Vancomycin versus placebo for treating persistent fever in patients with neutropenic cancer receiving piperacillin-tazobactam monotherapy.

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P=.52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P=.75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cancer.

Ocular findings in Saudi Arabian patients with sickle cell disease.

AIM: This study was set up to determine whether or not retinal changes occur in sickle cell disease in Saudi Arabian subjects with either the Benin, which exists in the south western part of the kingdom, or Asian haplotypes in the east, and to compare the findings with those in sickle cell disease in Jamaica. METHODS: Retinal examination and fluorescein angiography were performed in 61 patients with SS disease (40 eastern, 20 south western, 1 central region) and 10 with sickle cell beta(0) thalassaemia. RESULTS: Peripheral retinal vascular changes were common, and a qualitatively abnormal vascular border believed to imply risk of proliferative sickle retinography (PSR) was significantly more common in south western SS patients and PSR was shown in one of these. There were no differences in visual acuity, the presence of peripheral retinal patches, or the circumferential or posterior extent of peripheral retinal vessel closure between SS disease and sickle cell beta(0) thalassaemia or between SS disease in the two regions. Compared with the Jamaican Cohort Study, > 180 degrees of the peripheral retinal vasculature was seen significantly less frequent, suggesting factors inhibiting vascular remodeling in Saudi patients in early life. CONCLUSION: Sickle cell disease in Saudi Arabia affects the retina and represents a potential threat to vision. Changes occur whatever the haplotype, and is similar to that observed in Jamaica.

Multiple myeloma: A review of 92 cases at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

A review of 92 cases of multiple myeloma (66 males and 26 females) seen at the King Faisal Specialist Hospital and Research Centre from October 1975 through December 1987 revealed the age for affected patients ranged from 23 to 90 years (mean, 56 years). Six percent of the patients were less than 40 years old at the time of diagnosis. Bone pain was the most common presenting symptom in our patients (80%), most frequently involving the back. Anemia was the initial finding in 74%, followed by plasmacytoma (22.8%), hypecalcemia (19.6%), and renal insufficiency (18.5%). Skeletal survey abnormalities were seen in 92.4% of the cases, with osteolytic lesions as the predominant finding. Serum protein electrophoresis showed a monoclonal paraprotein in 78% of the cases, of which 55.5% were the IgG class. Free light chains were detected in the urine of 20 patients. The median survival time for all patients was 68 months. Twenty patients died of renal failure and/or infection. The combination of melphalan and prednison was used for treatment in 37 patients, while 31 patients received the M2 protocol and 19 patients received different therapy such as VCEP (vindesine, cyclophosphamide, VP 16 and prednisone), MPV (melphalan, prednisone, and vincristine) or high-dose melphalan. Five patients either refused treatment or died before treatment could be started.

Avascular necrosis of the femoral head in Saudi Arabians with homozygous sickle cell disease - risk factors.

Avascular necrosis of the femoral head (ANFH) in Saudi patients with homozygous sickle cell (SS) disease attending King Faisal Specialist Hospital and Research Centre (KFSH&RC) occurred in 29/118 (24.6%) patients or 32% of patients aged 10 years and above. This high prevalence was heavily influenced by symptomatic selection. Contrary to observations in patients of African origin, ANFH in Saudi subjects was not associated with high hemoglobin, low fetal hemoglobin levels or with alpha thalassemia. Bone densitometry failed to detect differences in bone mineral density or content between patients with and without ANFH. Levels of 25-OH vitamin D did not differ between patients with and without ANFH. Several patients showed very rapid and complete destruction of the femoral head suggestive of osteomyelitis of the femoral head or a pyogenic arthritis. ANFH appears common in Saudi patients with SS disease although an accurate prevalence is unknown. The lack of relationship with risk factors for ANFH identified in African SS disease highlights the need for further study in the Saudi SS population.

Bone marrow transplantation for infantile malignant osteopetrosis.

