Despite faster neutrophil recovery and shortened duration of hospitalization with GFs administered after PBSC transplantation, the measured clinical variables of febrile days, septic episodes, and transfusion requirements were similar between the study arms. The use of GFs post-PBSC transfusion is associated with a modest clinical benefit.

Hyperekplexia is a rare condition characterised by the presence of neonatal hypertonia and an exaggerated startle response. Mutations have been described in GLRA1, the gene encoding the al subunit of the glycine receptor, in dominant families with hyperekplexia and in a single sporadic case, thought to represent an autosomal recessive form of the disease.In this study the coding region of the GLRA1 was analysed in eight probands with hyperekplexia by restriction digest and sequencing. Two familial cases were found to possess the previously described G1192A (R271Q) mutation in exon 6. In an additional family in which hyperekplexia cosegregates with spastic paraparesis, a novel A to G transversion at nucleotide 1206 in exon 6 was detected that changes a lysine at amino acid 276 to a glutamate (K276E). In four sporadic cases no mutations were found. In addition, one familial case did not have a mutation in the coding region of the gene.

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Forty-three patients received etoposide, cyclophosphamide, and fractionated total body irradiation before allogeneic marrow transplantation. Fifteen patients had chronic myelogenous leukemia in chronic phase or acute leukemia in first remission (standard risk) and twenty-eight patients with more advanced disease (high risk). All patients received etoposide 1,500 mg/m2 intravenously on day -8, cyclophosphamide 60 mg/kg/day intravenously on days -7 and -6, and total body irradiation at 170 cGy twice a day on days -3, -2, and -1. During the first 100 days 12 high risk patients (43%) died from causes unrelated to relapse while none of the standard risk patients died. Renal and hepatic dysfunction were also significantly increased during the first 14 days in the high risk group. The addition of 1,500 mg/m2 of etoposide to the cyclophosphamide and total body irradiation was well tolerated for patients with standard risk. However, the regimen was poorly tolerated with high mortality in patients with more advanced disease.

Because of potential tumor contamination and inadequacy of current purging technique of bone marrow in patients with solid tumors, we investigated an alternative approach to high-dose therapy without autologous bone marrow (ABM) infusion. Three levels of nonmyeloablative doses of cyclophosphamide 4.5 to 5.25 g/m2, etoposide 750 to 1,200 mg/m2, and cisplatin 120 to 165 mg/m2 (CVP) were administered to patients with metastatic solid tumors. Patients were randomized to ABM (n = 46) or no-ABM (NABM) (n = 46) infusion after CVP to study the impact of ABM on hematopoietic recovery, morbidity, and mortality. All patients had ABM harvested, underwent conventional chemotherapy, and then received CVP. Seventy-three patients received two courses of similar doses. The following were the median days to absolute neutrophil count (ANC) of 0.1 x 10(9)/L: for the ABM arm, 19, 21, and 19 and for the NABM arm, 23, 20, and 21 at levels 1, 2, and 3, respectively, during course 1 (P = .01, .80, and .01, respectively). During course 2, ANCs to 0.1 x 10(9)/L and 0.5 x 10(9)/L were attained significantly faster at levels 1 and 3 in the ABM arm. ANC to 1.0 x 10(9)/L was comparable in both arms. Incidence of infection and duration of fever were similar in both arms. Although mortality and the incidence of delayed hematopoietic recovery were more frequent in the NABM arm, this was not statistically significant. Platelet recovery was consistently prolonged in course 2 in both arms, with demonstrable benefit of ABM in course 2 when dose levels were collectively considered. We conclude that (1) ABM enhanced recovery of ANC to 0.1 x 10(9)/L; (2) ABM did not decrease the incidence of infections and the duration of fever; and (3) CVP can be safely given without ABM to carefully selected patients.

