Age and TP53 mutation frequency in childhood malignant gliomas: results in a multi-institutional cohort.

Malignant astrocytoma is one of the most deadly primary central nervous system tumors. Although significant progress has been made in understanding the molecular pathways that lead to the development of these tumors in adults, comparatively little analysis has been done in childhood astrocytomas, which are less common and have a more favorable prognosis. Our previous studies of an institutional cohort of children with malignant gliomas suggested the existence of distinct molecular pathways of tumorigenesis in younger versus older children, based on the finding of a high frequency of TP53 mutations in tumors from children >3 years of age at diagnosis, compared with those from younger children. In the current study, the association between TP53 mutations and age was examined in greater detail using the multi-institutional group of children enrolled in Children's Cancer Group Study 945, the largest cohort of childhood high-grade gliomas analyzed to date. Seventy-seven tumors with centrally reviewed diagnoses of anaplastic astrocytoma or glioblastoma multiforme had sufficient archival histopathological material for microdissection-based genotyping. Sections were examined histologically, and topographic targets that contained malignant tissue were isolated by microdissection and subjected to PCR-based amplification and sequencing of TP53 exons 5-8. Twenty-six tumors (33.8%) had mutations in those exons. Mutations were observed in 2 of 17 tumors (11.8%) from children <3 years of age at diagnosis versus 24 of 60 tumors (40%) from older children, a difference that was statistically significant (P = 0.04), in agreement with our previous results. Whereas malignant gliomas in older children have a frequency of mutations comparable to tumors that arise in young adults, those from children <3 years old do not. The association between age and frequency of TP53 mutations among pediatric malignant gliomas indicates the probable existence of two distinct pathways of molecular tumorigenesis in younger versus older children.

Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group.

PURPOSE: Infants represent a very poor risk group for acute lymphoblastic leukemia (ALL). We report treatment outcome for such patients treated with intensive therapy on consecutive Children's Cancer Group (CCG) protocols. PATIENTS AND METHODS: Between 1984 and 1993, infants with newly diagnosed ALL were enrolled onto CCG-107 (n = 99) and CCG-1883 (n = 135) protocols. Postconsolidation therapy was more intensive on CCG-1883. On both studies, prophylactic treatment of the CNS included both high-dose systemic chemotherapy and intrathecal therapy, in contrast to whole-brain radiotherapy, which was used in earlier studies. RESULTS: Most patients (>95%) achieved remission with induction therapy. The most frequent event was a marrow relapse (46 patients on CCG-107 and 66 patients on CCG- 1883). Four-year event-free survival was 33% (SE = 4.7%) on CCG-107 and 39% (SE = 4.2%) on CCG- 1883. Both studies represent an improvement compared with a 22% (SE = 5.1%) event-free survival for historical controls. Four-year cumulative probabilities of any marrow relapse or an isolated CNS relapse were, respectively, 49% (SE = 5%) and 9% (SE = 3%) on CCG-107 and 50% (SE = 5%) and 3% (SE = 2%) on CCG-1883, compared with 63% (SE = 6%) and 5% (SE = 3%) for the historical controls. Independent adverse prognostic factors were age less than 3 months, WBC count of more than 50,000/microL, CD10 negativity, slow response to induction therapy, and presence of the translocation t(4;11). CONCLUSION: Outcome for infants on CCG-107 and CCG- 1883 improved, compared with historical controls. Marrow relapse remains the primary mode of failure. Isolated CNS relapse rates are low, indicating that intrathecal chemotherapy combined with very-high-dose systemic therapy provides adequate protection of the CNS. The overall unsatisfactory outcome observed for the infant ALL population warrants the future use of novel alternative therapies.

Effects of inferior temporal lesions on discrimination of stimuli differing in orientation.

