Lymphoma masquerading as infection.

During surgical training, medical students and residents constantly are reminded to culture every suspected tumor and send tissue for pathologic evaluation for every suspected abscess. A diagnosis of cancer can be missed easily if this procedure is not followed, delaying the diagnosis and possibly adversely affecting the patient's prognosis. The confusion also may be compounded by a sterile abscess, positive culture results or a negative biopsy specimen. Therefore it is imperative to do a biopsy and a culture on any suspect lesion. An additional workup and possible biopsy may be warranted for a nonhealing wound that has been treated appropriately. The cases of three patients with lymphoma that were treated as infectious processes are presented. In all three instances, the appropriate treatment was delayed because of a delay in diagnosis.

The treatment of sacral giant-cell tumours by serial arterial embolisation.

Giant-cell tumours of the sacrum are difficult to treat. Surgery carries a high risk of morbidity, local recurrence and mortality. Radiation is effective in some patients, but has a risk of malignant change. We evaluated the effectiveness of serial arterial embolisation as an alternative to surgery. Five patients with giant-cell tumours of the sacrum which had been primarily treated by serial embolisation were retrospectively reviewed for changes in the size of the tumour. In four the symptoms resolved with full return of function and arrest in the growth of the tumour. They remained free from growth, recurrence, or metastases at follow-up (4 to 17 years). One patient died from metastatic disease within 18 months of the initial diagnosis.

Hip disarticulation using the lateral approach: a new technique.

A new approach to hip disarticulation is described. This technique uses a laterally based racquet incision. The advantage of this incision is that it uses a lateral approach to the hip, which is familiar to orthopaedic surgeons. This approach is combined with a circumferential incision to facilitate exposure of neurovascular structures. By basing the incision on the lateral approach to the hip, dissection of large blood vessels is minimized, which helps to decrease operative blood loss. Viability of the soft tissue flaps is excellent, with only two minor wound complications occurring. Phantom limb pain was minimal, and no patient required pain medication beyond the 3-month postoperative routine. The three patients who chose to use prostheses had no difficulty from the incisions. The clinical significance of this study is to enable orthopaedic surgeons to do hip disarticulation using the familiar anatomy of the lateral approach to the hip.

Fluoroquinolone's effect on growth of human chondrocytes and chondrosarcomas. In vitro and in vivo correlation.

Clinical and in vitro studies have demonstrated that fluoroquinolones are toxic to chondrocytes; however, the exact mechanism of fluoroquinolone arthropathy is unknown. We investigated the toxicity of ciprofloxacin on normal cartilage and on cartilaginous tumors. Normal human cartilage, enchondroma, and chondrosarcoma explants were cultured either alone or with the addition of ciprofloxacin at 1, 10, or 20 mg/L of medium. Samples were collected up to twenty-one days after treatment and were processed for electron microscopy and conventional light microscopy. The specimens were characterized morphologically with use of conventional light microscopy, electron microscopy, and immunohistochemistry to identify extracellular matrix, cell proliferation, and apoptosis. Cultures of normal chondrocytes expressed type-II collagen. Electron microscopy revealed a large amount of glycogen in the cells; the presence of fat droplets, rough endoplasmic reticulum, and prominent Golgi apparatus; and a proteoglycan layer surrounding the cells. With prolonged ciprofloxacin treatment and with increased doses, there was an increase in dilated rough endoplasmic reticulum, the appearance of phagosomes, and disintegrated bundles of vimentin filaments. The treated chondrocytes showed a decrease in cell proliferation, but there was no induction of apoptosis or effect on the expression of extracellular matrix proteins. Ciprofloxacin-treated chondrosarcoma cultures and tissue samples showed changes in cartilage matrix composition. Ultrastructural analysis demonstrated clumped glycogen, dilation of endoplasmic reticulum, numerous abnormal lysosomes containing degeneration products, and a decreased proteoglycan deposit surrounding the tumor cells. Treated chondrosarcoma cells and tissue specimens did not proliferate, and apoptosis was induced. In contrast, the in vitro growth of other noncartilaginous malignant tumors like osteosarcoma and liposarcoma was unaffected by ciprofloxacin. Our results indicate that ciprofloxacin is toxic to chondrocytes. In vitro and in vivo treated chondrosarcomas are the most affected.

The use of 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) as a specific CYP2D6 probe in human liver microsomes.

