ABSTRACTS THAT MAY BE RELEVANT TO PERCHLORATE TOXICOLOGY
I. In Rancho Cordova we find the conjunction of juvenile-onset autoimmune
thyroid disease, osteomyelitis in the juvenile tibial shaft of unknown
etiology, thyroid and brain cancer, and rhabdomyosarcoma. Our rhabdomyosarcoma
cases were embryonic rather than alveolar, which is consistent (presuming
altered imprinting at 11p15) with the additional NDMA and TCE contamination
that the victims' fathers were also exposed to. One thyroid case was
coincident with the formation of a spinal hemangioma, and another accompanied
formation of a pleural effusion with loss of the lung.
1: Am J Med Genet 1997 Oct 3;72(1):30-3
Family with Graves disease, multinodular goiter, nonmedullary thyroid
carcinoma, and alveolar rhabdomyosarcoma.
Druker HA, Kasprzak L, Begin LR, Jothy S, Narod SA, Foulkes WD
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Benign thyroid disease is a risk factor for nonmedullary thyroid carcinoma
[Houlston and Stratton: Q J Med 88:685-693, 1995]. We report on a family
with 7 members with benign and/or malignant thyroid neoplasia; one affected
female died of a paravertebral alveolar rhabdomyosarcoma at age 20.
The occurrence of thyroid nodular hyperplasia, nonmedullary thyroid
cancer, and rhabdomyosarcoma in the same family may be due to chance,
common environmental factors, or, most likely, genetic predisposition.
PMID: 9295070, UI: 97439514
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2. At the apex of our perchlorate exposure, the specific abnormality
is the follicular/solid variant of papillary thyroid cancer (2 cases
on the same block):
1: Cancer Genet Cytogenet 2000 Aug;121(1):33-7
Structural and numerical aberrations of chromosome 22 in a case of follicular
variant of papillary thyroid carcinoma revealed by conventional and
molecular cytogenetics.
Perissel B, Coupier I, De Latour M, Cardot N, Penault-Llorca F, Jaffray
J, Giollant M, Fonck Y, Malet P
Laboratoire d'Histologie-Embryologie-Cytogenetique, Centre Jean-Perrin,
Clermont-Ferrand, France.
This study reports a case of papillary carcinoma with vesicular components
showing multiclonal aberrations of chromosome 22 as revealed by RHG-banding
cytogenetics and by fluorescence in situ hybridization (FISH; whole
chromosome 22 and BCR-ABL-specific locus probes, multi-FISH). Four clones
with chromosome 22 changes as the sole abnormality were seen. The main
abnormal clone lacked the whole chromosome 22. A del(22)(q11) was observed
in a second group of cells. The third clone had an idic(22). Finally,
FISH revealed a fourth abnormal cell population with a der(17)t(?17;22).
Some of these chromosome 22 alterations have been described in other
solid tumors such as meningiomas and neurinomas, suggesting a common
genetic pathway of tumor progression occurring in a multistep process.
Chromosome 22 changes do not seem to be involved in pure papillary thyroid
tumors and therefore could be related to the maintenance of a follicular-type
histological pattern.
PMID: 10958938, UI: 20416145
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3. The follicular or solid variant of papillary thyroid cancer is closely
associated with radioiodide fallout from the Chernobyl nuclear accident:
Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl
papillary thyroid carcinomas: biological, phenotypic, and clinical implications.
Unique Identifier: 20203783
Author: Rabes HM; Demidchik EP; Sidorow JD; Lengfelder E; Beimfohr C;
Hoelzel D; Klugbauer S
Source: Clin Cancer Res 2000 Mar;6(3):1093-103
Address: Institute of Pathology, Ludwig-Maximilians-University, Munich,
Germany. hm.rabes@lrz.uni-muenchen.de
Abstract:
Molecular genetic aberrations and the related phenotypes were investigated
in 191 papillary thyroid carcinomas (PTCs) from patients exposed at
young age to radioiodine released from the Chernobyl reactor. A high
prevalence of RET gene rearrangements (62.3%) with a significant predominance
of ELE1/RET (PTC3) over H4/RET (PTC1) rearrangements was found in PTCs
of the first post-Chernobyl decade. NTRK1 rearrangements were rare (3.3%).
In 3.3%, we observed novel types of RET rearrangements: GOLGA5/ RET
(PTC5), HTIF/RET (PTC6), RFG7/RET (PTC7), and an as yet undefined RFGX/RET.RET
rearrangements, preferentially ELE1/RET, are related to rapid tumor
development. At longer intervals after exposure to ionizing radiation,
the prevalence of RET rearrangements declines with a shift from ELE1/RET
to H4/RET, most significantly in female patients. The prevalence of
specific types of rearrangements is independent of age at irradiation.
A significantly higher prevalence of ELE1/RET was observed in the most
heavily contaminated Oblasts, Gomel and Brest, suggesting a preferential
formation of this type of rearrangement after high thyroid doses. RET
rearrangement is related to aggressive growth: Rearrangement-positive
PTCs were in a more advanced pT category and more frequently in the
pN1 category at presentation than rearrangement-negative PTCs. ELE1/RET
is related to the solid variant of PTC, H4/RET more frequently to typical
papillary structures. The genotype/phenotype evaluation of post-Chernobyl
PTCs reveals a characteristic spectrum of gene rearrangements that lead
to typical phenotypes with important biological and clinical implications.
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4. The PTC3 mutation that defines the follicular/solid variant of papillary
thyroid cancer is probably radiation-induced:
34
UI - 20065100
AU - Nikiforov YE; Koshoffer A; Nikiforova M; Stringer J; Fagin JA
TI - Chromosomal breakpoint positions suggest a direct role for radiation
in inducing illegitimate recombination between the ELE1 and RET genes
in radiation-induced thyroid carcinomas.
SO - Oncogene 1999 Nov 4;18(46):6330-4
AD - Department of Pathology, University of Cincinnati College of Medicine,
OH 45267-0529, USA.
