NF2 Research Highlights: 2004 & earlier

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• 2004 & prior

Otol Neurotol. 2004 Sep;25(5):811-7.

Vestibular schwannoma growth rates in neurofibromatosis type 2 natural history consortium subjects.

Slattery WH 3rd, Fisher LM, Iqbal Z, Oppenhiemer M.

House Ear Institute, Los Angeles, California 90057, USA

Abstract:
OBJECTIVE: To determine the amount of growth in vestibular schwannomas in Neurofibromatosis type 2 (NF2) patients from diagnosis through short-term (up to 2 yr) and long-term (up to 4 yr) follow-up.
STUDY DESIGN: Retrospective magnetic resonance imaging (MRI) films were obtained on subjects enrolled in the NF2 Natural History study and examined for changes in vestibular schwannoma size over time.
SETTING: Data were collected from nine foreign and domestic NF2 centers, including hospital-based, academic, and tertiary care centers.
SUBJECTS: NF2 patients with MRI data and at least one follow-up examination within 9 months to 2 years of diagnosis were included; n=56 patients with 84 lesions for evaluation of growth.
INTERVENTION: Routine, clinically obtained, magnetic resonance images were digitized and measured using image management software. Short-term follow-up was defined as up to 2 years (n=84 lesions), and long-term follow-up was defined as 3 to 4 years (n=29 lesions).
OUTCOME MEASURES: Vestibular schwannoma size was assessed using anterior-posterior, medial-lateral, and greatest diameter linear measurements. RESULTS: Vestibular schwannomas increased in size (at least 5 mm) in 8% of the vestibular schwannomas across short-term follow-up. At long-term follow-up, 13% of the tumors had increased in size. On average, schwannomas increased in greatest diameter 1.3 mm per year across short-term follow-up.
CONCLUSION: Slightly greater than 1 in 10 diagnosed NF2-related vestibular schwannomas increased in size by at least 5 mm by 4 years of follow-up, if still untreated at that time.

The Oncologist, Vol. 9, No. 4, 442-450.

Conformal Radiation Therapy for Childhood CNS Tumors. (FULL TEXT)

David G. Kirsch, Nancy J. Tarbell

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

Abstract:
Radiation therapy plays a central role in the management of many childhood brain tumors. By combining advances in brain tumor imaging with technology to plan and deliver radiation therapy, pediatric brain tumors can be treated with conformal radiation therapy. Through conformal radiation therapy, the radiation dose is targeted to the tumor, which can minimize the dose to normal brain structures. Therefore, by limiting the radiation dose to normal brain tissues, conformal radiation therapy offers the possibility of limiting the long-term side effects of brain irradiation.
In this review, we describe different approaches to conformal radiation therapy for pediatric central nervous system tumors including: A) three-dimensional conformal radiation therapy; B) stereotactic radiation therapy with arc photons; C) intensity-modulated radiation therapy; and D) proton beam radiation therapy. We discuss the merits and limitations of these techniques and describe clinical scenarios in which conformal radiation therapy offers advantages over conventional radiation therapy for treating pediatric brain tumors.

Am J Hum Genet. August 2004; 75(2): 231-239.

Genotype-Phenotype Correlations for Nervous System Tumors in Neurofibromatosis 2: A Population-Based Study (FULL TEXT)

Michael E. Baser¹, Lisa Kuramoto², Harry Joe², J. M. Friedman³, Andrew J. Wallace⁴, James E. Gillespie⁵, Richard T. Ramsden⁶, and D. Gareth R. Evans<sup>4

1</sup>Los Angeles; Departments of ²Statistics and ³Medical Genetics,
University of British Columbia, Vancouver;⁴University Department of Medical Genetics, St. Mary's Hospital, and Departments of ⁵Radiology and ⁶Otolaryngology, Manchester Royal Infirmary, Manchester, United Kingdom