Recently, a novel nonfluorescent probe 3-[2-(N,N-diethyl-N-methylammonium)-ethyl]-7-methoxy-4-methylcoumarin (AMMC), which produces a fluorescent metabolite AMHC (3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-hydroxy-4-methylcoumarin) was used with microsomes containing recombinant enzymes (rCYP) to monitor CYP2D6 inhibition in a microtiter plate assay. This article describes the studies that were performed in human liver microsomes (HLM) to establish the selectivity of AMMC toward CYP2D6. Metabolism studies in HLM showed that AMMC was converted to one metabolite identified by mass spectrometry as AMHC. Kinetic studies indicated an apparent K(m) of 3 microM with a V(max) of 20 pmol/min. mg of protein for the O-demethylation reaction. The O-demethylation of AMMC in HLM was inhibited significantly in the presence of a CYP2D6 inhibitory antibody. Using a panel of various HLM preparations (n = 12), a good correlation (r(2) = 0.95) was obtained between AMMC O-demethylation and bufuralol metabolism, a known CYP2D6 substrate, but not with probes for the other major xenobiotic metabolizing CYPs. Finally, only rCYP2D6 showed detectable metabolism in experiments conducted with rCYPs using AMMC at a concentration of 1.5 microM (near K(m)). However, at a concentration of 25 microM AMMC, rCYP1A also contributed significantly to the formation of AMHC. Knowing the experimental conditions under which AMMC was selective for CYP2D6, a microtiter assay was developed to study the inhibition of various compounds in HLM using the fluorescence of AMHC as an indication of CYP2D6 activity. The inhibition potential of various chemicals was found to be comparable to those determined using the standard CYP2D6 probe, bufuralol, which requires high-performance liquid chromatography separation for the analysis of its CYP2D6-mediated 1'-hydoxylated metabolite.

Concurrent administration of vinorelbine with human recombinant granulocyte-macrocyte stimulating factor.

Thirty-three patients with incurable neoplasms resistant to standard therapy received vinorelbine 10 mg/m(2)/day by continuous infusion with concurrent administration of rHGM-CSF 4 microg/m(2)/day. The duration of the vinorelbine infusion was individualized; the infusion was continued until early evidence of hematopoietic toxicity was noted. The concurrent administration of GM-CSF permitted a substantial increase in dose intensity of the anti-cancer agent without a corresponding increase in drug toxicity. There was no evidence that the anti-tumor effect of vinorelbine was compromised by the concurrent administration of GM-CSF.

Microvasculature and VEGF expression in cartilaginous tumors.

We examined the microvasculature and VEGF expression in 26 cartilaginous lesions (CL) including 5 enchondromas, 9 grade 1 chondrosarcoma (CS), 6 grade 2 CS, 4 grade 3 CS, 1 mesenchymal, and 1 myxoid chondrosarcoma. The degree of neovascularization was measured by counting microvessels on H&E and factor VIII related antigen immunostained slides. Vessels were divided into pericartilage vessels (PCV) and intracartilage vessels (ICV). PVC comprised vessels around the lobules or invading the lobules but themselves surrounded by noncartilaginous stroma (ie, fibrous stroma); ICV consisted of those vessels present inside the tumoral nodules and in direct apposition with malignant cells or tumoral stroma. A direct correlation was seen between histological type and grade of CS and pericartilage vessels. In contrast, ICV were found only in higher-grade CS. No enchondromas and only 1 of 9 grade 1 CS had ICV. This patient had Ollier's disease. All but 2 of the grade 2 CS showed ICV (average, 20.5). The exceptions were predominantly grade 1 CS with focal grade 2 areas and extensive areas of necrosis. All but 1 grade 3 CS had ICV, the exception being a case of metastatic CS to the lung. Malignant chondrocytes of high-grade lesions stained strongly for vascular endothelial growth factor (VEGF), a potent angiogenic factor. The only high-grade tumors that did not express VEGF did not show ICV either. Enchondromas and grade 1 CS, most without ICV, did not express VEGE In summary, PCV are present in all categories of tumoral cartilage and the number increases with histological grade; ICV are found in high-grade lesions, and the exceptions show extensive necrosis; VEGF expression by malignant chondrocytes is seen in high-grade lesions almost exclusively, and among these in those lesions that showed intracartilage vessels. It is possible that PCV are involved in supporting tumor growth, whereas ICV might be involved in the acquisition of metastatic potential by cartilage tumors. VEGF expression is strongly associated with the presence of ICV.

