Distribution and prognostic value of histopathologic data and immunohistochemical markers in gastrointestinal stromal tumours (GISTs): An analysis of the EORTC phase III trial of treatment of metastatic GISTs with imatinib mesylate.

Rationale: The 62005 EORTC phase III trial, comparing two doses of imatinib in patients with advanced GIST, reported a median progression-free survival of 25 months with a trend towards dose dependency for progression-free survival. The current analysis of that study aimed to assess whether histological/immunohistochemical parameters correlate with clinical response to imatinib.

Patients And Methods: Pre-treatment samples of GISTs from 546 patients enroled in phase III study were analysed for immunohistochemical characteristics, correlations with clinicopathological data, with survival and with tumours' genotype.

Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro.

Chondrosarcomas are highly resistant to conventional radiation and chemotherapy, and surgical removal is the only option for curative treatment. Consequently, there is nothing to offer patients with inoperable tumours and metastatic disease. The aim of this study is to investigate genes involved in cell cycle control: CDK4, CDKN2A/p16, cyclin D1, p21, p53, MDM2 and c-MYC, which may point towards new therapeutic strategies.

Results of diagnostic review in pediatric bone tumors and tumorlike lesions.

Background: Histological examination of bone tumors is one of the most difficult subjects in pathology. In this manuscript, correctness of initial histological diagnosis in pediatric bone tumors and tumorlike lesions was investigated.

Procedure: All 262 bone tumor specimens of children up to the age of 19 years reviewed from 1999 to 2003 by the Netherlands Committee on Bone Tumors were included.

Soft tissue tumours of the retroperitoneum.

Purpose. This review summarizes the more prevalent soft tissue tumours arising in the retroperitoneum and highlights some recent fundamental and diagnostic developments relevant to mesenchymal tumours.Discussion.

A phase II study of gefitinib for patients with advanced HER-1 expressing synovial sarcoma refractory to doxorubicin-containing regimens.

Rationale: Advanced synovial sarcomas (SyS) refractory to doxorubicin and ifosfamide are highly resistant to the currently available cytotoxic agents. Based on a report showing a specific overexpression of HER-1 in SyS, we investigated an HER-1 inhibitor, gefitinib, in refractory SyS.

Subjects And Methods: To establish the efficacy and safety of gefitinib in HER-1 - positive SyS refractory to one or two lines of doxorubicin- and ifosfamide-based chemotherapy, a phase II study was conducted from December 2002 to October 2005 by 12 centers of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

The clinical approach towards chondrosarcoma.

This review provides an overview of the histopathology, classification, diagnostic procedures, and therapy of skeletal chondrosarcoma. Chondrosarcomas that arise de novo are primary chondrosarcomas, whereas chondrosarcomas developing superimposed on pre-existing benign cartilage neoplasms such as enchondromas or osteochondromas are referred to as secondary chondrosarcomas. Conventional chondrosarcomas can be categorized according to their location in bone into central, peripheral, and juxtacortical chondrosarcomas.

Myxoid tumours of soft tissue: the so-called myxoid extracellular matrix is heterogeneous in composition.

Aim: Myxoid tumours of soft tissue are characterized by their so-called 'myxoid' extracellular matrix. The aim was to investigate the composition and possible function of this matrix which is poorly understood.

Methods And Results: Using Alcian Blue staining with and without pretreatment with hyaluronidase and application of the critical electrolyte concentration method followed by densitometry, the glycosaminoglycan composition of three different myxoid tumours was studied.

Telomere biology in giant cell tumour of bone.

Giant cell tumour of bone (GCTB) is a benign bone tumour known for the unpredictable clinical behaviour of recurrences and, in rare instances, distant metastases. It consists of uniformly distributed osteoclastic giant cells in a background of mononuclear rounded and spindle-shaped cells. Cytogenetically, telomeric associations are the most common chromosomal aberrations, which, however, are normally almost exclusively found in high-grade malignancies.

Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration "PALGA".

Introduction: Data on childhood bone tumors are mainly confined to reports on malignant tumors or on institutional registries. Incidence figures on both benign and malignant bone tumors in childhood are lacking.

Methods: From January 1999 to December 2003, 1474 newly diagnosed bone tumors in children up to 18 years were registered in Pathologisch Anatomisch Landelijk Geautomatiseerd Archief (the nationwide network and registry of histopathology and cytopathology in The Netherlands).

EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma.

Purpose: Angiomatoid fibrous histiocytoma (AFH) is a low-grade mesenchymal neoplasm which usually occurs in children and adolescents. Either FUS-ATF1 or EWSR1-ATF1 have been detected in the few cases published, pointing to the interchangeable role of FUS and EWSR1 in this entity. EWSR1-ATF1 also represents the most frequent genetic alteration in clear cell sarcoma, suggesting the existence of a molecular homology between these two histotypes.

Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation.

The initiating somatic genetic events in chordoma development have not yet been identified. Most cytogenetically investigated chordomas have displayed near-diploid or moderately hypodiploid karyotypes, with several numerical and structural rearrangements. However, no consistent structural chromosome aberration has been reported.

Lymphatics and bone.