Abstract:
Neurofibromatosis 2 (NF2) is an autosomal dominant disease that is characterized by tumors on the vestibular branch of the VIII cranial nerve, but other types of nervous system tumors usually occur as well. Genotype-phenotype correlations are well documented for overall NF2 disease severity but have not been definitively evaluated for specific types of non�VIII nerve tumors. We evaluated genotype-phenotype correlations for various types of non�VIII nerve tumors in 406 patients from the population-based United Kingdom NF2 registry, using regression models with the additional covariates of current age and type of treatment center (specialty or nonspecialty). The models also permitted consideration of intrafamilial correlation. We found statistically significant genotype-phenotype correlations for intracranial meningiomas, spinal tumors, and peripheral nerve tumors. People with constitutional NF2 missense mutations, splice-site mutations, large deletions, or somatic mosaicism had significantly fewer tumors than did people with constitutional nonsense or frameshift NF2 mutations. In addition, there were significant intrafamilial correlations for intracranial meningiomas and spinal tumors, after adjustment for the type of constitutional NF2 mutation. The type of constitutional NF2 mutation is an important determinant of the number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors.

Proc Natl Acad Sci U S A. 2004 May 18; 101(20): 7618-7623.

Rational design and characterization of a Rac GTPase-specific small molecule inhibitor (FULL TEXT)

Yuan Gao,^* J. Bradley Dickerson,^** Fukun Guo,^* Jie Zheng,^** and Yi Zheng^*.

^* Division of Experimental Hematology, Children's Hospital Research Foundation, Cincinnati, OH 45229; and
^** Department of Structure Biology, St. Jude Children's Research Hospital, Memphis, TN 38105

Abstract:
The signaling pathways mediated by Rho family GTPases have been implicated in many aspects of cell biology. The specificity of the pathways is achieved in part by the selective interaction between Dbl family guanine nucleotide exchange factors (GEFs) and their Rho GTPase substrates. Here, we report a first-generation small-molecule inhibitor of Rac GTPase targeting Rac activation by GEF. The chemical compound NSC23766 was identified by a structure-based virtual screening of compounds that fit into a surface groove of Rac1 known to be critical for GEF specification. In vitro it could effectively inhibit Rac1 binding and activation by the Rac-specific GEF Trio or Tiam1 in a dose-dependent manner without interfering with the closely related Cdc42 or RhoA binding or activation by their respective GEFs or with Rac1 interaction with BcrGAP or effector PAK1. In cells, it potently blocked serum or platelet-derived growth factor-induced Rac1 activation and lamellipodia formation without affecting the activity of endogenous Cdc42 or RhoA. Moreover, this compound reduced Trio or Tiam1 but not Vav, Lbc, Intersectin, or a constitutively active Rac1 mutant-stimulated cell growth and suppressed Trio, Tiam1, or Ras-induced cell transformation. When applied to human prostate cancer PC-3 cells, it was able to inhibit the proliferation, anchorage-independent growth and invasion phenotypes that require the endogenous Rac1 activity. Thus, NSC23766 constitutes a Rac-specific small-molecule inhibitor that could be useful to study the role of Rac in various cellular functions and to reverse tumor cell phenotypes associated with Rac deregulation.

J Neurooncol. 2004 Mar-Apr;67(1-2):159-65.

Aberrant CpG island methylation of multiple genes in ependymal tumors.

Alonso ME, Bello MJ, Gonzalez-Gomez P, Arjona D, de Campos JM, Gutierrez M, Rey JA.

Laboratorio de Oncogenetica Molecular, Dept. C. Experimental, Hospital Universitario La Paz, Madrid, Spain

Abstract:
Aberrant methylation of promoter CpG islands in human genes represents an alternative mechanism for genetic inactivation, and contributes to the development of human tumors. Nevertheless, thus far, few reports have analyzed methylation in ependymomas. We determined the frequency of aberrant CpG island methylation of several tumor-associated genes: p16(INK4a), RB1, MGMT, DAPK, TIMP3, THBS1, TP73, NF2 and Caspase 8 in a group of 27 ependymomas, consisting of 22 WHO grade II samples and five anaplastic WHO grade III tumors. The respective methylation indices (number of genes methylated/total genes analyzed) for both tumor groups was 0.195 and 0.198. Overall methylation rates greater than 20% were detected in MGMT, TIMP3, THBS1 and TP73. NF2 and Caspase 8 each presented hypermethylation in less than 10% of cases, and the cell-cycle regulators RB1/p16(INK4a) were hypermethylated in 4% and 18% of the samples, respectively, mostly affecting the low-grade forms. Our findings suggest that methylation commonly contributes to the inactivation of cancer-related genes in ependymomas.

