Malignant human gliomas are the most common formsof primary tumors in the central nerve system.Due to their location and invasive nature, treatmentso far has been mainly palliative. Thus, understandingthe molecular detail of tumor transformation and progressionis crucial for developing effective therapeutic strategy forthis fetal tumor. Among the genetic alternations foundin these tumors, p53 inactivation and PDGF/PDGFR activationrepresent the early events, and the loss ofchromosome 10 and gene amplification and rearrangement ofEGFR represent the late events. Studies with bothglioma cell lines and primary tumor tissues havestrongly suggested that TGF-α and EGFR function asan important autocrine loop in supporting proliferation ofhuman glioma, especially in high grade glioma, sinceelevated TGF-α expression is also found in thesehigh grade tumors. Furthermore, down regulation of theexpression of TGF-α by antisense constructs has beenshown to inhibit several types of human tumorcell growth including glioma. Other means of therapeuticapproaches using this autocrine loop as a targetalso include the use of monoclonal antibodies andtheir cytotoxic conjugated. Considerable understanding of the EGFR-mediatedsignal transduction pathways has become available recently, whichincluding GRB2/mSOS1 mediated MAP kinase activation; JAK/STATs pathway;PLC-γ pathway. However, much work still needs tobe done before a specific component of thesepathways can be applied for effective control oftumor growth in the clinic.

The autocrine loop of TGF-α/EGFR and brain tumors

Background: The incidence of brain tumors is increasing rapidly, particularly in the older population. Advances in molecular biology help to explain differences in biologic behavior and response to therapy of brain tumors in the elderly compared with younger patients. The number of elderly patients who desire and receive therapy for brain tumors and are included in clinical trials is increasing. Methods: This article reviews the literature on the epidemiology, clinical aspects, and therapy of brain tumors, with emphasis on the older patient population. Results: The increased incidence of brain tumors in the elderly is principally due to the increasing number of people who comprise the older population. Age and performance status are important independent prognostic indicators, together with tumor histology. Surgery, radiation therapy, and chemotherapy can benefit elderly patients with brain tumors with favorable histologies, tumor location, and good performance status. The response rates to available therapies are less favorable than in younger patients, and only a small number of elderly patients are enrolled in clinical studies addressing new treatment modalities. Conclusions: Brain tumors in the elderly have specific characteristics that determine their biologic behavior and response to therapy. There is a need for clinical studies designed for treatment of brain tumors in older patients, and requirements for rehabilitation and support systems for the elderly need to be addressed.

https://journals.sagepub.com/doi/pdf/10.1177/107327480000700604

Brain Tumors in the Older Person

Recent cases of nosocomial poisoning associated with the treatment of patients contaminated with organophosphate (OP) insecticides and the increasing potential for exposure to these chemicals elevate into sharper focus the continuing clinical and public health problem of pesticide poisoning. Despite a number of reports on the multiple aspects of OPs insecticides and their health effects, the general public and health services professionals, broadly defined, remain confused and misinformed about this class of chemicals. In this article we examine sources of exposure and current knowledge of health effects of OPs. The protection of health care workers is also discussed.

Current concepts: Organophosphate toxicity

The effects of transforming growth factor-α (TGF-α) on cell growth were studied in human glioma U251 cells transfected with antisense TGF-α vectors (pcDNAI.neo). Several antisense clones showed a marked decrease in growth rate in serum-free medium but not in medium containing 10% FBS, compared with those of parental cells and clones from sense or vector transfectants. Antisense clones also produced fewer and smaller colonies in anchorage-independent growth assays. Moreover, there was a reduction in TGF-α expression in these antisense clones at both the protein and mRNA levels, as determined by enzyme linked immuno-sorbent assay and reverse transcriptase polymerase chain reaction analysis. A U251 clone transfected by TGF-α antisense in a different vector (pMT/Ep) also showed a marked suppression in cell growth and TGF-α mRNA level. Finally, transfected clones with either vector system, showed decreased tumorigenicity in nude mice. In summary, a strong correlation between the inhibition of glioma cell growth and TGF-α expression was obtained from two different plasmid vectors, indicating that the expression of TGF-α could be specifically and effectively down-regulated by TGF-α antisense vector, which in turn led to growth inhibition. These studies suggests that TGF-α plays an essential role in controlling human glioma cell proliferation and may serve as a potential target for treatment of malignant glioma.

Transforming Growth Factor-α Antisense Vectors can Inhibit Glioma Cell Growth

To investigate the colonic adenoma-adenocarcinoma progression sequence, DNA ploidy analysis was performed on hyperplastic polyps to adenocarcinomas. DNA ploidy data were then compared with immunocytochemical staining for proliferating cell nuclear antigen (PCNA). In hyperplastic polyps to villous adenomas, all cases were diploid except one aneuploid villous adenoma. In three adenomas, diploidin situ adenocarcinomas were present. As diploid percentages decreased from hyperplastic polyps to villous adenomas, aneuploid percentages increased. In adenocarcinomas, the Dukes classification corresponded well to DNA ploidy status: all four stage A carcinomas were diploid, whereas three cases each of stage C1 and C2 carcinomas were aneuploid or multiploid. A surprising finding was that S-phase percentage in adenocarcinomas was not parallel with PCNA-positive tumor cell numbers. It is concluded that multistep adenoma-adenocarcinoma progression was partially reflected in DNA ploidy pattern from hyperplastic polyps to villous adenomas. In adenocarcinomas, the Dukes classification paralleled well the DNA ploidy status from stage A diploid to stage D aneuploid, but was not accompanied by increasing PCNA-positive cell numbers.

DNA ploidy and proliferating cell nuclear antigen in colonic adenomas and adenocarcinomas.

Molecular, genetic, and biologic aspects of primary brain tumors

Transverse myelitis (TM) occurs isolated or within other acquired demyelinating syndromes (ADS) such as neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS) or myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD).To describe and compare clinical and MRI features of children with ADS presenting with TM grouped according to antibody status and diagnosis of MS and NMOSD.Children with TM, radiological involvement of the myelon, MOG and aquaporin-4 antibody status were elegible.100 children were identified and divided into MOGAD (n=33), NMOSD (n=7), double seronegative TM (n=34), and MS (n=26). MOGAD children had mainly acute disseminated encephalomyelitis + TM/ longitudinally extensive TM (LETM) (42%) or isolated LETM (30%). In MOGAD, LETM was present in more than half of all children (55%) with predominant involvement of only the grey matter (73%). Leptomeningeal enhancement was highly predictive of MOGAD (16/30; p=0.003). In MS patients spinal MRI showed single (50%) or multiple short lesions (46%) with involvement of grey and white matter (68%). Double seronegative children presented with LETM (74%) and brain lesions were less frequent compared to the other groups (30%).Children with ADS presenting with TM reveal important radiological differences such as LETM with predominant involvement of spinal grey matter and leptomeningeal enhancement in MOGAD. 

C. A. Conrad

Papers

Molecular, genetic, and biologic aspects of primary brain tumors

MR imaging in children with transverse myelitis and acquired demyelinating syndromes.