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Biomedical subjects

G L Phillips

Publications and source records attributed to G L Phillips.

At least 73 records · Page 4Linked to original sources
PubMed1993

Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3.

To determine the frequency and clinical significance of acquired abnormalities of chromosome 3 at q21 and q25-26 in haematological malignancy, we reviewed the haematological and cytogenetic features of 24 patients with a 3q rearrangement identified amongst 1200 cases with clonal cytogenetic abnormalities detected at our institutions during a 12-year period. Thirteen patients presented with de novo acute myeloid leukaemia (AML), 10 with myelodysplasia (MDS) and one in blast phase of chronic myelogenous leukaemia. Twenty patients (83%) had megakaryocytic dysplasia and 14 (58%) had normal or increased numbers of megakaryocytes, but only four patients (16%) had absolute thrombocytosis > 500 x 10(9)/l (three with AML, one with MDS transforming to AML). A review of 205 cases of AML investigated in our institutions between 1985 and 1990 for whom cytogenetic results were obtained revealed that a platelet count > 500 x 10(9)/l at presentation was highly suggestive of an underlying 3q abnormality. A limited review of the literature on this subject confirmed that 15-20% of patients with a 3q abnormality will have thrombocytosis. The response of these patients to conventional antileukaemic therapy is uniformly poor, despite haematological and clinical differences between the subtypes of 3q rearrangements.

Acute Disease↗
PubMed1993

Teicoplanin versus vancomycin in the empirical treatment of febrile neutropenic patients.

Gram-positive infections have become prevalent among neutropenic patients with cancer. A prospective, randomized, double-blind trial of teicoplanin, 6 mg/kg every 12 h for three doses then every 24 h, versus vancomycin hydrochloride, 15 mg/kg every 12 h, in the empirical treatment of febrile neutropenic patients was undertaken among 50 consecutive patients with haematological malignancy. The patients also received piperacillin sodium, 3 g every 4 h, and tobramycin sulphate, 1.5-2 mg/kg every 8 h. Both groups (25 teicoplanin and 25 vancomycin) were comparable in age, sex, renal function, underlying disease and concurrent therapy. Among 22 patients (44%) with culture-proven infection, Gram-positive organisms were isolated in 15 (9 with bacteraemia) and Gram-negative in 11 (4 with bacteraemia). Mixed or polymicrobial infection occurred in 8 patients. Serum 1-h peak and trough levels at steady state were 41 +/- 15 and 12 +/- 3 mg/l for teicoplanin (at 14 +/- 4 days), and 40 +/- 10 and 8 +/- 5 mg/l for vancomycin (at 0.9 +/- 0.6 days). Mean elimination half-life and apparent volume of distribution at steady state were 80.5 +/- 21.5 h and 1.4 +/- 0.8 l/kg for teicoplanin, and 5.6 +/- 1.8 h and 0.6 +/- 0.2 l/kg for vancomycin. Empirical antimicrobial therapy was successful in 23 teicoplanin and 21 vancomycin patients, respectively (p = 0.67; two-tailed Fisher's exact test). Nephrotoxicity (serum creatinine > 110 mmol/l), however, was more common among vancomycin patients (10 versus 2; p = 0.02), while termination of treatment due to adverse effects was also more common among vancomycin patients (10 versus 2; p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Chemotherapy with high-dose cytosine arabinoside and mitoxantrone for poor-prognosis myeloid leukemias.