J Biol Chem. 2004 Feb 27;279(9):7812-8. Epub 2003 Dec 16.

Merlin Neutralizes the Inhibitory Effect of Mdm2 on p53. (FULL TEXT)

Hongtae Kim^��, Noh-Jin Kwak^��, Joo Yong Lee^�, Byung Hyune Choi^�, Young Lim^�, Young Jin Ko^�, Young-Hoon Kim^�, Pil-Woo Huh^�, Kweon-Haeng Lee^�?, Hyoung Kyun Rha^� and Young-Pil Wang^��.

^�Neuroscience Genome Research Center, the
^�Department of Occupational and Environmental Medicine, the
^?Department of Pharmacology, and the
^��Department of Thoracic and Cardiovascular Surgery,
The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea

Abstract:
The stability of p53 tumor suppressor is regulated by Mdm2 via the ubiquitination and proteasome-mediated proteolysis pathway. The c-Abl and PTEN tumor suppressors are known to stabilize p53 by blocking the Mdm2-mediated p53 degradation. This study investigated the correlation between p53 and merlin, a neurofibromatosis 2 (NF2)-related tumor suppressor, in association with the Mdm2 function. The results showed that merlin increased the p53 stability by inhibiting the Mdm2-mediated degradation of p53, which accompanied the increase in the p53-dependent transcriptional activity. The stabilization of p53 by merlin appeared to be accomplished through Mdm2 degradation, and the N-terminal region of merlin was responsible for this novel activity. This study also showed that overexpression of merlin-induced apoptosis of cells depending preferentially on p53 in response to the serum starvation or a chemotherapeutic agent. These results suggest that merlin could be a positive regulator of p53 in terms of tumor suppressor activity, and provide the promising therapeutic means for treating tumors with non-functional merlin or Mdm2 overexpression.

Clin Cancer Res. 2003 Nov 15;9(15):5601-6.

CpG island methylation in sporadic and neurofibromatis type 2-associated schwannomas. (FULL TEXT)

Pilar Gonzalez-Gomez¹, M. Josefa Bello¹, M. Eva Alonso¹, Jesus Lomas¹, Dolores Arjona¹, Jose M. de Campos⁵, Jesus Vaquero⁶, Alberto Isla², Luis Lassaletta³, Manuel Gutierrez⁴, Jose L. Sarasa⁷, and Juan A. Rey¹.

²Department of Neurosurgery,
³Department of Otolaryngology, and
⁴Department of Pathology, Hospital Universitario La Paz, Madrid;
⁵Department of Neurosurgey, Hospital del Rio Hortega, Valladolid;
⁶Department of Neurosurgery, Clinica Puerta de Hierro, Madrid; and
⁷Department of Pathology, Fundacion Jimenez Diaz, Madrid, Spain

Abstract:
Purpose: The purpose of this research was to examine the DNA methylation profile of schwannomas.
Experimental Design: We examined the DNA methylation status of 12 tumor-related genes (NF2, RB1, p14ARF, p16INK4a, p73, TIMP-3, MGMT, DAPK, THBS1, caspase-8, TP53, and GSTP1) in 44 sporadic and/or NF2-associated schwannomas using methylation-specific PCR.
Results: The most frequently methylated genes were THBS1 (36%), p73 (27%), MGMT (20%), NF2 (18%), and TIMP-3 (18%). The RB1/p16INK4a gene pair displayed aberrant methylayed alleles in 15% of cases, whereas methylation was relatively rare in the other genes (<5%). Methylation was tumor specific because it was absent in two nonneoplastic nerve sheath samples and two nonneoplastic brain samples studied as controls.
Conclusions: Our findings indicate that aberrant methylation seems to be a mechanism for NF2 gene inactivation, considered an early step in schwannoma tumorigenesis, and as well, aberrant hypermethylation of other tumor-related genes might represent secondary events that also contribute to the development of these tumors.

Mol Cell. 2003 Oct;12(4):841-9.

Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. (FULL TEXT)

Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe MB, Jacks T.

