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Biomedical subjects

G L Phillips

Publications and source records attributed to G L Phillips.

At least 55 records · Page 3Linked to original sources
PubMed1995

Prophylaxis for acute graft-versus-host disease following unrelated donor bone marrow transplantation.

Despite the use of conventional chemoprophylaxis regimens, patients receiving unrelated-donor BMT are at high risk of developing severe acute GVHD. We evaluated a prophylactic regimen combining CsA, MTX and anti-CD5-ricin A chain immunotoxin (H65-RTA) in 31 patients; pentoxifylline was also given to reduce the anticipated nephrotoxicity of CsA. In most cases, planned doses of CsA, MTX and H65-RTA were given (i.e. to 77%, 77% and 93% of patients, respectively). Although fluid retention requiring diuretic therapy was frequent, only 1 patient had a > 10% unexplained increase in body weight during the first 21 days post-BMT. Also, while significant increase of the baseline serum creatinine was noted in 7 patients, none required dialysis. One patient suffered a reversible allergic reaction to the immunotoxin; no other side effects attributable to this regimen were observed. All but 2 patients engrafted (1 died of fungemia on d + 19 and the other had persistent leukemia) and no late graft failures were observed. Seventeen patients developed acute GVHD grade > or = II (probability, 58% [95% CI 41-76%]); 7 had grade > or = III (probability, 24% [95% CI 12-43%]). In the 27 patients who achieved stable engraftment and have survived beyond d + 100, the 3-year probability of developing chronic GVHD was 66% (95% CI 48-84%). As of the last follow-up prior to 01 May 1994, 13 patients are alive in CR and one in relapse; 9 of these patients are off all immunosuppressives and well. Four other patients relapsed and died, and 13 died of other transplant-related causes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Polyclonal Epstein-Barr virus-associated lymphoproliferative disorder following autografting for chronic myeloid leukemia.

Epstein-Barr-associated lymphoproliferative disorders have been described as complications of immunodeficiency states including allogeneic BMT. There is, however, only one report in the English language literature of such a disorder after autografting. We report a 56-year-old man undergoing autologous BMT for CML in whom a rapidly progressive lymphoproliferative disorder showing the histology of typical post-transplant lymphoproliferative disorder with latent EBV presence developed at approximately 30 days after BMT. Therapy with corticosteroids, acyclovir and alpha-interferon was instituted and led to prompt resolution of symptoms and signs. There was no evidence of lymphoproliferative disease at 7 months after BMT. It is concluded that EBV-associated lymphoproliferative disorders may be a complication, albeit a rare one, of intensive therapy with autologous stem cell support.

Bone Marrow Transplantation↗
PubMed1995

Recovery from rhabdomyolysis after allogeneic BMT: report of a case with speculation on causation.

A case of fulminant rhabdomyolysis occurring 4 months after allogeneic BMT for CML is reported. The patient developed rhabdomyolysis following the empiric institution of antibacterial and anti-tuberculous medication. His inpatient course was complicated by the development of acute anuric renal failure and a severe myopathy. With aggressive supportive care, both of these complications resolved, making this patient the only reported survivor of rhabdomyolysis occurring after BMT.

Bone Marrow Transplantation↗
PubMed1995

Treatment of myeloma using intensive therapy and allogeneic bone marrow transplantation.

Over a 5-year period we evaluated 65 myeloma patients aged < or = 55 years as potential candidates for intensive therapy and allogeneic BMT. Twenty six (40%) patients were transplanted; the median duration of disease was 4 months (range 2-58 months) and median number of prior regimens was 1 (range 1-5); all but five patients had chemosensitive disease. Conditioning regimens included combinations of BU+CY+MEL in 14 patients, BUCY2 in eight and CY+TBI in four. Donors were HLA-matched siblings in 19 cases, one antigen mismatched siblings in three and unrelated donors in four. All patients received CsA, plus either methylprednisolone (n = 5) or MTX with or without other agents (n = 19). Grade III or IV regimen-related toxicity (RRT) was relatively infrequent (3 patients) and was not seen in nine patients conditioned with BU (total dose 12 mg/kg) + MEL (100 mg/m2) + CY (90 mg/m2). Grade II-IV acute GVHD occurred in 20 patients, and was the cause of death in three. Chronic GVHD also caused three deaths. Thirteen of 21 evaluable patients (62%) achieved a CR and six achieved a PR. Actuarial progression-free survival (PFS) was 40% (95% confidence interval (CI) 19-61%) at a median follow-up of 14 months (range 3-56 months); the PFS was 52% (95% CI 24-74%) in chemoresponsive patients, compared with 0% in chemoresistant patients (P = 0.0066).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Allogeneic bone marrow transplantation for severe aplastic anemia: the Vancouver experience.