Forty-seven patients with poor-prognosis myeloid leukemias received induction therapy with high-dose cytosine arabinoside (HDara-C), 1.5-3.0g/m2 for 8-10 doses, and mitoxantrone (DHAD), 12-15 mg/m2 for 3 doses. Complete remissions were achieved in 21 [45%, 95% confidence interval (CI) 30.2-59.9%] of the patients, including 11 of 14 with acute myelogenous leukemia (AML) in first relapse (79%, 95% CI 49.2-95.3%), 4 of 8 with refractory anemia with excess blasts in transformation (RAEBiT) (50%, 95% CI 15.4-84.6%), and 4 of 6 (67%, 95% CI 22.3-95.7%) previously untreated elderly AML patients. Patients with secondary AML and advanced chronic myelogenous leukemia had a very low response rate. The incidence of reversible toxicity was low and only 3 treatment-related deaths occurred. After reinduction, 8 of 9 AML patients < or = 60 years of age were ultimately able to undergo intensive therapy and either autologous 4-hydroperoxycyclophosphamide-purged bone marrow (7 patients) or peripheral blood stem cell (1 patient) transplantation with satisfactory hematological recovery. We conclude that HDara-C and DHAD is an effective antileukemic regimen in selected AML and RAEBiT patients, and that its use may allow subsequent successful autologous BMT in appropriate patients.

Adult↗
PubMed1993

Culture purging in leukemia: past, present, and future.

Over the past 5 years we have been evaluating the feasibility of using cultured marrow autografts to allow patients with chronic myeloid leukemia (CML) to receive intensive, potentially curative therapy. The rationale for this approach is based on two important findings. The first is that leukemic stem cells (operationally defined as Ph-positive long-term culture-initiating cells, or LTC-IC) are present in the marrow of many CML patients at relatively low levels by comparison to co-existing normal stem cells (i.e., Ph-negative LTC-IC). The second finding is that leukemic LTC-IC are selectively "purged" following their incubation in vitro for 10 days under LTC conditions. As a result, cultured CML marrow preparations show, on average, a 300-fold selection in favour of normal LTC-IC. However, there is considerable variation in the initial normal and leukemic LTC-IC content of marrow samples from different CML patients. Thus in only approximately one third of cases does the number of leukemic LTC-IC in the marrow decrease to undetectable levels within the first 10 days of culture with the number of co-existing normal LTC-IC remaining at or above 1/50th of the average value for normal marrow. We have now transplanted 22 such CML patients with 10 day cultured marrow autografts following their treatment with myeloablative therapy. Fifteen of these patients were in first chronic phase and 7 had more advanced disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Marrow↗
PubMed1993

Therapy-related acute myelogenous leukemia associated with 11q23 chromosomal abnormalities and topoisomerase II inhibitors: report of four additional cases and brief commentary.

We report 4 additional cases of therapy-related acute myelogenous leukemia (t-AML) with the translocation t(9;11)(p22q23). Chemotherapy for the primary malignancy (breast carcinoma in 2, non-Hodgkin's lymphoma in 2) included agents with topoisomerase II inhibitory activity (doxorubicin in 2; doxorubicin and etoposide in 1; doxorubicin, etoposide and mitoxantrone in 1) as well as alkylators. In agreement with previous reports, the leukemia was monoblastic (FAB M5 subtype) in all 4 patients, with only 1 having prior myelodysplasia, and the latency period from primary therapy was relatively short (24-48 months). All patients received potentially curative treatment for the leukemia which included allogeneic bone marrow transplantation in 3; however, all died (3 of t-AML and 1 of lymphoma). Therapy-related AML associated with exposure to agents with topoisomerase II inhibitory activity (epipodophyllotoxins and anthracyclines) is a distinct entity, the genetic basis and optimal treatment of which remain to be determined.

Adult↗
PubMed1993

Induction therapy for acute myelogenous leukemia in patients over 60 years with intermediate-dose cytosine arabinoside, mitoxantrone and etoposide.

Twenty-three patients greater than age 60 years with acute myelogenous leukemia (AML) received induction therapy with continuous infusion cytosine arabinoside (1.5 g/m2/day, day 1-3), mitoxantrone (10 mg/m2/day, day 1-3) and etoposide (800 mg/m2, day 4). Patients entering complete remission (CR) were eligible to receive an identical consolidation cycle. Eighteen of the 23 patients (78%; 95% confidence interval 56% to 93%) entered CR. Twelve of these received consolidation therapy and 4 of these remain in remission at 3 to 20 months. Hematologic toxicity of the regimen was acceptable; only 1 patient died following therapy (having attained a CR). Non-hematologic toxicity was mostly mild (grade 2 or less) with one episode of grade 3 cerebellar toxicity. While this regimen induces a high CR rate in patients > age 60 years, relapses remain common and overall survival is too early to assess.