The RET/PTC3 rearrangement is formed by fusion
of the ELE1 and RET genes, and is highly prevalent in radiation-induced
post-Chernobyl papillary thyroid carcinomas. We characterized the breakpoints
in the ELE1 and RET genes in 12 post-Chernobyl pediatric papillary carcinomas
with known RET/PTC3 rearrangement. We found that the breakpoints within
each intron were distributed in a relatively random fashion, except
for clustering in the Alu regions of ELE1. None of the breakpoints occurred
at the same base or within a similar sequence. There was also no evidence
of preferential cleavage in AT-rich regions or other target DNA sites
implicated in illegitimate recombination in mammalian cells. Modification
of sequences at the cleavage sites was minimal, typically involving
a 1-3 nucleotide deletion and/or duplication. Surprisingly, the alignment
of ELE1 and RET introns in opposite orientation revealed that in each
tumor the position of the break in one gene corresponded to the position
of the break in the other gene. This tendency suggests that the two
genes may lie next to each other but point in opposite directions in
the nucleus. Such a structure would facilitate formation of RET/PTC3
rearrangements because a single radiation track could produce concerted
breaks in both genes, leading to inversion due to reciprocal exchange
via end-joining.
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5. But the radiation-induced PTC3 mutation alone is not sufficient to
cause the cancer:
1: Oncol Res 1999;11(9):421-7Related Articles, Books
Human N-ras, TRK-T1, and RET/PTC3 oncogenes, driven by a thyroglobulin
promoter, differently affect the expression of differentiation markers
and the proliferation of thyroid epithelial cells.
Portella G, Vitagliano D, Borselli C, Melillo RM, Salvatore D, Rothstein
JL, Vecchio G, Fusco A, Santoro M
Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale
delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e
Molecolare, Facolta di Medicina e Chirurgia, Universita Federico II,
Naples, Italy. portella@unina.it
The ras family members and the tyrosine kinases RET and TRK are frequently
activated in human tumors of the thyroid gland. To ascertain the effects
of these oncogenes in cultured thyroid cells we have generated expression
vectors containing activated versions of the three genes under the control
of the thyroid-specific thyroglobulin gene promoter. Here we show that
the expression of the three oncogenes differently affects thyroid differentiation.
While the TRK-T1 oncogene interferes with the capability of thyroid
cells of trapping iodide and only marginally affects thyroglobulin gene
expression, both RET/PTC3 and N-ras(Gln61-Lys) induce a dramatic reduction
of thyroglobulin mRNA and alleviate TSH dependency for cellular growth.
However, none of the three oncogenes is able to induce the appearance
of neoplastic transformation markers, such as growth in semisolid medium
and tumorigenicity in athymic mice. This indicates that genetic events
additional to TRK, RET, or N-ras activation are required for fully malignant
transformation of thyroid cells.
PMID: 10821536, UI: 20279556
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6. One of the factors that controls the aggressiveness, and thus the
clinical expression, of thyroid cancer is the CD44 protein.
1: J Pathol 2000 Nov;192(3):321-327
Reduced CD44 standard expression is associated with tumour recurrence
and unfavourable outcome in differentiated thyroid carcinoma.
Bohm JP, Niskanen LK, Pirinen RT, Kiraly K, Kellokoski JK, Moisio KI,
Eskelinen MJ, Tulla HE, Hollmen S, Alhava EM, Kosma VM
Department of Pathology and Forensic Medicine, University of Kuopio
and Kuopio University Hospital, Finland.
[Record supplied by publisher]
CD44 was detected with an antibody recognizing all forms of CD44 (CD44
standard) and others specific for its v3 and v6 variant isoforms; their
prognostic value was evaluated in 213 patients with differentiated thyroid
carcinoma (DTC). The staining patterns of CD44 standard (s) and CD44v6
in tumour tissue were quite similar, 176 cases (83%) being highly positive
for CD44s and 153 cases (72%) for CD44v6. Only 18 (9%) tumours showed
high expression of CD44v3. Papillary carcinomas were significantly more
often high expressors of CD44s and CD44v6 than follicular carcinomas
(p<0.001 for both). Age older than 60 years, distant metastases,
and advanced pTNM stage were related to loss of expression of CD44s
(p<0.001, p=0.021, and p=0.003, respectively). Tumour recurrence
and cancer-related mortality were related to the reduced level of CD44s
(p=0.049 and p=0.042). CD44v3 did not associate with any of the clinicopathological
factors. In univariate analysis, CD44s was the only significant prognostic
factor for disease-free survival (p=0.0488). In multivariate analysis,
CD44s and thyroglobulin level were significant prognostic factors for
disease-free survival (p=0.040 and p<0.001, respectively). The reduced
level of CD44s in DTC patients seems to be an independent prognostic
factor for unfavourable disease outcome. Copyright 2000 John Wiley &
Sons, Ltd.
PMID: 11054715
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7. CD44 function is linked to the merlin tumor suppressor protein that
interacts via CD44 with the hyaluronase that dissolves hyaluronic acid:
1: Ann N Y Acad Sci 2000 Jun;910:106-18; discussion 118-20Related Articles,
Books, LinkOut
CD44 acts both as a growth- and invasiveness-promoting molecule and
as a tumor-suppressing cofactor.
Herrlich P, Morrison H, Sleeman J, Orian-Rousseau V, Konig H, Weg-Remers
S, Ponta H
Forschungszentrum Karlsruhe, Institut fur Toxikologie und Genetik, Germany.
genetik@igen.fzk.de
High-molecular-weight splice variants of the CD44 transmembrane protein
family have been implicated in tumorigenesis and metastasis formation.
By contrast, in certain tumors--for example, Burkitt's lymphoma, neuroblastomas,
and prostate cancer--loss of CD44 expression seems to accompany transformation.
Here we describe two modes of action of CD44 proteins. They can bind
growth factors and present them to their authentic high-affinity receptors,
and thus promote proliferation and invasiveness of cells. Under these
conditions the CD44 proteins recruit ERM proteins--for example, ezrin
or moesin--to their cytoplasmic tails, thereby producing links to the
cytoskeleton. This mode of action could account for the tumor-promoting
action of CD44 proteins. The second mode of action of CD44 proteins
comes into play when cells reach confluent growth conditions. Under
specific conditions, binding of another ligand, the ECM component hyaluronate,
leads to the activation and binding to the CD44 cytoplasmic tail of
the tumor suppressor protein merlin. The activation of merlin confers
growth arrest, so-called contact inhibition. This function of CD44 proteins
defines them as tumor suppressors. The type of action of CD44 on a given
cell will depend on the isoform pattern of CD44 expressed, on the cellular
equipment with ERM protein members, on the nature of the ECM, and on
yet-unknown conditions.