We report a retrospective analysis of the experience of a single centre in treating severe aplastic anemia (SAA) with allogeneic bone marrow transplant (BMT). Between 1982 and 1992, we transplanted 21 patients with SAA (14 males, 7 females); median age at BMT was 15 y (range 2-40 y); median time from diagnosis of SAA to BMT was 29 d (range 6 d-5.5 y). Thirteen patients had received multiple transfusions before BMT. Patients were conditioned with cyclophosphamide 50 mg/kg for 4 d, +/- total body irradiation 300-500 cGy as a single fraction; 1 patient received total nodal irradiation (750 cGy) plus antithymocyte globulin. Sixteen patients received bone marrow from human leucocyte antigen (HLA)-identical siblings, 3 from haplo-identical parents, and 2 from unrelated volunteer donors; graft-versus-host disease (GVHD) prophylaxis was variable. Three patients failed to fully engraft following BMT; 2 achieved successful engraftment following a second BMT. Six of 20 evaluable patients (30%) developed grade II-IV acute GVHD, of whom 3 died; 3 patients developed limited and 5 patients (31%) developed extensive chronic GVHD, of whom 1 died. Fourteen patients (67%) are alive and well following BMT with a median follow-up of 6 y (range 2.1-11 y). Survival was superior in patients receiving sibling-donor BMT (75%) compared with those receiving parent- or unrelated-donor BMT (40%). We conclude that allogeneic BMT remains an important mode of treatment for SAA, but long-term survival remains limited by graft failure and GVHD.

Adolescent↗
PubMed1994

Autografting with cultured marrow in chronic myeloid leukemia: results of a pilot study.

Incubation of chronic myeloid leukemia (CML) marrow for 10 days in vitro causes a marked and selective loss of very primitive Philadelphia chromosome (Ph)+ as compared with Ph- progenitors. We have autografted 22 patients with CML (16 in first chronic phase [group 1] and 6 with more advanced disease [group 2]) with marrow treated in this way to facilitate restoration of Ph- hematopoiesis after intensive therapy. Hematologic recovery to greater than 0.5 x 10(9)/L neutrophils occurred in 16 patients, and to greater than 20 x 10(9)/L platelets in 15 of 21 evaluable patients at a median of 29 and 48 days postautograft, respectively. Regenerating marrow cells were 100% Ph- in 13 patients and 75% to 94% Ph- in 3. Between 4 and 36 months (median 12) postautograft, Ph+ cells became detectable in all but 1 (who died in remission) of the 13 patients who achieved complete cytogenetic remission. Four of 7 evaluable patients treated with low-dose interferon alpha were returned to complete cytogenetic remission. Thirteen group 1 patients (81%) are alive 1.0 to 5.7 years (median 2.6) after autografting: 4 in complete cytogenetic remission, 2 in hematologic remission, 6 in chronic phase, and 1 in myeloid blast phase. Three group 2 patients (50%) are alive at 2.6, 3.8, and 4.3 years after autografting: 1 in partial cytogenetic remission, 1 in chronic phase, and 1 in accelerated phase. Thus, autografts of cultured marrow can result in prolonged restoration of Ph- hematopoiesis for some patients with CML.

Adult↗
PubMed1994

Kinetics of committed and primitive blood progenitor mobilization after chemotherapy and growth factor treatment and their use in autotransplants.