Aged↗
PubMed1993

Combination of t(14;18) and a Burkitt's type translocation in B-cell malignancies.

The combination of chromosomal translocations associated with bcl-2 rearrangement [t(14;18)] and c-myc rearrangement [t(8;14), t(8;22), or t(2;8)] has infrequently been detected in lymphoproliferative disorders. We have recently identified four cases of a B-cell malignancy exhibiting this dual translocation. In addition to t(14;18), one case had t(8;14) and three had the t(8;22). One case presented as de novo acute lymphoblastic leukemia (ALL-L2), two as de novo high grade lymphomas and the fourth evolved to a "blastic" phase from a previously documented follicular lymphoma. Immunophenotyping and molecular analysis was performed on three of the cases: all were negative for terminal deoxynucleotidyl transferase (TdT) but were CD10 positive. Two of the three cases with t(8;22) were negative for surface immunoglobulin (SIg) and positive for HLA-DR. Rearrangement of the oncogene bcl-2 was identified in a single case by polymerase chain reaction (PCR) only. Similar to cases reported in the literature, all patients had a poor clinical outcome despite aggressive therapy. Dual translocation lymphoid malignancy has a relatively characteristic morphology and the diagnosis should be considered when there is a history of an antecedent low grade lymphoma or when there is discordance between the "blastic" morphology and the immunophenotype (TdT- and/or SIg+). Confirmation requires demonstration of the characteristic translocations. Recognition of this entity has significant clinical implications that may require consideration of alternate treatment strategies.

Adult↗
PubMed1993

The elusive peripheral blood hemopoietic stem cell.

Long-term culture initiating cells (LTC-IC) are primitive hemopoietic progenitors that give rise to clonogenic cells when provided with a supportive feeder layer of mesenchymal cells. These LTC-IC possess many of the characteristics expected of marrow-repopulating "stem cells" including high proliferative and multilineage-differentiative capacity and resistance to 4-hydroperoxy-cyclophosphamide (4-HC) killing. In addition, stem cells are known to persist and may proliferate in murine LTC, and human marrow grown in LTC has been successfully used as hemopoietic support for myeloablative therapy. LTC-IC, as well as clonogenic precursors, circulate in normal peripheral blood, and the concentration of both progenitor types can be increased by cytotoxic chemotherapy and/or growth factors. When mobilized peripheral blood cells are used as hemopoietic support for high-dose chemo/radiotherapy, engraftment has often been more rapid than that achieved with autologous marrow. Thus, primitive hemopoietic cells circulate in human blood, which can enable hemopoietic reconstitution following aggressive therapy for malignant disease.

Blood Transfusion, Autologous↗
PubMed1993

Allogeneic bone marrow transplantation for poor-prognosis non-Hodgkin's lymphoma.

Twenty-one patients with non-Hodgkin's lymphoma (NHL) felt to be incurable with conventional chemotherapy underwent high-dose chemo +/- radiotherapy and allogeneic sibling donor transplant. The median patient age was 27 years (range 6-47 years); 13 were male and 8 female. By the working formulation, 6 patients at diagnosis had low-grade NHL, 8 intermediate-grade, and 7 high-grade disease. Three patients were in first remission at transplant, 3 in an advanced remission, 5 had failed to respond to initial therapy while 4 had a partial response to initial therapy, and 6 were in relapse (first or beyond). Sixteen patients were conditioned with cyclophosphamide, etoposide and total body irradiation (TBI), 4 with cyclophosphamide and TBI, and one with a combination of busulfan, melphalan and cyclophosphamide. GVHD prophylaxis was variable. At last follow-up, 8 of 21 patients remain alive and progression-free at a median of 37.5 months (range 6-58 months); actuarial event-free survival is 38% (95% confidence interval 17-58%). Thirteen patients died at a median of 2 (range 0.5-8) months post-BMT, 5 from regimen-related toxicity, 3 from acute GVHD, 2 from infections related to chronic GVHD and 3 from disease progression. Factors which were adverse predictors of progression-free survival included low-grade disease, presence of B symptoms at BMT, Karnofsky performance status at BMT and female sex. We concur with previous workers in concluding that allogeneic BMT may offer effective therapy for selected patients with incurable NHL. Major issues to be considered include timing of BMT and disease status at BMT.

