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Biomedical subjects

D G Savage

Publications and source records attributed to D G Savage.

At least 19 recordsLinked to original sources
PubMed2006

Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystemic autosomal recessive disease due to primary thymidine phosphorylase (TP) deficiency. To restore TP activity, we performed reduced intensity allogeneic stem cell transplantations (alloSCTs) in two patients. In the first, alloSCT failed to engraft, but the second achieved mixed donor chimerism, which partially restored buffy coat TP activity and lowered plasma nucleosides. Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven.

Adult↗
PubMed2006

Primary Burkitt lymphoma of the uterine corpus.

This study reports the first well-documented case of sporadic Burkitt lymphoma arising in and confined to the uterine corpus in a 40-year-old woman who presented with vaginal bleeding. Endometrial curettings showed a diffuse infiltrate of medium sized lymphocytes with the characteristic morphologic and immunophenotypic features of Burkitt lymphoma. Fluorescence in-situ hybridization demonstrated the t(8;14)(q24;q32) translocation. There was no evidence of extra-uterine disease and the patient is alive without disease 10 months after hysterectomy and chemotherapy. This report demonstrates that Burkitt lymphoma can present as isolated, organ confined disease at unusual sites and with protean symptoms.

Adult↗
PubMed2005

Pilot study of tandem high-dose chemotherapy and autologous stem cell transplantation with a novel combination of regimens in patients with poor risk lymphoma.

In an effort to improve the outcome of poor-risk lymphoma patients, we evaluated a novel regimen of tandem high-dose chemotherapy (THDC) with autologous stem cell transplantation. A total of 41 patients (median age 40 years, range 15-68 years) with poor-risk non-Hodgkin's lymphoma and Hodgkin's disease were enrolled. THDC consisted of melphalan (180 mg/m2) and escalating dose mitoxantrone (30-50 mg/m2) (MMt) for the first conditioning regimen, and thiotepa (500 mg/m2), carboplatin (800 mg/m2), and escalating dose etoposide phosphate (400-850 mg/m2), (ETCb) as the second regimen. In all, 31 patients (76%) completed both transplants, with a median time between transplants of 55 days (range 26-120). The maximum tolerated dose was determined as 40 mg/m2 for mitoxantrone and 550 mg/m2 for etoposide phosphate. The overall toxic death rate was 12%. Following high-dose chemotherapy, 10 of 24 evaluable patients (42%) were in CR. The two-year overall survival and event-free survival is 67% (95% CI, 52-81%) and 45%, (95% CI, 29-61%) for the 41 patients enrolled; and 69% (95% CI, 525-586%) and 48% (95% CI, 30-67%) for the 31 patients completing both transplants. This THDC regimen is feasible but with notable toxicity in heavily pretreated patients; its role in the current treatment of high-risk lymphoma remains to be determined.

Adolescent↗
PubMed2004

Outcomes of unrelated cord blood transplantation in pediatric recipients.

We report results of unrelated cord blood transplants (UCBT) in 29 pediatric recipients in one center and the risk factors associated with survival. Median age: 9 years (0.5-20); diagnosis: ALL (9), AML (4), CML (1), HD (3), HLH (1), NHL (3), NBL (2); B-thal (1), FA (1), FEL (1), Krabbe (1), WAS (1), SAA (1); median follow-up: 11 months; conditioning: total body irradiation (TBI)-ablative (14), chemotherapy-ablative (6) and reduced intensity chemotherapy (9); GVHD prophylaxis: MMF/FK506 (18), cyclosporin A (CsA)+steroids+/-MMF (7) or CsA+methotrexate (MTX) (4); median total nucleated cells (TNC): 3.8 x 10(7)/kg (1.1-11); median CD34+: 2.3 x 10(5)/kg (0.2-9.9); and HLA match: 2 (6/6), 5 (5/6), 22 (4/6). Neutrophil engraftment by cumulative incidence curves 63% (median 28 (95% confidence interval (CI) 18-32)). Probability of >/=grade II acute graft-versus-host disease (aGVHD) by day +60 27%, >/=grade III aGVHD 20% and chronic graft-versus-host disease 3%. Estimated 1-year overall survival (OS) 46% (95% CI 30-71) and standard risk 60% (95% CI 29-100%). Variables associated with improved survival by multivariate analysis include non-TBI-ablative conditioning (P=0.024), CD34+/kg (P=0.038) and gender (P=0.048). These results suggest that CD34/kg cell dose and non-TBI-ablative conditioning may be important variables influencing OS following UCBT in pediatric recipients. Given the small number of patients, these results should be viewed cautiously.

