Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present a series of 31 cases of optic glioma associated with neurofibromatosis type 1 in patients under 11 years of age. They represent 64% of all the optic gliomas seen in our service between September 1965 and September 1993. The optic nerves were affected in 25 cases (83%); 9 children (30%) had a isolated, unilateral tumor; 16 (53%) had involvement of the optic chiasm as well as of one or both optic nerves. In 6 cases (19%) only the chiasm was affected, with or without involvement of other intracerebral structures. A coincidental orbital plexiform neurofibroma was associated with a poor prognosis. Other complications included 8 cases (26%) presenting with slowly developing aqueductal stenosis requiring treatment with a shunt. High-resolution computed-tomographic scans provided well-defined images for the diagnosis of optic nerve glioma, but magnetic resonance imaging was the preferred procedure for the diagnosis of gliomas involving the chiasm and the optic tracts and radiations, particularly if there was no mass effect. In our patients, tumor growth was hardly noticeable during follow-up even up to 20 years, with no difference between patients who were treated with radiation and those who were not treated. However, endocrine disturbances developed in all cases subjected to radiotherapy, and were less frequent in untreated patients. Aqueductal stenosis was observed with similar frequency among both treated or untreated patients. Three patients died, two due to complications of hydrocephalus secondary to aqueductal stenosis and one because of respiratory problems due to compression of the hypothalamus and brainstem by the chiasm tumor. Two of the 3 patients who died had orbital plexiform neurofibroma.
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PMID:Optic gliomas in neurofibromatosis type 1 (NF-1). Presentation of 31 cases. 802 21

This article describes some types of growth in plexiform neurofibroma (PNF) on magnetic resonance images (MRI). This tumor is almost exclusively associated with NF1. On MRI, the tumor is depicted as a hyperintensive area on T2-weighted images. We distinguished 3 patterns of tumor growth: first, the superficial and non-invasive tumors, that are restricted to the cutis and subcutis, only eventually having outgrowth to the muscles beneath and are slow growing. Second, the displacing PNF that develop in deeper layers of the skin or within the body. They can grow to a large extent but do not invade adjacent muscles or skin. Thirdly, the invasive type with no visible margins that cannot be resected without adjacent structures or organs. A combination of these tumors can sometimes be noted, e.g. a displacing tumorous nerve developing in a large lumpy, non-invasive PNF. These categories might be used as a current guideline for medical advice, surgical treatment planning and medication trials.
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PMID:Growth type of plexiform neurofibromas in NF1 determined on magnetic resonance images. 1282 Mar 28

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with highly variable expression generally ascribed to random factors. However, evidence is presented for patterns suggesting non-stochastic processes as follows: (1) We have seen a MZ twin pair concordant for renal vascular hypertension, and another for unilateral ptosis. Other concordances have been reported, including both malformations and tumors, and combinations as well. (2) Four children were seen with a distinct ipsilateral association of glaucoma or iris anomaly, optic glioma, plexiform neurofibromas arising from the trigeminal nerve and its branches, and sphenoid dysplasia. Other cases in the literature support milder forms of this association. (3) We saw six children with apparent gynecomastia or premature thelarche without endocrine abnormalities. Tissue samples from four of these showed an unusual fibrous plexiform neurofibroma. Interestingly, five of the six cases were African Americans, and constitutional factors affecting fibrous reactions may also be involved here.A tentative hypothesis is presented suggesting vascular fields involving defined areas that can: (1) Support tumor growth. They would be the "soil" determining the ability and the extent of growth. There would, however, still be a need for a "second hit" tumor transformation. (2) Affect blood supply to organs, creating structural anomalies. NF1 involves a vasculopathy, and would predispose to vulnerabilities of such fields. Genetic factors could induce superimposed susceptibilities of specific fields, leading to twin concordances. "Hits" affecting specific fields would increase the likelihood of multiple abnormalities that could include both tumors and structural findings. Finally, tumors may follow the contours of existing fields. The breast is an area normally primed for growth, and the observation of clitoromegally secondary to tumor involvement suggests that such fields exist elsewhere.
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PMID:Non-random associations and vascular fields in neurofibromatosis 1: a pathogenetic hypothesis. 1677 Aug 9