Adolescent↗
PubMed1993

Donor leucocyte infusions after chemotherapy for patients relapsing with acute leukaemia following allogeneic BMT.

Four patients with acute myeloid leukaemia relapsed within 6 months of allogeneic BMT. Three patients were treated with cytosine arabinoside and amsacrine while the fourth received no chemotherapy. All patients received infusions of leucocytes obtained by repeated leukapheresis from the original bone marrow donor. Three patients developed GVHD requiring immunosuppressive therapy. One of these achieved a complete remission which has been sustained for more than 1 year with 100% donor haematopoiesis. The other patients died with persistent leukaemia 45-134 days after the infusions of donor cells. We conclude that the addition of marrow donor leucocytes to salvage chemotherapy may produce durable remissions in patients with acute myeloid leukaemia relapsing after BMT and that this may be due to a graft-versus-leukaemia effect.

Adult↗
PubMed1993

Treatment of multiple myeloma with intensive chemotherapy followed by autologous BMT using marrow purged with 4-hydroperoxycyclophosphamide.

In August 1988 we began a program in which multiple myeloma patients achieving < or = 10% marrow plasma cells and > or = 50% reduction in paraprotein levels after the VAD (vincristine, doxorubicin, dexamethasone) regimen underwent bone marrow harvest, ex vivo marrow purging with 4-hydroperoxycyclophosphamide (4-HC) and marrow cryopreservation. Conditioning with a regimen of high-dose busulfan (total dose 16 mg/kg), cyclophosphamide (120 mg/kg) and melphalan (90 mg/m2) (BU + CY + MEL) followed by autologous BMT was then carried out. Seventeen of the 24 patients who received VAD (71%, 95% confidence interval [CI] 49 to 87%) were eligible for bone marrow harvest. One patient was not harvested because of non-medical reasons; two patients who underwent marrow harvest had gross plasmacytosis present in biopsies performed intraoperatively and did not undergo BMT. Fourteen patients (58%, 95% CI 37 to 78%) received BU + CY + MEL and 4-HC-purged autologous BMT. The median time to recovery of 0.5 x 10(9)/l neutrophils was 19 days (range 14 to 26) while the last platelet transfusion was given on a median of day 32 (range 10 to 46) post-BMT in the evaluable patients. The major non-hematologic toxicity was hepatic; two patients in complete remission died of hepatic veno-occlusive disease. Another patient succumbed to fungal infection despite neutrophil recovery. The remaining 11 patients achieved responses (complete in six and partial in five) associated with a normal performance status.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy.

About 30% of adults with acute lymphoblastic leukemia (ALL) and 20% to 40% of children and adults with acute myelogenous leukemia (AML) never achieve remission, even with intensive chemotherapy. Most die of resistant leukemia, often within 6 months or less. In this study of 126 patients with resistant ALL or AML, allogeneic bone marrow transplants from HLA-identical siblings produced remissions in 113 of 115 (98%) evaluable patients. The 3-year probability of leukemia-free survival was 21% (95% confidence interval, 15% to 29%). Leukemia-free survival was similar in ALL (23%, 12% to 40%) and AML (21%, 14% to 31%). Only 3 of 27 patients at risk relapsed more than 2 years posttransplant.

Adolescent↗
PubMed1992

The effects of cisplatin on murine metaphase II oocytes.

