Mast-cell stabilization to decrease neurofibroma growth. Preliminary experience with ketotifen

Riccardi, Vincent M.

doi:10.1001/archderm.123.8.1011

Cited by 48 publications

(44 citation statements)

References 1 publication

(1 reference statement)

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“…Oral treatment with the mast cell blocker, ketotifen, has been shown to have several beneficial effects, including the unequivocal mitigation of neurofibroma-associated pruritus and avoidance of excessive bleeding during surgical treatment of neurofibromas. 12,13 Less convincing has been the influence of oral ketotifen treatment on changes in the number and/or size of the various types of neurofibromas. Unfortunately, further interest in this treatment approach languished until the demonstration by Zhang et al 27 that mast cells are key elements of the natural history of NF1 neurofibromas, at least in knockout mice.…”

Section: Medical Treatmentmentioning

confidence: 99%

“…For example, as I pointed out over 20 years ago, mast cells play a key role in the origin and progression of neurofibromas. 12,13,15 Ultimately, NF1 is a genetic disorder that is particularly efficient at producing neurofibromas. It is one of the most common of all human genetic disorders, with a prevalence of about one in 3000 and a mutation rate of about one in 10,000.…”

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confidence: 99%

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The genetic predisposition to and histogenesis of neurofibromas and neurofibrosarcoma in neurofibromatosis Type 1

Riccardi¹

2007

FOC

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The author addresses the issue of neurofibroma classification and implications for treatment. He emphasizes the importance of understanding that not all neurofibromas are the same and that the key differences between the types of neurofibromas involve which portions of the nerve sheath contribute to the distinctive behavior of the different types of lesions. Endoneurial neurofibromas derive from cellular elements ordinarily restricted to the endoneurium. Perineurial neurofibromas arise within individual fascicles of a nerve and are largely confined thereby, precluding a breach of the epineurium. Epineurial neurofibromas are contained only by the epineurium, and ultimately that portion of the nerve sheath is breached by these lesions. Whether the perineurium is present or breached becomes the key element for exploiting this approach to neurofibroma origins, behaviors, and treatment, surgical and medical. With respect to surgical treatment, perineurial neurofibromas will have clean planes of dissection about the involved nerve. In contrast, endoneurial and epineurial neurofibromas infiltrate adjacent tissues, leading to surgical challenges. With respect to pharmaceutical approaches, the integrity of the perineurium is likely to prove critical: a specific function of the perineurium is to serve as a barrier to various materials, microbiological or chemical. Thus, drugs that might be effective when the perineurium is absent or rent may be less effective (or not effective at all) if the perineurium is intact, as is expected in cases of perineurial neurofibromas.

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Section: Medical Treatmentmentioning

confidence: 99%

mentioning

confidence: 99%

The genetic predisposition to and histogenesis of neurofibromas and neurofibrosarcoma in neurofibromatosis Type 1

Riccardi¹

2007

FOC

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“…Further histological analyses have shown significant increases of mast cell number in only the neurofibroma tissue, as compared to surrounding tissue [32]. Based on these observations and his own clinical observations, Vincent Riccardi hypothesized that mast cells might directly modulate neurofibroma tissue [33], although histamine-release inhibitors, while effective at symptom control, ultimately did not affect neurofibroma progression [34,35].…”

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confidence: 99%

The Plexiform Neurofibroma Microenvironment

Yang

Staser

2012

Cancer Microenvironment

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Dynamic interactions between tumorigenic cells and surrounding cells, including immunomodulatory hematopoietic cells, can dictate tumor initiation, progression, and transformation. Hematopoietic-stromal interactions underpin the plexiform neurofibroma, a debilitating tumor arising in individuals afflicted with Neurofibromatosis type 1 (NF1), a common genetic disorder resulting from mutations in the NF1 tumor suppressor gene. At the tissue level, plexiform neurofibromas demonstrate a complex microenvironment composed of Schwann cells, fibroblasts, perineural cells, mast cells, secreted collagen, and blood vessels. At the cellular level, specific interactions between these cells engender tumor initiation and progression. In this microenvironment hypothesis, tumorigenic Schwann cells secrete pathological concentrations of stem cell factor, which recruit c-kit expressing mast cells. In turn, activated mast cells release inflammatory effectors stimulating the tumorigenic Schwann cells and their supporting fibroblasts and blood vessels, thus promoting tumor expansion in a feed-forward loop. Bone marrow transplantation experiments in plexiform neurofibroma mouse models have shown that tumorigenesis requires Nf1 haploinsufficiency in the hematopoietic compartment, suggesting that tumor microenvironments can depend on intricate interactions at both cellular and genetic levels. Overall, our continued understanding of critical tumor-stromal interactions will illuminate novel therapeutic targets, as shown by the first-ever successful medical treatment of a plexiform neurofibroma by targeted inhibition of the stem cell factor/c-kit axis.

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“…In this context I would point out that there have been several reports of treating systemic mastocytosis and mastocytomas with mast cell blockers, including ketotifen, for which there is already substantial experience in treating persons with NF1 [4,28,29]. The case report of Graves et al [30] is especially relevant in this setting.…”

Section: Vitamin D and Nf1: The Mast Cell Connectionmentioning

confidence: 99%

Hiding in Plain Sight: A Consideration of NF1-Associated Hypovitaminosis D and its Treatment

Riccardi¹

2014

J Genet Syndr Gene Ther

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This article deals with the autosomal dominant human genetic disorder, Neurofibromatosis Type 1 (NF1), and has three main foci. The first is the general principle that substantial advances in understanding the pathogenesis of a genetic disorder can derive from the timely reconsideration of material previously overlooked or otherwise not given its due. There are times when the key to a supposed "mystery" is hiding in plain sight. The second focus is the specific consideration of selected elements of an apparent vitamin D deficiency in NF1. And the third focus of this article reconsiders the mast cell in NF1 pathogenesis, including the potential of NF1 being a "mastocytosis" of sorts, with the prospect of additional grounds for treatment with mast cell blockers, for example, ketotifen.

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Mast-cell stabilization to decrease neurofibroma growth. Preliminary experience with ketotifen

Cited by 48 publications

References 1 publication

The genetic predisposition to and histogenesis of neurofibromas and neurofibrosarcoma in neurofibromatosis Type 1

The genetic predisposition to and histogenesis of neurofibromas and neurofibrosarcoma in neurofibromatosis Type 1

The Plexiform Neurofibroma Microenvironment

Hiding in Plain Sight: A Consideration of NF1-Associated Hypovitaminosis D and its Treatment

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