PMID: 10911909, UI: 20369562
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8. Presumably, a population with pre-existing abnormalities in CD44
function would be more sensitive to radioiodide fallout, and exhibit
a
flair up of thyroid cancer after an exposure. This was true in Rancho
Cordova after Chernobyl where both perchlorate and nitrosodimethylamine
were in the drinking water (7 cases instead of spatial/temporal expectation
of 1 case) , and may be true elsewhere:
1: Eur J Cancer Prev 1996 Feb;5(1):75-81
A post-Chernobyl rise in thyroid cancer in Connecticut, USA.
Mangano JJ
Radiation and Public Health Project, Brooklyn, NY 11215, USA.
Recent analyses of children in Belarus and the Ukraine are the first
to document large numbers of excess thyroid cancer cases only 4 years
after exposure to radiation. In Connecticut (USA), a thyroid cancer
increase of a much smaller magnitude occurred in 1990-93, 4-7 years
after the Chernobyl accident, for both children and adults. Similar
changes also occurred in the states of Iowa and Utah, which like Connecticut
were exposed to low levels of radionuclides from Chernobyl fallout during
May and June of 1986. Historical data from Connecticut also reveal substantial
increases in thyroid cancer incidence about 5 years after large releases
of iodine-131 from distant US nuclear weapons plants, after the largest
atmospheric US atomic weapons tests in Nevada, and after substantial
releases of iodine-131 from the Millstone nuclear power plant in Connecticut.
Further analysis of this apparent 5-year latency period will enhance
understanding of ionizing radiation's effects on thyroid function and
on human health in general.
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9. In the cancer registry data, the resonance of Rancho Cordova's temporary
thyroid cancer cluster was most closely associated with high concentrations
of nitrosodimethylamine in the water as opposed to perchlorate. This
is suggestive of multiple synergistic effects such as nitrosamine impact
on the liver:
1: J Toxicol Sci 1994 Nov;19(4):227-34
Thyroid proliferative lesions induced by anti-thyroid drugs in rats
are not always accompanied by sustained increases in serum TSH.
Onodera H, Mitsumori K, Takahashi M, Shimo T, Yasuhara K, Kitaura K,
Takahashi M, Hayashi Y
Division of Pathology, National Institute of Health Sciences, Tokyo,
Japan.
To examine changes in serum TSH and determine whether the sustained
excess is necessary for the development and/or progression of thyroid
tumors, male F344 rats were administered drinking water containing thiourea
(TU), at 0.1 or 0.05%, or sulfadimethoxine (SM), at 0.025 or 0.0125%,
for one week in Experiment I. All of the treated animals showed decreased
serum levels of T3 and T4 and an increased TSH. In Experiment II, male
rats were given a s.c. injection of N-bis(2-hydroxypropyl) nitrosamine
(DHPN:1500 mg/kg BW) and, starting one week later, received drinking
water containing the same doses of TU or SM as in Experiment I for the
following 20 weeks. Thyroid follicular proliferative lesions were induced
in most rats treated with TU and SM. However, these treated animals
did not demonstrate any consistent alterations in serum T3, T4 and TSH
levels, except for the high dose TU group. The present studies thus
suggest that thyroid tumors can grow even under conditions of fluctuating
serum TSH levels during the progression phase, although TSH stimulation
might be an absolute requirement in the early phase of tumor development.
PMID: 7533849, UI: 95190954
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10. Of course, cancer factor ecology is complicated, and there is more
than one way to trigger the formation of the same type of tumor. Here's
an example of a potential thyroid-bone positive feedback loop via calcitonin
and insulin-like growth factors:
1: Appl Immunohistochem Molecul Morphol 2000 Jun;8(2):110-9Related Articles,
Books
Insulin-like growth factor 1 expression in thyroid tumors.
Maiorano E, Ciampolillo A, Viale G, Maisonneuve P, Ambrosi A, Triggiani
V, Marra E, Perlino E
Istituto di Anatomia Patologica, Universita degli Studi di Bari, Italy.
emaiorano@anatopat.uniba.it
Insulin-like growth factor 1 (IGF-1) likely is involved in thyrocyte
proliferation via autocrine mechanisms, but limited data are available
on its in vivo expression in thyroid neoplasms. This prompted us to
explore IGF-1 expression at the protein and mRNA levels and IGF-1 receptor
(IGF-1rec) immunoreactivity in normal and neoplastic thyroids (50 adenomas
and 53 carcinomas). We documented increased IGF-1 and IGF-1rec immunoreactivity
in adenomas (31 of 50 and 40 of 50 cases, respectively) and carcinomas
(38 of 53 and 42 of 53 cases) compared with normal thyroid, which only
showed minimal immunoreactivity for the ligand and its receptor. A corresponding
up-regulation of IGF-1 mRNA was documented in carcinomas, whereas adenomas
exhibited down-regulated expression of IGF-1 mRNA. Immunoreactivity
for IGF-1 and cognate receptor positively correlated with tumor diameter
and wide intrathyroidal extension but not with patients' gender and
age or with the stage of the tumors and the occurrence of lymph node
metastases. These data emphasize a possible role of the IGF-1 system
in thyroid tumorigenesis, as indicated by in vitro studies. In addition,
the evaluation of IGF-1 and IGF-1rec immunoreactivity might have clinical
implications, because it positively correlates with the aggressiveness
of these tumors.
PMID: 10937058, UI: 20392739
1: Calcif Tissue Int 2000 Sep;67(3):247-54
Calcitonin increases the concentration of insulin-like growth factors
in serum-free cultures of human osteoblast-line cells.
Farley J, Dimai HP, Stilt-Coffing B, Farley P, Pham T, Mohan S
Departments of Medicine and Biochemistry, Loma Linda University, Loma
Linda, California, USA.