This study was undertaken to determine if cisplatin can induce aneuploidy in murine oocytes treated prior to ovulation. Control animals were injected with intraperitoneal (ip) saline and the treatment animals were divided into three different dose schedules for ip cisplatin. After ovulation induction, the oocytes were processed for cytogenetic analysis and the chromosomes were counted. There were significantly less oocytes ovulated in the treatment groups when compared to control animals. There was a significant increase in hypohaploid cells counted in the 7.5 mg/kg treatment group, but the percentages of hyperhaploid and polyploid cells were not increased in the treatment groups. The cytogenetic effects of cisplatin in vivo and in vitro are reviewed.

Aneuploidy↗
PubMed1992

Venoocclusive liver disease after bone marrow transplantation: findings at duplex sonography.

Ascites, thickening of the gallbladder wall, and reversal of portal flow are documented sonographic findings in venoocclusive disease of the liver. The frequency and specificity of these findings and their relationship to the severity of this disease have not been studied. In an attempt to clarify these issues, 65 patients who had bone marrow transplantations were prospectively studied with serial B-scans and duplex color Doppler sonography. For all patients, assessment included liver size and texture, thickening of the gallbladder wall (greater than 10 mm), and presence of ascites. Doppler flow velocity profiles were obtained from the portal vein, hepatic veins, and inferior vena cava. The hepatic artery resistive index (RI) was calculated. Twenty volunteers were also studied to establish normal flow values. Nineteen patients had documented venoocclusive disease, nine had hepatic graft-vs-host disease (GVHD) (five after proved venoocclusive disease), two had hepatitis, and 40 had no clinical or biochemical evidence of liver injury after bone marrow transplantation. Ascites (n = 16), thickening of the gallbladder wall (n = 8), hepatomegaly (n = 8), and altered liver texture (n = 3) were not distinguishing features of venoocclusive disease. Mean hepatic artery RI was as follows (ranges are in parentheses): control group, 0.69 (0.58-0.76); venoocclusive disease patients, 0.81 (0.75-0.87); GVHD patients, 0.69 (0.63-0.71); all other patients after bone marrow transplantation, 0.66 (0.61-0.71). The RI values in venoocclusive disease were significantly elevated, but an incremental rise in RI with increasing severity of the disease was not seen. Abnormalities in portal vein flow were seen in only two patients: in one with fatal venoocclusive disease, reversed portal flow developed, and in one with GVHD, portal vein thrombosis developed. Contrary to previous reports, no correlation between abnormalities in portal flow and venoocclusive disease was seen. Flow velocities in the hepatic veins and the inferior vena cava were not significantly different from values in the volunteer group. These results suggest that a significant elevation of the hepatic artery RI may be a sensitive index of liver damage related to venoocclusive disease after bone marrow transplantation and an important distinguishing sonographic feature.

Blood Flow Velocity↗
PubMed1992

The human hematopoietic stem cell in vitro and in vivo.

A quantitative assay for a primitive human hematopoietic cell has been developed. The cell identified has been assigned the operational designation of long-term culture (LTC)-initiating cell based on its ability when cultured on supportive fibroblast monolayers to give rise to daughter cell(s) detectable by standard in vitro colony assays. Three lines of evidence support the view that the LTC-initiating cell assay may allow the relatively specific enumeration of totipotent cells with in vivo reconstituting potential. These involve the demonstration: (1) that conditions in analogous murine long-term cultures stimulate the extensive amplification (self-renewal) of some totipotent long-term repopulating cells, (2) that most of the LTC-initiating cells in normal human bone marrow are phenotypically different from most of the colony-forming cells present in the same cell suspensions in their possession of a number of characteristics specifically associated with transplantable stem cells; and (3) that cultured marrow cells from patients with chronic myeloid leukemia which, after maintenance under LTC conditions for 10 days contain some normal LTC-initiating cells but no detectable leukemic LTC-initiating cells, can after autografting reconstitute the hematopoietic system with normal cells.

Animals↗