PURPOSE: Most patients diagnosed with malignant osteopetrosis die during infancy or early childhood from hemorrhage and infection due to bone marrow failure. Allogeneic bone marrow transplantation (BMT) has been reported to provide curative therapy for this disorder. We report our experience with eight patients with malignant osteopetrosis who underwent BMT. PATIENTS AND METHODS: Between May 1987 and August 1992, eight children with malignant osteopetrosis underwent allogeneic BMT. Median age at BMT was 9 months (range, 2-36 months). Six patients received marrow from HLA-identical sibling donors, one from phenotypically matched father, and one from a one antigen mismatched father. BMT conditioning for all patients was busulfan 16 mg/kg and cyclophosphamide 200 mg/kg each administered over 4 days. Graft versus host disease (GVHD) prophylaxis included cyclosporin A in six patients or cyclosporin A and methotrexate in two patients. RESULTS: Six patients, including those who received bone marrow from their father's, engrafted as documented by bone marrow biopsy showing an increase in osteoclasts in all cases and by chromosomal analysis in four patients. Two patients died without engraftment. Three out of six patients engrafted are alive and well at the follow-up of 48, 63, and 81 months. Serum calcium, alkaline, and acid phosphatase levels normalized within 2 months. These patients have full bone marrow reconstitution. Serial radiologic studies revealed bone marrow remodelling and a new nonsclerotic bone formation. Vision improved dramatically in the youngest patient. CONCLUSION: BMT offers cure to patients with malignant osteopetrosis with reconstitution of bone marrow and correction of metabolic disturbances. In our experience, reversibility in neurosensory deficit is possible when BMT is done at an early age.

Engraftment failure following bone marrow transplantation in children with thalassemia major using busulfan and cyclophosphamide conditioning.

Thirteen children older than 3 years of age with beta-thalassemia major underwent allogeneic bone marrow transplantation (BMT) from a full human leukocyte antigen (HLA) matched sibling donor in a single institution. These patients received busulfan (Bu). 16 mg/kg followed by cyclophosphamide (Cy) 200 mg/kg for conditioning. Eight of the 13 patients (Group 1) engrafted and have a median age of 13 years (range 5-15 years). The five patients (Group 2) who failed to engraft have a median age of 6 years (range 3-8 years). The association with the following factors was found to be statistically significant: age (older in Group 1), duration of nadir of white blood count (WBC) of < or = .1 x 10(9)/L (longer in Group 1), and the dose of Bu administered to each patient calculated on the basis of body surface area (higher dose in Group 1). The high rate of engraftment failure (5 out of 13) may be related to the suboptimal systemic exposure of Bu in younger children leading to inadequate bone marrow ablation when the standard dose of 16 mg/kg is used.

Bone marrow transplantation for autosomal recessive osteopetrosis. A report from the Working Party on Inborn Errors of the European Bone Marrow Transplantation Group.

The outcomes of 69 patients who received allogeneic bone marrow grafts for autosomal recessive osteopetrosis in the period between 1976 and 1994 were analyzed retrospectively. Four patients received bone marrow transplants (BMT) without prior myeloablative conditioning; transient osteoclast function was demonstrated in one of them. Sixty-five patients received myeloablative pretreatment. Recipients of a genotypically human leukocyte antigen (HLA)-identical BMT had an actuarial probability for 5-year survival, with osteoclast function, of 79%; recipients of a phenotypically HLA-identical bone marrow graft from a related or unrelated donor, or one HLA-mismatched graft from a related donor, had an actuarial probability for 5-year survival, with osteoclast function, of 38%; patients who received a graft from an HLA-haplotype mismatched related donor had a probability for 5-year survival of only 13%. The main problems in haplotype-nonidentical BMT were graft failure and BMT-related complications such as sepsis, bleeding, and interstitial pneumonia. Osteoclast function developed in all patients with full engraftment. Recovery of osteoclast function was associated with severe hypercalcemia in 24% of the patients with engraftment, especially those older than 2 years of age. At the time of BMT, severe visual impairment was present in 35% of the patients; of the 15 patients who had visual impairment at the time that a successful BMT was performed, two had improvement after BMT (13%). Within the total group, one patient had neurodegeneration. Engraftment of healthy donor cells had no influence on the progression of that abnormality and BMT thus had no beneficial effect on this phenotype of osteopetrosis. In general, however, early BMT remains the only curative treatment for autosomal recessive osteopetrosis.

Bone marrow transplantation in patients with Fanconi anemia: experience with cyclophosphamide and total body irradiation conditioning regimen.

Eleven patients with Fanconi anemia (FA) underwent bone marrow transplantation (BMT) between March 1985 and May 1990 in a single institution. Ten patients received bone marrow from healthy full human leukocyte antigen (HLA) matched siblings and one patient from her father (one antigen mismatch). Ten patients were conditioned with cyclophosphamide (Cy) at a dose of 5 mg/kg per day for 4 days followed by total body irradiation (TBI) for a total of 600 cGy over 3 days. Six of the 11 patients are alive and have normal reconstitution of their bone marrow. Median follow-up was 72 months (range 42-84). Three of the 10 patients who received Cy and TBI (two HLA compatible, one antigen mismatch) had graft failure. Five patients developed at least grade III acute graft-versus-host disease (GVHD). The rates of graft failure and GVHD are, however, still significantly high. Modification of the conditioning regimen and GVHD prophylaxis is needed to improve the outcome.

Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients.

The efficacy and safety of oral fluconazole versus a polyene regimen in preventing mycoses in neutropenic patients was compared. Patients with haematological malignancy or bone marrow transplantation received as antifungal prophylaxis either fluconazole 200 mg daily or a regimen consisting of clotrimazole trouches 10 mg twice daily with mycostatin, 500,000 I.U. four times daily, benadryl and cepacol mouthwash. Ninety patients at risk for fungus infection were evaluable. Four of 42 patients (9.5%; confidence interval 2%-23%) on fluconazole and 17 of 48 patients (35.4%; confidence interval 22%-52%) (p < 0.01) on the clotrimazole regimen developed a clinically significant fungal infection, including 3 (7.1%) and 11 (22.9%) patients respectively who had severe fungal infection, mainly pulmonary aspergillosis. Death directly due to a fungal infection within 100 days of the start of prophylaxis occurred in 2 of 42 patients (4.8%) and 9 of 48 patients (18.8%) respectively (p < 0.06). Kaplan-Meier analysis showed that the chance of survival on fluconazole was statistically greater than for the clotrimazole regimen (p < 0.04). A decrease of candidal colonisation of the gastrointestinal and genitourinary tracts occurred only in patients receiving fluconazole. No significant toxicity occurred. A 200 mg daily dose of fluconazole given to these patients thus appears to be well tolerated and to provide a protective effect against the development of fungal infection and death from severe fungal disease.

Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Infection Program.

Combinations of beta-lactams plus aminoglycosides have been standard therapy for suspected infections in granulocytopenic cancer patients, especially those with profound long-lasting granulocytopenia. With the advent of new broad-spectrum bactericidal antibiotics such as extended-spectrum cephalosporins or carbapenems, the need to combine beta-lactams with aminoglycosides became more controversial. The objective of this prospective randomized multicenter study was to compare the efficacy, safety, and tolerance of meropenem monotherapy with those of the combination of ceftazidime plus amikacin for the empirical treatment of fever in granulocytopenic cancer patients. Of 1,034 randomized patients, 958 were assessable in the intent-to-treat analysis for response to antibacterial therapy, including 483 in the meropenem group and 475 in the ceftazidime-plus-amikacin group. The median durations of neutropenia were 16 and 17 days, respectively. A successful outcome was reported in 270 of 483 (56%) patients treated with monotherapy compared with 245 of 475 (52%) patients treated with the combination group (P = 0.20). The success rates in the monotherapy group and the combination group were similar by type of infection (single gram-negative bacteremia, single gram-positive bacteremia, clinically documented infection, and possible infection). The occurrence of further infections assessed in patients for whom the allocated regimen was not modified did not differ between the two groups (12% in both groups). Mortality due to the presenting infection or further infection was relatively low (8 patients treated with the monotherapy compared with 13 patients treated with the combination). A total of 1,027 patients were evaluable for adverse events; the proportion of those who developed adverse effects was similar between the two groups (29% in both groups), and only 19 (4%) patients in the monotherapy group and 31 (6%) in the combination group experienced an adverse event related or probably related to the study drug. Allergic reactions were the only reason for stopping the protocol antibiotic(s) (3 and 5 patients, respectively). This study confirms that monotherapy with meropenem is as effective as the combination of ceftazidime plus amikacin for the empiric treatment of fever in persistently granulocytopenic cancer patients, and both regimens were well tolerated.

Two different forms of homozygous sickle-cell disease - abstract

Haematological, clinical and some molecular genetic features have been compared in two groups of patients with homozygous sickle-cell (SS) disease in Saudi Arabia, 33 patients from the Eastern Province (eastern) and 30 from the South Western Province (Western). Eastern patients all had the Asian haplotype of DNA polymorphisms within the beta globin gene cluster whereas Western patients were more variable but predominantly of the Benin haplotype. Eastern patients had significantly more deletional alpha thalassaemia, higher levels of total haemoglobin and foetal haemoglobin, and lower of HBA, mean volume reticulocytes, and platelets. Clinically, Eastern patients had a greater persistence of splenomegaly, less dactylitis, less acute chest syndrome, a more normal body build and greater subscapular skin fold thickness. Painful crises occurred with equal frequency in both groups. Avascular necrosis of the femoral head was common in both groups. The disease in the Eastern province has many mild features consistent with the higher HbF levels and more frequent alpha thalassaemia but bone pathology (painful crises, avascular necrosis of the femoral head, osteomyelitis) remains common. The disease in the West is more severe, consistent with the Benin haplotype suggesting an African origin (AU)