Adolescent↗
PubMed2001

Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of a haematopoietic stem cell clone with a PIG-A mutation (the PNH clone) in an environment in which normal stem cells are lost or failing: it has been hypothesized that this abnormal marrow environment provides a relative advantage to the PNH clone. In patients with PNH, generally, the karyotype of bone marrow cells has been reported to be normal, unlike in myelodysplastic syndrome (MDS), another clonal condition in which cytogenetic abnormalities are regarded as diagnostic. In a retrospective review of 46 patients with a PNH clone, we found a karyotypic abnormality in 11 (24%). Upon follow-up, the proportion of cells with abnormal karyotype decreased significantly in seven of these 11 patients. Abnormal morphological bone marrow features reminiscent of MDS were common in PNH, regardless of the karyotype. However, none of our patients developed excess blasts or leukaemia. We conclude that in patients with PNH cytogenetically abnormal clones are not necessarily malignant and may not be predictive of evolution to leukaemia.

Adolescent↗
PubMed2000

Gemcitabine for relapsed or resistant lymphoma.

BACKGROUND: Gemcitabine therapy has not been widely assessed in the treatment of hematological malignancies. We have examined the efficacy and safety of gemcitabine in patients with relapsed or resistant lymphoma. PATIENTS AND METHODS: Gemcitabine (1 g/m2) was given weekly for 7 consecutive weeks, followed by a week off treatment. The drug was then given for 3 consecutive weeks, followed by a week off treatment; this regimen was continued until disease progression or drug intolerance. Fifteen patients have enrolled. Most have been extensively pre-treated for advanced diffuse large-cell or mantle-cell lymphoma. RESULTS: The drug was well tolerated; no patient suffered treatment-related sepsis, hemorrhage or death. Non-hematopoietic toxicity led to discontinuation of gemcitabine therapy in two patients. Dose reductions or delays were required for about two-thirds of treatments. Of 13 evaluable patients, one had a complete response, 3 a partial response, 3 stable disease, and 6 disease progression. After 6 infusions of gemcitabine, a patient with advanced Hodgkin's disease has had a complete remission lasting 21 months. CONCLUSIONS: Gemcitabine has substantial activity and acceptable toxicity in heavily pre-treated patients with advanced lymphoma. Further study is warranted.

Aged↗
PubMed2000

Etiology and diagnostic evaluation of macrocytosis.

BACKGROUND: Elevation of mean cell volume (MCV) is a common clinical problem, but the etiologic spectrum and optimal diagnostic evaluation of macrocytosis are not well defined. METHODS: We studied 300 consecutive hospitalized adult patients with MCV values > or = 100 fL. Assessment included complete blood counts, morphologic review, liver function tests, and levels of serum cobalamin (Cbl), methylmalonic acid, and total homocysteine. RESULTS: The most common cause of macrocytosis was drug therapy, followed by alcohol, liver disease, and reticulocytosis. Megaloblastic hematopoiesis accounted for less than 10% of cases. MCV values > 120 fL were usually caused by Cbl deficiency. Anisocytosis, macro-ovalocytosis, and teardrop erythrocytes were most prominent in megaloblastic hematopoiesis. Elevated levels of serum methylmalonic acid and total homocysteine were useful in the diagnosis of Cbl deficiency. CONCLUSIONS: Drugs and alcohol are the most common causes of macrocytosis in hospitalized patients in a New York City teaching hospital. We have formulated tentative guidelines for the evaluation of high MCV values in this setting.

Adult↗
PubMed1999

A phase I study of high-dose BCNU, etoposide and escalating-dose thiotepa (BTE) with hematopoietic progenitor cell support in adults with recurrent and high-risk brain tumors.

This phase I dose-escalation study was performed to determine the tolerability of three-drug combination high-dose BCNU (B) (450 mg/m2), escalating-dose thiotepa (500-800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days in 22 adults with malignant primary brain tumors. Patients received G-CSF and hematopoeitic support with peripheral blood progenitor cells (PBPC) (n = 18) or both PBPC and marrow (n = 4). The maximum tolerated dose of thiotepa with acceptable toxicity was determined as 800 mg/m2. The 100-day mortality rate was 9% (2/22). Grade III/IV toxicities included mucositis (71%), diarrhea (29%), nausea/vomiting (19%), and hepatic toxicity (14%). Neurological toxicities occurred in 24% and included seizures (two patients) and encephalopathy (three patients). Encephalopathy was transient in two patients and progressive in one patient. All patients had neutropenic fever. Median time to engraftment with absolute neutrophil count (ANC) >0.5 x 10(9)/l was 10 days (range 8-30 days). Platelet engraftment >20 x 10(9)/l occurred after 11 days (range 9-65 days). In the eighteen patients supported solely with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho = -0.78, p = 0.001) and platelet engraftment (rho = -0.76, p = 0.002). Overall, 11% of evaluable patients (2/18) had a complete response to BTE. Median time to tumor progression (TTP) was 9 months, with an overall median survival of 17 months. BCNU (450 mg/m2), thiotepa (800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days is a tolerable combination HDC regimen, the efficacy of which warrants further investigation in adults with optimally resected chemoresponsive brain tumors.