The current studies were intended to determine whether the anabolic
effects of calcitonin (CT) on human osteoblast-line cells were (1) unique
to osteosarcoma cells or also evident in osteoblast-line cells derived
from normal human bone; and/or (2) associated with effects on several
insulin-like growth factor (IGF) system components. Preliminary studies
identified several osteoblastic cell lines, derived from normal human
bone, which showed calcitonindependent increases in cell proliferation,
alkaline phosphatase activity, and/or (45)Ca uptake (P < 0.05-P <
0.001). Two of these cell lines-(human vertebrae) HBV-155 and HBV-163-were
included with the human osteosarcoma cell line, SaOS-2, in most of our
subsequent studies of calcitonin effects on selected IGF system components:
IGF-II, IGF-I, and IGF binding proteins -3, -4, and -5. The results
of those studies revealed that a 48 hour exposure to salmon CT caused
a dose-dependent (0.03-3 mU/ml) increase in the net extracellular level
of IGF-II (r = 0.96, P < 0.01) in serum-free cultures of SaOS-2 cells,
with a maximal 60% increase at the highest tested dose (P < 0.02).
Similar effects were seen with HBV-163 cells (r = 0.90, P < 0.01)
and HBV-155 cells (r = 0.55, P < 0.02). The effect of calcitonin
on the extracellular level of IGF-II was biphasic with respect to time:
it decreased at 6 hours (P < 0.005 and P < 0.001, for SaOS-2 cells
and HBV-163 cells, respectively) and increased at 24 hours (P < 0.02
and P < 0.05). These calcitonin-dependent increases in the extracellular
level of IGF-II were associated with parallel increases in IGF-I (P
< 0.005 for SaOS-2 cells and P < 0.03 for HBV-163 cells), but
calcitonin did not affect the extracellular level of transforming growth
factor (TGF)-beta. The calcitonin-dependent changes in IGF-II were not
associated with changes in the extracellular levels of IGF binding proteins
-3, -4, or -5. Finally, our studies showed that two other members of
the CT superfamily-CT gene-related peptide and amylin-did not mimic
the effect of CT to increase the extracellular level of IGF-II. Together,
these data demonstrate that human osteoblast-line cells derived from
normal human bone can respond to CT, and that those responses can include
CT dose- and time-dependent increases in the extracellular levels of
IGF-I and IGF-II.
PMID: 10954780, UI: 20413458
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11. The hyaluronic acid/CD44/merlin system is particularly important
in preventing cancers at points of friction in connective tissue, such
as at the junction of the central and peripheral nervous system (neurinomas,
meningiomas) and the pleura of the lung (mesothelioma, solitary fibrous
tumors):
1: Childs Nerv Syst 2000 Jul;16(7):406-16
Meningiomas of the central nervous system occurring below the age of
17: report of 24 cases not associated with neurofibromatosis and review
of literature.
Amirjamshidi A, Mehrazin M, Abbassioun K
Department of Neurosurgery, Tehran University of Medical Sciences, Sina
Hospital, Iran.
The objective of this work was to gain more insight into the controversial
characteristics of meningiomas occurring during childhood and adolescence.
Management of meningiomas is an important field in pediatric neurosurgery.
Every pediatric neurosurgeon has tried to resolve the problems relating
to the clinical characteristics, biological behavior and outcome of
this interesting and almost benign pathology, which rarely occurs in
the first two decades of life. The records on central nervous system
(CNS) tumors held by the two major neurosurgery centers of Tehran Medical
University and Arad General Hospital were prospectively collected during
last 15 years. Complete medical records are available for all 24 cases,
and long-term follow-up was achieved 19 patients. All the cases were
diagnosed and treated after the introduction of computed tomographic
(CT) scanning. Angiography and magnetic resonance imaging (MRI) were
performed as complementary studies in some cases. The sample consisted
of 13 girls and 11 boys. The age range at the time of diagnosis varied
between 2 and 17 years, with a mean of 9.47 and standard deviation of
3.43. Fifteen patients were below 10 years of age (62.5%), and 9 of
them were between 10 and 17 years old (37.5%). The most common presenting
symptoms, in declining order of frequency, were headache, epilepsy and
focal neurological deficits. Similar cases associated with neurofibromatosis
either at the time of presentation with meningioma or during the follow-up
period were excluded (5 cases). The size of the presenting tumor was
more than 5 cm in diameter in 17 cases. The locations of the lesions,
taken as the site of the presumed widest dural base in each case were:
spinal, orbital, ethmoidal and sphenoethmoidal in 1 case each, petroclival
in 2, and tentorial or supratentorial in 18 patients. The only predisposing
factor in this series of childhood meningiomas was whole-axis irradiation
for previous malignancy in the case presenting with cervical intradural
meningioma. There have been no surgical deaths, and gross total excision
of the lesions was achieved in 21 cases. Tumor recurrence was observed
during the follow-up period in 6 cases (25%). The follow-up period varied
between 2 and 165 months, with a median interval of 130.2 months. This
series of pediatric CNS meningiomas comprises almost 1.08% of all meningiomas
operated on by the authors during the last 15 years and it also accounts
for about 1.1% of all pediatric CNS tumors encountered. This series
of patients has certain characteristics regarding sex distribution,
unusual size, peculiar localizations, special histological features
and benign clinical behavior distinguishing it from other series reported
in the literature.
PMID: 10958549, UI: 20412754
1: Genes Chromosomes Cancer 1999 Mar;24(3):238-42
Frequent mutations of NF2 and allelic loss from chromosome band 22q12
in malignant mesothelioma: evidence for a two-hit mechanism of NF2 inactivation.
Cheng JQ, Lee WC, Klein MA, Cheng GZ, Jhanwar SC, Testa JR
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia,
Pennsylvania 19111, USA.
We previously reported NF2 mutations in malignant mesothelioma (MM)
cell lines and corresponding primary tumors. We have now generated polyclonal
antibodies that specifically recognize the C-terminus of the NF2 protein.
Western blot analysis was performed on 25 MM cell lines, 14 of which
showed no NF2 expression. Single-strand conformation polymorphism and
DNA sequence analyses revealed NF2 mutations in each of these 14 cell
lines. To explore the mechanism of inactivation of NF2, loss of heterozygosity
analysis was performed with two microsatellite markers located in the
vicinity of the NF2 locus in chromosome band 22q12. Eighteen of the
25 cell lines (72%) showed losses at one or both loci tested. All cases
exhibiting mutation and/or aberrant expression of NF2 showed allelic
losses, suggesting that inactivation of NF2 in MM occurs via a two-hit
mechanism.