Peripheral blood cells (PBCs) collected by leukapheresis after progenitor mobilization with chemotherapy and growth factors have been used successfully to replace marrow autografts in protocols requiring stem-cell support. Moreover, such transplants are often associated with more rapid recovery of blood cell counts than is routinely achieved with bone marrow. While conditions that mobilize colony-forming cells (CFCs) into the circulation are becoming increasingly well characterized, little information is available as to how these or other mobilizing treatments may influence the release of more primitive cells into the peripheral blood. To quantitate the peripheral blood content of such cells, we used the long-term culture-initiating cell (LTC-IC) assay, which detects a cell type that is able to produce progeny CFCs after a minimum of 5 weeks in cultures containing marrow fibroblasts. In this report, we present the findings on 21 patients who were transplanted over a 7-year period at our institution with PBCs alone. PBCs were collected in steady-state (n = 6) or during the recovery phase after high-dose cyclophosphamide (Cy; n = 15, nine with and six without additional growth factor administration). PBCs collected from another 11 patients given granulocyte colony-stimulating factor (G-CSF) were transplanted together with autologous marrow. Time-course studies of nine patients after Cy +/- granulocyte-macrophage CSF (GM-CSF) showed that CD34+ cells, CFCs, and LTC-ICs fell from normal to undetectable levels after Cy, and increased at the time of white blood cell (WBC) recovery: LTC-ICs to a mean of sixfold and CFCs to a mean of 26-fold higher than normal. The mean number of CD34+ cells, CFCs, and LTC-ICs present in the PBC harvest was twofold to 10-fold higher after mobilization than in steady-state collections; however, more than 2-log interpatient variability was observed. After PBC transplantation, the median time to a WBC count more than 10(9)/L was 12 days; polymorphonuclear leukocyte (PMN) count more than 0.5 x 10(9)/L, 15 days; and platelet count more than 20 x 10(9)/L, 17 days, although patients who received fewer than 1.5 x 10(5) CFCs/kg had a more than 50% chance of delayed count recovery (> 28 days). Patients who received Cy + GM-CSF-stimulated PBCs had more rapid and consistent platelet recoveries as compared with other groups receiving Cy mobilized or steady-state PBCs alone, and a rapid WBC recovery after Cy predicted a rapid WBC recovery after transplantation.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Separation↗
PubMed1994

Malignant melanoma of the vulva treated by radical hemivulvectomy. A prospective study of the Gynecologic Oncology Group.

BACKGROUND: Beginning in 1983, the Gynecologic Oncology Group (GOG) conducted a prospective clinicopathologic study of primary malignant melanoma of the vulva. The objectives of this study were to determine the relationship of histopathologic parameters and microstaging to the International Federation of Gynaecology and Obstetrics (FIGO) staging and prognosis. METHODS: All patients with primary untreated malignant melanoma of the vulva and no history of previous or subsequent other primary invasive malignancy were eligible for study entry. All patients were required to have modified radical hemivulvectomy as minimal therapy. Groin dissection was optional. Histopathologic specimens were reviewed for capillary space involvement, Clark's level, Breslow's depth of invasion, cell type, and melanin distribution. Patient characteristics were analyzed in their relationship to groin node status and recurrence-free interval. RESULTS: Between 1983 and 1990, 81 patients were entered in the study. Of these, 71 were evaluable. Thirty-four patients underwent radical hemivulvectomy, and 37 patients underwent radical vulvectomy. In addition, 56 patients underwent groin node dissection. The factors that were independently correlated with groin node status were: capillary lymphatic space involvement (p = 0.0001) and central primary tumor location (i.e., bilateral/clitoral/T3) (P = 0.003). The other factors that were significant--clinical tumor size, vulvar staging (FIGO), GOG performance status, and Breslow's depth of invasion--were not independent predictors of positive nodes. The factor with the highest significant correlation with recurrence-free interval was the 1992 staging system of the American Joint Committee on Cancer (AJCC) for malignant melanoma of the skin. Using multiple regression, AJCC stage was the only independent prognostic factor. In the absence of AJCC stage, Breslow's depth of invasion was the most prognostic. CONCLUSION: The biologic behavior of vulvar melanoma is similar to other nongenital cutaneous malignant melanoma.

Adult↗
PubMed1994

Intensive therapy and autotransplantation in Hodgkin's disease.