Adult↗
PubMed1999

Pancytopenia in Zimbabwe.

BACKGROUND: There has been little systematic study of the clinical spectrum of pancytopenia, and the optimal diagnostic approach to pancytopenia remains undefined. METHODS: The authors studied 134 hospitalized pancytopenic patients in Zimbabwe in both consecutive and nonconsecutive fashion. RESULTS: The most common cause of pancytopenia was megaloblastic anemia, followed by aplastic anemia, acute leukemia, acquired immunodeficiency syndrome (AIDS), and hypersplenism. Severe pancytopenia was usually due to aplastic anemia. Patients with aplastic anemia and acute leukemia were usually children, whereas those with megaloblastic anemia were adults. Moderate to severe anemia was noted throughout the series, but was most striking in patients with megaloblastic anemia, aplastic anemia, and acute leukemia. The mean corpuscular volume (MCV) was elevated in most patients with megaloblastic hematopoiesis, aplastic anemia, and acute nonlymphocytic leukemia. Normal or low MCV values were noted in almost one third of patients with megaloblastic anemia. Anisocytosis, poikilocytosis, macroovalocytosis, microcytosis, fragmentation, and teardrop erythrocytes were more prominent on the blood films of patients with megaloblastic anemia. CONCLUSIONS: Megaloblastic anemia, aplastic anemia, and AIDS are the most common causes of pancytopenia in Zimbabwe. Aplasia is the most frequent cause of severe pancytopenia. The authors have formulated tentative guidelines for the evaluation of pancytopenic patients in this setting.

Acquired Immunodeficiency Syndrome↗
PubMed1998

High-dose thiotepa and etoposide-based regimens with autologous hematopoietic support for high-risk or recurrent CNS tumors in children and adults.

The prognosis in patients with primary brain tumors treated with surgery, radiotherapy and conventional chemotherapy remains poor. To improve outcome, combination high-dose chemotherapy (HDC) has been explored in children, but rarely in adults. This study was performed to determine the tolerability of three-drug combination high-dose thiotepa (T) and etoposide (E)-based regimens in pediatric and adult patients with high-risk or recurrent primary brain tumors. Thirty-one patients (13 children and 18 adults) with brain tumors were treated with high-dose chemotherapy: 19 with BCNU (B) and TE (BTE regimen), and 12 with carboplatin (C) and TE (CTE regimen). Patients received growth factors and hematopoietic support with marrow (n = 15), peripheral blood progenitor cells (PBPC) (n = 11) or both (n = 5). The 100 day toxic mortality rate was 3% (1/31). Grade III/IV toxicities included mucositis (58%), hepatitis (39%) and diarrhea (42%). Five patients had seizures and two had transient encephalopathy (23%). All patients had neutropenic fever and all pediatric patients required hyperalimentation. Median time to engraftment with absolute neutrophil count (ANC) >0.5 x 10(9)/l was 11 days (range 8-37 days). Time to ANC engraftment was significantly longer (P = 0.0001) in patients receiving marrow (median 14 days, range 10-37) than for PBPC (median 9.5 days, range 8-10). Platelet engraftment >50 x 10(9)/l was 24 days (range 14-53 days) in children. In adults, platelet engraftment >20 x 10(9)/l was 12 days (range 9-65 days). In 11 patients supported with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho = -0.87, P = 0.009) and platelet engraftment (rho = -0.85, P = 0.005), with CD34+ dose predicting time to engraftment following HDC. Overall, 30% of evaluable patients (7/24) had a complete response (CR) (n = 3) or partial response (PR) (n = 4). Median time to tumor progression (TTP) was 7 months, with an overall median survival of 12 months. These TE-based BCNU or carboplatin three-drug combination HDC regimens are safe and tolerable with promising response rates in both children and older adults.

Adolescent↗
PubMed1997

Paranasal sinusitis following allogeneic bone marrow transplant.

