National Cancer Institute®
Last Modified: August 1, 2002
1
UI - 12113242
AU - Verma S; Bramwell V
TI -
Dose-intensive chemotherapy in advanced adult soft tissue sarcoma.
SO - Expert Rev Anticancer Ther 2002 Apr;2(2):201-15
AD - University of Ottawa, 503 Smyth Road, Ottawa, ON, Canada.
shailendra.verna@cancercare.on.ca
The treatment of metastatic soft tissue sarcomas in adults is one of the
most challenging areas in oncology. While multidisciplinary management
of early-stage, localized disease has led to a number of improved
outcomes, therapy of unresectable or advanced disease remains
problematic. Virtually every conventional cytotoxic agent has been
systematically assessed in this malignancy, yet only a handful have
demonstrated significant activity. Adriamycin and ifosfamide are the
only chemotherapeutic drugs to have consistently produced response rates
of over 20% when given as single agents and these two drugs have been
exhaustively studied alone or in combination. Recent efforts to improve
response rates and, by inference, disease-free survival and overall
survival, have involved exploration of high-dose regimen incorporating
growth factors and/or autologous cellular support. In this article, the
status of dose-intensive chemotherapy in advanced adult soft tissue
sarcomas (excluding pediatric histologies, such as Ewing's sarcoma and
rhabdomyosarcoma) will be discussed. Emphasis will be placed on data
from randomized Phase III trials but information from Phase I/II studies
will also be reviewed and recommendations will be made on a systematic
analysis of the data.
2
UI - 12115562
AU - Soderstrom M; Bohling T; Ekfors T; Nelimarkka L; Aro HT; Vuorio E
TI -
Molecular profiling of human chondrosarcomas for matrix production and
cancer markers.
SO - Int J Cancer 2002 Jul 10;100(2):144-51
AD - Skeletal Research Program, Department of Medical Biochemistry and
Molecular Biology, University of Turku, Turku, Finland.
Chondrosarcoma is the second most common malignant bone tumor,
characterized by production of abundant extracellular matrix resembling
hyaline cartilage. To better understand the molecular pathogenesis of
chondrosarcoma, we analyzed 12 chondrosarcomas for their production of
connective tissue components and SOX9, a key regulator of normal
chondrocyte differentiation. Furthermore, 10 chondrosarcoma samples were
screened for additional changes in gene expression using cDNA array
analysis. In Northern analysis, several tumors were found to express
type II collagen mRNA at levels comparable to fetal cartilage used as a
control. Interestingly, the highest levels of type II collagen mRNA were
seen in 2 of the 3 grade 3 chondrosarcomas, which also exhibited the
highest mRNA levels of SOX9 and "prechondrogenic" pro alpha 1(IIA)
collagen. Expression of SOX9 in human chondrosarcomas is novel and
suggests that chondrosarcomas originate from a multipotent stem cell
committed to differentiation along the chondrogenic pathway. Results of
the cDNA array analyses emphasize the heterogeneous nature of
chondrosarcoma as no single transcript was systematically up- or
downregulated in all tumors analyzed. Among the interesting changes
observed was upregulation of decorin mRNA in 7 of the 10 tumors
analyzed. Further studies are needed to determine whether decorin plays
a role in the pathogenesis of chondrosarcoma. The cDNA arrays also
revealed discrepancies from Northern and RNase protection analyses in
transcript levels of matrix components, emphasizing the need to validate
cDNA array data with other techniques. Copyright 2002 Wiley-Liss, Inc.
3
UI - 12118030
AU - Wendtner CM; Abdel-Rahman S; Krych M; Baumert J; Lindner LH; Baur A;
TI -
Hiddemann W; Issels RD
Response to neoadjuvant chemotherapy combined with regional hyperthermia
predicts long-term survival for adult patients with retroperitoneal and
visceral high-risk soft tissue sarcomas.
SO - J Clin Oncol 2002 Jul 15;20(14):3156-64
AD - Department of Internal Medicine III, Diagnostic Radiology and Institute
for Biostatistics and Epidemiology, Klinikum Grosshadern Medical Center,
Ludwig-Maximilians-University, Munich, Germany.
Clemens.Wendtner@med3.med.uni-muenchen.de
PURPOSE: To determine the efficacy of neoadjuvant chemotherapy combined
with regional hyperthermia (RHT) for local tumor control and overall
survival (OS) in adult patients with retroperitoneal or visceral (RP/V)
high-risk soft tissue sarcomas (HR-STS). PATIENTS AND METHODS: From 1991
to 1997, 58 patients with HR-STS at RP/V sites were prospectively
treated with four cycles of etoposide, ifosfamide, and doxorubicin
combined with RHT followed by surgery, adjuvant chemotherapy, and
radiation. RESULTS: Objective response rate assessable in 40 patients
was 13% (five partial responses). Including minor responses (n = 8), the
radiographic response rate was 33%. The pathologic response rate
assessable in 26 patients after surgical resection was 42%. Median OS
was 31 months. At a median observation time of 74 months, 5-year
probability of local failure-free survival (LFFS), distant
metastasis-free survival, event-free survival, and OS were 25%, 51%,
20%, and 32%, respectively. Averaged minimum temperatures (T(min)) and
time-averaged temperatures achieved in 50% (T(50)) and 90% (T(90)) of
all measured tumor sites differed significantly between responders and
nonresponders (T(min), 39.3 degrees C v 38.0 degrees C; P =.002; T(50),
40.9 degrees C v 40.3 degrees C; P =.038; T(90), 40.1 degrees C v 39.3
degrees C; P =.017). At 5-year follow-up, probability of LFFS (59% v 0%;
P <.001) and OS (60% v 10%; P <.001) was significantly in favor of
patients responding to neoadjuvant thermochemotherapy. CONCLUSION:
Response to neoadjuvant chemotherapy combined with RHT is predictive for
an improved local tumor control resulting in a long-term survival
benefit for patients with HR-STS at unfavorable RP/V sites; however, the
impact of RHT has to be defined in a randomized phase III trial.