PMID: 10451704, UI: 99381011
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12. A hereditary condition known as neurofibromatosis type II can inhibit
the function of merlin, but it is not the only way merlin can be inhibited:
1: Nat Med 1998 Aug;4(8):915-22Related Articles, Books, LinkOut
The involvement of calpain-dependent proteolysis of the tumor suppressor
NF2 (merlin) in schwannomas and meningiomas.
Kimura Y, Koga H, Araki N, Mugita N, Fujita N, Takeshima H, Nishi T,
Yamashima T, Saido TC, Yamasaki T, Moritake K, Saya H, Nakao M
Department of Tumor Genetics and Biology, Kumamoto University School
of Medicine, Honjo, Japan.
Neurofibromatosis type 2 (NF2) protein, also known as merlin or schwannomin,
is a tumor suppressor, and NF2 is mutated in most schwannomas and meningiomas.
Although these tumors are dependent on NF2, some lack detectable NF2
mutations, which indicates that alternative mechanisms exist for inactivating
merlin. Here, we demonstrate cleavage of merlin by the ubiquitous protease
calpain and considerable activation of the calpain system resulting
in the loss of merlin expression in these tumors. Increased proteolysis
of merlin by calpain in some schwannomas and meningiomas exemplifies
tumorigenesis linked to the calpain-mediated proteolytic pathway.
PMID: 9701243, UI: 98364973
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13. If perchlorate adversely affects the hyaluronic acid/CD44/merlin
tumor suppressor system, there may be inherited distributions of the
perchlorate-concentrating sodium-iodide symporter that make a
person more vulnerable (choroid plexus tissue contains NIS):
1: Pediatr Neurosurg 2000 Feb;32(2):73-6
Ectopic choroid plexus within a juvenile arachnoid cyst of the cerebellopontine
angle: cause of cyst formation or reason of cyst growth.
Schuhmann MU, Tatagiba M, Hader C, Brandis A, Samii M
Department of Neurosurgery, Medical School Hannover, Germany. mschuh@gmx.de
The unusual and rare case of a 6-year-old boy is reported who presented
with an arachnoid cyst located in the cerebellopontine angle incorporating
an ectopic piece of choroid plexus tissue. A microneurosurgical cyst
wall resection was performed and the plexus tissue identified and removed.
The rare occurrence of ectopic choroid plexus tissue within cysts of
the CNS is discussed. Copyright 2000 S. Karger AG, Basel
Publication Types:
·Review ·Review, tutorial
PMID: 10838504, UI: 20298404
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14. Both the potential for and establishment of merlin-related tumors
can transform into more lethal connective tissue tumors:
1: Br J Cancer 2000 Aug;83(3):407-11
Cancers in the first-degree relatives of children with brain tumours.
Hemminki K, Li X, Vaittinen P, Dong C
Department of Biosciences at Novum, Karolinska Institute, Huddinge,
Sweden.
We used the nationwide Swedish Family-Cancer Database with 2060 childhood
brain tumours diagnosed in the period 1958-1996 to analyse the risk
of this tumour by parental cancers and in siblings of childhood brain
tumour probands. Groups of patients were compared by calculating standardized
incidence ratios (SIRs) for brain tumours in offspring. 1.3% of brain
tumour patients had a parent with nervous system cancer; SIRs were 2.4
and 1.88 for diagnostic ages < 5 and < 15 years, respectively.
The data showed distinct patterns of familial risks for childhood brain
tumours, the SIR was 10.26 for brain astrocytoma given a parent with
meningioma. Parental colon cancer was associated with offspring ependymoma
(SIR 3.70), and parental salivary gland cancers with offspring medulloblastoma
(SIR 13.33, but two cases only). SIR for sibling nervous system cancer
from childhood brain tumour probands was 3.55 up to age 61.
PMID: 10917560, UI: 20372228
1: Chung Hua I Hsueh Tsa Chih (Taipei) 2000 Jun;63(6):492-7
Malignant meningioma with rhabdoid transformation.
Lee WH, Chen A, Chao DG, Harn HJ, Lin SZ
Department of Pathology, Tri-Service General Hospital, National Defense
Medical Center, National Defense University, Taipei, Taiwan, ROC.
We report a rare case of recurrent meningioma with malignant change
and rhabdoid transformation in a 54-year-old woman who presented with
severe headache and progressive weakness of the right extremities. The
patient had a history of atypical meningioma and had undergone a craniotomy
to remove a tumor nine years earlier. We discuss the distinctive morphologic,
immunohistochemical staining and ultrastructural features of a recurrent
malignant meningioma. A meningioma with rhabdoid transformation may
indicate aggressive biologic and clinical behavior of the tumor.
PMID: 10925541, UI: 20381594
Primary Osteorhabdomyosarcoma (Malignant Mesenchymoma) of Bone: A Case
Report and Review of the Literature Jo Van Dorpe, M.D., Raf Sciot, M.D.,
Ph.D., Ignace Samson, M.D., Rita De Vos, Ph.D., Peter Brys, M.D., Baudewijn
Van Damme, M.D., Ph.D.
Primary malignant mesenchymoma of bone is a rare neoplasm consisting
of two or more unrelated malignant mesenchymal components other than
fibrosarcoma or malignant fibrous histiocytoma. The literature reports
fewer than 15 cases, most of which were composed of osteosarcoma and
liposarcoma. We report an exceedingly rare case of primary malignant
mesenchymoma of bone composed of osteosarcoma and rhabdomyosarcoma (osteorhabdomyosarcoma),
arising in the right proximal tibia of a 21-year-old woman. We review
the literature and compare primary malignant mesenchymoma of bone with
dedifferentiated chondrosarcoma and conventional intramedullary osteosarcoma.
Genes Dev 2000 Jul 1;14(13):1617-30
Conditional biallelic Nf2 mutation in the mouse promotes manifestations
of human neurofibromatosis type 2.