Department of Biology and Center for Cancer Research, MIT, Cambridge, MA 02139, USA.

Abstract:
The Nf2 tumor suppressor gene codes for merlin, a protein whose function has been elusive. We describe a novel interaction between merlin and p21-activated kinase 1 (Pak1), which is dynamic and facilitated upon increased cellular confluence. Merlin inhibits the activation of Pak1, as the loss of merlin expression results in the inappropriate activation of Pak1 under conditions associated with low basal activity. Conversely, the overexpression of merlin in cells that display a high basal activity of Pak1 resulted in the inhibition of Pak1 activation. This inhibitory function of merlin is mediated through its binding to the Pak1 PBD and by inhibiting Pak1 recruitment to focal adhesions. This link provides a possible mechanism for the effect of loss of merlin expression in tumorigenesis.

Genes Dev. 2003 May 1;17(9):1090-100. Epub 2003 Apr 14.

NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions.

Dominique Lallemand¹, Marcello Curto¹, Ichiko Saotome¹, Marco Giovannini², and McClatchey AI¹.

¹MGH Cancer Center and Harvard Medical School Department of Pathology, Charlestown, Massachusetts 02129, USA;
²INSERM 434, Fondation Jean Dausset-CEPH, 75010, Paris, France

Abstract:
Mutation of the Neurofibromatosis 2 (NF2) tumor suppressor gene leads to cancer development in humans and mice. Recent studies suggest that Nf2 loss also contributes to tumor metastasis. The Nf2-encoded protein, merlin, is related to the ERM (ezrin, radixin, and moesin) family of membrane:cytoskeleton-associated proteins. However, the cellular mechanism whereby merlin controls cell proliferation from this location is not known. Here we show that the major cellular consequence of Nf2 deficiency in primary cells is an inability to undergo contact-dependent growth arrest and to form stable cadherin-containing cell:cell junctions. Merlin colocalizes and interacts with adherens junction (AJ) components in confluent wild-type cells, suggesting that the lack of AJs and contact-dependent growth arrest in Nf2-/- cells directly results from the absence of merlin at sites of cell:cell contact. Our studies indicate that merlin functions as a tumor and metastasis suppressor by controlling cadherin-mediated cell:cell contact.
Keywords:
NF2, merlin, tumor suppressor, metastasis, cytoskeleton, adherens junction.

Am J Hum Genet. 2002 October; 71(4): 715-723.

Predictors of the Risk of Mortality in Neurofibromatosis 2.

Michael E. Baser, J. M. Friedman,¹ Dana Aeschliman,² Harry Joe², Andrew J. Wallace³, Richard T. Ramsden⁴, and D G R Evans³.

Departments of ¹Medical Genetics and ²Biostatistics, University of British Columbia, Vancouver, Canada
³Department of Medical Genetics, St. Mary's Hospital, and ⁴Department of Otolaryngology, Manchester Royal Infirmary, Manchester, UK

Abstract:
To evaluate clinical and molecular predictors of the risk of mortality in people with neurofibromatosis 2 (NF2), we analyzed the mortality experience of 368 patients from 261 families in the United Kingdom NF2 registry, using the Cox proportional-hazards model and the jackknife method. Age at diagnosis, intracranial meningiomas, and type of treatment center were informative predictors of the risk of mortality. In Cox models, the relative risk of mortality increased 1.13-fold per year decrease in age at diagnosis (95% confidence interval [CI] 1.08-1.18) and was 2.51-fold greater in people with meningiomas compared with those without meningiomas (95% CI 1.38-4.57). The relative risk of mortality in patients treated at specialty centers was 0.34 compared with those treated at nonspecialty centers (95% CI 0.12-0.98). In a separate model, the relative risk of mortality in people with constitutional NF2 missense mutations was very low compared with those with other types of mutations (nonsense or frameshift mutations, splice-site mutations, and large deletions), but the CI could not be well quantified because there was only one death among people with missense mutations. We conclude that age at diagnosis, the strongest single predictor of the risk of mortality, is a useful index for patient counseling and clinical management (as are intracranial meningiomas). To ensure optimal care, we recommend that people with NF2 be referred to specialty treatment centers.