4
UI - 12124838
AU - Little DJ; Ballo MT; Zagars GK; Pisters PW; Patel SR; El-Naggar AK;
TI -
Garden AS; Benjamin RS
Adult rhabdomyosarcoma: outcome following multimodality treatment.
SO - Cancer 2002 Jul 15;95(2):377-88
AD - Department of Radiation Oncology, University of Texas M.D. Anderson
Cancer Center, Houston, Texas 77030, USA.
BACKGROUND: Childhood rhabdomyosarcoma (RMS) has a relatively good
prognosis. Outcome for adults with this disease is poorly documented due
to its rarity. METHODS: The clinicopathologic features, treatment
methods, and disease outcome were reviewed retrospectively for 82 adults
with locoregional RMS treated between 1960 and 1998. Patients with
distant metastasis at diagnosis were excluded. Actuarial univariate and
multivariate statistical methods were used to evaluate outcome. RESULTS:
Patient ages ranged from 17 to 84 years (median, 27 years). Histologic
subtypes were embryonal (34%), pleomorphic (43%), and alveolar (23%).
Anatomic sites of origin were head and neck (52%), trunk (26%), and
extremity (7%). Tumor size was 5 cm or smaller in 51% of patients.
Regional lymph node metastasis was present in 33% of patients at
presentation. Treatment consisted of radiation alone in 11%, radiation
and surgery in 18%, radiation and chemotherapy in 34%, and all three
modalities in 37%. With a median follow-up of 10.5 years, the 10-year
actuarial disease-free and overall survival rates were 41% and 40%,
respectively. The 10-year actuarial local, lymph node, and metastatic
control rates were 75%, 82%, and 53%, respectively. The major
determinant of metastatic control and survival was primary tumor size (<
or = 5 vs. > 5 cm). Local control was satisfactory (10-year rate of 87%)
for sites other than parameningeal (50% at 10 years). Patients whose
disease responded to chemotherapy had a significantly better metastasis
free period (72% at 10 years) than those whose disease failed to respond
(19% at 10 years). CONCLUSIONS: Adult RMS is a highly malignant tumor
with a significant incidence of metastatic recurrence. Continuing
investigation of new and potentially more effective chemotherapy is
crucial. Local control is satisfactory for sites other than
parameningeal where new radiation technologies such as
intensity-modulated therapy may be necessary to safely deliver adequate
doses. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10669
5
UI - 12127408
AU - Maire G; Pedeutour F; Mrozek K; Rys J; Iliszko M; Limon J
TI -
COLIA1-PDGFB gene fusion in dermatofibrosarcoma protuberans. molecular
analysis of a case with an unusual large marker containing sequences
from chromosomes 7, 8, 17, 21, and 22.
SO - Cancer Genet Cytogenet 2002 Jun;135(2):197-9
6
UI - 12095566
AU - Fisher B; Won M; Macdonald D; Johnson DW; Roa W
TI -
Phase II study of topotecan plus cranial radiation for glioblastoma
multiforme: results of Radiation Therapy Oncology Group 9513.
SO - Int J Radiat Oncol Biol Phys 2002 Jul 15;53(4):980-6
AD - Department of Radiation Oncology, London Regional Cancer Centre, London,
Ontario, Canada. barb.fisher@lrcc.on.ca
PURPOSE: A Phase II trial was conducted by the Radiation Therapy
Oncology Group (RTOG) to compare the survival of patients with
glioblastoma multiforme treated with topotecan combined with standard
cranial radiotherapy (RT) for matched patients treated in prior RTOG
studies. A secondary objective was to document the acute and late
toxicities of this combination of chemotherapy and RT. METHODS AND
MATERIALS: Eighty-seven patients with histologically confirmed
glioblastoma multiforme received standard cranial RT (60 Gy/30 fractions
in 6 weeks) plus topotecan 1.5 mg/m2 per day i.v. for 5 d/wk every 3
weeks for 3 cycles. Eighty-four patients were evaluated, of whom 60
(71%) were > or =50 years, 44 (52%) were men, and 61 (73%) had a
Karnofsky performance status of > or =80. Twenty-nine percent of
patients had undergone biopsies, 48% partial resections, and 21% gross
total resections. Two resections were unspecified as to the extent of
tumor removal. Fourteen percent of patients were recursive partitioning
analysis Class III, 46% were Class IV, 35% were Class V, and 5% were
Class VI. RESULTS: The median survival was 9.3 months. Sixty-seven
patients (80%) had progression. The 1-year survival rate was 32%. One
patient remained alive without recurrence. RTOG 9513 patients were
matched with patients in an RTOG clinical trial database from previous
clinical trials. The matching variables were age, Karnofsky performance
status, mental status, and prior surgery. No statistically significant
difference was found between the survival of the study patients and that
of the matched patients from the RTOG database. Fifty-four percent of
patients had Grade IV acute toxicity. The toxicity was primarily
hematologic. Four patients had Grade III late central nervous system
toxicities. CONCLUSION: Topotecan administered at a dose of 1.5 mg/m2
per day i.v. for 5 d/wk every 3 weeks for 3 cycles given concurrently
with standard cranial RT for glioblastoma does not produce a
statistically significant survival advantage over previously tested
therapies. Other methods of administration of topotecan or other
camptothecins may provide more effective radiosensitization.
7
UI - 12097603
AU - AuCoin DP; Colletti KS; Xu Y; Cei SA; Pari GS
TI -
Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) contains
two functional lytic origins of DNA replication.
SO - J Virol 2002 Aug;76(15):7890-6
AD - Department of Microbiology and Cell and Molecular Biology Program,
University of Nevada School of Medicine, Reno, Nevada 89557, USA.
