Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors.

Patients with basal cell nevus syndrome have a high incidence of multiple basal cell carcinomas, medulloblastomas, and meningiomas. Because somatic PATCHED (PTCH) mutations have been found in sporadic basal cell carcinomas, we have screened for PTCH mutations in several types of sporadic extracutaneous tumors. We found that 2 of 14 sporadic medulloblastomas bear somatic nonsense mutations in one copy of the gene and also deletion of the other copy. In addition, we identified missense mutations in PTCH in two of seven breast carcinomas, one of nine meningiomas, and one colon cancer cell line. No PTCH gene mutations were detected in 10 primary colon carcinomas and eighteen bladder carcinomas.

Hyperfractionated craniospinal radiation therapy for primitive neuroectodermal tumors: early results of a pilot study.

PURPOSE: To report the early results of hyperfractionated craniospinal radiation therapy with and without adjuvant chemotherapy for primitive neuroectodermal brain tumors (PNETs). METHODS AND MATERIALS: Thirty-nine patients with PNETs were classified as good-risk (23) or poor-risk (16), based on postoperative magnetic resonance imaging and a cytological examination of cerebrospinal fluid. All patients received hyperfractionated craniospinal radiation therapy; poor-risk patients subsequently received adjuvant chemotherapy with cisplatin, lomustine, and vincristine. The first six patients received 72 Gy to the primary tumor site and 24 Gy to the rest of the craniospinal axis. Subsequent patients received 30 Gy to the craniospinal axis. RESULTS: During a median of 1.9 years of follow-up (range 4 months to 3.5 years), there have been ten treatment failures in 39 patients, five in the good-risk group and five in the poor-risk group. Three failures occurred in the primary tumor site in areas that received 72 Gy; two were in poor-risk patients with residual disease after surgery; one was in a good-risk patient who had a gross total resection. Three failures occurred in the spine and craniospinal fluid of patients treated with 24 Gy. Four occurred in areas treated to 30 Gy; two of these were in areas thought to be undertreated because of treatment planning errors. Adjuvant chemotherapy was difficult to give to poor-risk patients because of poor bone marrow recovery, even with relatively low doses of lomustine (75 mg/m2). CONCLUSION: We think a dose of 24 Gy to the craniospinal axis is inappropriate because three of the six patients who received it had treatment failures outside the primary site. Whether 30 Gy is an appropriate dose for good-risk patients is still unclear. Even after a dose of 30 Gy, chemotherapy was difficult to give; this potentially limits the impact of adjuvant chemotherapy in poor-risk patients. Further follow-up is necessary to evaluate the use of hyperfractionated radiation therapy alone or with chemotherapy in patients with PNETs.

Hyperfractionated radiation therapy for gliomas of the brainstem in children and in adults.

Between February 1984 and September 1990, 60 patients with brainstem gliomas were treated with hyperfractionated radiotherapy in the Department of Radiation Oncology at the University of California, San Francisco. Forty-one children (< or = 18 years) and 19 adults were treated with 100 cGy twice daily with 4-8 hr between doses. Thirty-one patients (21 children and 10 adults) received total doses of 66-72 Gy and 29 patients (20 children and nine adults) received 74-78 Gy. Median follow-up was 208 weeks for all patients (214 weeks for children, 157 weeks for adults). Twenty-three patients (14 children and nine adults) were alive at the time of analysis, surviving 59-359 weeks following treatment. Median actuarial survival was 73.6 weeks overall (72 weeks for children, 190 weeks for adults; p = 0.43). Survival at 12 and 24 months was 65% and 38%, respectively (63% and 32%, for children; 68% and 53% for adults). All patients had pretreatment magnetic resonance imaging by which tumors were classified as either focal or diffuse. No significant pretreatment prognostic factors for adults were identified. In children, significant favorable prognostic factors on univariate analysis were older age (p = 0.001), tumor location in thalamus or midbrain (p = 0.002), focal appearance on MRI scan (p < 0.001) and duration of symptoms > 2 months prior to treatment (p < 0.001). Thirty-five patients had tumor biopsies, leading to a diagnosis in 33 (22 children and 11 adults). Children with moderately anaplastic astrocytomas survived significantly longer than those with glioblastoma multiforme or unbiopsied tumors (p < 0.001). Only duration of symptoms > 2 months remained significant as a favorable prognostic indicator for children on multivariate analysis (p < 0.001). Survival was not significantly different for patients receiving < or = 72 Gy and those receiving > 72 Gy (p = 0.18). No subgroup of patients showed significantly better survival with the higher dose. These findings indicate that hyperfractionated radiotherapy is effective treatment for adults and a subgroup of better prognosis children with brainstem gliomas. There is a subgroup of pediatric patients with extremely poor prognosis for whom even this aggressive treatment does little to extend survival. We conclude that there is no benefit to increasing total dose above 72 Gy for any of the groups analyzed.