Prenat Diagn. 2002 Jun;22(6):519-24.

First application of preimplantation genetic diagnosis to neurofibromatosis type 2 (NF2).

Abou-Sleiman PM, Apessos A, Harper JC, Serhal P, Winston RM, Delhanty JD.

UCL Centre for Preimplantation Genetic Diagnosis, Department of Obstetrics and Gynaecology, University College London, 86-96 Chenies Mews, London WC1E 6HX, UK

Abstract:
Neurofibromatosis type 2 (NF2) is a dominantly inherited cancer predisposition syndrome that is caused bymutations in the NF2 gene. We report here the first clinical preimplantation genetic diagnosis (PGD) forNF2. A protocol was developed to simultaneously amplify the mutation and a single nucleotide polymorphism (SNP) located within the gene. The mutation and polymorphism were analysed by simultaneous fluorescent single-strand conformation polymorphism (SSCP) on an automated DNA sequencer. The mutation, carried by the male partner, was a single base pair substitution affecting a splice site in intron 4 of the gene. The female partner was infertile due to polycystic ovary syndrome and would require IVF to conceive. The couple was found to be informative at a linked intragenic SNP situated in the 5' untranslated region of the gene. The SNP was included in the assay to reduce the risk of misdiagnosis due to allele dropout (ADO). The couple underwent three cycles of treatment during which a total of 43 blastomeres were biopsied from 31 embryos. Amplification at both loci was obtained in 35 cells (81%). A total of five embryos were transferred, two in the first cycle, two in the second and one in the third. No pregnancy ensued. The results of the diagnoses indicated that, in this couple, the inheritance of the mutation may be non-Mendelian. Out of a total of 32 embryos tested only four were found not to carry the mutation. The reasons for this apparent skew remain unknown.

Reprod Biomed Online. 2002 May-Jun;4(3):218-22.

Preimplantation diagnosis for neurofibromatosis.

Verlinsky Y, Rechitsky S, Verlinsky O, Chistokhina A, Sharapova T, Masciangelo C, Levy M, Kaplan B, Lederer K, Kuliev A.

Reproductive Genetics Institute and IVF Illinois, Chicago, USA

Abstract:
Preimplantation genetic diagnosis (PGD) has recently been performed for inherited cancer predisposition determined by p53 tumour suppressor gene mutations, suggesting the usefulness of PGD for late onset disorders with genetic predisposition, including those caused by the germline mutations of other tumour suppressor genes. Here PGD was performed for two couples, one at risk for producing a child with maternally derived neurofibromatosis type I (NF1), and the other with paternally derived neurofibromatosis type II (NF2). The procedure involved a standard IVF protocol, combined with testing of oocytes or embryos prior to their transfer back to the patients. Maternal mutation Trp-->Ter (TGG-->TGA) in exon 29 of the NF1 gene was tested by sequential PCR analysis of the first and second polar bodies, and paternal L141P mutation in exon 4 of the NF2 gene by embryo biopsy at the cleavage stage. In both cases, multiplex nested PCR was applied, involving NF1 and NF2 mutation analysis simultaneously with the 3 and 2 linked markers, respectively. Of 57 oocytes tested in four PGD cycles for NF1 mutation, 26 mutation-free oocytes were detected, from which eight were preselected for transfer, two in each cycle. These produced two clinical pregnancies, one confirmed to be mutation free by chorionic villus sampling but ending in a stillbirth, and the other still ongoing. Of 18 embryos analysed in a cycle performed for NF2 mutation, eight mutation-free embryos were detected, three of which were transferred back to the patient, resulting in a singleton pregnancy and the birth of a mutation-free child. This suggests that PGD is a useful approach for avoiding the birth of children with inherited cancer predisposition, determined by NF1 and NF2 gene mutations.

Planta Med. 2002 May;68(5):397-401.

Cytotoxic action of acetyl-11-keto-beta-boswellic acid (AKBA) on meningioma cells.

Park YS, Lee JH, Bondar J, Harwalkar JA, Safayhi H, Golubic M.

Cleveland Clinic Foundation, Department of Neurosurgery, Cleveland, OH 44195, USA.