We used a transient-transfection replication assay to identify two
functional copies of the human herpesvirus 8 (HHV8) lytic origin of DNA
replication (oriLyt). BCLB-1 cells were transfected with HHV8 subgenomic
fragments containing the putative lytic origin along with a plasmid
expressing viral transactivator open reading frame (ORF) 50. The HHV8
left-end oriLyt (oriLyt-L) lies between ORFs K4.2 and K5 and is composed
of a region encoding various transcription factor binding sites and an
A+T-rich region and a G+C repeat region. The right-end oriLyt (oriLyt-R)
maps between ORF 69 and vFLIP, a region similar to the RRV oriLyt, and
is an inverted duplication of oriLyt-L.
8
UI - 12131151
AU - Thompson LD; Gannon FH
TI -
Chondrosarcoma of the larynx: a clinicopathologic study of 111 cases
with a review of the literature.
SO - Am J Surg Pathol 2002 Jul;26(7):836-51
AD - Department of Endocrine and Otorhinolaryngic-Head & Neck Pathology,
Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
thompson@afip.osd.mil
Chondrosarcomas of the larynx are rare tumors accounting for about 0.5%
of all laryngeal primary tumors. A total of 111 laryngeal chondrosarcoma
cases, diagnosed between 1970 and 1997, were retrieved from the
Otorhinolaryngic-Head & Neck Tumor Registry of the Armed Forces
Institute of Pathology. There was a 3.6:1 male/female ratio of patients
25-91 years of age (mean, 64.4 years). Patients presented most
frequently with hoarseness (n = 72 patients) present for a mean of 28.2
months. The majority of tumors involved the cricoid cartilage (n = 77)
with a mean size of 3.5 cm. All tumors were invasive and malignant by
radiology and/or histology (into bone within the ossified laryngeal
cartilages in 52 tumors). Most tumors were low-grade lesions: grade 1 (n
= 51), grade 2 (n = 54); there were six grade 3 tumors. An associated
benign chondroma with (n = 41 tumors) or without ischemia (n = 24
tumors) was noted. All patients had surgery and five had radiation
therapy. Wide excision or voice-sparing surgery was used in 73 patients,
whereas 37 patients had a laryngectomy. Recurrences occurred in 20 (18%)
patients, 10 of whom underwent salvage laryngectomy. At the last
follow-up, 102 patients had no evidence of disease (alive or dead, mean
11.2 years) and five patients had evidence of disease (alive, one
patient, 6.5 years; dead, four patients, mean 6.4 years). The six
patients with high-grade chondrosarcoma were all without disease at the
last follow-up (mean, 15.1 years). There was no difference in clinical
outcome based on grade (p = 0.210), location (p = 0.078), or treatment
(p = 0.607) but was worse for patients with a myxoid-type chondrosarcoma
(p = 0.044). Primary laryngeal chondrosarcomas are typically low- to
moderate-grade lesions involving the cricoid cartilage, frequently
associated with a chondroma. They usually portend an excellent overall
long-term prognosis with initial conservative voice-sparing surgery.
9
UI - 10364341
AU - Zoeteweij JP; Eyes ST; Orenstein JM; Kawamura T; Wu L; Chandran B;
TI -
Forghani B; Blauvelt A
Identification and rapid quantification of early- and late-lytic human
herpesvirus 8 infection in single cells by flow cytometric analysis:
characterization of antiherpesvirus agents.
SO - J Virol 1999 Jul;73(7):5894-902
AD - Dermatology Branch, National Cancer Institute,National Institutes of
Health, Bethesda, Maryland 20892, USA.
Human herpesvirus 8 (HHV-8) infection is associated with Kaposi's
sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's
disease. In this study, we used monoclonal antibodies (MAbs) directed
against HHV-8 lytic cycle-associated proteins encoded by open reading
frame (ORF) 59 (nuclear PF-8 protein) and ORF K8.1 (viral envelope
glycoprotein K8.1 [gpK8.1]) to investigate HHV-8 lytic infection in
single cells. Lytically infected cells were labeled with MAbs, stained
with fluorescently conjugated secondary Abs, and analyzed by flow
cytometry. A 3-day stimulation of HHV-8-positive PEL cell lines (BCBL-1
and BC-3) with 12-O-tetradecanoylphorbol-13-acetate (30 nM) or n-butyric
acid (0.3 mM) maximized the expression of lytic-phase viral proteins and
minimized cell toxicity. The absolute number of expressing cells was
inducer and cell line dependent. Expression of PF-8 occurred earlier and
more frequently (in up to 20% of cells) than did expression of gpK8.1. A
subset of PF-8 positive cells (25%) co-expressed gpK8.1, representing
the majority of gpK8.1 expressing cells. Acyclovir, foscarnet,
cidofovir, and PMEA reduced the number of cells expressing gpK8.1, but
not the number expressing the nonstructural early lytic gene product
PF-8. By contrast, alpha interferon (IFN-alpha) and IFN-beta reduced
expression of both PF-8 and gpK8.1, implying an overall inhibitory
effect on viral gene transcription or translation. In summary, we have
characterized and quantified HHV-8 lytic infection in single cells by
dual measurement of early- and late-lytic-cycle HHV-8 protein
expression. This technique should prove useful for screening of possible
antiherpesvirus agents and for detailed phenotypic characterization of
HHV-8-infected cells in vitro and in patients with HHV-8-associated
diseases.
10
UI - 11290599
AU - Wang QJ; Jenkins FJ; Jacobson LP; Kingsley LA; Day RD; Zhang ZW; Meng
TI -
YX; Pellett PE; Kousoulas KG; Baghian A; Rinaldo CR Jr; Pellet PE
Primary human herpesvirus 8 infection generates a broadly specific
CD8(+) T-cell response to viral lytic cycle proteins.
SO - Blood 2001 Apr 15;97(8):2366-73
AD - Department of Infectious Diseases and Microbiology, Graduate School of
Public Health, University of Pittsburgh, Pennsylvania 15261, USA.