In attempt to identify major clinical features of paranasal sinusitis following allogeneic BMT, we reviewed 44 consecutive cases diagnosed at the Hammersmith Hospital between August 1993 and December 1995. All patients had symptoms and signs characteristic of sinusitis. Plain radiographs and/or CT scans revealed fluid levels in 86.4% of patients, opacification in 9.1%, and marked mucosal thickening in 4.5%. Two-thirds of patients were diagnosed within 120 days of BMT. The WBC was less than 1 x 10(9)/1 in 16.3% of patients, the neutrophil count was less than 0.5 x 10(9)/1 in 18.6%, and serum immunoglobulins were depressed (< 6.7 g/l) in 40.6%. Grade III-IV acute GVHD was present in 25.6% of patients and grade I-II in 66.7%; 68.6% developed chronic GVHD. There were 70.5% of patients receiving corticosteroids. Specific pathogens could not be identified in most cases. Pneumonia was present in 10 patients, seven of whom had Aspergillus species identified by bronchoalveolar lavage. Parainfluenza virus was isolated in three patients and Pseudomonas aeruginosa in two. Although all patients received antimicrobial therapy, 70.5% developed chronic sinusitis. Fatal complications did not occur. In 94 consecutive patients receiving allografts for CML during the period of study, WBC and neutrophil counts were lower 3 months post-BMT in patients who developed sinusitis (P < 0.02). Patients receiving higher doses of total body irradiation (13.2 and 14.4 Gy) had a greater probability of developing sinusitis (P = 0.023). Sinusitis occurred in only one of 37 patients receiving autologous transplants in the same period. Sinusitis is common following allogeneic BMT. Leukopenia is often present, but microbiological diagnosis is difficult, and progression to chronic sinusitis common.

Adolescent↗
PubMed1997

Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for defining chronic phase on probabilities of survival and relapse.

We studied actuarial survival and relapse in 251 patients with chronic myeloid leukaemia (CML) treated by bone marrow transplantation (BMT) from HLA-identical sibling donors at a single institution. According to the institutional criteria used to define disease phase at the time of BMT. the 5-year probabilities of survival were 58.1% (95% confidence interval 50-66%) for 205 chronic-phase patients and 21.5% (95%CI 12-37%) for 46 advanced-phase patients (P<0.00001); the corresponding values for relapse were 34.8% (95%CI 27-44%) versus 72.7% (95%CI 46-89%). When disease phase was defined strictly according to the criteria of the International Bone Marrow Transplant Registry, the survival for 154 chronic-phase patients increased to 60.1% (95%CI 51-69%) and that for 97 advanced-phase patients increased to 37.6% (95%CI 28-48%). There was a parallel change in probabilities of relapse in the two patient groups (33.9% [95%CI 25-44%] and 51.3% [95%CI 37-66%], respectively). We also observed that patients transplanted in advanced phase had a higher incidence of grades III-IV acute graft-versus-host disease (P=0.001) and transplant-related mortality (P=0.02) than those undergoing BMT for chronic-phase disease. We recommend that transplant centres reporting results of BMT should always specify the precise criteria used for defining disease phase in order to ensure that results between different centres are strictly comparable.

Adolescent↗
PubMed1997

Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period.

To determine major presenting features of chronic myeloid leukaemia (CML) in current practice, we have reviewed the records of 430 patients with CML referred to the Hammersmith Hospital for allogeneic bone marrow transplantation since 1981. Approximately 20% of cases were diagnosed incidentally. Symptoms such as fatigue and weight loss were associated with greater degrees of leucocytosis and splenomegaly and lower haemoglobin levels. Most bleeding patients had normal or elevated platelet counts, suggesting that platelet dysfunction was the primary cause of haemorrhage. Although thrombocytosis was common, thrombosis was not seen. Male patients and the relatively young presented with higher WBC counts and larger spleens. The reason that these groups were diagnosed with more advanced leukaemia is not clear. Although retrospective and limited to a select group of relatively young patients, this is the largest series to be reported on CML at diagnosis, and the first such report in modern clinical practice.

Adolescent↗
PubMed1997

Allografting for chronic myeloid leukemia.

Allogeneic stem cell transplantation is the only curative therapy for chronic myeloid leukemia. There have been several recent advances in this field. Early data suggest that blood-derived stem cells are an effective substitute for bone marrow. Allografting can be performed using progenitor cells from other family members, unrelated donors, and umbilical cord blood. Evidence of early relapse can be detected by assays for the fusion gene, BCR-ABL, using the polymerase chain reaction. Most patients who relapse following allogeneic stem cell transplantation can be treated effectively by transfusion of lymphocytes from their original donors.