Giovannini M, Robanus-Maandag E, van der Valk M, Niwa-Kawakita M, Abramowski
V, Goutebroze L, Woodruff JM, Berns A, Thomas G
INSERM U434, Fondation Jean Dausset, CEPH, Paris, France.
Hemizygosity for the NF2 gene in humans causes a syndromic susceptibility
to schwannoma development. However, Nf2 hemizygous mice do not develop
schwannomas but mainly osteosarcomas. In the tumors of both species,
the second Nf2 allele is inactivated. We report that conditional homozygous
Nf2 knockout mice with Cre-mediated excision of Nf2 exon 2 in Schwann
cells showed characteristics of neurofibromatosis type 2. These included
schwannomas, Schwann cell hyperplasia, cataract, and osseous metaplasia.
Thus, the tumor suppressor function of Nf2, here revealed in murine
Schwann cells, was concealed in hemizygous Nf2 mice because of insufficient
rate of second allele inactivation in this cell compartment. The finding
of this conserved function documents the relevance of the present approach
to model the human disease.
PMID: 10887156, UI: 20347039
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15. This hypothetical disruption of merlin may express itself differently
depending on co-occurence with other carcinogenic factors and genetic
predispositions. High incidence or unusual expression of connective
tissue problems at potential perchlorate sites should receive more scrutiny:
Hill Air Force Base outside Ogden, UT is a major perchlorate processing
center and subject of the following study. The question arises as to
why osteosarcomas are elevated at Hill and in the potash mining village
of Allan, Saskatchewan, which also may have perchlorate in its water
supply. Osteosarcoma rates are also elevated in the Seattle area, where
there are a high proportion of aerospace workers and their families
that may have been exposed to perchlorate at previous workplaces in
other states.
1: Occup Environ Med 1998 Mar;55(3):161-71
Mortality and cancer incidence of aircraft maintenance workers exposed
to trichloroethylene and other organic solvents and chemicals: extended
follow up.
Blair A, Hartge P, Stewart PA, McAdams M, Lubin J
Division of Cancer Epidemiology and Genetics, National Cancer Institute,
Bethesda, MD 20892-7364, USA.
OBJECTIVES: To extend the follow up of a cohort of 14,457 aircraft maintenance
workers to the end of 1990 to evaluate cancer risks from
potential exposure to trichloroethylene and other chemicals. METHODS:
The cohort comprised civilians employed for at least one year between
1952 and 1956, of whom 5727 had died by 31 December 1990. Analyses compared
the mortality of the cohort with the general population of Utah and
the mortality and cancer incidence of exposed workers with those unexposed
to chemicals, while adjusting for age, sex and calendar time. RESULTS:
In the combined follow up period (1952-90), mortality from all causes
and all cancer was close to expected (standardised mortality ratios
(SMRs) 97 and 96, respectively). Significant excesses occurred for ischaemic
heart disease (SMR 108), asthma (SMR 160), and cancer of the bone (SMR
227), whereas significant deficits occurred for cerebrovascular disease
(SMR 88), accidents (SMR 70), and cancer of the central nervous system
(SMR 64). Workers exposed to trichloroethylene showed non-significant
excesses for non-Hodgkin's lymphoma (relative risk (RR) 2.0), and cancers
of the oesophagus (RR 5.6), colon (RR 1.4), primary liver (RR 1.7),
breast (RR 1.8), cervix (RR 1.8), kidney (RR 1.6), and bone (RR 2.1).
None of these cancers showed an exposure-response gradient and RRs among
workers exposed to other chemicals but not trichloroethylene often had
RRs as large as workers exposed to trichloroethylene. Workers exposed
to solvents other than trichloroethylene had slightly increased mortality
from asthma, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer.
CONCLUSION: These findings do not strongly support a causal link with
trichloroethylene because the associations were not significant, not
clearly dose-related, and inconsistent between men and women. Because
findings from experimental investigations and other epidemiological
studies on solvents other than trichloroethylene provide some biological
plausibility, the suggested links between these chemicals and non-Hodgkin's
lymphoma, multiple myeloma, and breast cancer found here deserve further
attention. Although this extended follow up cannot rule out a connection
between exposures to solvents and some diseases, it seems clear that
these workers have not experienced a major increase in cancer mortality
or cancer incidence.
PMID: 9624267, UI: 98287331
Wichita is another Boeing site and home of Raytheon missiles. Perchlorate
contamination in the Wichita area, it it exists, may date from the development
of rocket-assisted Boeing B-47 jet bombers and the more recent Raytheon
Patriot surface-to-air missile.
1 : South Med J 1987 Nov;80(11):1429-31
Maffucci's syndrome complicated by carcinoma of the breast, pituitary
adenoma, and mediastinal hemangioma.
Marymont JV, Fisher RF, Emde GE, Limbird TJ
Department of Laboratory Medicine, Wesley Medical Center, Wichita, Kan.
We have described a 39-year-old woman with Maffucci's syndrome, large
mediastinal hemangiomas, infiltrating adenocarcinoma of the breast,
and pituitary adenoma. This is the fifth reported case of Maffucci's
syndrome with a coexistent pituitary adenoma, a frequency that cannot
be explained by chance alone. There has been only one previously reported
case in which the patient had a widened mediastinum, but the etiology
was not discussed. Three of the four previously described patients with
Maffucci's syndrome and a pituitary adenoma also had a proven or possible
associated epithelial neoplasm. While this association is tenuous, it
is considered worthy of comment.
PMID: 2825361, UI: 88070872
It stands to reason that if enivronmental perchlorate increases the
risks of sarcomas, a disproportionate number of those persons will be
treated by military doctors. A military expert on tumors like rhabdomyosarcoma
and anti-myeloperoxidase linked-pulmonary granulomas is Col. J. Thomas
Stocker of the Armed Forces Institute of Pathology in Bethesda, Maryland
jstocker@usuhs.mil . Of particular
interest is Maffucci's syndrome, a very rare conjunction of sarcomas
and hemangiomas:
1 : Am J Pediatr Hematol Oncol 1993 Nov;15(4):427-9
Acute lymphoid leukemia associated with Maffucci's syndrome.
Rector JT, Gray CL, Sharpe RW, Hall FW, Thomas W, Jones W
Department of Laboratory Medicine, Naval Hospital, San Diego, California
92134-5000.