Abstract:
Acetyl-11-keto-beta-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate of the tree Boswellia serrata (frankincense). Because pentacyclic triterpenes have antiproliferative and cytotoxic effects against different tumor types, we investigated whether AKBA would act in a similar fashion on primary human meningioma cell cultures. Primary cell cultures were established from surgically removed meningioma specimens. The number of viable cells in the absence/presence of AKBA was determined by the non-radioactive cell proliferation assay. The activation status of the proliferative cell marker, extracellular signal-regulated kinase-1 and -2 (Erk-1 and Erk-2) was determined by immunoblotting with the antibody that recognizes the activated form of these proteins. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2 - 8 microM. At low micromolar concentrations, AKBA rapidly and potently inhibited the phosphorylation of Erk-1/2 and impaired the motility of meningioma cells stimulated with platelet-derived growth factor BB. The cytotoxic action of AKBA on meningioma cells may be mediated, at least in part, by the inhibition of the Erk signal transduction pathway. Because of the central role the Erk pathway plays in signal transduction and tumorigenesis, further investigation into the potential clinical use for AKBA and related boswellic acids is warranted.

Adv Exp Med Biol. 2002;507:387-93.

Acetyl-11-keto-beta-boswellic acid (AKBA) is cytotoxic for meningioma cells and inhibits phosphorylation of the extracellular-signal regulated kinase 1 and 2.

Park YS, Lee JH, Harwalkar JA, Bondar J, Safayhi H, Golubic M.

Department of Neurosurgery, Cleveland Clinic Foundation, 9500 Euclid Avenue/NB2-120A, Cleveland, OH 44195, USA.

Abstract:
Acetyl-11-keto-beta-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate from the stem of the tree Boswellia serrata (frankincense). AKBA has been recently identified as a novel, orally active, non-redox and non-competitive 5-lipoxygenase inhibitor that also inhibits topisomerase I and II in vitro. Because natural pentacyclic triterpenes have an antiproliferative effect against different tumor types, we investigated the effects of AKBA on the proliferation of 11 primary cell cultures established from human surgical specimens of meningiomas, common central nervous system tumors. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2-8 microM. At similar, physiologically achievable concentrations, AKBA rapidly (within minutes) and potently inhibited the phosphorylation of extracellular signal-regulated kinase 1 and 2 (Erk-1 and Erk-2) in meningioma cells stimulated with platelet-derived growth factor BB. High expression level of 5-LO was detected in primary meningioma cells and surgical specimens by immunoblotting analysis, suggesting the possible role of 5-LO in meningioma tumorigenesis. Considering the critical importance of the Erk-1/2 signal transduction pathway not only in meningiomas but in other human neoplasms, the interruption of signaling through this evolutionarily conserved pathway might be one of the mechanisms by which AKBA induces suppression of proliferation and apoptosis of different tumor types.

Anticancer Res. 2001 Jul-Aug;21(4B):2895-900.

Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.

Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR, Ming-Shiang W, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH, Wang YJ, Tsai CC, Hsieh CY.

Department of Internal Medicine, National Taiwan University College of Medicine, Taipei andrew@ha.mc.ntu.edu.tw

Abstract:
Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.

Arch Dis Child 1999;81:496-499 (December)

Paediatric presentation of type 2 neurofibromatosis. (FULL TEXT)

D G R Evans^a, J M Birch^b, R T Ramsden^c.

^a Department of Medical Genetics St Mary's Hospital, Manchester, UK,
^b CRC Paediatric and Familial Cancer Research Group, Royal Manchester Children's Hospital, Manchester, UK,
^c Department of Otolaryngology, Manchester Royal Infirmary, Oxford Road, Manchester, UK