Description of a 96-well plate assay to measure cytochrome P4503A inhibition in human liver microsomes using a selective fluorescent probe.

The standard method to evaluate CYP3A inhibition is to study the conversion of the specific CYP3A probe testosterone to its 6 beta-hydroxy metabolite in human liver microsomes, in the absence and presence of potential inhibitors. Quantification of the 6 beta-hydroxy metabolite is achieved by HPLC resulting in a tedious and time-consuming assay. In order to increase the P450 inhibition throughput, efforts were made to find a CYP3A probe that would produce a fluorescent metabolite. This paper reports the discovery of DFB as a potential CYP3A fluorescent probe. DFB was significantly metabolized in human microsomes (approximately 1-2 nmol/(min. mg protein)) to give the fluorescent compound DFH. The involvement of CYP3A in the metabolism of DFB was determined using multiple approaches. First, incubations conducted with microsomes made from cell lines expressing single CYPs (Gentest Supersomes) indicated that CYP3A played a major role in the metabolism of DFB. Secondly, immunoinhibition studies conducted with CYP3A antibody resulted in >95% inhibition of DFB metabolism in HLM. Thirdly, inhibition studies with specific CYP1A1, 1A2, 2C8/9, 2C19, 2D6, and 2E1 chemical inhibitors did not suppress DFB activity in HLM. However, ketoconazole, miconazole, nicardipine, and nifedipine, all known CYP3A inhibitors, completely abolished the formation of DFH in HLM. The potency of several inhibitors determined using DFB and testosterone as CYP3A probes was consistent (R = 0.98). Finally, a good agreement was obtained for the formation of DFH and production of 6 beta-hydroxytestosterone when DFB and testosterone were incubated separately with various human liver microsome preparations (R = 0.94, N = 11). In order to use DFH as a fluorescent CYP3A marker in a 96-well plate format, it was important to remove the excess of NADPH at the end of the incubation because the fluorescence of NADPH interferes with DFH detection. This was achieved by adding oxidized glutathione and glutathione reductase to convert NADPH to NADP(+) which is not fluorescent. The liquid-handling steps were fully automated in a 96-well plate format and a template was designed to generate IC(50) curves and to address potential fluorescent interferences from the test compounds. The assay was found to be reproducible (intraday variability <10% and interday variability indicated less than a 2-fold variation in the IC(50) values) and is now routinely used in our laboratory to evaluate CYP3A inhibition of NCEs.

Therapy of desmoid tumors and fibromatosis using vinorelbine.

In patients with either desmoids or fibromatosis who do not tolerate vinblastine and methotrexate because of neurotoxicity, the combination of vinorelbine and methotrexate can be substituted in most. Patients with the same condition who had not been previously treated with a combination of vinblastine and methotrexate responded well to the combination of vinorelbine and methotrexate, with significantly less neurotoxicity and a similar objective and subjective response rate. Sixty percent of patients had either a substantial partial remission or a complete remission. In no patients did the disease progress while they were receiving this therapy. Symptomatic relief, primarily of pain, occurred in 80% of patients. While minimal neurotoxicity was seen in 16% of these patients, it did not interfere with the completion of therapy. The combination of vinorelbine and methotrexate appears to be active in the treatment of both desmoid tumors and fibromatosis and is associated with significantly less neurotoxicity then that seen with the combination of vinblastine and methotrexate. No long-term toxicity was seen in any patient in this series.

Concurrent administration of vinorelbine with recombinant human granulocyte colony-stimulating factor: an effective method of increasing dose intensity.

Thirty-three patients with incurable neoplasms resistant to standard therapy received vinorelbine 8 mg/m2 to 10 mg/m2 per day by continuous infusion with concurrent administration of recombinant human granulocyte colony-stimulating factor 5 microm/m2 per day. The duration of the vinorelbine infusion was individualized; the infusion was continued until early evidence of hematopoietic toxicity was noted. The concurrent administration of recombinant human granulocyte colony-stimulating factor permitted a substantial increase in dose intensity of the anticancer agent without a corresponding increase in drug toxicity. There was no evidence that the antitumor effect of vinorelbine was compromised by the concurrent administration of recombinant human granulocyte colony-stimulating factor.