Intensive therapy and autologous marrow or peripheral blood stem cell transplantation is often utilized in Hodgkin's disease patients whose disease has progressed after primary conventional chemotherapy. A number of studies have described long-term disease-free survival in up to 50% of transplanted patients. High-dose chemotherapy conditioning regimens such as "CBV" or "BEAM" have been used more often than regimens containing total body irradiation. Usually unpurged autologous bone marrow has been utilized as the source of hematopoietic stem cell reconstitution, although recently the use of "primed" peripheral blood stem cells has increased markedly. The challenges of transplant-related toxicity and recurrence of disease post-transplant are discussed, as well as possible strategies to reduce these problems. The use of autologous transplantation is discussed in three clinical settings: patients who have failed to enter a complete remission (CR) after primary chemotherapy, those who have relapsed within 12 months of attaining a CR and those who have relapsed after a longer (i.e., > or = 12 months) first CR. When compared with conventional salvage chemotherapy, transplantation appears to produce a higher long-term disease-free survival rate in all of these patient groups. However, assessment of an advantage for autotransplantation, particularly in patients with long first remissions, is difficult without a Phase III trial. On the other hand, recently updated results from our center indicate that 72% of patients relapsing after long initial remissions benefit from autotransplantation at this point in their disease course, and that transplant-related mortality is low in this setting. Other issues addressed include the potential role of autologous transplantation as consolidation therapy in selected high-risk patients in an initial CR, as well as the utility of conventional chemotherapy and involved-field radiotherapy in conjunction with autotransplantation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Preferential pericentric lesions and aneuploidy induced in mouse oocytes by the topoisomerase II inhibitor etoposide.

Etoposide (VP-16) is used as an antineoplastic drug in humans. It inhibits topoisomerase II(topoII) activity by forming a ternary complex (DNA-etoposide-topoII). This complex prevents the DNA-strand rejoining activity of topo II, which results in DNA-strand breaks and the formation of structural chromosome aberrations. Topo II activity is also required for removing regions of DNA catenation prior to chromosome segregation. The possibility exists that patients undergoing etoposide chemotherapy may incur genetic damage and, consequently, may be at a greater risk for developing secondary tumors and having genetically abnormal offspring. We studied the ability of etoposide for inducing both structural chromosome aberrations and aneuploidy in mouse oocytes. Different dosages of etoposide were given to female mice at various times before and after human chronic gonadotrophin injection, and ovulated oocytes were collected 17 h later. The proportions of chromatid acentric fragments and of hyperploid metaphase II oocytes were significantly higher (P < 0.01) in the etoposide groups than in concurrent controls. These results indicate that both structural and numerical aberrations can be induced without direct interaction with DNA or with the various organelles associated with chromosome segregation. Additionally, unlike other compounds (vinblastine, colchicine, benomyl, and griseofulvin) that induce both meiotic delay (ovulated metaphase I oocytes and polyploidy) and aneuploidy, etoposide did not cause meiotic delay in oocyte maturation.

Aneuploidy↗
PubMed1994

Establishment and characterization of a human leukemic cell line (SR-91) with features suggestive of early hematopoietic progenitor cell origin.

The characterization of a cell line (designated SR-91) from a patient with clinical and morphological diagnosis of acute lymphoblastic leukemia (CD3-, CD2+, CD7+, germline TCR genes) who relapsed early after allogeneic bone marrow transplantation, is reported. The line was established from blood cells obtained at diagnosis and placed in suspension culture with medium conditioned by 5637 cells. SR-91 cells are negative for lymphoid surface markers (CD3-, CD2-, CD7-) but positive for markers indicative of myeloid progenitor cells, such as CD33 and CD34. It is likely that the conditioned medium has induced myeloid differentiation from a lymphohematopoietic progenitor cell. After establishment, cells proliferated in response to GM-CSF stimulation but they are not factor-dependent and do not produce GM-CSF. No proliferative response to IL-1, IL-2, IL-3, IL-4, IL-6 or M-CSF was observed. Cells were completely resistant to anti-proliferative effects of tumor necrosis factor-alpha and interferon-alpha or -gamma, and showed no lysis after incubation with freshly isolated natural killer cells or IL-2-activated natural killer cells.

Adult↗
PubMed1994

Granulocyte-macrophage colony-stimulating factor after autologous marrow transplantation for Hodgkin's disease.