Summary:A 12-year-old girl with Fanconi anaemia (FA) received a bone marrow transplant from her HLA-identical brother following conditioning with cyclophosphamide (20 mg/kg), thoraco-abdominal radiation (TAI) (4 Gy) and equine anti-thymocyte globulin (ATG) (90 mg/kg). Engraftment was delayed and initially tenuous, and was followed by mixed chimerism (MC) over a follow-up period of 2 years. DNA analysis of engraftment was performed on whole peripheral blood and on separated granulocytes, B and T lymphocytes using PCR detection of CA tandem repeat polymorphisms. At 10 weeks post BMT, granulocytes were predominantly donor, but B and T lymphocytes recipient, in origin. Over the subsequent 90 weeks, granulocytes and B lymphocytes were donor-derived, whilst T cells showed persistent MC but with an increasing donor component. Marrow haemopoietic function (Hb, ANC and platelet count) improved gradually in parallel with a rise in the proportion of donor lymphocyte engraftment. We postulate that a population of recipient lymphocytes survived conditioning and in turn delayed the development of full donor chimerism. Although transient MC has been described after allogeneic BMT in FA, its association with delayed engraftment, and persistence for more than 1 year post BMT, has not been documented clearly. Keywords: mixed chimerism; delayed engraftment; Fanconi anaemia; bone marrow transplantation; child Allogeneic BMT is currently the only curative treatment for bone marrow failure in Fanconi anaemia (FA). In patients undergoing BMT, host lymphoid and haemopoietic cells usually decline progressively, resulting in replacement by donor cells within 1-2 months of transplantation. We report a case of FA who had delayed engraftment followed by persistent, mixed chimerism (MC) after receiving a BMT from an HLA-identical sibling donor. Case reportA 7-year-old girl presented with a recent history of increased bruising. She had no congenital abnormalities or dysmorphic features apart from clinodactyly, and her growth was normal. Her full blood count (FBC) showed Hb 9.0 g/dl, mean corpuscular volume (MCV) 106 fl, WBC 5.3 (ANC 1.8) × 10 9 /l and platelets 25 x 10 9 /l. Chromosomal fragility in response to mitomycin-C was increased in comparison to an age-matched control, establishing the diagnosis of FA. She was observed closely as her FBC gradually deteriorated, and by 12 years of age she had received three blood and two platelet transfusions within a 14 month period. Since she had an older HLA-identical sibling donor, in whom FA had been excluded by a normal FBC and chromosomal fragility studies, she proceeded to allogeneic BMT. She was conditioned with low-dose cyclophosphamide (CY) (5 mg/kg on days −5 to −2, total dose 20 mg/kg), thoraco-abdominal irradiation (TAI) (4 Gy) on day −1, and equine anti-thymocyte globulin (ATG) (30 mg/kg on days −5 to −3, total dose 90 mg/kg). GVHD prophylaxis consisted of cyclosporine (CYA) only. She received unmanipulated bone marrow (nucleated cell dose 2.6 × 10 8 /kg). The recipient was CMV negative...

Peripheral blood cells (PBC) can hasten hematopoietic recovery after high-dose chemotherapy. To determine if PBC apheresed after mobilization further enhance hematopoietic recovery over that achieved with autologous bone marrow (ABM) and recombinant human granulocyte- macrophage colony-stimulating factor (rhGM-CSF), 14 patients with metastatic solid tumors were supported by ABM and rhGM-CSF during the first course of high doses of cyclophosphamide, etoposide, and cisplatin (CVP) and 11 of these 14 patients by mobilized PBC with ABM and rhGM-CSF during the second CVP. Each patient served as his or her own control. Identical doses of CVP were administered in both courses: cyclophosphamide 5.25 g/m2, etoposide 1,200 mg/m2, and cisplatin 165 to 180 mg/m2. PBC were collected on day 10 after mobilization with cyclophosphamide (3 g/m2) intravenously (IV) on day 1, doxorubicin (50 mg/m2) as a continuous IV infusion over 48 hours starting day 2, and rhGM-CSF as a daily 4-hour IV infusion starting day 4 at 0.6 mg/m2 for 14 days. Comparing recovery in the 11 patients to receive two cycles of therapy, the median days to an absolute neutrophil count of 0.1 x 10(9)/L and 0.5 x 10(9)/L were not statistically significant between the two courses; neither was there a difference in the incidence of fever and bacteremia. The median number of days to platelet count of 0.02 x 10(12)/L unmaintained by platelet transfusion was 20 from marrow infusion for course 1 and 16 for course 2 (P = .059). The median number of days to a platelet count of 0.05 x 10(12)/L was significantly shortened: 24 and 19 days for courses 1 and 2, respectively (P = .045). Patients who received PBC required fewer number of platelet transfusions. Extramedullary toxicities were not different between the groups. Our finding of enhanced early recovery of platelets and reduced platelet transfusion requirement is in concordance with other studies.

Cyclosporine and methotrexate at standard doses (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11, total 45 mg/m2) are effective in the prophylaxis of acute graft-vs.-host disease. However, the combination has significant early toxicities with delayed engraftment, increased mucositis, and hepatotoxicity. We modified the combination by adding single-dose methylprednisolone and lowered the total dose of methotrexate to 35 mg/m2 (5 mg/m2 on days 1, 3, and 6, and then 10 mg/m2 on days 11 and 18) and then to 20 mg/m2 (5 mg/m2 on days 1, 3, 6, and 11) in an attempt to decrease these side effects in two sequential consecutive groups of patients. We demonstrated that the modified regimens maintained the efficacy with reduced toxicities. The rate of engraftment was comparable to cyclosporine alone and the hepatotoxicity was reduced with reduced doses of methotrexate. Factors such as early immunosuppression of the host, intravenous immunoglobulin, the timing of steroid administration, nucleotide free diet and germ free environment may contribute to the effectiveness of the combination and permit reduction of methotrexate dose.