High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours.

BACKGROUND: The outcome for patients with recurrent or progressive Ewing's sarcoma family of tumours (ESFT) is poor. High dose therapy (HDT) has been used for a number of years in an attempt to improve survival; however, evidence for the efficacy of this treatment remains limited. PATIENTS AND METHODS: Between 1992 and 2004, 33 patients with recurrent or progressive ESFT were treated with HDT with bone marrow (n=2), peripheral blood stem cell (n=30), or bone marrow and peripheral blood stem cell support (n=1), at a single institution. HDT was with busulphan and melphalan in 22 patients; melphalan and etoposide in seven patients, three with total body irradiation (TBI); melphalan in three patients (2 with TBI), and busulphan and cyclophosphamide in one patient. RESULTS: The 2 and 5 year event free survival was 42.5% (95% CI, 26-59%) and 38.2% (95% CI, 21-55%) respectively. There was one treatment related death from colitis, and grade 4 infection was observed in two patients. CONCLUSIONS: Long-term survival can be attained in patients with recurrent or refractory ESFT treated with HDT. However, this treatment is associated with severe toxicity. A need remains for prospective randomised clinical trials of HDT in this group of patients.

Single center experience of a new intensive induction therapy for ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties.

PURPOSE: To examine the feasibility, tolerability, and toxicity of an intensified induction regimen (vincristine, ifosfamide, doxorubicin, and etoposide [VIDE]) in patients with newly diagnosed Ewing's family of tumors (EFT); to assess ability to maintain dose-intensity, and predictability of peripheral-blood stem cell mobilization. PATIENTS AND METHODS: Thirty patients were treated with vincristine 1.4 mg/m2 (maximum 2 mg) on day 1, doxorubicin 20 mg/m2, ifosfamide 3 g/m2 plus mesna and etoposide 150 mg/m2 on days 1 to 3. Cycles were given every 21 days for up to six cycles. RESULTS: One-hundred and seventy cycles of VIDE were given. The median treatment interval was 21 days (21 to 42) and nadir count: hemoglobin 8.3 (6.3 to 11.9), neutrophils 0.045 (0.0 to 2.1), and platelets 45 (3 to 343). There were 96 episodes of infection requiring hospitalization (56%). Growth factor support reduced infectious complications by 34%. Etoposide dose was reduced, or omitted, in 24% of cycles. Four patients did not complete six cycles due to unacceptable toxicity and one patient progressed on treatment. Twenty patients underwent peripheral-blood stem cell harvesting, 15 after cycle 3, and five after cycle 4. Median CD34+ yield was 4.6 x 106/kg per patient (1.8 to 14.5). Overall response to treatment, measured in 24 patients, was 88%. Seven of 11 patients undergoing surgery achieved greater than 90% necrosis of tumor (64%). CONCLUSION: VIDE is an effective induction regimen with substantial but acceptable toxicity that allows predictable mobilization of stem cells. Maintenance of dose-intensity is feasible in the majority of patients. Growth factors play a role in maintaining dose-intensity and reduce infectious complications.

A pilot study of short-course intensive multiagent chemotherapy in metastatic and axial skeletal osteosarcoma.

BACKGROUND: This pilot study was undertaken to assess the feasibility, toxicity and response to short-course multiagent chemotherapy followed by high-dose chemotherapy (HDC) in patients with poor prognosis osteosarcoma. PATIENTS AND METHODS: A total of 30 patients entered the study. Chemotherapy consisted of four blocks of multiagent chemotherapy administered sequentially over a short period in a dose-intensive manner. This therapy was followed by HDC which consisted of carboplatin at an AUC8 x 3 days, etoposide 400 mg/m(2) x 3 days and cyclophosphamide 60 mg/kg x 2 days. RESULTS: A total of 227 cycles of chemotherapy were administered. The main toxicity (for blocks 1-4) was haematological. There were two treatment-related deaths: one post HDC due to sepsis and one during surgery. High-dose chemotherapy was administered to 11 patients (10 with extremity tumours and only one with a pelvic tumour). Twenty-seven patients underwent surgery to the primary. Histological response was assessed in 23 patients. Seven patients (30%) had >90% necrosis. Eight patients underwent pulmonary metastatectomy. The median survival time for the whole group was 16 months. The 2- and 3-year survival rates were 50% and 21% for those with extremity tumours and 19% and 13% for those with axial skeletal tumours. CONCLUSIONS: Dose-intensive multiagent chemotherapy though feasible in the group of patients with extremity tumours did not significantly improve the treatment outcome compared with conventional relapse therapy. Inferior survival rates in the axial skeletal group are attributed to less intensive treatment and poor local tumour control.

Widespread bone disease in acute myeloid leukaemia.

We describe a 11-year-old boy with acute myeloid leukaemia who presented with widespread bone disease. Spine X-rays revealed multiple crush fractures and there were multiple hot spots on the bone scan. The bone-mineral density was markedly reduced but there was no hypercalcaemia or hypercalcuria. Bone marrow aspirate revealed 98% blast cells and a balanced translocation between chromosomes 10 and 17 in seven of nine metaphases. Plasma interleukin-6 level before chemotherapy was high at 53 pg/ml. We postulate that the mechanism for bony destruction in this case was similar to that in the adult disease myeloma.