Recombinant yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to 10 patients after autologous bone marrow transplantation for Hodgkin's disease given as a 24-h continuous intravenous infusion from the day of marrow infusion until the patient had obtained an absolute neutrophil count of 1.5 x 10(9)/L for 2 consecutive days or until day 30, whichever occurred first. Results were compared with results from 18 historical control patients who did not receive GM-CSF but were otherwise treated in a similar fashion. The infusion of GM-CSF led to a significantly faster neutrophil and monocyte recovery compared to the patients in the historical control group. The median days to achieve an absolute neutrophil count for the GM-CSF group and the control group were 0.5 x 10(9)/L; 9.5 and 14 days; 1.0 x 10(9)/L: 10 and 18 days; 1.5 x 10(9)/L: 11 and 29 days. No significant difference was found with respect to platelet engraftment and red cell transfusion requirements. GM-CSF therapy was discontinued at a median of 12 days. Hospitalization was also shorter for the GM-CSF group (22.5 vs. 26.5 days) and no patient in the GM-CSF group had to be readmitted after initial discharge. The incidence of documented infections was similar among both patient groups and no difference was noted in terms of antimicrobial usage. Some side effects occurred with the continuous infusion of GM-CSF, particularly fluid retention, dyspnea, fever, diarrhea, and bone pain leading to early discontinuation of GM-CSF in 2 patients. The data suggest that a continuous 24-h infusion of GM-CSF significantly accelerates myeloid engraftment, leading to earlier discharge from the hospital.

Adolescent↗
PubMed1994

Transplantation of patients with high risk acute myeloid leukemia in first remission with autologous marrow cultured in interleukin-2 followed by interleukin-2 administration.

Relapse rates in patients after autologous bone marrow transplantation (BMT) for acute myeloid leukemia (AML) continue to be high despite the use of aggressive conditioning regimens. Based on studies in the murine system a clinical protocol was developed that utilizes immunotherapy to obtain a graft-versus-leukemia (GVL) effect both pre-BMT (to purge leukemic cells from the autograft) and post-BMT (to eradicate residual leukemia in the patient). As part of a phase I study, 10 consecutive patients (median age 41 years, range 15-60 years) with 'high risk' AML (i.e. any of the following: FAB M5, WBC of > or = 50 x 10(9)/l at diagnosis or 'unfavorable' cytogenetic abnormalities) were transplanted at a median of 32 days (range 13-128 days) after achieving first remission. Marrow cells to be autografted were first cultured for 8 days at 37 degrees C in standard long-term culture medium (containing 12.5% horse serum, 12.5% fetal calf serum and 10(-6) M hydrocortisone) to which 1000 U/ml of interleukin-2 (IL-2) was also added. During this time patients received busulfan 4 mg/kg for 4 days and cyclophosphamide 60 mg/kg for 2 days). On the day of transplantation (day 0), the cultured marrow cells were collected from the flasks and infused over 1 h. Between days 0 and 7 patients were given escalating doses of subcutaneous IL-2 (2, 4 and 6 x 10(5) U/m2/day, 3-4 patients/dose level). Side-effects attributable to IL-2 were generally mild, dose-dependent and consisted of fever and malaise.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Autografting in chronic myeloid leukemia with cultured marrow: update of the Vancouver Study.

When chronic myeloid leukemia (CML) marrow is set up in long-term culture (LTC), Philadelphia chromosome (Ph)-positive (Ph+) cells typically decline and Ph-negative (Ph-) hematopoietic cells often become detectable. In 1987, we initiated a study to evaluate the feasibility of using 10-day cultured marrow autografts to allow intensive treatment of CML. Patients were selected on the basis of a previous assessment of the frequencies of normal and leukemic LTC-initiating cells (LTC-IC) remaining in their marrow after 10 days of LTC. Of the 87 patients evaluated, 36 (41%) were considered eligible, and 22 (15 in first chronic phase [CP], Group 1; and 7 with more advanced disease, Group 2) were autografted with 10-day cultured marrow after intensive therapy. Satisfactory hematological recovery occurred in 16 patients, and of these, only Ph- cells were detected in 13 (nine in Group 1), with 76-94% Ph- cells in the other three (two in Group 1). Ph+ cells reappeared between 4 and 36 months post-autograft in all but one of the 13 patients in whom complete (morphological and cytogenetic) remission had been achieved; the remaining patient died in remission. Nine of these twelve patients were then treated with alpha-interferon (IFN-alpha) 1-3 x 10(6) units/m2, 3-7 days/week; four returned to complete remission, three developed increasing numbers of Ph+ cells, and two are still too early to evaluate. Fifteen patients (12 in Group 1) remain alive and well, nine in hematological remission (eight in Group 1), 9 to 64 months (median 28) post-autograft.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Gas-chromatographic analysis of busulfan for therapeutic drug monitoring.