Blood Donors↗
PubMed1996

Intermediate-dose busulphan before autografting for advanced-phase chronic myeloid leukaemia.

Between June 1994 and October 1995 we performed 11 autografts in nine patients with advanced-phase chronic myeloid leukaemia (CML) using an attenuated cytoreductive regimen consisting of busulphan 8 mg/kg given in divided doses over 4 d. Five patients were restored to chronic phase. Four patients survived > 50 weeks and one remains well at 79 weeks. Toxicity was generally mild. Four procedures were managed entirely in the out-patient clinic. Therefore autografting after this 'intermediate' dose busulphan provides good palliation for patients with advanced CML with relatively little toxicity. Attenuated autografting should offer major advantages in terms of quality of life and cost for patients with advanced-phase CML.

Adult↗
PubMed1996

Assessment of brain changes with registered MR before and after bone marrow transplantation for chronic myeloid leukemia.

PURPOSE: To determine the frequency and nature of changes to the brain resulting from chemotherapy, radiation therapy, and bone marrow transplantation for chronic myeloid leukemia and to compare the sensitivity of conventional and registered MR scans for detecting these changes. METHODS: In 15 patients, conventional T1-weighted, T2-weighted, and fluid-attenuated inversion recovery MR sequences, as well as T1-weighted radio frequency spoiled 3-D volume MR scans were performed before, 4 to 6 days after, and up to 339 days after transplantation (13 allografts, two autografts). A subvoxel registration program was used to match the volume images precisely so that small changes could be detected after subtraction of scans. Five healthy adult control subjects were also studied on two occasions 1 month apart. RESULTS: Studies performed 4 to 339 days after transplantation showed ventricular enlargement and cortical atrophy in all 13 patients who had allografts. The changes were evident at 4 to 6 days after transplantation and became more obvious during later follow-up examinations. Similar changes were seen in one patient with an autograft but no significant change was seen in the other patient with an autograft or in the five control subjects. Accurately registered volume scans were more sensitive than unregistered conventional scans in detecting early (9/10 versus 0/10), intermediate (12/13 versus 3/12), and late (10/10 versus 4/9) ventricular enlargement on follow-up examinations. The same applied to cortical atrophy (9/10 versus 0/10, 12/13 versus 0/12, and 10/10 versus 0/9). CONCLUSION: The specific cause and clinical significance of these changes are uncertain. Subvoxel registration of serial MR images may reveal changes that are poorly seen or not apparent on conventional scans.

Adolescent↗
PubMed1995

Neurological complications of acquired cobalamin deficiency: clinical aspects.

Neuropsychiatric syndromes occur in about 40% of Cbl-deficient patients and are characterized by progressive and variable damage to the spinal cord, peripheral nerves and cerebrum. The first abnormality is usually sensory impairment, most often presenting as distal and symmetrical paraesthesiae of the lower limbs and frequently associated with ataxia. Almost all patients demonstrate loss of vibratory sensation, often in association with diminished proprioception and cutaneous sensation and a Romberg sign. Corticospinal tract involvement is common in more advanced cases, with abnormal reflexes, motor impairment and, ultimately, spastic paraparesis. A minority of patients exhibit mental or psychiatric disturbances or autonomic signs, but these rarely if ever occur in the absence of other neurological changes. Because N2O inactivates Cbl, abuse of the gas may lead to typical Cbl neuropathy. Haematological changes are minimal and serum Cbl levels and Schilling tests normal in most patients. The severity of neurological abnormalities prior to treatment correlates with the duration of symptoms and the haemoglobin level. Initial severity, symptom duration and initial haemoglobin also correlate with residual neurological damage after Cbl therapy. The inverse correlation between severity of anaemia and neurological damage is not understood. Diagnosis of Cbl neuropathy can usually be made in the presence of the typical neuropsychiatric abnormalities, a low serum Cbl level and evidence of megaloblastic haemopoiesis. In some patients serum MMA and HCYS determinations or a therapeutic trial may be required. A neurological response usually occurs within the first 3 months, although further improvement may occur with time. Patients with advanced disease may be left with major residual disability. Therefore early diagnosis is critical. Pharmacological doses of folic acid reverse the haematological abnormalities of Cbl deficiency. This may allow neuropathy to develop or progress and make recognition of deficiency more difficult. There is no clear evidence that folic acid therapy precipitates or exacerbates Cbl neuropathy. Haematological improvement may occur in a fraction of patients receiving small doses of folate, but the data are inadequate to predict the danger of low levels of folate supplementation in the general population.

Humans↗