Human herpesvirus 8 (HHV-8) is a recently discovered gammaherpesvirus
that is the etiologic agent of Kaposi sarcoma (KS). The natural history
of primary HHV-8 infection, including clinical outcome and host immune
responses that may be important in preventing disease related to HHV-8,
has not been elucidated. The present study characterized the clinical,
immunologic, and virologic parameters of primary HHV-8 infection in 5
cases detected during a 15-year longitudinal study of 108 human
immunodeficiency virus type 1 seronegative men in the Multicenter AIDS
Cohort Study. Primary HHV-8 infection was associated with mild,
nonspecific signs and symptoms of diarrhea, fatigue, localized rash, and
lymphadenopathy. There were no alterations in numbers of CD4(+) or
CD8(+) T cells or CD8(+) T-cell interferon gamma (IFN-gamma) production
to mitogen or nominal antigen. CD8(+) cytotoxic T-lymphocyte precursor
(CTLp) and IFN-gamma reactivity were detected during primary HHV-8
infection, with broad specificity to 5 lytic cycle proteins of HHV-8
encoded by open reading frame 8 (ORF 8; glycoprotein B homolog of
Epstein-Barr virus), ORF 22 (gH homolog), ORF 25 (major capsid protein
homolog), ORF 26 (a minor capsid protein homolog), or ORF 57 (an early
protein homolog), in association with increases in serum antibody titers
and appearance of HHV-8 DNA in blood mononuclear cells. CD8(+) T-cell
responses to HHV-8 decreased by 2 to 3 years after primary infection.
This antiviral T-cell response may control initial HHV-8 infection and
prevent development of disease.
11
UI - 11342455
AU - Davis DA; Rinderknecht AS; Zoeteweij JP; Aoki Y; Read-Connole EL; Tosato
TI -
G; Blauvelt A; Yarchoan R
Hypoxia induces lytic replication of Kaposi sarcoma-associated
herpesvirus.
SO - Blood 2001 May 15;97(10):3244-50
AD - HIV and AIDS Malignancy Branch, the Dermatology Branch, and the Medicine
Branch, National Cancer Institute, National Institutes of Health,
Bethesda, MD, USA. dadavis@helix.nih.gov
There is substantial evidence that Kaposi sarcoma-associated herpesvirus
(KSHV) plays an important role in the pathogenesis of all forms of
Kaposi sarcoma (KS). It has been noted that KS commonly occurs in
locations, such as the feet, where tissue may be poorly oxygenated. On
the basis of this observation, the potential role of hypoxia in the
reactivation of KSHV replication was explored by studying 2
KSHV-infected primary effusion lymphoma B-cell lines (BC-3 and BCBL-1)
latently infected with KSHV. Acute and chronic exposure of these cells
to hypoxia (1% O(2)) induced KSHV lytic replication, as indicated by an
increase in intracellular lytic protein expression and detection of
virus in cell supernatants by Western immunoblotting. In addition,
hypoxia increased the levels of secreted viral interleukin-6. Moreover,
hypoxia enhanced the lytic replication initiated by the viral inducer
12-O-tetradecanoylphorbol-13-acetate. Desferoxamine and cobalt chloride,
2 compounds that increase the intracellular levels of hypoxia-inducible
factor 1, were also able to induce KSHV lytic replication. These studies
suggest that hypoxia is an inducer of KSHV replication. This process may
play an important role in the pathogenesis of KS.
12
UI - 12082396
AU - Nishimura K; Ueda K; Sakakibara S; Ishikawa K; Chen J; Okuno T;
TI -
Yamanishi K
Functional analysis of Kaposi's sarcoma-associated herpesvirus RTA in an
RTA-depressed cell line.
SO - J Hum Virol 2001 Nov-Dec;4(6):296-305
AD - Department of Microbiology, Osaka University Medical School, Osaka,
Japan.
OBJECTIVE: The viral transcriptional activator encoded by Kaposi's
sarcoma-associated herpesvirus (KSHV) open reading frame 50 (RTA) is
expressed in the immediate-early phase of reactivation. We isolated an
RTA-depressed cell line, BLS50-4, by subcloning from the KSHV-infected
cell line, BCBL-1. RESULTS: In addition to RTA, induction of some lytic
gene expressions was also remarkably reduced in BLS50-4 cells, but that
of the K8.1 and ORF65 gene expressions was not. Both the replication of
the KSHV genome and the release of KSHV DNA into the medium were greatly
reduced. Transfection of RTA into BLS50-4 cells restored the expression
of K9 (vIRF) and ORF59, but not K8.1. CONCLUSIONS: Thus, we showed that
expression of late genes was not directly controlled by RTA, unlike the
other groups concluded. We also showed that, by isolating the
RTA-depressed cell line, the RTA protein had a critical role in viral
DNA replication and the expression of several lytic genes.
13
UI - 12004355
AU - Nascimento AF; McMenamin ME; Fletcher CD
TI -
Liposarcomas/atypical lipomatous tumors of the oral cavity: a
clinicopathologic study of 23 cases.
SO - Ann Diagn Pathol 2002 Apr;6(2):83-93
AD - Department of Pathology, Brigham and Women's Hospital and Harvard
Medical School, Boston, MA 02115, USA.
Liposarcomas in the oral cavity have rarely been described, with less
than 50 reported cases to date and a purported predominance of the
myxoid type. We reviewed our experience with 23 atypical lipomatous
tumors/liposarcomas of the oral cavity. Twelve patients were men, 10
were women, and gender was not stated in one case. Age at presentation
ranged from 28 to 83 years (median, 49.5 years). The most commonly
affected site was the tongue and most cases presented as a slowly
growing, painless mass. The clinical impression was lipoma or fibroma in
the majority of cases. Tumor size ranged from 0.6 to 8.0 cm (median, 1.5
cm). Five cases were well circumscribed, 5 cases were focally
infiltrative, and 13 cases had markedly infiltrative margins. Twenty-one
cases were classified as atypical lipomatous tumors (of which 10 showed
spindle cell features), one as dedifferentiated liposarcoma, and one as
myxoid liposarcoma. Follow-up data was available in 13 of the 23 cases.