Loss of heterozygosity for chromosome 22 DNA sequences in human meningioma.

Monosomy of chromosome 22 in meningioma was the first consistent cytogenetic anomaly reported for a solid tumor. Although most meningiomas are isolated sporadic lesions, multiple and familial occurrences have been reported, usually in cases of documented neurofibromatosis 2 (NF2). Previous reports have placed the NF2 locus on chromosome 22, flanked by the markers D22S1 and D22S28. We report a restriction fragment-length polymorphism study of 16 meningiomas conducted using chromosome 22 probes. None of the patients had clinical findings or a family history of NF2, although two of them eventually developed multiple intracranial meningiomas. Detectable loss of chromosome 22 sequences was observed in 50% of informative patients. Deletion mapping of tumors with preserved sequences showed that the loss of chromosome 22 DNA overlapped the region previously linked to NF2, but also included a sequence distal to the NF2 locus. These results suggest that the oncogenesis of human meningioma involves inactivation of a chromosome 22 locus that may be in close proximity to the gene for NF2.

Chromosome arm 17p deletion analysis reveals molecular genetic heterogeneity in supratentorial and infratentorial primitive neuroectodermal tumors of the central nervous system.

The current World Health Organization (WHO) classification groups together both infratentorial neoplasms (medulloblastomas) and their supratentorial counterparts as primitive neuroectodermal tumors (PNETs), implying a common origin. Previous analyses of medulloblastoma have shown loss of chromosome arm 17p as the most frequent genetic abnormality: the molecular genetic constitution of supratentorial PNETS has not been systematically studied. We therefore examined 8 hemispheric PNETs and 35 medulloblastomas with 17p restriction fragment length polymorphism (RFLP) and microsatellite markers. We also examined the TP53 tumor suppressor gene by a combined polymerase chain reaction-denaturing gradient gel (PCR-DGGE) technique. Our results showed that all of the 17p markers tested were preserved in all of the supratentorial PNET specimens. In contrast, loss of distal chromosome arm 17p was detected in 37% of the medulloblastomas. Analysis of the TP53 gene showed 2 mutations in the medulloblastomas and no mutations in the supratentorial tumors. These results show that the most common molecular genetic abnormality in infratentorial PNETS is absent in their supratentorial counterparts and suggests that alternative pathways and genetic events may be involved in their etiology.

Congenital nasal masses: CT and MR imaging features in 16 cases.

The imaging studies of 16 children with pathologically proved nasal encephaloceles (eight), nasal dermal sinuses/nasal dermoids (seven), and nasal cerebral heterotopias, more commonly known as nasal gliomas (one), were retrospectively reviewed and compared with normal control subjects to define the normal anatomy and analyze deformities caused by these lesions. Nasal encephaloceles were always identified as complex masses of mixed soft tissue and CSF intensity that were contiguous with intracranial structures. The nasal glioma appeared as a mixed-intensity mass that, on the basis of the CT scan, appeared to be continuous with intracranial structures. Nasal dermal sinuses could only be identified as they coursed through the skin and subcutaneous soft tissue. They could not be identified when intraosseous. Moreover, on CT and, particularly, on MR, a number of potential diagnostic pitfalls were encountered. The most important of these was the normal fat deposition that occurs within bone during normal maturation and during aeration of the frontal sinuses and nasal bones. These fatty changes can easily be mistaken for fatty tumors if they are not recognized as normal anatomic changes. Interestingly, the classic plain film findings for congenital nasal masses were present only in the encephaloceles and nasal glioma; dermoids and dermal sinuses showed none of the classic plain film findings. In the six patients who had both CT and MR, the masses were easily identified and characterized by each imaging method. Congenital nasal masses are well characterized by both CT and MR. It is important to understand the normal changes in the anatomy of the nasofrontal region in the pediatric age group to avoid false-positive diagnoses in this region.

MR evaluation of spinal dermal sinus tracts in children.

