TAp73 is a marker of glutamine addiction in medulloblastoma.

Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

Preoperative and postoperative neurological, neuropsychological and behavioral impairment in children with posterior cranial fossa astrocytomas and medulloblastomas: the role of the tumor and the impact of the surgical treatment.

INTRODUCTION: The aim of the present study was to prospectively investigate if a correlation might exist between preoperative and postoperative neurological conditions, neuroradiological/intraoperative findings and results of a complete neuropsychological evaluation in children with posterior fossa medulloblastomas and astrocytomas. MATERIALS AND METHODS: Of the 65 children admitted at the Pediatric Neurosurgery of the UCSC of Rome between January 2005 and October 2009, 41 were selected; the only two exclusion criteria were represented by age under 24 months and severe neurological conditions, seen that in both cases it would not have been a possible reliable evaluation. All children underwent a preoperative and immediate postoperative complete MR study. Hydrocephalus was graded on the Evans score; brainstem infiltration was defined on intraoperative findings. Neuropsychological assessment consisted of a battery of tests tailored on the patient's age, cognitive level, and level of cooperation. Post operative neuropsychological evaluation was performed at a mean time of 2.5 min (2 mos, max 4.5 mos) from the operation, before any eventually needed adjuvant treatment (i.e., chemotherapy, radiotherapy). RESULTS: Concerning neurological status, we found a statistically significant relation between the presence of oculomotor impairment and both verbal fluency deficits (p = 0.044) and imagery disorders (p = 0.03); also, the presence of ataxia/dysmetria was significantly correlated to attention dysfunction (p = 0.01) and, more tightly, to planning dysfunction (p = 0.006). For neuroradiological/intraoperative features, Intelligence Quotient (IQ) impairment was significantly correlated to the intraoperative evidence of tumor infiltration of the brainstem (p = 0.003), a severe hydrocephalus at diagnosis (p = 0.001) and the histological diagnosis of medulloblastoma (MB) (p = 0.002). For selective skills, a significant correlation was found between linguistic processing deficits and the evidence of dentate nuclei infiltration (blindly defined on MR); procedural memory defects and imagery disorders related to the severity of the hydrocephalus (p = 0.02), infiltration of the brain stem (p = 0.01) and a histological diagnosis of MB (p = 0.01). After surgery no patient showed a worsening of his/her cognitive profile; the relationships between clinical, intraoperative, and radiological findings were substantially confirmed. DISCUSSION: Our results support the hypothesis that when present, neuropsychological impairment is already present at diagnosis and that the most statistically significant factors, which might be related with cognitive deficits in the preoperative as well as in the postoperative period, are tumor infiltration of the brainstem, the severity of hydrocephalus, and a histological diagnosis of MB.

Neurogenic stunned myocardium after acute hydrocephalus.

Neurogenic stunned myocardium (NSM) is a syndrome of cardiac stunning after a neurological insult. It is commonly observed after aneurysmal subarachnoid hemorrhage but is increasingly being reported after other neurological events. The underlying mechanism of NSM is believed to be a hypothalamic-mediated sympathetic surge causing weakened cardiac contractility and even direct cardiac myocyte damage. The authors report 2 cases of NSM in pediatric patients after acute hydrocephalus. Both patients experienced severe cardiac dysfunction in the acute phase but ultimately had a good neurological outcome and a full cardiac recovery. The identification, treatment, and outcome in 2 rare pediatric cases of NSM are discussed, and the history of the brain-cardiac connection is reviewed.

The pathophysiologic mechanism of cerebellar mutism.

OBJECTIVE: Cerebellar mutism (CM) is a postoperative complication of mainly pediatric posterior fossa surgery. Multiple theories exist for explaining this phenomenon. We have made an attempt to further understand this entity given a particularly interesting case as it relates to multiple pathophysiologic pathways. METHODS: We have reviewed the details surrounding a particularly interesting case of CM. A retrospective analysis of this patient's clinical history and recovery is described. An extensive literature review has been performed in conjunction with an attempt to help elucidate details and a better understanding of CM. RESULTS: A thorough analysis of existing theories as to the pathophysiologic mechanism of CM has been performed as it relates to the details of this particular case. A case is described in which a child exhibiting CM abruptly improved and made a relatively quick recovery after the triggering of the melodic speech pathway by way of watching and beginning to sing along with a video. It appears that this incident involving a familiar song catalyzed various speech pathways, which apparently were in some state of shock. This phenomenon seems to be a temporary entity involving not only the mechanical coordination of speech production, but also the initiation of speech itself. CONCLUSIONS: Evidence exists for a pathophysiologic pathway for speech by way of coordinating phonation and articulation. In addition, there seems to exist a pathway by which the initiation of speech may be altered or halted by posterior fossa pathology, namely, vermian or dentate nuclear injury. In particular to this case, we found that the incidental appreciation of other forms of speech, melodic in this instance, may be the key to help stimulate and accelerate the recovery from CM.