Five others were lost to follow-up after a short period. Eleven patients
remained free of disease without local recurrence or metastasis during
the period of follow-up that ranged from 10 months to 9 years (median,
24 months). Two patients had multiple local recurrences. Our study shows
that atypical lipomatous tumor is the most common type of malignant
fatty tumor to arise in the oral cavity with an apparently low risk of
recurrence if widely excised, although follow-up is relatively limited
thus far. Copyright 2002, Elsevier Science (USA). All rights reserved.
14
UI - 12007018
AU - Brownlee NA; Hazen-Martin DJ; Garvin AJ; Re GG
TI -
Functional and gene expression analysis of the p53 signaling pathway in
clear cell sarcoma of the kidney and congenital mesoblastic nephroma.
SO - Pediatr Dev Pathol 2002 May-Jun;5(3):257-68
AD - Department of Pathology and Laboratory Medicine, Medical University of
South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA.
Mutation of p53 has been implicated in progression of classical Wilms
tumor (WT) into the anaplastic variant (AWT), drug resistance, and poor
prognosis. Because of prognostic similarities, clear cell sarcoma of the
kidney (CCSK) has been classified with AWT and other aggressive
pediatric renal tumors, apart from congenital mesoblastic nephroma
(CMN), which is instead a relatively benign tumor of neonates.
Initially, CCSK and CMN were assumed to be ontologically related, but
the role of p53 in the pathogenesis of either disease has not been
sufficiently evaluated as in AWT. We examined the status of p53 in CMN
and CCSK in comparison to AWT by immunohistochemistry and mRNA analysis
of p53, the downstream effector p21(WAF-1/CIP-1) ( p21), the multidrug
resistance gene MDR-1, a putative target of p53, and the p53-antagonist
Mdm-2. Surprisingly, strong p53 nuclear immunoreactivity was found in
cultures from two CMN specimens, but not in frozen or fixed tumor tissue
from five other CMN specimens, nor in cell lines or tumor tissue from
CCSK. Sequence analysis excluded p53 mutations. The size of the p53 mRNA
in CMN and CCSK primary tumors excluded gross deletions or
rearrangements. Low levels of Mdm-2 mRNA in CCSK and CMN primary tumors
and cultures did not support a role for Mdm-2. Absence of MDR-1 mRNA
excluded MDR-1 in the drug-resistant phenotype of CCSK.
Cisplatin-induced p21 transactivation assays and G(1) cell cycle arrest
analyses showed that p21 transactivation and G(1) arrest occurred in
both CCSK and CMN cultures, demonstrating integrity of the p53 signal
transduction pathway. Absence of p53 functional abnormalities excluded
relationships between CCSK and CMN as in AWT, supporting the association
of cellular CMN with congenital fibrosarcomas as more recently proposed.
15
UI - 12007020
AU - Leuschner I; Heuer T; Harms D
TI -
Induction of drug resistance in human rhabdomyosarcoma cell lines is
associated with increased maturation: possible explanation for
differentiation in recurrences?
SO - Pediatr Dev Pathol 2002 May-Jun;5(3):276-82
AD - Kiel Paediatric Tumor Registry, Institute for Paediatric Pathology,
University of Kiel, Michaelisstrasse 11, D-24105 Kiel, Germany.
In rhabdomyosarcoma (RMS) of childhood and adolescence very little is
known about interactions of cytotoxic drugs and tumor cells. In
recurrent RMS the tumor cells are often more mature than in the primary
tumor. The biological properties of these cells are still a subject of
controversy. We investigated two human (RD2 and TE 671) cell lines by
cultivating them with doxorubicin, cisplatinum, and etoposide. Degree of
differentiation and proliferation rate were estimated morphologically
and by means of immunohistochemistry and a monolayer proliferation
assay. Both morphological and immunohistochemical maturation was
measurable in most resistant cell lines. An increase in myosin
expression was most marked in the etoposide- and doxorubicin-resistant
RD cell lines. The proliferation rate was decreased in almost all
resistant cell lines. Nevertheless, the resistant cell lines tolerated
high-dose levels of cytotoxic drugs at a higher proliferation rate than
parental cell lines cultivated under similar conditions. The maturation
seen in some recurrent tumors of RMS can be simulated in vitro by
cultivating cell lines with cytotoxic drugs at sublethal doses.
Interestingly, the resistance-associated induced maturation was not
accompanied by p170 expression. After comparing these in vitro results
with the maturation seen in RMS specimens after chemotherapy, we
conclude that chemotherapy-induced differentiation in vivo might be a
morphological sign of chemoresistance.
16
UI - 12112526
AU - Chen GK; Lacayo NJ; Duran GE; Wang Y; Bangs CD; Rea S; Kovacs M; Cherry
TI -
AM; Brown JM; Sikic BI
Preferential expression of a mutant allele of the amplified MDR1 (ABCB1)
gene in drug-resistant variants of a human sarcoma.
SO - Genes Chromosomes Cancer 2002 Aug;34(4):372-83
AD - Oncology Division, Department of Medicine, Stanford University School of
Medicine, 269 Campus Drive, Stanford, CA 94305-5151, USA.
Activation of the MDR1 (ABCB1) gene is a common event conferring
multidrug resistance (MDR) in human cancers. We investigated MDR1
activation in MDR variants of a human sarcoma line, some of which
express a mutant MDR1, which facilitated the study of allelic gene
expression. Structural alterations of MDR1, gene copy numbers, and
allelic expression were analyzed by cytogenetic karyotyping,
oligonucleotide hybridization, Southern blotting, polymerase chain
reaction, and DNA heteroduplex assays. Both chromosome 7 alterations and
several cytogenetic changes involving the 7q21 locus are associated with
the development of MDR in these sarcoma cells. Multistep-selected cells
and their revertants contain three- to six-fold MDR1 gene amplification
compared with that of the drug-sensitive parental cell line MES-SA and
single-step doxorubicin-selected mutants. MDR1 gene amplification
precedes the emergence of a mutant allele in cells that were coselected
with doxorubicin and a cyclosporin inhibitor of P-glycoprotein (P-gp).