The MR studies of seven pediatric patients with surgically proved spinal dorsal dermal sinuses were reviewed retrospectively. Five of the seven had associated congenital tumors (three epidermoids, two dermoids). The subcutaneous portions of the spinal tracts and intramedullary portions of tumor were easily identified with the use of standard spin-echo techniques. However, except for limited areas where they were lined by fat, the intraspinal portions of the dermal sinuses were poorly seen. Moreover, diffuse subarachnoid tumor was missed in two patients. Three-dimensional Fourier transform gradient-echo acquisition using a volumetric radiofrequency pulse as a "spoiler" proved to be helpful in evaluating these abnormalities. Optimal radiologic workup of patients with dorsal dermal sinuses awaits the development of new MR imaging sequences. For now, heavily T1-weighted MR sequences should be obtained and supplemented with sonography in infants and with CT myelography in older children.

Intracerebral arteriovenous fistulas associated with intraparenchymal varix in childhood: case reports.

This report describes three children, each of whom developed an unusual malformation consisting of one or more intracerebral arteriovenous fistulas and a large intraparenchymal venous varix. Their clinical symptoms were similar to those produced by aneurysms of the vein of Galen: increasing head circumference, seizures, hemorrhage, and developmental delay. We treated each child with endovascular embolization and/or surgery and obtained complete closure of all fistulas without mortality.

Antimigraine treatment for slit ventricle syndrome.

Slit ventricle syndrome is characterized by chronic or recurring headaches associated with subnormal ventricular volume in patients who have undergone shunt treatment for hydrocephalus. There appear to be at least three pathophysiological mechanisms that cause this syndrome: 1) intermittent shunt malfunction; 2) intracranial hypotension; and 3) paroxysms of increased intracranial pressure in the presence of normal shunt function. To treat seven patients with slit ventricle syndrome caused by paroxysms of elevated intracranial pressure, we successfully used antimigraine therapy rather than standard calvarial expansion procedures. None of these patients has required shunt revision or calvarial expansion during a mean follow-up period of 2 years. The symptoms of slit ventricle syndrome may be a form of "acquired" migraine in shunt patients. We suggest that, in clinically stable patients with normal shunt function, treatment against migraine may stabilize symptoms resulting from paroxysms of increased intracranial pressure. Such treatment may prevent unnecessary shunt revisions and/or calvarial expansion procedures.

The "filum intermedium" sign: focal in utero spinal cord infarct and extraspinal thecal sac. Case report.

This report describes the unique case of a child born with paraplegia and a neurogenic bladder who was found to have a dysplastic, nonossified T-12 vertebral body, midline fusion of the T-12 neural arches, obliteration of the spinal canal at T-12, and an extraspinal thecal sac in the T11-L1 region. Neural tissue was focally absent from T9-12, but neural structures above and below were preserved. Narrowing of the thecal sac on myelograms and sagittal magnetic resonance images signifies in utero focal infarction of the spinal cord after neurulation but before formation of the posterior half of the spinal canal. The infarction resulted in severe focal narrowing of the thecal sac from T10-L1, resembling a premature and duplicated filum terminale; to denote the radiographic appearance of these anomalies, the authors have coined the term "filum intermedium" sign. The extremely unusual radiographic findings in this child illustrate the important interactions between neural tube, neural crest, and somite in the development of the spinal cord and spinal column. Correlation of the radiographic findings with the embryological differentiation and migration of these structures suggests that the spinal anomalies were caused by a focal insult, probably vascular in origin, occurring between the sixth and eighth weeks of gestation. The identification of a focally narrowed thecal sac and spinal cord (the "filum intermedium" sign) localizes the time of the insult to between the first and third month of gestation, and therefore is a useful marker in understanding developmental malformation of the spinal cord.

Metastatic juvenile pilocytic astrocytoma. Case report.

The authors report the case of a metastatic juvenile pilocytic astrocytoma of the hypothalamic region in a 10-year-old boy. Eight years after craniotomy and radiation therapy, the tumor spread via cerebrospinal fluid pathways to the left cerebellar tonsil and the lumbosacral region. Histological evaluation of both the original hypothalamic and the new lumbosacral masses showed features of a slow-growing juvenile pilocytic astrocytoma with no evidence of malignant transformation. The clinical implications and possible mechanisms of metastatic spread are discussed.

Intracranial arachnoid cysts in children. A comparison of the effects of fenestration and shunting.

