of plexin-A3 knockout mice shows that plexin-A3 contributes to Sema3F and Sema3A signaling and that plexin-A3 regulates the development of hippocampal axonal projections in vivo.

Resection of insular gliomas: the importance of lenticulostriate artery position.

OBJECT: The object of this study was to identify characteristic preoperative angiographic and MR imaging features of safely resectable insular gliomas and describe the surgical techniques and postoperative clinical outcomes. METHODS: Thirty-eight patients with insular gliomas underwent transsylvian resection between 1995 and 2007. Patient demographics, presenting symptoms, pathological findings, and neurological outcomes were retrospectively reviewed. Preoperative MR imaging-defined tumor volumes were superimposed onto the preoperative stereotactic cerebral angiograms to determine whether the insular tumor was confined lateral to (Group I) or extended medially around (Group II) the lenticulostriate arteries (LSAs). RESULTS: Twenty-five patients (66%) had tumors situated lateral to the LSAs and 13 (34%) had tumors encasing the LSAs. Insular gliomas situated lateral to the LSAs led to significant medial displacement of these vessels (161 +/- 39%). In 20 (80%) of these 25 cases the boundaries between tumor and brain parenchyma were well demarcated on preoperative T2-weighted MR images. In contrast, there was less displacement of the LSAs (130 +/- 14%) in patients with insular gliomas extending around the LSAs on angiography. In 11 (85%) of these 13 cases, the tumor boundaries were diffuse on T2-weighted MR images. Postoperative hemiparesis or worsening of a preexisting hemiparesis, secondary to LSA compromise, occurred in 5 patients, all of whom had tumor volumes that extended medial to the LSAs. Gross-total or near-total resection was achieved more frequently in cases in which the insular glioma remained lateral to the LSAs (84 vs 54%). CONCLUSIONS: Insular gliomas with an MR imaging-defined tumor volume located lateral to the LSAs on stereotactic angiography displace the LSAs medially by expanding the insula, have well-demarcated tumor boundaries on MR images, and can be completely resected with minimal neurological morbidity. In contrast, insular tumors that appear to surround the LSAs do not displace these vessels medially, are poorly demarcated from normal brain parenchyma on MR images, and are associated with higher rates of neurological morbidity if aggressive resection is pursued. Preoperative identification of these anatomical growth patterns can be of value in planning resection.

Successful management of an anterior thoracic Type IV spinal arteriovenous malformation with two associated aneurysms utilizing vertebrectomy. Technical note.

Anteriorly located Type IV thoracic arteriovenous malformations (AVMs) are difficult to treat surgically. Although high-flow fistula subtypes are amenable to treatment using endovascular techniques, low-flow fistulas should be treated surgically. There are few reports discussing the diagnosis, behavior, and treatment of these spinal fistulas due to their low incidence. Posterior surgical approaches to Type IV spinal AVMs reported in the literature have been associated with high morbidity rates or aborted procedures. The authors report the successful management of a T-12 Type IV spinal AVM with an emphasis on approach, interoperative angiography, and the use of modern instrumentation. To the authors' knowledge, this is also the first reported case of multiple arterial-side aneurysms in a Type IV AVM of the anterior spinal artery.

Acute renal insufficiency, supraventricular tachycardia, and confusion after recombinant human bone morphogenetic protein-2 implantation for lumbosacral spine fusion.

The authors report on a case of a patient who received recombinant human bone morphogenetic protein-2 (rhBMP-2) to augment spinal fusion for the first and third of 3 lumbosacral fusion surgeries. After receiving rhBMP-2 the first time, the patient became febrile and developed mild acute renal insufficiency and transient supraventricular tachycardia (SVT). The second operation was complicated only by perioperative fever. When the patient received rhBMP-2 again during the third operation, he developed fever, acute oliguric renal insufficiency, symptomatic SVT with hypoxemia, confusion, and joint pain. No clear cause of these problems was identified; however serum analysis revealed the presence of an antibody to rhBMP-2. The authors discuss potential mechanisms for the patient's putative reaction to rhBMP-2, as the findings from a literature review suggest this is the first such reaction to be reported.

In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B.