Monkeys with inferior temporal (IT) cortex lesions were compared with normal and operated control monkeys on a series of two-choice visual discrimination problems. In some problems, the discriminanda were different patterns or objects whereas, in other problems, the discriminanda were identical patterns or objects presented in different orientations. The animals with IT lesions were significantly impaired in learning to discriminate the different patterns and objects; however, they were not impaired in learning to discriminate stimuli which differed only in orientation by 60 degrees or more. These results help to specify further the role of the IT cortex in visual associative learning by demonstrating that there are some types of visual discriminations which are not sensitive to IT lesions.

Stimulus equivalence after inferior temporal lesions in monkeys.

Monkeys with inferior temporal cortex lesions and unoperated monkeys were trained to discriminate pairs of objects and then tested for transfer after the original discriminanda were made larger or smaller, rotated, or presented as two-dimensional projections. The two groups of monkeys transferred equally well to the discriminanda altered in size or orientation, but only the unoperated animals transferred to the two-dimensional representation.

Ablations of the mammillary nuclei in monkeys: effects on postoperative memory.

A new procedure was developed for ablating the mammillary nuclei in nonhuman primates via direct visual exposure. Using this technique, monkeys receiving lesions of the mammillary nuclei were compared to control animals after surgery to assess the retention of preoperatively acquired visuospatial discriminations and subsequent postoperative ability to attain a demanding spatial memory task. Although the lesions proved to be accurate and complete, no changes in gross behavior or deficits in preoperatively acquired visual and spatial behaviors were noted. The monkeys with mammillary body lesions were, however, impaired in their ability to acquire postoperatively the demanding spatial memory task. These findings are consistent with previous investigations suggesting that the mammillary bodies are involved in the acquisition of spatial discriminations and skills.

Crystalloids of prostatic carcinoma: relationship to Bence-Jones crystals.

Previously undemonstrated protein crystalloid structures were found to occur in the malignant acini of prostatic carcinomas in 23% of cases systematically reviewed. Histochemically and immunohistochemically, they appear closely related, if not identical, to Bence-Jones crystals. Thus, the prostatic carcinoma cell is the first neoplastic cell besides those of the lymphocytic-plasmacytic series shown to produce such crystalline structures. Like the proteolytic splitting of amyloid from Bence-Jones proteins, it is postulated that prostatic epithelium may enzymatically split corpora amylacea from a Bence-Jones-like protein which it synthesizes. It is further postulated that malignant prostatic cells may lack the necessary enzymatic machinery to accomplish this with resultant accumulation of crystalloids within their acini. Prostatic crystalloids were never found in benign glands with rare exceptions and then were limited to benign appearing glands adjacent to carcinoma. The presence of such crystalloids in microscopic sections of prostate may be of diagnostic aid in determining the presence of malignancy or of a premalignant state.

Tumors of the pilosebaceous unit induced in the rat by the intravenous administration of 7,12-dimethylbenz(A)anthracene.

Six of 70 female Sprague-Dawley rats given a single intravenous injection of 7,12-dimethylbenz[a]anthracene (DMBA) developed 7 pilosebaceous tumors. Two of the tumors showed differentiation toward the upper portion of the pilosebaceous unit while 5 showed differentiation toward the lower portion. Each tumor was examined histochemically for the presence of inner root sheath keratin of the hair follicle using the carbamido diacetyl reaction for citrulline and for hair shaft keratin using boiling ninhydrin reagent. The 2 tumors of the upper portion of the pilosebaceous unit were sebaceous adenomas which were accompained by a keratinizing epithelim like that of the sebaceous gland duct and upper pilosebaceous canal. Histochemically, the keratin was not like that of hair shaft nor inner root sheath. The 5 tumors showing differentiation toward components of the lower pilosebaceous unit were trichoepitheliomas. They were composed of structures which, to varying degrees, recapitulated the organization of the normal hair follicle. Within these follicular structures, both inner root sheath and hair shaft type keratins were found. The occurrence of skin tumors after the intravenous administration of DMBA was unexpected since it is uncommon for skin tumors to be produced by the systematic administration of chemical carcinogens and they have never been described after the oral administration of DMBA. That the route of administration may influence tumor production with this carcinogen is suggested by the fact that the only other reported tumors, which were squamous carcinomas, also followed intravenous injection of DMBA.