Hepatitis C virus infection: review and implications for the orthopedic surgeon.

Hepatitis C virus (HCV), a single-stranded ribonucleic acid virus identified in 1989, is estimated to have infected 1%-2% of the United States population. The incidence of HCV in patients requiring orthopedic surgery may be as high as 5%. Surgeons and operating room personnel are at risk for blood-borne diseases transmitted during surgery. The orthopedic surgeon must be aware of viral infection with this pathogen for the safety of the entire operating room team. Further, screening for HCV is routinely done when a patient donates autologous blood prior to elective surgery, and the orthopedic surgeon is often the first or only physician informed of a positive result. The surgeon should know how to interpret the result, advise the patient, and incorporate the diagnosis of HCV into the plan for the proposed surgery. We will review the natural history, transmission, evaluation of, and current treatment for infection with this blood-borne virus.

Rothmund-Thomson syndrome and osteosarcoma.

A 10-year-old girl with Rothmund-Thomson syndrome developed a fibular osteosarcoma. Standard chemotherapy produced intolerable toxicity, necessitating a modification of therapy. Initial DNA repair studies on skin fibroblasts were abnormal, but repeat studies failed to reproduce the defects.

Suppressor T-cell deficiency in primary sclerosing cholangitis. Case and family study.

Primary sclerosing cholangitis is considered to be an autoimmune disease of the liver in which there is an association with the HLA phenotypes B8 and DR3 and in which circulating autoantibodies occur. Abnormalities of immune regulation may be present but whether or not they are primary or acquired is not known. This report is of a patient with primary sclerosing cholangitis who was homozygous for HLA B8 DR3, had a circulating antinuclear antibody, and a defect in nonspecific suppressor T-cell activity despite glucocorticosteroid treatment. Nevertheless, family studies revealed no evidence of an immunoregulatory defect in first-degree relatives despite the presence of Raynaud's phenomenon and malignancy in two sisters.

An immunogenetic study of suppressor cell activity in autoimmune chronic active hepatitis.

Some patients with autoimmune chronic active hepatitis as well as their disease-free first degree relatives show decreased suppressor cell activity of peripheral blood T lymphocytes. Studies were therefore undertaken in families ascertained by the presence of a single chronic active hepatitis patient to determine if this abnormality of immune regulation represents a genetic phenotype simply controlled by a gene or genes at a putative disease susceptibility locus and, further, if this locus showed linkage to either the HLA or the immunoglobulin constant region loci. In addition to determining circulating autoantibody status and genotyping for HLA and immunoglobulin allotypes, suppressor T cells were evaluated by surface markers and by determining their ability to suppress IgG secretion in vitro. The results suggest that immunoregulatory dysfunction in autoimmune chronic active hepatitis is a familial abnormality, but that this abnormality occurs independent of circulating autoantibody status and of the segregation of genes for HLA or immunoglobulin allotypes.

Small intestinal absorption of amino acids and a dipeptide in pancreatic insufficiency.

In this study a perfusion technique has been used to investigate in vivo jejunal absorption and transmural potential difference evoked by the neutral amino acids phenylalanine (56 or 20 mmol/l) and glycine (20 mmol/l), the dibasic amino acid lysine (56 or 5 mmol/l), and a dipeptide glycyl-l-phenylalanine (20 mmol/l) in 11 children with pancreatic insufficiency due to cystic fibrosis and in three children with other causes of exocrine pancreatic insufficiency. Net absorption and potential difference evoked by phenylalanine in both cystic fibrosis and pancreatic insufficiency, and net absorption of glycine in cystic fibrosis were significantly reduced; but the absorption of lysine and glycyl-l-phenylalanine was normal. Absorption of the constituent amino acids from the dipeptide was normal or increased in cystic fibrosis. Thus, these studies show a defect in active absorption of neutral amino acids in cystic fibrosis with pancreatic insufficiency and exocrine pancreatic insufficiency. We speculate that pancreatic factors participate in neutral amino acid absorption.

Acute inflammatory bowel disease in childbood: a new disease?

Three children aged between 7 and 11 years, after an acute onset of diarrhoea and vomiting, developed protracted diarrhoea and severe loss of weight. None had been abroad. No significant aetiological agent was found. There was evidence of acute inflammatory disease on proximal small intestinal biopsy, and some evidence of more widespread gut involvement--of the rectum in Cases 1 and 2, and the terminal ileum in Cases 2 and 3. The disease resolved spontaneously and without relapse.

Cows' milk-sensitive enteropathy.

Serial small intestinal biopsies related to withdrawal and challenge with cows' milk are described in 5 infants with cows' milk protein intolerenace. On the basis of these serial observations the existence of a cows' milk-sensitive enteropathy in infancy is clearly established. The cows' milk-sensitive mucosal lesion varied in its severity ranging from a partly flat mucosa to a mild degree of partial villous atrophy. Intraepithelial lymphocyte counts rose after a positive milk challenge, but on only one occasion to a level outside the normal range. The technique of serial biopsies related to dietary milk enables a firm diagnosis of cows' milk intolerance to be made upon the basis of a single milk challenge. Clinically this appears to be a temporary condition which disappears by the age of 2 years.