Effect of adjuvant chemotherapy on localized dedifferentiated low-grade osteosarcoma: a systematic review.

PURPOSE: Dedifferentiated low-grade osteosarcomas, which are considered high grade malignancies, can arise from the dedifferentiation of parosteal and low-grade osteosarcomas. Usually, localized dedifferentiated low-grade osteosarcomas are treated by wide resection, and the efficacy of adjuvant chemotherapy is controversial. We conducted a systematic review of studies that investigated the rates of mortality and significant events, such as recurrence and metastases, in localized dedifferentiated low-grade osteosarcoma patients who received wide resection only and in those who received wide resection and (neo-)adjuvant chemotherapy. METHODS: We identified 712 studies through systematic searches of Embase, PubMed, and the Cochrane Central Register of Controlled Trials databases. Of those studies, seven were included in this review and none were randomized controlled trials. In the seven studies, 114 localized dedifferentiated low-grade osteosarcoma patients were examined. RESULTS: Mortality rates of the resection plus chemotherapy (R + C) and the resection only (Ronly) groups were 20.3% and 11.4%, respectively [overall pooled odds ratio, 1.59 (P = 0.662); heterogeneity I2, 0%]. The local recurrence or distant metastasis rate in the R + C group was 36.7% and that in the Ronly group was 28.6% [overall pooled odds ratio, 1.37 (P = 0.484); heterogeneity I2 was 0%]. CONCLUSIONS: Results show a limited efficacy of adjuvant chemotherapy for localized dedifferentiated low-grade osteosarcoma. However, because this was a systematic review of retrospective studies that examined a small number of patients, future randomized controlled trials are needed.

Tissue invasion and metastasis: Molecular, biological and clinical perspectives.

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), ß-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-ß), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.

Primary osteogenic sarcoma of a finger proximal phalanx: a case report and literature review.

Osteogenic sarcoma of the small bones of the hand is rare with only 15 cases documented. We describe a 12-year-old boy with an osteogenic sarcoma of the proximal phalanx of the middle finger. Wide excision in the form of ray amputation with a wide surgical margin was performed after neoadjuvant chemotherapy consisting of combined high-dose methotrexate, doxorubicin, ifosfamide, and cisplatin. To restore maximum function the index ray was transferred to the base of the third metacarpal. Adjuvant chemotherapy was administered subsequently. At 28-month follow-up evaluation there was no evidence of local recurrence of disease or distant metastasis and both function and appearance were good.

Possible involvement of bcl-2 suppression in wild-type p53 gene-dependent cell growth repression in rat osteosarcoma cells.

We recently obtained 3 cloned cell lines demonstrating the p53 mutation from a lung metastatic nodule of a rat transplantable osteosarcoma. In this study, we applied wild-type p53 gene transfer to the rat osteosarcoma cells by lipofection to investigate the effects on cell growth, expression of genes such as waf1/p21, bcl-2, and bax, and nucleosomal DNA fragmentation due to apoptosis. Reconstitution of the p53 gene inhibits cellular growth, and this growth-suppressive effect is partly due to apoptosis involving bcl-2 gene suppression in this tumor type. This rat osteosarcoma model is similar in biologic behavior to human cases and thus is very suitable for further investigation of tumorigenesis and gene therapy for osteosarcoma.

Delay in administration of CDDP until completion of AGM-1470 treatment enhances antimetastatic and antitumor effects.

The efficacy of cis-diammine dichloroplatinum (CDDP) therapy in combination with continuous administration of angiogenesis inhibitor o-(chloroacetyl-carbamoyl) fumagillol (AGM-1470) was evaluated experimentally using a transplantable rat osteosarcoma line previously established in our laboratory. AGM-1470 (2.5 mg/kg body weight/week) was administered by Alzet osmotic pumps for 2 weeks starting from 7 days after tumor inplantation and CDDP (1.25 mg/kg) was given on days 21 and 24. The number of lung metastatic nodules was counted and the wet weights of the primary tumors were measured 5 weeks after tumor inplantation. Values with administration of CDDP 3 days after discontinuation of AGM-1470 were significantly lower than when the two agents were coadministered (P < 0.05). This animal model should facilitate optimization of the timing of combination therapy.