Plexiform neurofibromas are peripheral nerve sheath tumors that arise frequently in neurofibromatosis type 1 (NF1) and have a risk of malignant progression. Past efforts to establish xenograft models for neurofibroma involved the implantation of tumor fragments or heterogeneous primary cultures, which rarely achieved significant tumor growth. We report a practical and reproducible animal model of plexiform-like neurofibroma by xenograft of an immortal human NF1 tumor-derived Schwann cell line into the peripheral nerve of scid mice. The S100 and p75 positive sNF94.3 cell line was shown to possess a normal karyotype and have apparent full-length neurofibromin by Western blot. These cells were shown to have a constitutional NF1 microdeletion and elevated Ras-GTP activity, however, suggesting loss of normal neurofibromin function. Localized intraneural injection of the cell line sNF94.3 produced consistent and slow growing tumors that infiltrated and disrupted the host nerve. The xenograft tumors resembled plexiform neurofibromas with a low rate of proliferation, abundant extracellular matrix (hypocellularity), basal laminae, high vascularity, and mast cell infiltration. The histologic features of the developed tumors were particularly consistent with those of human plexiform neurofibroma as well. Intraneural xenograft of sNF94.3 cells enables the precise initiation of intraneural, plexiform-like tumors and provides a highly reproducible model for the study of plexiform neurofibroma tumorigenesis. This model facilitates testing of potential therapeutic interventions, including angiogenesis inhibitors, in a relevant cellular environment.
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PMID:Plexiform-like neurofibromas develop in the mouse by intraneural xenograft of an NF1 tumor-derived Schwann cell line. 1733 73

Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, which include myeloid leukemia, optic glioma, and plexiform neurofibroma. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, nontumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation, accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate neurofibroma tissue, mediate key mitogenic signals that contribute to vascular ingrowth, collagen deposition, and tumor growth. Thus, the plexiform neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system that depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and are clearly relevant to medical management of these neurofibromas.
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PMID:Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression. 2207 53

Plexiform neurofibromas of the foot are rare and often present with significant pain, deformity, and functional impairment secondary to their locally invasive behavior. While treatment has traditionally focused on attempts at radical resection, a lack of consensus among surgeons has hindered the establishment of a well-defined algorithm to guide the management of these highly co-morbid peripheral nerve sheath tumors. We present the case of an advanced plexiform neurofibroma of the right foot in a 24-year-old male with neurofibromatosis type 1. The patient presented following accelerated tumor growth with extensive osseous erosion, intractable pain, and progressive ankle instability that limited his capacity to ambulate and wear shoes. A modified transtibial amputation with a vascularized fibular bone graft (Ertl procedure) was performed without complication. Following graduated rehabilitation, postoperatively, the patient regained functional independence and was able to ambulate without pain in a customized prosthesis after 3 months. Plexiform neurofibromas of the foot present a complex challenge for foot and ankle surgeons. On the basis of our experience and previously reported cases, we advocate for amputation over aggressive attempts at advanced limb salvage for patients with extensive skeletal destruction, joint instability, and/or intractable pain caused by tumor mass effect.
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PMID:Management of advanced plexiform neurofibromatosis of the foot presenting with skeletal deformation and intractable pain: an indication for proximal amputation. 2549 57

Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous disorders. Some NF1 patients develop benign large plexiform neurofibroma(s) at birth, which can then transform into a malignant peripheral nerve sheath tumor (MPNST). There is no curative treatment for this rapidly progressive and easily metastatic neurofibrosarcoma. Photodynamic therapy (PDT) has been developed as an anti-cancer treatment, and 5-aminolevulinic (ALA) mediated PDT (ALA-PDT) has been used to treat cutaneous skin and oral neoplasms. Doxycycline, a tetracycline derivative, can substantially reduce the tumor burden in human and animal models, in addition to its antimicrobial effects. The purpose of this study was to evaluate the effect and to investigate the mechanism of action of combined doxycycline and ALA-PDT treatment of MPNST cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the combination of ALA-PDT and doxycycline significantly reduce MPNST survival rate, compared to cells treated with each therapy alone. Isobologram analysis showed that the combined treatment had a synergistic effect. The increased cytotoxic activity could be seen by an increase in cellular protoporphyrin IX (PpIX) accumulation. Furthermore, we found that the higher retention of PpIX was mainly due to increasing ALA uptake, rather than activity changes of the enzymes porphobilinogen deaminase and ferrochelatase. The combined treatment inhibited tumor growth in different tumor cell lines, but not in normal human Schwann cells or fibroblasts. Similarly, a synergistic interaction was also found in cells treated with ALA-PDT combined with minocycline, but not tetracycline. In summary, doxycycline can potentiate the effect of ALA-PDT to kill tumor cells. This increased potency allows for a dose reduction of doxycycline and photodynamic radiation, reducing the occurrence of toxic side effects in vivo.
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PMID:Doxycycline potentiates antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy in malignant peripheral nerve sheath tumor cells. 2855 25

Plexiform neurofibromas are congenital peripheral nerve sheath tumors characteristic of neurofibromatosis type 1 (NF1)-a frequent neurocutaneous disorder caused by mutations of the NF1 tumor suppressor gene. Since plexiform neurofibromas are a major cause of the burden of disease and may also progress to malignancy, many efforts have been undertaken to find a cure for these tumors. However, neither surgery nor medication has so far produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor selumetinib. Here, we report an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1.
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PMID:Trametinib Induces Neurofibroma Shrinkage and Enables Surgery. 3114 29