The best operative intervention for children with arachnoid cysts remains the subject of controversy. Recent reports stress that craniotomy for cyst fenestration is associated with a low incidence of morbidity and mortality and may leave the child shunt-independent. The cases of 40 pediatric patients with arachnoid cysts treated between 1978 and 1989 are reported. Five children with mild symptoms and small cysts that remained stable on follow-up studies have not required surgical intervention. Of 15 patients with cysts initially treated by fenestration, 10 (67%) showed no clinical or radiographic improvement postoperatively and have undergone cyst-peritoneal (eight patients) or ventriculoperitoneal (VP) shunting (one patient), or revision of a VP shunt placed for hydrocephalus before cyst fenestration (one patient). Two other patients with existing VP shunts required no further procedures. Thus, only three (20%) of 15 patients initially treated by fenestration remain shunt-independent after a median follow-up period of 8 years. The 20 other patients were initially treated by cysts shunting and all improved postoperatively; shunt revision has been necessary in six (30%) of these 20 patients because of cysts recurrence. Cyst location influenced the success of shunt treatment; none of the seven middle cranial fossa cysts treated by shunting have required revision, but results with cysts in other locations were less favorable. In all locations, though, shunting was more successful than fenestration. It is concluded that cyst-peritoneal or cyst-VP shunting is the procedure of choice for arachnoid cysts in most locations, including those in the middle cranial fossa.

Medulloblastoma: freedom from relapse longer than 8 years--a therapeutic cure?

Seventy-seven patients presenting with medulloblastoma between 1958 and 1986 were treated at Stanford University Medical Center and studied retrospectively. Multimodality therapy utilized surgical extirpation followed by megavoltage irradiation. In 15 cases chemotherapy was used as adjunctive treatment. The 10- and 15-year actuarial survival rates were both 41% with an 18-year maximum follow-up period (median 4.75 years). There were no treatment failures after 8 years of tumor-free survival. Gross total removal of tumor was achieved in 22 patients (32%); the surgical mortality rate was 3.9%. No significant difference was noted in the incidence of metastatic disease between shunted and nonshunted patients. The classical form of medulloblastoma was present in 67% of cases while the desmoplastic subtype was found in 16%. Survival rates were best for patients presenting after 1970, for those with desmoplastic tumors, and for patients receiving high-dose irradiation (greater than or equal to 5000 cGy) to the posterior fossa. Although early data on freedom from relapse suggested a possible beneficial effect from chemotherapy, long-term follow-up results showed no advantage from this modality of treatment. The patterns of relapse and survival were examined; 64% of relapses occurred within the central nervous system, and Collins' rule was applicable in 83% of cases beyond the period of risk. Although patients treated for recurrent disease could be palliated, none were long-term survivors. The study data indicate that freedom from relapse beyond 8 years from diagnosis can be considered as a cure in this disease. Long-term follow-up monitoring is essential to determine efficacy of treatment and to assess survival patterns accurately.

Treatment options and prognosis for multicentric juvenile pilocytic astrocytoma.

Little is known about the risk of developing multicentric disease in patients with juvenile pilocytic astrocytoma (JPA), and even less about its prognosis. Only five cases have been reported. Between 1986 and 1992, the authors treated 90 patients with either primary or recurrent JPA, 11 of whom developed multicentric spread. Ten patients had primary tumors in the hypothalamic region, eight were under 4 years of age at initial diagnosis, all had initially undergone a subtotal resection or biopsy, and 10 received postoperative multiagent chemotherapy or irradiation for residual disease. Multicentric spread was discovered immediately to 108 months after initial diagnosis; nine patients were asymptomatic at the time. Most patients received chemotherapy for the multicentric disease, which was found throughout the craniospinal axis. During 21 to 148 months of follow-up monitoring, seven patients had stabilization or regression of multicentric disease and four died. Patients with hypothalamic region tumors were 23 times more likely to develop multicentric spread than were those with primary tumors located elsewhere (p < 0.001). Based on this review, it is concluded that multicentric spread of JPA occurs more frequently than was previously recognized. In patients with subtotally resected JPA and several years of follow-up review via magnetic resonance imaging, the incidence of recurrence in a site different from the original was 12%. Patients with subtotally resected JPA in the hypothalamic region should be considered to be at high risk for developing multicentric spread. Chemotherapy appears useful in stabilizing multicentric disease. Earlier detection and intervention may result in longer disease-free survival in patients with multicentric spread of JPA.