Pemphigus vulgaris preceded by herpetiform-like skin lesions with negative immunofluorescence findings.

We report a case of pemphigus vulgaris in a 63-year-old woman. At the first onset, she developed herpetiform-like skin lesions. Their histology showed eosinophilic spongiosis and intraepidermal blister formation with an infiltrate of eosinophils. Both direct and indirect immunofluorescence studies were negative. She remained in remission for 6 years. At the second onset, she developed bullous skin lesions; histological examination disclosed suprabasal acantholysis and infiltration of eosinophils. Direct immunofluorescence revealed IgG and C3 deposits at the cell surface, predominantly in the lower epidermis. Indirect immunofluorescence using normal human skin as a substrate demonstrated anti-cell surface IgG antibodies at a titer of 1:160. Immunoblot analysis showed that the patient's serum reacted only with a 130 kD protein. This case indicates that pemphigus vulgaris can follow herpetiform-like skin lesions with negative immunofluorescence findings after a long remission time.

Intraepidermal expression of basement membrane components in the lesional skin of a patient with dystrophic epidermolysis bullosa.

The patient was a 15-year-old male. Since birth, he had developed blistering and erosion of the skin. Biopsy skin specimen of the bullous lesions showed subepidermal blister formation. Electron microscopic examination revealed that tissue separation had occurred at the sublamina densa level. By indirect immunofluorescence using antibodies specific for alpha 6 integrin, laminin 5, type IV collagen, and type VII collagen, all of these basement membrane components were detected as coarse granular intracytoplasmic deposits only in the basal and suprabasal cells of the blister roof. In the non-blistered regions, these basement membrane components showed a linear pattern similar to that seen in normal skin. These findings suggest that intraepidermal expression of basement membrane components was closely related to the blister formation. The biological meaning of intraepidermal expression of basement membrane components were also discussed.

A case of nonscarring inflammatory epidermolysis bullosa acquisita: characterization of IgG autoantibodies by immunofluorescence, immunoblotting and immunogold electron microscopy.

We report a case of nonscarring inflammatory epidermolysis bullosa acquisita in a 59-year-old Japanese woman. She developed blisters and erosions on her lip, trunk and extremities. Sodium aurothiomalate was effective for the skin lesions. The patient had been free from bullous skin lesions for the last 13 years and had shown no scarring. Indirect immunofluorescence (IF) study on 1 M NaCl-split skin revealed IgG autoantibodies against the dermal side of the split skin. Immunoblotting using normal human dermal extracts disclosed IgG autoantibodies reactive with the 290 and 145 kD antigens. Circulating IgG autoantibodies were deposited on the lamina densa by immunoelectron microscopy. IF mapping using several antibodies for the components of the basement membrane zone revealed blister formation at the lamina densa. These results suggest that the cleavage at the lamina lucida does not necessarily exclude the diagnosis of EBA and that the definite diagnosis of EBA should be confirmed by immunoblotting or immunoelectron microscopic study.

Linear IgA bullous dermatosis with circulating IgG autoantibodies to the 230 kD epidermal antigen.

The patient was a 54-year-old woman with wide-spread bullous lesions on her trunk and oral mucosa. Histologic examination revealed a subepidermal blister with infiltration of neutrophils and eosinophils. Direct immunofluorescence showed an exclusively IgA deposition at the basement membrane zone (BMZ). Indirect immunofluorescence showed that the blister fluid, but not the serum, contained IgG antibodies against the BMZ antigen on the epidermal side of salt-split skin. Using immunoblot analysis with normal human epidermal extracts, both serum and blister fluid reacted with the 230 kD epidermal antigen. Using colloidal gold and direct immunoelectron microscopy, IgA deposition was detected in the lamina lucida. Clinically, the skin lesions responded well to dapsone. We diagnosed this case as linear IgA bullous dermatosis (LABD) with IgG class circulating autoantibodies against the epidermal 230 kD antigen. These antibodies were considered to be secondary to the damage to the epidermal basal keratinocyte in this case.