There is controversy regarding whether lymphatic vessels are present or absent in bone. Although lymphangiomas have been described in bone, lymphatic vessels have not been identified morphologically with certainty in any other benign or malignant bone tumors or in normal human bone. In this study, we determined by immunohistochemistry, using 2 specific lymphatic endothelial cell markers, LYVE-1 and podoplanin, whether lymphatics are present in normal bone and a wide range of primary and secondary bone neoplasms.

Does parosteal liposarcoma differ from other atypical lipomatous tumors/well-differentiated liposarcomas? A molecular cytogenetic study using combined multicolor COBRA-FISH karyotyping and array-based comparative genomic hybridization.

Parosteal adipocytic tumors of the bone are extremely rare. As a result, (cyto-) genetic data on this entity are essentially lacking. In the literature there is debate as to whether these lesions should be classified according to the criteria used in soft-tissue tumor pathology, or if they should be considered a separate bone tumor entity.

Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study.

Purpose: Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin.

Patients And Methods: This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days.

The role of noncartilage-specific molecules in differentiation of cartilaginous tumors: lessons from chondroblastoma and chondromyxoid fibroma.

Background: Chondroblastoma (CB) and chondromyxoid fibroma (CMF) are benign tumors of bone morphologically recapitulating cartilage differentiation. CMF can resemble high-grade central chondrosarcoma (HGCCS) because of its cellular atypia. The mechanism that drives this morphologic spectrum of cartilage differentiation is unclear.

MR imaging characteristics in primary lymphoma of bone with emphasis on non-aggressive appearance.

Purpose: To assess the heterogeneity of magnetic resonance (MR) imaging characteristics in primary lymphoma of bone (PLB), in particular the non-aggressive appearance.

Subjects And Methods: In a retrospective study, MR imaging features were analyzed in 29 patients with histologically proven PLB. The following parameters were evaluated: tumor size, bone marrow and extension into soft tissues, signal characteristics of bone marrow and soft-tissue components, including enhancement, and involvement of cortical bone (complete disruption, focal destruction, permeative destruction and cortical thickening).

Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi.

Purpose: The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with (99m)Tc-sestamibi.

Methods: Doxorubicin-sensitive (143B-luc(+)) and resistant (MNNG/HOS-luc(+)) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray.

Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability.

Germline mutations in nuclear genes encoding mitochondrial enzymes fumarate hydratase (FH) and succinate dehydrogenase (subunits SDHB/C/D) have been implicated in the development of tumor syndromes referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis (HPGL), respectively. FH and SDH are operating in the tricarboxylic acid cycle (the TCA cycle, the Krebs cycle). In the FH and SDH deficient tumors, accumulation of the substrates, fumarate and succinate, has been shown to cause stabilization of hypoxia inducible factor 1 alpha (HIF1 alpha).

Differences in telomerase expression by the CD1a+ cells in Langerhans cell histiocytosis reflect the diverse clinical presentation of the disease.

Langerhans cell histiocytosis (LCH) is a disease characterized by an uncontrolled clonal proliferation of Langerhans cells, whose aetiology is still unclear. The clonal nature of LCH could support the hypothesis that it is a neoplastic disease with unlimited growth potential. One requirement for unlimited proliferation is the maintenance of telomere length.

The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions.

Background: Multiple osteochondromas is a hereditary syndrome that is characterized by the formation of cartilage-capped bony neoplasms (osteochondromas), for which exostosis (multiple)-1 (EXT1) has been identified as a causative gene. However, 85% of all osteochondromas present as solitary (nonhereditary) lesions in which somatic mutations in EXT1 are extremely rare, but loss of heterozygosity and clonal rearrangement of 8q24 (the chromosomal locus of EXT1) are common. We examined whether EXT1 might act as a classical tumor suppressor gene for nonhereditary osteochondromas.

Identification of markers to characterize and sort human articular chondrocytes with enhanced in vitro chondrogenic capacity.

Objective: To identify markers associated with the chondrogenic capacity of expanded human articular chondrocytes and to use these markers for sorting of more highly chondrogenic subpopulations.

Methods: The chondrogenic capacity of chondrocyte populations derived from different donors (n = 21) or different clonal strains from the same cartilage biopsy specimen (n = 21) was defined based on the glycosaminoglycan (GAG) content of tissues generated using a pellet culture model. Selected cell populations were analyzed by microarray and flow cytometry.

Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup.

Background: Previous randomized controlled trials that used the two-drug chemotherapy regimen of cisplatin and doxorubicin as the conventional arm showed no evidence of benefit from an increase in the number of agents or the length of treatment. It was then proposed that survival could be improved by increasing the planned dose intensity of cisplatin and doxorubicin.

Methods: Previously untreated patients with nonmetastatic, high-grade, central osteosarcoma of an extremity were randomly assigned to Regimen-C (conventional treatment with six 3-week cycles of cisplatin [100 mg/m2 by 24-hour infusion] and doxorubicin [25 mg/m2/day by 4-hour infusion for 3 days]) or to Regimen-DI (intensified treatment with identical total doses of cisplatin and doxorubicin, planned as six 2-week cycles supported by granulocyte colony stimulating factor (G-CSF).

Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas.

Mutational inactivation of EXT1 or EXT2 is the cause of hereditary multiple osteochondromas. These genes function in heparan sulphate proteoglycan (HSPG) biosynthesis in the Golgi apparatus. Loss of heterozygosity of the EXT1 locus at 8q24 is frequently found in solitary osteochondromas, whereas somatic mutations are rarely found.