Resection of dominant opercular gliosis in refractory partial epilepsy. Report of two cases.

Frontal opercular gliosis in the dominant hemisphere caused medically refractory partial epilepsy in two patients. Both patients were aphasic during their seizures, but otherwise had normal speech. Magnetic resonance images showed well-demarcated lesions resembling tumors in each patient; on heavily T2-weighted images, the lesions were hyperintense compared with normal brain. Cortical mapping with subdural grids localized speech to the area of the lesions; therefore, the resections were performed under local anesthesia and speech was tested throughout the procedure. Postoperatively, both patients were seizure-free and had no new neurological deficits. Well-demarcated lesions, even in the dominant operculum, can be safely removed in patients with medically refractory partial epilepsy.

Diffuse leptomeningeal involvement by a ganglioglioma in a child. Case report.

Gangliogliomas are tumors composed of neuronal and glial elements that typically grow slowly by expansion only. This report describes a 20-month-old girl with a ganglioglioma that extensively involved the subarachnoid space; microscopic foci of tumor were found in the brain and spinal cord. Despite chemotherapy and radiation therapy, the child died 5 months after diagnosis. Molecular genetic analysis showed loss of chromosome 17p DNA sequences in the tumor tissue.

Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration.

OBJECT: The outcome for children with recurrent malignant brain tumors is poor. The majority of patients die of progressive disease within months of relapse, and other therapeutic options are needed. The goal of this Phase I study was to evaluate the safety of in vivo suicide gene therapy in 12 children with recurrent, malignant, supratentorial brain tumors. METHODS: After optimal repeated tumor resection, multiple injections of murine vector-producing cells shedding murine replication-defective retroviral vectors coding the herpes simplex virus thymidine kinase type 1 (HSV-Tk1) gene were made into the rim of the resection cavity. Fourteen days after the vector-producing cells were injected, ganciclovir was administered for 14 days. The retroviral vector that was used only integrated and expressed HSV-Tk1 in proliferating cells, which are killed after a series of metabolic events lead to cell death. The median age of the patients was 11 years (range 2-15 years). Treated brain tumors included seven malignant gliomas, two ependyminomas, and three primitive neuroectodermal tumors. The patients were treated with one of three escalating dose concentrations of vector-producer cells. Four transient central nervous system adverse effects were considered possibly related to the vector-producing cells. In no child did permanent neurological worsening or ventricular irritation develop, and tests for replication-competent retroviruses yielded negative findings. CONCLUSIONS: This Phase I study demonstrates that in vivo gene therapy in which a replication-defective retroviral vector in murine vector-producing cells is delivered by brain injections can be performed with satisfactory safety in a select group of children with localized supratentorial brain tumors.

Ovarian steroid hormones and cerebral function.

PIP: This study reviews the available literature concerning clinical evidence of the effects of ovarian steroid hormones on the brain. The negative effects of estrogen on chorea gravidarum and in women using oral contraception (OC) is well known. Estrogens, however, can at times be beneficial in patients with movement disorders. The fall of progesterone level at menstruation can be associated with catamenial epilepsy, while estrogen increases epileptiform electroencephalogram activity. Both estrogens and progesterone affect neurotransmitters by altering absolute concentration and turnover in brain tissue. By interfering with monoamine oxidase, estrogens may increase dopamine, and it is possible that they can worsen brain pseudotumor, although data available are not very clear on this point. The possible role of ovarian or male steroid hormones in other neurological disorders is unknown. Further studies are needed, since it is apparent that not all types of abnormal movements respond in the same way to treatment with such steroids.^ieng

Reproductive function in temporal lobe epilepsy: the effect of temporal lobectomy.

We have examined sexual and reproductive changes in 25 patients (11 men and 14 women; mean follow-up 13 years) with temporal lobe epilepsy who underwent temporal lobectomy. Five men and two women had sexual dysfunction preoperatively, in particular, decreased libido. This improved after temporal lobectomy in three of these patients. One woman developed a partial Klüver-Bucy syndrome. Reproductive dysfunction was present in one man (oligospermia) and in ten women (four had the onset of seizures either at pregnancy or menarche; four had increased frequency of seizures during menarche or pregnancy, and two had amenorrhea). The man fathered two children post-operatively, and an appreciable improvement in both the seizure activity and the reproductive dysfunction was noted in the majority of the women.