Heterogeneous pattern of gene expression in cloned cell lines established from a rat transplantable osteosarcoma lung metastatic nodule.

We have established three cloned cell lines (COS1NR, COS2NR and COS4NR) from the lung metastatic nodule of a highly metastatic variant of rat transplantable osteosarcoma, C-SLM. All three clones shared the same morphological characteristics and tumorigenicity, but their growth rates in vitro and metastatic ability in vivo differed from each other. Single-strand conformation polymorphism (SSCP) analysis revealed all three clones to have the same p53 gene mutation and parent C-SLM tumor. On the other hand, Northern blot analysis showed a different pattern of expression for the genes, c-fos, c-jun, c-Ha-ras, transin (rat stromelysin), bone Gla protein (osteocalsin) and nm23/NDP kinase. These results indicate the presence of a heterogeneous cell population in terms of the different pattern of gene expression in a lung metastatic nodule of rat osteosarcoma and the present newly established cell lines will be useful for further investigation of the biological behavior of osteosarcomas.

Efficacy of CDDP and AGM-1470 chemotherapy against lung metastasis in rat osteosarcoma depends on the timing of combined administration.

The efficacy of combination therapy with cis-diammine-dichloroplatinum (II) (CDDP) and o-(chloroacetyl-carbamoyl) fumagillol (AGM-1470) was evaluated experimentally using a transplantable rat osteosarcoma line, previously established in our laboratory, with a high potential for metastasis. Tumor-bearing male Fischer 344 rats were administered CDDP (2.5 mg/kg) together with, or after discontinuation of, AGM-1470 treatment (10 mg/kg/body weight/week). When CDDP was administered three days after discontinuation of AGM-1470 the most pronounced antimetastatic effects were observed, although the antitumor effect was approximately the same.

Alternative RNA splicing of the MLL gene in normal and malignant cells.

The human MLL (mixed-lineage leukemia or myeloid-lymphoid leukemia) gene belongs to the trithorax gene family of which the Drosophila trithorax (trx) gene is known to regulate homeotic genes through alternative RNA splicing. To test if such a splicing mechanism also operates in MLL, we evaluated mRNA transcripts from a large number of normal and malignant human cells, making use of RT-PCR, PCR cloning, DNA sequencing and Northern blot analysis. Our findings indicate that different cell types transcribe MLL mRNA species lacking exons that generally encode putative regulatory domains such as AT hooks (exon 3), repression domain (exon 6), zinc finger motifs (exon 8) and activation domain (exon 18). Such findings suggest that posttranscriptional regulation by alternative RNA splicing may play an important role in MLL gene expression and provides the rationale for a mechanism by which this gene, with multiple functional domains, could produce discrete protein products that may prove critical in the regulation of human homeobox genes.

MLL tandem duplication and multiple splicing in adult acute myeloid leukemia with normal karyotype.

Rearrangement of the MLL (myeloid-lymphoid or mixed-lineage leukemia) gene through a reciprocal chromosomal translocation is found in 5% of adult acute myeloid (AML) and 10% of pediatric acute lymphoid (ALL) leukemia. More than 25 different reciprocal chromosomal translocations, with an 11q23 breakpoint, fuse the MLL gene (also named ALL-1, HRX and Htrx1) to a second partner gene. These leukemias have poor prognosis and frequently have a monocytic, lymphoid or biphenotypic (myeloid and lymphoid) antigen expression in blast cells. Approximately 20-30% of patients diagnosed as having adult de novo, AML have normal chromosomes by metaphase analysis and the majority of these patients have good prognosis. With the use of reverse transcriptase-polymerase chain reaction (RT-PCR) technique and Southern blot analysis, we found that seven of 34 such patients (21%) had a tandem partial duplication of exons 2 to 6 or 2 to 8 of the MLL gene. These seven patients showed a median survival of 2.7 months, compared to a 6.8 months median survival for all other patients in the study. If confirmed on a large series of patients, our findings may help differentiate AML with normal karyotype and poor prognosis from those with normal karyotype and a more favorable prognosis.