PURPOSE: Maffucci's syndrome is a nonhereditary congenital disorder
associated with multiple enchondromas, soft tissue hemangiomas, or lymphangiomas.
It carries an associated high risk of the development of malignant neoplasms,
particularly sarcomatous transformation of an enchondroma, as well as
other malignant mesodermal and nonmesodermal neoplasms. Hematopoietic
malignancies arising in Maffucci's syndrome are exceedingly rare. We
report the case of a 14-year-old girl with Maffucci's syndrome who developed
acute lymphoid leukemia. PATIENTS AND METHODS: The patient presented
at 18 months of age with enchondromatosis. Maffucci's syndrome was established
at 10 years of age after the appearance of multiple hemangiomas. RESULTS:
At 14 years of age the patient developed fatigue, frequent nosebleeds,
easy bruising, and weight loss, with circulating blasts in the peripheral
blood. Bone marrow examination showed replacement of marrow spaces with
leukemic blasts. Immunohistochemical and flow cytometric findings were
consistent with a diagnosis of acute lymphoblastic leukemia with myeloid
antigen expression. CONCLUSIONS: The occurrence of acute leukemia in
a patient with Maffucci's syndrome may represent predisposition to yet
another malignancy and reflect further expression of a generalized mesodermal
dysplasia in these patients. It also emphasizes the need for aggressive
surveillance in patients with Maffucci's syndrome.
PMID: 8214367, UI: 94027693
1 : J Vasc Surg 1992 Sep;16(3):364-71Related Articles, Books
Maffucci's syndrome (hemangiomatosis osteolytica): a report of four
cases.
Collins PS, Han W, Williams LR, Rich N, Lee JF, Villavicencio JL
Uniformed Services University of the Health Sciences, Bethesda, MD.
Maffucci's syndrome is a congenital nonfamilial syndrome combining dyschondroplasia,
(enchondromatosis) and hemangiomatosis. It is a rare disease; only 200
cases have been reported throughout the world in the past 140 years.
Over the past 20 years, four patients have been admitted with signs
and symptoms consistent with Maffucci's syndrome. Three were children
ages 3, 7, and 9 years. The fourth was 23 years old. Two were male and
two female. All had hemangiomas at birth, and all had skeletal deformities
and enchondromas. All complained of pain and heaviness of the involved
extremity. Three patients had the arterial inflow evaluated with arteriograms,
and one had magnetic resonance imaging. Two also had venograms. Two
patients had excision of their hemangiomas, and one had sclerotherapy
and compression therapy. All had bone biopsies performed. None of the
enchondromas or the soft tissue lesions had undergone sarcomatous transformation.
Publication Types:
·Review ·Review of reported cases
PMID: 1522638, UI: 92395717
The Southampton-Portsmouth area is the British equivalent to Norfolk
or San Diego:
Atypical chondrodysplasia: a further variant of multiple enchondromatosis
with vertebral involvement?
Hegarty SE, Fairhurst JJ, Temple IK
Department of Paediatric Radiology, Southampton University Hospitals
NHS Trust, Tremona Road, Southampton SO16 1XT, UK.
We report the case of a child with asymmetrical enchondromatosis and
vertebral involvement, who presented in utero, and postulate its relationship
to similar rarely reported cases.
PMID: 9880642, UI: 99099092
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16. Other hypothetical mechanisms of perchlorate may be shock-dependent
reaction with phosphoric acid in bones, and accumulation of intrathyroidal
sulfite secondary to inhibition of sulfite oxidase (a human enzyme very
similar to the nitrate reductases presumed to reduce perchlorate in
plants). The latter effect may present itself in a manner similar to
sulfite-generating thyroid drugs like propylthiouracil:
1: Arthritis Rheum 2000 Feb;43(2):405-13Related Articles, Books, LinkOut
Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis:
prevalence among patients with high titers of antimyeloperoxidase
antibodies.
Choi HK, Merkel PA, Walker AM, Niles JL
Arthritis Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
OBJECTIVE: The triggers that induce antineutrophil cytoplasmic antibody
(ANCA)-positive vasculitis (APV) are largely unknown. However, there
have been reports suggesting that hydralazine, propylthiouracil, and
several other drugs may cause some cases of APV, and the majority of
these cases have been associated with antimyeloperoxidase (anti-MPO)
ANCA. Our experience led us to hypothesize that cases of high titers
of anti-MPO antibodies are often drug-associated. METHODS: In this study,
we determined the prevalence of exposure to hydralazine, propylthiouracil,
and other drugs previously implicated in APV among 30 patients with
vasculitis and the highest titers of anti-MPO antibodies newly detected
in our laboratory between 1994 and 1998. The clinical, histologic, and
other serologic features of these 30 patients were also examined. RESULTS:
The 30 study patients accounted for 12% of the 250 new patients with
APV and anti-MPO who were tested during the study period. All 30 study
subjects had anti-MPO titers that were more than 12 times the median
titer of the 250 patients. Ten (33%) of the 30 patients had been exposed
to hydralazine and 3 (10%) had been exposed to propylthiouracil. An
additional 5 patients (17%) had been exposed to 1 of the other previously
reported candidate drugs: 2 to penicillamine, 2 to allopurinol, and
1 to sulfasalazine. One of the patients exposed to hydralazine had also
been exposed to allopurinol. In all cases, the clinical and histologic
findings were typical of APV. There was a strong association between
the presence of antielastase and/ or antilactoferrin antibodies and
exposure to candidate drugs. CONCLUSION: These data suggest that a sizable
proportion of cases of APV with high titers of anti-MPO antibodies are
drug-associated, especially following exposure to hydralazine or propylthiouracil.
We recommend that the use of these drugs should be sought in cases of
anti-MPO-positive vasculitis,
particularly among patients with high titers of these antibodies.
PMID: 10693882, UI: 20155549
Makiyama Y, Ito M, Akiyama F, Sega H, Togashi K, Hasegawa T, Suzuki
E Arakawa M, Gejyo F
Department of Medicine (II), Niigata University School of Medicine,
Japan.