Allele-specific oligonucleotide hybridization showed that the endogenous
mutant allele was present as a single copy, with multiple copies of the
normal allele. Reselection of revertant cells with doxorubicin in either
the presence or the absence of the P-gp inhibitor resulted in exclusive
reexpression of the mutant MDR1 allele, regardless of the presence of
multiple wild-type MDR1 alleles. These data provide new insights into
how multiple alleles are regulated in the amplicon of drug-resistant
cancer cells and indicate that increased expression of an amplified gene
can result from selective transcription of a single mutant allele of the
gene. Copyright Wiley-Liss, Inc.
17
UI - 12112531
AU - Actor B; Cobbers JM; Buschges R; Wolter M; Knobbe CB; Reifenberger G;
TI -
Weber RG
Comprehensive analysis of genomic alterations in gliosarcoma and its two
tissue components.
SO - Genes Chromosomes Cancer 2002 Aug;34(4):416-27
AD - Abteilung Molekulare Genetik, Deutsches Krebsforschungszentrum,
Heidelberg, Germany.
Gliosarcoma is a variant of glioblastoma multiforme characterized by two
components displaying gliomatous or sarcomatous differentiation. We
investigated 38 gliosarcomas for aberrations of tumor-suppressor genes
and proto-oncogenes that are commonly altered in glioblastomas.
Amplification of CDK4, MDM2, EGFR, and PDGFRA were found in 11% (4/35),
8% (3/38), 8% (3/38), and 3% (1/35) of the tumors, respectively. Nine of
38 gliosarcomas (24%) carried TP53 mutations. PTEN mutations were
identified in 45% (9/20) of the investigated tumors. Twenty gliosarcomas
were analyzed by comparative genomic hybridization (CGH). Chromosomal
imbalances commonly detected were gains on chromosomes 7 (15/20; 75%), X
(4/20; 20%), 9q, and 20q (3/20, 15% each); and losses on chromosomes 10
and 9p (7/20, 35% each), and 13q (3/20, 15%). Five different high-level
amplifications were mapped to 4q12-q21 (1 case), 6p21 (1 case), 7p12 (2
cases), proximal 12q (4 cases), and 14q32 (1 case) by CGH. Southern blot
and/or differential PCR analyses identified amplification of PDGFRA
(4q12), CCND3 (6p21), EGFR (7p12), CDK4 (12q14) and/or MDM2
(12q14.3-q15), and AKT1 (14q32.3) in the respective tumors. Separate
analysis of the gliomatous and sarcomatous components of eight
gliosarcomas by CGH after microdissection and universal DNA
amplification revealed that both components shared 57% of the
chromosomal imbalances detected. Taken together, our data indicate that
the genomic changes in gliosarcomas closely resemble those found in
glioblastomas. However, the number of chromosomes involved in imbalances
in gliosarcomas was significantly lower than that in glioblastomas,
indicating a higher genomic stability in gliosarcomas. In addition, we
provide further support for the hypothesis that the gliomatous and
sarcomatous components are derived from a single precursor cell clone,
which progressed into subclones with distinct morphological features
during tumor evolution. According to our data, gain/amplification of
genes on proximal 12q may facilitate the development of a sarcomatous
phenotype. Copyright 2002 Wiley-Liss, Inc.
18
UI - 12124330
AU - Mertens F; Stromberg U; Mandahl N; Cin PD; De Wever I; Fletcher CD;
TI -
Mitelman F; Rosai J; Rydholm A; Sciot R; Tallini G; Van Den Berghe H;
Vanni R; Willen H
Prognostically important chromosomal aberrations in soft tissue
sarcomas: a report of the Chromosomes and Morphology (CHAMP) Study
Group.
SO - Cancer Res 2002 Jul 15;62(14):3980-4
AD - Department of Clinical Genetics, Lund University Hospital, SE-221 85
Lund, Sweden. fredrik.mertens@klingen.lu.se
Cytogenetic analysis has not only provided important information on the
pathogenesis of soft tissue tumors but, by disclosing distinct
chromosomal rearrangements in different histopathological entities, has
also come to serve as a valuable diagnostic tool. Little is known as yet
about the potential prognostic impact of cytogenetic features detected
in these tumors. A total of 239 benign and 221 malignant soft tissue
tumors with clonal chromosome aberrations were subdivided according to
general karyotypic features, such as degree of complexity and ploidy
level, and rearrangements of specific chromosomal regions. The
cytogenetic variables were analyzed regarding clinical outcome, using
time to metastasis as the end point. Selected variables were then
compared with established clinicopathological predictors of metastasis
development. When the entire material was considered, 167 of 268
investigated cytogenetic variables were associated with clinical
outcome. Focusing on the subset of 151 patients with high-grade sarcoma,
17 variables were identified that, besides grade and size, were
associated with increased risk of metastasis development. A final Cox
regression analysis identified five independent cytogenetic predictors
of adverse outcome; breakpoints in chromosome regions 1p1, 1q4, 14q1,
and 17q2, and gain of regions 6p1/p2. An increasing effect on metastatic
risk was seen with increasing involvement of the selected cytogenetic
variables, even when different histopathological types were studied
separately. We conclude that cytogenetic data provide independent
prognostic information in soft tissue sarcomas. Furthermore, our results
point to specific areas of the genome harboring genes that may influence
the metastatic potential of sarcoma cells.
19
UI - 12133991
AU - Sato Y; Nabeta Y; Tsukahara T; Hirohashi Y; Syunsui R; Maeda A; Sahara
TI -
H; Ikeda H; Torigoe T; Ichimiya S; Wada T; Yamashita T; Hiraga H; Kawai
A; Ishii T; Araki N; Myoui A; Matsumoto S; Umeda T; Ishii S; Kawaguchi
S; Sato N
Detection and induction of CTLs specific for SYT-SSX-derived peptides in
HLA-A24(+) patients with synovial sarcoma.