Limb salvage with osteoarticular allografts after resection of proximal tibia bone tumors.

A retrospective study was performed between 1980 and 1995 on 38 recipients of proximal tibial allografts after wide resection of benign and malignant tumors. Twenty-one (55%) patients experienced one or more complications. Of the 26 patients who received chemotherapy, 15 (58%) experienced one or more complications, whereas of the 12 patients who did not receive chemotherapy, six (50%) experienced one or more complications. In the chemotherapy group, there were 12 (46%) fractures, four (15%) infections, three (12%) nonunions, and four (15%) instabilities. In the nonchemotherapy group there were three (25%) infections, two (17%) fractures, one (8%) instability, and one (8%) nonunion. These complications were managed adequately with multiple subsequent surgical procedures. Three patients underwent amputations for deep wound infections. Twelve (32%) patients underwent removal of the allograft, and the limb was salvaged by reallografting or by total knee arthroplasty. The results of both groups were 66% (25 of 38 patients) satisfactory (good or excellent). The chemotherapy group had a significantly higher incidence of fractures. All other complication rates and functional outcomes were not significantly different between these groups.

Soft-tissue complications of intra-arterial chemotherapy for extremity sarcomas.

High-grade sarcomas have a high rate of local recurrence as well as distant metastases. This has led to the development of intra-arterial chemotherapy (IAC) as part of a multimodal approach to control local disease and/or reduce the extent of surgical resection. Intra-arterial catheters are positioned by an interventional radiologist into the feeding vessels of the tumor. Adriamycin and 5-fluorodeoxyuridine are infused intra-arterially. Cisplatinum, with or without granulocyte colony stimulating factor, is given systemically. Patients usually experience acute self-limited soft-tissue inflammation in the treated area. In our experience of 118 patients, 3 patients experienced soft-tissue necrosis that required excision and reconstruction. The first was treated for synovial sarcoma of a metatarsal. After IAC with Adriamycin, she sloughed the skin, subcutaneous tissue, and some of the posterior compartment musculature of her calf. This tissue was debrided. A gastrocnemius flap and skin graft were used for coverage. She is free of disease and ambulatory. The second patient was treated with IAC Adriamycin for a radial head chondrosarcoma. She developed soft-tissue slough, which became infected with Pseudomonas. She required extensive debridement of the skin, subcutaneous tissue, and muscle, and was subsequently reconstructed with a latissimus flap and a split-thickness skin graft (STSG). She later developed a local recurrence requiring amputation. The latissimus was elevated and used to cover the distal stump. She also is free of disease. The third patient was treated with IAC Adriamycin for Ewing's sarcoma of the right femur. This was complicated by fat necrosis and persistent pain. Subsequent radiotherapy only worsened her symptoms. She underwent wide excision and muscle flap/STSG repair, which relieved her pain. She is currently ambulatory and free of disease. In conclusion, as the use of IAC continues, its complications may become more common. Our experience with this previously unknown entity is illustrated and therapeutic options are discussed.

Infusional chemotherapy combined with recombinant human granulocyte colony stimulating factor: advantages and limitations.

We have studied the simultaneous administration of granulocyte colony stimulating factor (G-CSF), given concomitantly with an infusion of either doxorubicin or ifosphamide--the former, both intraarterially (i.a.) and intravenously (i.v.), the latter, intravenously--to a group of patients with various malignancies. Such simultaneous administration enabled us to substantially increase the dosage intensity of both, thereby increasing the effectiveness of each drug. No untoward effects have been noted to date.

Purification and characterization of fully functional human osteoclast precursors.