A 62-year-old woman had been treated with propylthiouracil(PTU) for
hyperthyroidism. Because bloody sputum, dyspnea, and severe hypoxemia
developed, the patient was admitted to our hospital. Chest X-ray and
chest computed tomographic (CT) films disclosed diffuse infiltrative
shadows in both lung fields. Bronchoalveolar lavage revealed abundant
hemosiderin-laden macrophages. Alveolar hemorrhage associated with myeloperoxidase-antineutrophil
cytoplasmic antibody (MPO-ANCA) positive vasculitis syndrome was diagnosed
because of the high serum level of MPO-ANCA. After the initiation of
steroid therapy and termination of PTU, the infiltrative shadows in
both lung fields disappeared, PaO2 improved, and MPO-ANCA decreased.
There have been some reports of MPO-ANCA positive vasculitis syndrome
developing during PTU therapy, but most were concerned with renal disease.
We concluded that PTU and similar agents should be given consideration
as one of the possible causes of MPO-ANCA-induced alveolar hemorrhage.
PMID: 10846402, UI: 20305757
1: Scand J Immunol 1997 Jul;46(1):78-85
Antibody reactivity against thyroid peroxidase and myeloperoxidase in
autoimmune thyroiditis and systemic vasculitis.
Haapala AM, Hyoty H, Parkkonen P, Mustonen J, Soppi E
Department of Clinical Microbiology University Hospital of Tampere,
Finland.
Potential cross-reactivity between thyroid peroxidase (TPO) and myeloperoxidase
(MPO) molecules was evaluated by analysing the binding of 199 TPO antibody-
and MPO antibody-positive sera to TPO and MPO molecules. Sera from six
patients with autoimmune thyroiditis (AITD) and four patients with systemic
vasculitis (SV) with different TPO-MPO antibody findings were then chosen
for further analyses. All six patients with AITD had TPO antibodies
in enzyme immunoassay (EIA) and four of them had simultaneously MPO
antibodies in EIA. In AITD patients antibody binding to TPO could not
be inhibited by adding native MPO to the serum diluent, suggesting that
the possible cross-reactive epitopes were exposed in the denaturated
MPO molecule. Similarly, the MPO ab reactivity of patients with systemic
vasculitis could not be inhibited by native TPO. To study whether TPO
and MPO antibodies recognize linear epitopes, the binding of antibodies
to synthetic TPO and MPO peptides was analysed. Several TPO and MPO
peptides were reactive, including peptides reacting with both TPO and
MPO antibody-positive sera. One of the most cross-reactive peptides
contained AA 586-601 in TPO, showing also particularly high AA homology
(88%) with MPO (AA 594-609). The results suggest that TPO and MPO molecules
contain cross-reactive epitopes that are exposed in denaturated molecules
and may thus cause false positive antibody findings in solid phase EIA
assays.
PMID: 9246211, UI: 97388994
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17. Sub-clinical autoimmune problems may express themselved epidemiologically
via reportable diseases like tuberculosis or
endocrinological measures like elevated free T4.
1: Rheumatology (Oxford) 2000 Apr;39(4):417-20Related Articles, Books,
LinkOut
Prevalence of rheumatic manifestations and antineutrophil cytoplasmic
antibodies in haematological malignancies. A prospective study.
Hamidou MA, Derenne S, Audrain MA, Berthelot JM, Boumalassa A, Grolleau
JY
Department of Internal Medicine, University Hospital, Hotel-Dieu, 44093
Nantes, France.
OBJECTIVE: To evaluate the prevalence of antineutrophil cytoplasmic
antibodies (ANCA) and rheumatic manifestations associated with chronic
haematological malignancies. METHODS: Two groups of patients were prospectively
studied (group I: 60 patients with myelodysplastic syndromes and group
II: 140 patients with lymphoid malignancies) for clinical 'immune' manifestations
and ANCA. RESULTS: In the myelodysplastic group, six patients had ANCA-negative
systemic medium-size vasculitis, one had systemic vasculitis with cytoplasmic
ANCA, one relapsing polychondritis, one giant cell arteritis, one polymyalgia
rheumatica, one polyarthritis and two fasciitis. In group II, two patients
had ANCA-negative systemic vasculitis, two had leucocytoclastic vasculitis
associated with tuberculosis, two had polyarthritis, one polymyalgia
rheumatica and one giant cell arteritis. Six sera were ANCA-positive
with perinuclear pattern in four cases, atypical pattern in one and
cytoplasmic pattern in one. Two sera had anti-myeloperoxidase (MPO)
specificity, and others had no known specificity; none had anti-proteinase
3 (PR3) specificity. Global prevalence of ANCA in our cohort was 3%,
similar to the French general population. CONCLUSION: Polyarteritis
nodosa-type systemic vasculitis and polymyalgia rheumatica were the
most frequent findings (18%) in myelodysplastic syndromes and particularly
in chronic myelomonocytic leukaemia. ANCA were not helpful for the diagnosis
of vasculitis. Vasculitis associated with infection, in particular tuberculosis,
must be ruled out.
PMID: 10817775, UI: 20278301
1: J Clin Endocrinol Metab 2000 Nov;85(11):3996-9
A characteristic serpin cleavage product of thyroxine-binding globulin
appears in sepsis sera.
Jirasakuldech B, Schussler GC, Yap MG, Drew H, Josephson A, Michl J
Department of Medicine, State University of New York Health Sciences
Center, Brooklyn 11203, USA.
T4-binding globulin (TBG), the principal thyroid hormone-binding protein
of serum, is a member of the serine protease inhibitor (serpin) superfamily.
We report a characteristic serpin cleavage product of TBG in sepsis
sera. At 49-50 kDa, the TBG remnant is 4-5 kDa smaller than the intact
protein and is the same molecular mass as a TBG cleavage product produced
by incubation with polymorphonuclear elastase. Incubation with polymorphonuclear
leukocytes also produces the 49- to 50-kDa remnant, and this proteolysis
is stimulated by zymosan activation. Polymorphonuclear cell cleavage
of TBG increases the ratio of free/bound T4. As previously described,
in vitro cleavage of TBG by elastase also increases free/bound T4. These
findings are consistent with the hypothesis that serine proteases present
at inflammatory sites cleave TBG, releasing its hormonal ligands.
PMID: 11095421, UI: 20544530
