National Cancer Institute®
Last Modified: August 1, 2002
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. firstname.lastname@example.org
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.
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.
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.
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
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
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. email@example.com
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.
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.
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. firstname.lastname@example.org
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.
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.
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.
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. email@example.com
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.
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.
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.
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.
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.
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.
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.
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. firstname.lastname@example.org
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.
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.
UI - 11981942
AU - Watanabe K
TI - Leiomyosarcoma versus myofibrosarcoma.
SO - Am J Surg Pathol 2002 Mar;26(3):393-4; discussion 394-6
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. email@example.com
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.
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.
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
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.
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.
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.
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. firstname.lastname@example.org
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.
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.