Medulloblastoma: therapy and biologic considerations.

Tremendous strides have been made in both the treatment and the biologic understanding of medulloblastoma. Present optimal treatment can cure most medulloblastoma patients. A substantial minority of patients, however, will have recurrent or progressive disease. Recent studies have demonstrated that the success of treatment is not simply a matter of chance, but rather can be predicted based on specific biologic markers. These markers predict outcome independent of clinical staging and make clear that medulloblastomas are a biologically diverse group of tumors with variable clinical behavior. Molecular biologic investigation, including replication of tumorigenesis in transgenic mice, has further elucidated the complex biology of medulloblastoma. Current standard and investigational treatments, however, do not yet make use of biologic markers that predict risk of recurrence. Practical limitations have slowed the pace at which treatment paradigms can be revised to incorporate biologic insights. Mouse medulloblastoma models may provide an important bridge between biologic investigation and the development of new therapeutic approaches.

Treatment of human glioma and medulloblastoma tumor lines in athymic mice with diaziquone and diaziquone-based drug combinations.

We used diaziquone (NSC 182986) alone and in combination with other antineoplastic drugs to treat six human glioma and one human medulloblastoma tumor lines growing s.c. in athymic mice. Pharmacokinetic studies of diaziquone in the plasma of athymic mice indicated rapid clearance with a half-life of approximately 11.5 min. Diaziquone produced significant growth delays in at least one experiment using each of seven different tumor lines, and it produced consistent and significant delays in five of the seven. There was no obvious difference between a single dose and a dose administered once daily for 5 days, and tumor regressions to a volume smaller than that at treatment were uncommon in any of the single-drug experiments. Using our most extensively characterized human glioma line, D-54 MG, we found striking enhancement of the therapeutic effect by using nontoxic combinations of either diaziquone and carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, NSC 409962) or diaziquone and procarbazine (NSC 77213). These combinations produced significant increases in the median growth delay, significant increases in the number of tumor regressions, and some instances in which no palpable tumors were present 100 days after treatment. In contrast, in experiments using diaziquone -based chemotherapy combinations with either cyclophosphamide, cis-platinum, or vincristine, there was only slight enhancement of the therapeutic effect. These results, using human glioma and medulloblastoma tumor lines in athymic mice, suggest a broad range of activity of diaziquone against primary nervous system tumors and enhancement of its therapeutic effect with either 1,3-bis(2-chloroethyl)-1-nitrosourea or procarbazine. If Phase II and Phase III clinical trials corroborate these findings, the value of the nude mouse system for the evaluation of new therapeutic approaches to brain neoplasms would be further confirmed.

[Origin of short latency somatosensory evoked potential following median nerve stimulation].

Short latency somatosensory evoked potentials (S-SEP) to median nerve stimulation recorded from scalp-shoulder derivation consisted of four positivities (P1, P2, P3 and P4) and one negativity (N). There is still, however, significant controversy regarding the generators of these peaks. The purpose of the present study is to attempt to solve some of the controversies by comparing the potentials recorded on surface montages with intrasurgical tracing obtained while monitering evoked potentials. This is complemented by analysis of S-SEP in patients with disorders of the cervical cord, brain stem or thalamus. Average latency of each component in normal subjects (N = 17) was as follows; P1: 7.6 +/- 0.6 ms P2: 9.6 +/- 0.7 ms, P3: 11.8 +/- 0.8 ms, P4: 12.9 +/- 0.5 ms, N: 17.7 +/- 0.8 ms. The peak latency of P1 was always shorter than that of negativity recorded over the Erb's point following the median nerve stimulation. The peak latency of P2 corresponded to that of the earliest negativity of spinal evoked potential, recorded from the epidural dorsal surface of the lower cervical cord during the operation, which was considered as the potential of afferent volley at the posterior root or spinal entry portion. In a case with severe spondylotic radiculopathy, P2 and following components were abolished. The peak latency of P3 corresponded to that of negative potential recorded over the high cervical dorsal column or cuneate nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)