Abstract:
BACKGROUND: Neurofibromatosis type 2 (NF2) is a highly penetrant autosomal dominant condition predisposing affected individuals to schwannomas and meningiomas. The proportion of children presenting with meningioma or schwannoma who have NF2 is not well described, and neither is the mode of presentation in most children with the inherited disease.
AIMS: To determine the frequency of childhood meningioma and schwannoma cases caused by NF2 and the mode of presentation.
METHODS: The records of the Manchester Children's Tumour Registry from 1954 were searched for cases of meningioma and schwannoma. Paediatric presentation in a large UK series of NF2 was also studied.
RESULTS: 18% (61/334) of patients with NF2 on the UK database presented in the paediatric age group (0-15 years), frequently with the symptoms of an isolated tumour. More than half had no family history to alert the clinician to their susceptibility. Three of 22 children presenting with a meningioma on the Manchester Children's Tumour Registry have gone on to develop classic features of NF2.
CONCLUSIONS: Clinicians should suspect NF2 in children presenting with meningioma, schwannoma, and skin features, such as neurofibromas/schwannomas, but fewer than 6 caf� au lait patches, who thus fall short of a diagnosis of neurofibromatosis type 1.

Neurosurg Focus. 1998 Sep 15;5(3):e2.

Outcomes after gamma knife radiosurgery in solitary acoustic tumors and neurofibromatosis Type 2.

Kondziolka D, Subach BR, Lunsford LD, Bissonette DJ, Flickinger JC.

Departments of Neurological Surgery and Radiation Oncology, and the Center for Image-Guided Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania.

Abstract:
Surgeons perform stereotactic radiosurgery as the main alternative to acoustic tumor (vestibular schwannoma) resection. The goals of radiosurgery include preservation of neurological function and prevention of tumor growth. Longer-term outcomes are not well documented for patients with solitary tumors or those with neurofibromatosis Type 2 (NF2). To define outcomes, the authors evaluated 462 consecutive patients with solitary acoustic tumors and 40 patients with NF2 (total of 45 tumors treated) who underwent radiosurgery between 1987 and 1998. Serial imaging studies, clinical evaluations, and a patient survey were performed. The average tumor margin dose was 15 Gy, and the mean transverse tumor diameter was 22 mm. In patients with solitary tumors, prior resection had been performed in 111 patients (24%); 27 patients experienced tumor recurrence after a "total resection." The clinical tumor control rate (no resection required) was 98%. In non-NF2 patients followed for at least 5 years, 100 tumors (61.7%) were smaller, 53 (32.7%) remained unchanged in size, and nine (5.6%) were slightly larger. Resection was performed in four patients (2.4%). Neurological deficits after radiosurgery all occurred within the first 28 months. The rates of facial and trigeminal neuropathy varied with radiosurgery technique. In patients with NF2, 16 tumors were smaller, 28 remained unchanged, and one enlarged (overall 98% control rate at median 3-year follow up). Resection was performed in three patients (7%). Useful hearing was preserved in six (43%) of 14 NF2 patients who had useful hearing before radiosurgery. Radiosurgery provided long-term tumor control associated with high rates of neurological function preservation. No further tumor surgery was necessary in 98% of patients with solitary tumors followed for a minimum of 5 years.

Oncogene. 1998 Jul 16;17(2):173-8.

Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin.

Chen YR, Tan TH.

The Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas USA.

Abstract:
Curcumin, a dietary pigment in curry, suppresses tumor initiation and tumor promotion. Curcumin is also a potent inhibitor for AP-1 and NF-kappaB activation. In this report, we show that curcumin inhibits JNK activation by various agonists including PMA plus ionomycin, anisomycin, UV-C, gamma radiation, TNF-alpha, and sodium orthovanadate. Although both JNK and ERK activation by phorbol 12-myristate 13-acetate (PMA) plus ionomycin were suppressed by curcumin, the JNK pathway was more sensitive. The IC50 (50% inhibition concentration) of curcumin was between 5-10 microM for JNK activation and was 20 microM for ERK activation. In transfection assays, curcumin moderately suppressed MEKK1-induced JNK activation; however, it effectively blocked JNK activation caused by co-transfection of TAK1, GCK, or HPK1. Curcumin did not directly inhibit JNK, SEK1, MEKK1 or HPK1 activity. Although curcumin suppressed TAK1 and GCK activities at high concentrations, this inhibition cannot fully account for the JNK inhibition by curcumin in vivo. Our data suggest that curcumin may affect the JNK pathway by interfering with the signaling molecule(s) at the same level or proximally upstream of the MAPKKK level. Taken together, the inhibition of the MEKK1-JNK pathway reveals a possible mechanism of suppression of AP-1 and NF-kappaB signaling by curcumin, and may explain the potent anti-inflammatory and anti-carcinogenic effects of this chemical.