The identification and purification of human osteoclast precursors is essential to further our understanding of the mechanisms that control human osteoclast differentiation. Osteoclastoma tissue potentially provides a rich source of human osteoclast precursors, and in previous studies we have demonstrated the existence of a population of mononuclear cells within this tissue that is reactive with osteoclast-selective vitronectin receptor monoclonal antibodies. In this study, mononuclear cells expressing the vitronectin receptor, as defined by their ability to react with a murine monoclonal antibody to the beta 3 chain of the vitronectin receptor (87MEM1), were isolated from collagenase digests of osteoclastoma tissue using a fluorescence activated cell sorter. Based on their fluorescence signal and size, approximately 2-3% of the viable cells (typically 2 x 10(5)) were obtained and prepared for further phenotyping. The isolated cells demonstrated a number of phenotypic characteristics of osteoclasts: positive tartrate-resistant acid phosphatase (TRAP) activity, reactivity with human osteoclast-selective antibodies, expression of calcitonin receptors, cathepsin K (a novel osteoclast-selective cysteine proteinase) mRNA, and osteopontin mRNA and protein. These phenotypic characteristics were also detected in mononuclear cells within cryostat sections of the native osteoclastoma tissue as well as in resorption lacunae of sections of human bone. In contrast, isolated peripheral blood monocytes were negative for TRAP activity and osteopontin expression and, unlike the osteoclastoma-derived cells, demonstrated strong nonspecific esterase activity. Significantly, when the osteoclastoma-derived 87MEM1 positive cells were cocultured on whale dentine for 1-3 weeks with stromal cells, extensive resorption of the dentine surface was observed. This is the first demonstration of the purification of human osteoclast precursors. These cells provide an homogeneous cell population for studying cellular events that occur during human osteoclast differentiation.

Plantar fibromatosis: a review of primary and recurrent surgical treatment.

Plantar fibromatosis can be quite disabling to the patient, as well as a technical challenge to the surgeon. Patients who undergo previous local excisions and in whom aggressive recurrences develop are difficult to manage successfully. We present a consecutive series of five primary procedures on patients with painful plantar fibroma and seven revision operations on patients with recurrent plantar fibroma. The average follow-up was 47 months (range, 22-66 months) in the primary group and 40 months (range, 21-78 months) in the revision group. The overall results were satisfactory in four of the five primary operations, with only one recurrence. In the revision group, five of seven results were satisfactory with no recurrences. The major complication that led to unsatisfactory results was the development of a postoperative neuroma. In this article, we outline our present surgical techniques of wide primary excision and a staged revision procedure with delayed split-thickness skin graft closure. These techniques can be used successfully to manage this disabling, progressive disease.

Therapy of desmoid tumors, fibromatosis, and related neoplasms.

Forty-seven patients with unresectable desmoid tumors and 32 patients with unresectable fibromatosis were treated with various anti-neoplastic agents including methotrexate, vinblastine, etoposide, actinomycin D, and fluorouracil. A combination of methotrexate with either vinblastine or etoposide was found to be effective in yielding long-term control to both groups of patients. Fluorouracil and actinomycin D were less effective. Other than a significant but slowly reversible peripheral neuropathy in 6 patients, therapy was well tolerated and no long-term hematologic, pulmonary, hepatic, or cardiac toxicity was noted in any patient.

Dose intensification by the simultaneous use of rhg-csf and anticancer chemotherapy.

We have studied the simultaneous administration of rhG-CSF with doxorubicin, the latter given by continuous infusion either intra-arterially or intravenously, in a group of patients with various sarcomas. This has enabled us to substantially increase the dosage intensity of doxorubicin with a marked decrease in both hematologic and oral toxicity. While the data concerning anti-tumor activity is preliminary we believe that this combination has been responsible for a substantial increase in the effectiveness of doxorubicin in controlling the sarcomas. No adverse effect from combining doxorubicin given by infusion with rhG-CSF has been noted to date.

Plantar fibromatosis: a benign aggressive neoplasm with a characteristic appearance on MR images.

PURPOSE: To define the magnetic resonance (MR) imaging characteristics of plantar fibromatosis. MATERIALS AND METHODS: Sixteen patients (19 feet) with proved plantar fibromatosis underwent preoperative MR imaging at 1.5 T. A control group of 19 people (24 feet) also underwent MR imaging. RESULTS: Twenty-seven lesions (mean size, 2.2 x 1.0 cm) were identified. All had infiltrative upper margins. Four (15%) of the 27 grew deep to the aponeurosis; 25 (92%) exhibited some signal intensity heterogeneity. All 27 of the lesions on T1-weighted conventional spin-echo (SE) images, seven (78%) of the nine on T2-weighted conventional SE images, and 17 (94%) of the 18 on T2-weighted fast SE images were isointense to minimally hyperintense (to the signal intensity of adjacent muscle). Five (83%) of the six lesions on short inversion time inversion-recovery images were hyperintense. Enhancement was variable on contrast material-enhanced images; nine (60%) of the 15 lesions on these images showed marked enhancement. CONCLUSION: Plantar fibromatosis is a benign but infiltrative neoplasm with a characteristic location and appearance on MR images.