NF-kappa B is a major inducible transcription factor in many immune and inflammatory reactions. Its activation involves the dissociation of the inhibitory subunit I kappa B from cytoplasmic NF-kappa B/Rel complexes, following which the Rel proteins are translocated to the nucleus, where they bind to DNA and activate transcription. Phosphorylation of I kappa B in cell-free experiments results in its inactivation and release from the Rel complex, but in vivo NF-kappa B activation is associated with I kappa B degradation. In vivo phosphorylation of I kappa B alpha was demonstrated in several recent studies, but its role is unknown. Our study shows that the T-cell activation results in rapid phosphorylation of I kappa B alpha and that this event is a physiological one, dependent on appropriate lymphocyte costimulation. Inducible I kappa B alpha phosphorylation was abolished by several distinct NF-kappa B blocking reagents, suggesting that it plays an essential role in the activation process. However, the in vivo induction of I kappa B alpha phosphorylation did not cause the inhibitory subunit to dissociate from the Rel complex. We identified several protease inhibitors which allow phosphorylation of I kappa B alpha but prevent its degradation upon cell stimulation, presumably through inhibition of the cytoplasmic proteasome. In the presence of these inhibitors, phosphorylated I kappa B alpha remained bound to the Rel complex in the cytoplasm for an extended period of time, whereas NF-kappa B activation was abolished. It appears that activation of NF-kappa B requires degradation of I kappa B alpha while it is a part of the Rel cytoplasmic complex, with inducible phosphorylation of the inhibitory subunit influencing the rate of degradation.

Sequential hydrolysis of proline-containing peptides with immobilized aminopeptidases.

Proline-containing polypeptides are shown to be sequentially degraded by two aminopeptidases. Clostridial aminopeptidase (EC 3.4.11-) cleaves off any N-terminal amino acid residue including proline from polypeptide chains, but does not cleave the N-terminal secondary peptide bonds involving a prolyl nitrogen. Aminopeptidase P (EC 3.4.11.9) cleaves exclusively such secondary bonds. The two enzymes were immobilized by coupling them covalently to porous amino glass beads. Highly stable preparations were obtained with unchanged pH optimum and thermal stability. The applicability of clostridial aminopeptidase to sequence determination was demonstrated by the time-dependent hydrolysis of enkephalin and Substance P octapeptide. Sequential hydrolysis with the two immobilized enzymes was demonstrated with the proline-containing (Pro-Gly-Pro)10, [Asn1, Val5]angiotensin II, bradykinin, Substance P and tuftsin. Absence of endopeptidase activities was demonstrated by resistance of cytochrome c to hydrolysis and by the ordered release of amino acids during the sequential degradation by immobilized clostridial aminopeptidase and aminopeptidase P.

Soluble and immobilized clostridial aminopeptidase and aminopeptidase P as metal-requiring enzymes.

The dependence of enzymatic activity on Co2+ concentration was found to be bell-shaped for the soluble and immobilized clostridial aminopeptidase (alpha-aminoacyl-peptide hydrolase, EC 3.4.11.13) and aminopeptidase P (aminoacylpropyl-peptide hydrolase, EC 3.4.11.9), with maxima in the 3-18 microM range of Co2+ concentration. The Co2+-enzyme association constants derived from the activation of soluble, glass- and cellulose-bound clostridial aminopeptidase by Co2+ were KE-Co = 5.2 X 10(5), 4.5 X 10(6) and 2.0 X 10(5) M-1, respectively; for soluble and glass-bound aminopeptidase P, the KE-Co were 1.5 X 10(5) and 8.2 X 10(5) M-1, respectively. Kinetic measurements indicate the involvement of Co2+ in the enzyme-substrate binding. Cobalt-citrate (Co-cit) acted as a useful metallobuffer and protected both enzymes against inhibition by high concentrations of CoSO4. For association of citrate with Co2+ under the assay conditions, KCo-cit was determined as (5.3 +/- 1.4) X 10(3) M-1 by anodic stripping polarography. In contrast to the rapid association of Co2+ with soluble and glass-bound clostridial aminopeptidase (less than 1 min at 4 degrees C), the dissociation process was very slow (hours to days), being slower for the glass-bound than for the soluble and cellulose-bound enzyme. For aminopeptidase P, both processes were rapid. All the interactions were shown to be reversible.

Lateralized neocortical control of T lymphocyte export from the thymus I. Increased export after left cortical stimulation in behaviorally active rats, mediated by sympathetic pathways in the upper spinal cord.

Electrical stimulation of left temporo-parieto-occipital (TPO) cortex in adult male Wistar rats during their behaviorally active phase (nighttime) transiently increased circulating levels of CD4+ and CD8+ T lymphocytes. Comparable stimulation of this cortex on the right decreased circulating levels of these cells. Responses to left or right cortical stimulation were diminished or absent in behaviorally inactive rats (daytime). Since blood glucocorticoid levels were similar before and after left or right stimulation, they did not appear to account for the lateralized changes observed. These lateralized effects were mediated by spinal cord autonomic pathways emerging at Tl-T7 levels. In adult thymectomized rats, CD4+ and CD8+ T cells failed to increase after left sided stimulation. The results suggest that lateralized cerebral cortical functions can acutely and differentially influence blood T cell subset numbers. The results demonstrate a direct neocortical influence on thymic export of mature T cells, mediated by the sympathetic nervous system.