Hum Genet. 1996 Nov;98(5):534-8.

Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes.

Kluwe L, Bayer S, Baser ME, Hazim W, Haase W, Funsterer C, Mautner VF.

Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany.

Abstract:
Neurofibromatosis 2 (NF2) is an autosomal inherited disorder that predisposes carriers to nervous system tumors. To examine genotype-phenotype correlations in NF2, we performed mutation analyses and gadolinium-enhanced magnetic resonance imaging of the head and full spine in 59 unrelated NF2 patients. In patients with vestibular schwannomas (VSs) or identified NF2 mutations, the mild phenotype was defined as < 2 other intracranial tumors and < or = 4 spinal tumors, and the severe phenotype as either > or = 2 other intracranial tumors of > 4 spinal tumors. Nineteen mutations were found in 20 (34%) of the patients and were distributed in 12 of the 17 exons of the NF2 gene, including intron-exon boundaries. Seven mutations were frameshift, six were nonsense, four were splice site, two were missense, and one was a 3-bp in frame deletion. The nonsense mutations included one codon 57 and two codon 262 C-->T transition in CpG dinucleotides. The frameshift and nonsense NF2 mutations occurred primarily in patients with severe phenotypes. The two missense mutations occurred in patients with mild phenotypes, and three of the four splice site mutations occurred in families with both mild and severe phenotypes. Truncating NF2 mutations are usually associated with severe phenotypes, but the association of some mutations with mild and severe phenotypes indicates that NF2 expression is influenced by stochastic, epigenetic, or environmental factors.

Am. J. Hum. Genet. 51:486-496, 1992

Neurofibromatosis Type 2 Appears to Be a Genetically Homogeneous Disease

Steven A. Narod^*, Dilys M. Parry^T, Jillian Parboosingh^*, Gilbert M. Lenoir,^�, Martin Ruttledge^#, Georges Fischer¹, Roswell Eldridge^$, Robert L. Martuza^**, Marina Frontali^$1, Jonathan Haines^tt, James F. Gusella^tt, and Guy A. Rouleau^*.

^*McGill Centre for Human Genetics, Montreal; ^tClinical Epidemiology Branch, National Cancer Institute, and ^tNeuroepidemiology Branch, National Institute of Neurological and Communicative Disorders and Stroke, Bethesda; ^�International Agency for Research on Cancer, and ¹Neurosurgical Department, Hopital Neurologique and University of Lyon, Lyon; ^#Ludwig Institute for Cancer Research and Department of Clinical Genetics, Karolinska Hospital, Stockholm; ^**Department of Surgery and ttNeurogenetics Laboratory, Massachusetts General Hospital, Boston; and ^ttlnstituto Medicine Sperimentale, Rome

Abstract:
Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome characterized by the development of vestibular schwannomas and other tumors of the nervous system, including cranial and spinal meningiomas, schwannomas, and ependymomas. The presence of bilateral vestibular schwannomas is sufficient for the diagnosis. Skin manifestations are less common than in neurofibromatosis type 1 (NF1; von Recklinghausen disease). The apparent clinical distinction between NF1 and NF2 has been confirmed at the level of the gene locus by linkage studies; the gene for NF1 maps to chromosome 17, whereas the gene for NF2 has been assigned (in a single family) to chromosome 22. To increase the precision of the genetic mapping of NF2 and to determine whether additional susceptibility loci exist, we have performed linkage analysis on 12 families with NF2 by using four polymorphic markers from chromosome 22 and a marker at the NF1 locus on chromosome 17. Our results confirm the assignment of the gene for NF2 to chromosome 22 and do not support the hypothesis of genetic heterogeneity. We believe that chromosome 22 markers can now be used for presymptomatic diagnosis in selected families. The NF2 gene is tightly linked to the D22S32 locus (maximum lod score 4.12; recombination fraction 0). A CA-repeat polymorphism at the CRYB2 locus was the most informative marker in our families (lod score 5.99), but because the observed recombination fraction between NF2 and CRYB2 was 10 cM, predictions using this marker will need to be interpreted with caution.

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