SO - J Immunol 2002 Aug 1;169(3):1611-8
AD - Department of Orthopedic Surgery, Sapporo Medical University School of
Medicine, Japan.
To investigate the immunogenic property of peptides derived from the
synovial sarcoma-specific SYT-SSX fusion gene, we synthesized four
peptides according to the binding motif for HLA-A24. The peptides, SS391
(PYGYDQIMPK) and SS393 (GYDQIMPKK), were derived from the breakpoint of
SYT-SSX, and SS449a (AWTHRLRER) and SS449b (AWTHRLRERK) were from the
SSX region. These peptides were tested for their reactivity with CTL
precursors (CTLps) in 16 synovial sarcoma patients using HLA-A24/SYT-SSX
peptide tetramers and also for induction of specific CTLs from four
HLA-A24(+) synovial sarcoma patients. Tetramer analysis indicated that
the increased CTLp frequency to the SYT-SSX was associated with
pulmonary metastasis in synovial sarcoma patients (p < 0.03). CTLs were
induced from PBLs of two synovial sarcoma patients using the peptide
mixture of SS391 and SS393, which lysed HLA-A24(+) synovial sarcoma
cells expressing SYT-SSX as well as the peptide-pulsed target cells in
an HLA class I-restricted manner. These findings suggest that aberrantly
expressed SYT-SSX gene products have primed SYT-SSX-specific CTLps in
vivo and increased their frequency in synovial sarcoma patients. The
identification of SYT-SSX peptides may offer an opportunity to design
peptide-based immunotherapeutic approaches for HLA-A24(+) patients with
synovial sarcoma.
20
UI - 11981942
AU - Watanabe K
TI -
Leiomyosarcoma versus myofibrosarcoma.
SO - Am J Surg Pathol 2002 Mar;26(3):393-4; discussion 394-6
21
UI - 12099655
AU - Karakousis CP; Zografos GC
TI -
Radiation therapy for high grade soft tissue sarcomas of the extremities
treated with limb-preserving surgery.
SO - Eur J Surg Oncol 2002 Jun;28(4):431-6
AD - State University of New York at Buffalo, School of Medicine and
Biomedical Sciences, Kaleida Health, Millard Fillmore Gates Hospital,
Buffalo, NY, 14209, USA. ckarakousis@kaleidahelth.org
AIM: It is common to use either pre- or post-operative radiation for
high grade sarcomas undergoing limb-conserving surgery. Since 1977, we
have adopted a selective policy of post-operative radiation, given only
in patients with inadequate surgical margins. METHODS: A retrospective
review of 114 patients (1977-1995) with high grade adult soft tissue
sarcomas of the extremities was carried out. Amputation was required in
10 (9%). Patients with a minimum surgical margin <2 cm (n=33) received
adjuvant radiation (29%). RESULTS: No complications occurred in 81/114.
Wound complications were infection (14%), seroma (6%), haematoma (4%),
dehiscence (4%) and skin edge necrosis (2%). Remedial operations were
required in four (3%). Overall, the local recurrence rate was 23/114.
Patients with surgery only (n=57) or surgery plus systemic chemotherapy
(n=24) manifested local recurrence in 15/81 (19%) and those with surgery
plus radiation (n=21) or surgery and radiation and chemotherapy (n=12)
suffered local recurrence in 8/33. The local recurrence rate for tumours
< or =5 cm was 6/32 and for those >5 cm 17/82, P=1.0. The 5 year
survival rate was 60% for tumours < or =5 cm (n=32) and 46% for tumours
> or =5 cm (n=82) (P=0.009). CONCLUSIONS: (1) Limb preservation was
feasible in 91% of patients. (2) When the local treatment modality was
surgery alone ('wide' margins) the local recurrence rate was 19%, and
when it was surgery plus radiation (narrow margins) it was 24%. (3)
Selective use of radiation (in patients with narrow margins) and
reliance on surgery alone in cases amenable to wide resection may be a
legitimate alternative to universal application of radiation with
conservative resection. Copyright 2002 Elsevier Science Ltd. All rights
reserved.
22
UI - 12099656
AU - Behranwala KA; Clark MA; Thomas JM
TI -
Soft-tissue tumours of the perineum.
SO - Eur J Surg Oncol 2002 Jun;28(4):437-42
AD - Sarcoma and Melanoma Unit, Royal Marsden NHS Trust, London, UK.
AIM: Primary perineal tumours in adults are rare entities that have been
infrequently reported (one clinical series of nine patients with sarcoma
and isolated case reports). We present our experience of perineal
tumours better to characterize and define the natural history of this
condition. METHODS: Perineal tumours occurring in adults (>18 years)
Sarcoma Unit prospective database. RESULTS: Nineteen perineal
soft-tissue tumours (12 malignant and seven benign) were evaluated and
treated at the Royal Marsden Hospital during this period. Liposarcoma
(n=3) and aggressive angiomyxoma (n=4) were the most frequent
histological subtypes. Three malignant and four benign tumours were
larger than 10 cm. Most tumours were located deep to the deep fascia.
Local recurrence in those with sarcoma occurred in one of five patients
with negative microscopic margins and in one of two patients who had
positive microscopic margins. One patient each with aggressive
angiomyxoma and fibromatosis recurred locally. CONCLUSION: Aggressive
treatment in the form of wide local excision is associated with fewer
local recurrences in adults with primary perineal soft-tissue tumours.
The aim of surgical treatment should be to obtain negative resection
margins without causing disturbance to urinary or anorectal function.
23
UI - 12142799
AU - Odone-Filho V; Cristofani LM; Bonassa EA; Braga PE; Eluf-Neto J
TI -
In vitro fertilization and childhood cancer.
SO - J Pediatr Hematol Oncol 2002 Jun-Jul;24(5):421-2
24
UI - 12173385
AU - Estourgie SH; Nielsen GP; Ott MJ
TI -
Metastatic patterns of extremity myxoid liposarcoma and their outcome.