The development and validation of a gas chromatographic assay method for determination of total and free busulfan concentrations in human plasma for pharmacokinetic studies is reported. 1,6-Bis(methanesulfonyloxy)hexane, the internal standard, and a potential metabolite, 3-hydroxysulfolane, were synthesized. Plasma and plasma ultrafiltrate samples containing busulfan and internal standard were extracted with ethyl acetate and derivatized with 2,3,5,6-tetrafluorothiophenol prior to gas chromatographic determination. The 63Ni electron-capture detector provided a limit of detection of 0.0600 microgram/ml with a limit of quantitation of 0.100 microgram/ml busulfan in biological samples. Calibration curves were linear from 0.100 to 3.00 micrograms/ml in plasma (500 microliters) and 0.100 to 2.00 micrograms/ml in plasma ultrafiltrate (100 microliters). Extraction and derivatization yields ranged from 78.4% to 89.6% and 56.0% to 71.3%, respectively. Specificity of this assay for busulfan in the presence of its potential metabolites was demonstrated. Also, plasma samples containing co-administered drugs gave no response under these conditions. Clinical samples obtained following administration of a 1 mg/kg oral busulfan dose demonstrate the applicability of this method to analysis of total and free plasma concentrations.

Busulfan↗
PubMed1993

High-dose chemotherapy and autologous bone marrow transplantation for patients with poor prognosis nonseminomatous germ cell tumours.

Twenty-one patients with poor prognosis nonseminomatous germ cell tumours (six with extreme burden disease at presentation in whom partial remission had been achieved with initial induction therapy, and 15 with recurrent disease after induction therapy) were treated with high-dose chemotherapy and autologous bone marrow transplantation (BMT). The first six received etoposide 3.0 g m-2, ifosfamide 6.0 g m-2 and carboplatin 1.2 g m-2 (Regimen 1), and the subsequent 15 received etoposide 2.4 g m2 (continuous infusion), cyclophosphamide 7.2 g m-2 and carboplatin 0.8 g m-2 (Regimen 2) followed by infusion of previously stored autologous marrow. Regimen 1 was associated with considerable renal toxicity and mucositis, whereas Regimen 2 was relatively well tolerated. Two patients died as a consequence of the treatment: one of candidemia and one of interstitial pulmonary fibrosis. Only one of 17 patients who were autografted in or approaching marker remission subsequently developed disease progression (event-free survival 82%, 95% confidence interval [CI] 55% to 94%), whereas all four patients who had progressive disease at autografting subsequently developed further disease progression and died. Fourteen patients remain well and free of disease 0.5 to 6.5 years (median 3.3) post-BMT (event-free survival 67%, 95% CI 43% to 83%). A strategy of prompt reinduction followed by high-dose chemotherapy and autologous BMT at the first sign of failure of standard therapy may allow cure to be a realistic expectation.

Adolescent↗
PubMed1993

High-dose therapy for lymphoma.

Use of modern chemoradiotherapy for Hodgkin's disease and non-Hodgkin's lymphoma has increased the number of patients with these malignancies who are cured. However, patients who fail to achieve or maintain a complete remission using these advanced therapies have a poor prognosis and are appropriate candidates for high-dose therapy that requires some type of hematopoietic stem cell support. The patterns of use of this therapy in such patients, the attempts to predict which patients will most benefit from high-dose therapy, and the various ancillary measures that can be taken to decrease the toxicity of high-dose therapy with stem cell rescue are the subject of this review.

Bone Marrow Purging↗