[A device for rapid elevation of plasma methotrexate (MTX) concentration and its maintenance in high-dose MTX therapy].

For 5 osteosarcomas and one synovial sarcoma, 24 courses of high-dose methotrexate (MTX) therapy were performed. At MTX doses of 300 mg/kg with several infusion patterns, the plasma MTX concentrations were measured by fluorescence polarization immunoassay. In the various types of infusions, five hours oblique and five hours bolus infusions were well maintained at 1,000 micromol/l for several hours. In particular, five hours bolus infusion of MTX needed only 20 minutes to reach 822 micromol/l and maintained 1,000 micromol/l during almost the entire infusion period. Optimization of chemotherapy for sarcomas by MTX requires individual adaptation of the infusion pattern.

Localized cutaneous amyloidosis simulating lichen simplex chronicus.

We report a case of localized cutaneous amyloidosis in a 42-year-old Japanese woman. Skin lesions were confined to the nuchal area, and the clinical appearance resembled that of lichen simplex chronicus. Our experience with this case indicates that, in cases presenting with persistent skin lesions simulating lichen simplex chronicus, amyloid should be specifically looked for in biopsy material.

Efficacy of the angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (AGM-1470) on osteosarcoma growth and lung metastasis in rats.

The efficacy of the anti-angiogenic agent, O-(chloroacetyl-carbamoyl)fumagillol (AGM-1470), against primary tumor growth and spontaneous lung metastasis was evaluated experimentally using a transplantable osteosarcoma line in rats previously established in our laboratory. Male Fischer 344 rats bearing the tumor with a high potential for metastasis received intermittent or continuous subcutaneous administrations of AGM-1470. Both treatment regimens resulted in significant inhibitions of spontaneous lung metastasis and primary tumor growth in a dose-dependent manner, with continuous administration of AGM-1470 exerting the most pronounced inhibitory effects on both parameters.

Ultrastructural cytochemical demonstration of proteoglycans and calcium in the extracellular matrix of chondroblastomas.

To clarify the characteristics of the extracellular matrix of chondroblastomas, six cases were studied under the electron microscope, with special reference to proteoglycans and calcium in the cellular areas. In ruthenium hexammine trichloride (RHT)-stained sections the matrix was observed to be composed of rounded or polygonal fine granules and unbanded thin filaments that appeared to link neighboring granules together. Treatment with potassium-pyroantimonate showed intracellular accumulation of precipitates, mainly localized within the cisternae of the rough endoplasmic reticulum as well as in the extracellular matrix. The presence of calcium in the precipitates was confirmed using x-ray energy dispersive analysis. These findings, similar to characteristic features observed in calcifying systems, support the theory that chondroblastomas are of chondrogenic origin.

Effects of novobiocin on the induction of gamma-glutamyltranspeptidase positive foci in the liver of rats treated with diethylnitrosamine.

Effects of novobiocin on the induction of gamma-glutamyltranspeptidase(GGT)-positive foci, an early lesion occurring during hepatocarcinogenesis, after diethylnitrosamine(DEN) initiation were investigated in Fischer 344 rats. Animals were given DEN at a dose of 20 mg/kg b. w. followed by novobiocin at doses of 50, 100 and 200 mg/kg b. w. The latter two doses, but not 50 mg/kg b. w., significantly inhibited the development of GGT-positive foci, providing evidence of the possible involvement of mono(ADP-ribosyl)ation in the initiation phase of hepatocarcinogenesis in rats.