SO - J Surg Oncol 2002 Jun;80(2):89-93
AD - School of Medicine, University of Utrecht, Utrecht, The Netherlands.
BACKGROUND AND OBJECTIVES: Extremity myxoid liposarcomas have a unique
extrapulmonary metastatic potential. We studied the metastatic pattern
of extremity liposarcomas to determine what types of posttreatment
imaging may be of value in the follow-up these patients. METHODS:
Twenty-two patients from a total of 128 patients with primary extremity
liposarcoma were treated at a tertiary care institution for subsequent
months (range: 6-270 months). Data on these patients was prospectively
collected and then retrospectively analyzed for effect of metastatic
pattern and treatment on outcome. RESULTS: Of these 22 patients,
extrapulmonary metastases developed in 10, combined pulmonary and
extrapulmonary metastases developed in 6, and isolated pulmonary
metastases developed in 6. Of the 16 patients with extrapulmonary
metastases, 13 were of the myxoid subtype. Of the 49 patients with
extremity myxoid liposarcomas, metastases developed in 14 (29%). The
most common sites of metastases among these 14 patients include: the
retroperitoneum, 10 patients (71)%; intra-abdominal extra-hepatic, 7
patients (50%); spinal/paraspinal, 6 patients (43%). Only 3 of the
patients are alive and disease free and all 3 of these patients are from
the subgroup of 10 patients with only extra-pulmonary metastases (2
intra-abdominal and 1 retroperitoneal). CONCLUSIONS: Extremity myxoid
liposarcomas have an unusually high predilection for extra-pulmonary
metastases, frequently without any pulmonary metastases. After treatment
of the primary tumor, these patients should be followed with periodic
chest X-ray and abdominal/pelvic computed tomography (CT) scans. Any
back or neurologic complaints should prompt additional imaging of the
appropriate spinal area. Consideration should be given to surgical and
adjuvant treatment of metastatic disease when appropriate.
25
UI - 12173386
AU - Pisters PW; Sondack VK
TI -
Metastatic patterns of extremity liposarcoma and their outcome.
SO - J Surg Oncol 2002 Jun;80(2):94-5
AD - Sarcoma Service, M. D. Anderson Cancer Center, Houston, Texas, USA.
26
UI - 12107558
AU - Drabick JJ; Davis BJ; Lichy JH; Flynn J; Byrd JC
TI -
Human herpesvirus 8 genome is not found in whole bone marrow core biopsy
specimens of patients with plasma cell dyscrasias.
SO - Ann Hematol 2002 Jun;81(6):304-7
AD - Hematology/Oncology Service, Walter Reed Army Medical Center,
Washington, DC 20307-5000, USA. Joseph.Drabick@NA.AMEDD.ARMY.MIL
Recently, molecular evidence of the gamma herpesvirus, human herpesvirus
8 (HHV-8), was found in the nonmalignant bone marrow stromal cells of
patients with multiple myeloma using a polymerase chain reaction
(PCR)-based assay. Other investigators have been unable to confirm
either the presence of HHV-8 using molecular techniques or serologic
evidence of prior infection with HHV-8. In order to maximize the
likelihood of detection of small quantities of the virus and minimize
the risk of potential nucleic acid contamination, we used entire bone
marrow biopsy core specimens for DNA extraction and amplification. These
specimens included both malignant plasma cells and bone marrow stromal
cells and were subjected to minimal manipulation prior to DNA extraction
and PCR. We tested eight patients with various plasma cell dyscrasias
and compared them to negative controls with non-Hodgkin's lymphoma using
standard PCR assays utilizing the KS330(233)primers and probe for HHV-8.
This assay is reproducibly positive in Kaposi's sarcoma tissue. We found
no evidence of HHV-8 DNA in either the lymphoma controls or the samples
from patients with the plasma cell dyscrasias using these methods. We
conclude that HHV-8 is unlikely to play a major role in the pathogenesis
of the plasma cell dyscrasias in the majority of patients with these
diseases. This report adds to the body of evidence that HHV-8 is not
associated with plasma cell dyscrasias like multiple myeloma.
27
UI - 12139229
AU - Murta EF; Oliveira GP; Prado Fde O; De Souza MA; Murta BM; Adad SJ
TI -
Association of uterine leiomyoma and Chagas' disease.
SO - Am J Trop Med Hyg 2002 Mar;66(3):321-4
AD - Discipline of Gynecology and Obstetrics, Faculty of Medicine of
Triangulo Mineiro, Uberaba, Minas Gerais, Brazil.
eddiemuta@mednet.com.br
With the aim of studying the frequency of Chagas' disease among
sufferers of uterine leiomyoma, we analyzed women older than 35 years
who underwent surgery and presented with leiomyoma on
anatomicopathological examination. The diagnosis of Chagas infection was
based on positivity to at least two of three serological tests:
enzyme-linked immunosorbent assay, passive hemagglutination, and
immunofluorescence. The study was case controlled, matching for age,
skin color, and parity. The control group consisted of women undergoing
surgery for other benign gynecological alterations. During this period,
118 women presented with uterine leiomyoma, 27.1% of whom were
serologically positive for Chagas' disease versus 16.1% of the controls
(P < 0.05). Matching by skin color and parity showed that 40% of the
white multiparous women with uterine leiomyoma had Chagas' disease
versus 10% of the controls (P < 0.05). We concluded that there appears
to be an association between Chagas' disease and uterine leiomyoma.
28
UI - 12165444
AU - Sandberg A; Bridge J
TI -
Updates on the cytogenetics and molecular genetics of bone and soft
tissue tumors: alveolar soft part sarcoma.
SO - Cancer Genet Cytogenet 2002 Jul 1;136(1):1-9
AD - Department of DNA Diagnostics, St. Joseph's Hospital and Medical Center,
350 West Thomas Road, Phoenix, AZ 85013,USA.
29
UI - 12168660
AU - Rapp TB; Yang L; Conrad EU 3rd; Mandahl N; Chansky HA
TI -
RNA splicing mediated by YB-1 is inhibit