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Biomedical subjects

D C Matthews

Publications and source records attributed to D C Matthews.

At least 37 records · Page 2Linked to original sources
PubMed1998

Immunotherapy in acute myelogenous leukemia and myelodysplastic syndrome.

Disease recurrence following successful bone marrow transplantation remains a major impediment in the management of patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A variety of monoclonal antibodies that deliver drugs or toxins to the site of activity, have been used in an attempt to augment marrow transplantation. Examples of three different monoclonal antibody techniques (naked antibody, drug antibody conjugations, and radiolabeled antibodies) are discussed. CD33 is an attractive antigen to use as a target for treating AML because it is present on most AML cells. Naked antibodies are limited in their ability to kill tumor cells, although studies to date suggest there may be a role in antileukemic therapy for unlabeled anti-CD33 humanized M195 antibody after the tumor burden has been reduced by chemotherapy. Calicheamicin, a novel and toxic drug moiety conjugated to anti-CD33 antibody, is currently under investigation in patients with refractory or relapsed AML. Results from a Phase I investigation were encouraging. Three different radiolabeled monoclonal antibodies have been evaluated in Phase I/II studies--131I-labeled anti-CD33 (p67) antibody, 213Bi-labeled humanized M195 antibody, and 131I-anti-CD45 antibody. CD45 is a cell-surface antigen broadly expressed by all circulating leukocytes and lymphocytes. Initial studies demonstrated that substantially greater doses of radiation could be delivered to targeted organs compared with nontargeted organs using 131I-anti-CD45 antibody. This approach offers the potential for augmenting leukemia therapy without increased risk of toxicity.

Antibodies, Monoclonal↗
PubMed1997

Tobacco smoking and periodontal diseases.

There is a growing body of scientific evidence indicating that nicotine contributes to the progression of periodontal disease, and is detrimental to healing following periodontal therapy. Smokers show a higher prevalence and greater severity of periodontal disease than non-smokers. Nicotine has toxic effects on peripheral, circulation, which cause gingival vasoconstriction. As a result, a decreased number of immune cells are available in the gingival tissue, which translates into a weakened defence-reparative system. Nicotine can also depress primary and secondary immune response by reducing the chemotactic and phagocytic activities of leukocytes. Clinically, smoking has been associated with increased pocket depths, calculus deposition,alveolar bone loss, acute necrotizing ulcerative gingivitis, and osteoporosis in postmenopausal women. Despite efforts by various investigators, the precise mechanisms underlying the effects of smoking on periodontal status and wound healing remain unresolved. This paper reviews the relationship between smoking and periodontal disease. It also includes a historical overview of the research, and a review of the effects of smoking on oral bacteria, the immune system and exocrine glands. In addition, risk assessment for periodontal disease, clinical features of smokers' periodontitis, response of smokers' periodontal disease to treatment, and ideas for future research are discussed.

Age Factors↗
PubMed1996

Bone marrow transplantation for sickle cell disease.

BACKGROUND: We investigated the risks and benefits of allogeneic bone marrow transplantation in children with complications of sickle cell disease. METHODS: Twenty-two children less than 16 years of age who had symptomatic sickle cell disease received marrow allografts from HLA-identical siblings between September 1991 and April 1995. The indications for transplantation included a history of stroke (n = 12), recurrent acute chest syndrome (n = 5), and recurrent painful crises (n = 5). Patients were prepared for transplantation with busulfan, cyclophosphamide, and antithymocyte globulin. RESULTS: Twenty of the 22 patients survived, with a median follow-up of 23.9 months (range, 10.1 to 51.0), and 16 patients had stable engraftment of donor hematopoietic cells. In three patients the graft was rejected and sickle cell disease recurred; in a fourth patient graft rejection was accompanied by marrow aplasia. In 1 of the 16 patients with engraftment, there was stable mixed chimerism. Two patients died of central nervous system hemorrhage or graft-versus-host disease. Kaplan-Meier estimates of survival and event-free survival at four years were 91 percent and 73 percent, respectively. Among patients with a history of acute chest syndrome, lung function stabilized; among patients with prior central nervous system vasculopathy who had engraftment, stabilization of cerebrovascular disease was documented by magnetic resonance imaging. CONCLUSIONS: Allogeneic stem-cell transplantation can be curative in young patients with symptomatic sickle cell disease.

Adolescent↗
PubMed1996

Allogeneic marrow transplantation for refractory anemia: a comparison of two preparative regimens and analysis of prognostic factors.

From 1990 to 1993 we performed a prospective study of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in 30 patients with refractory anemia (RA) undergoing related (n = 17) or unrelated (n = 13) donor marrow transplantation. Nineteen patients survive disease free (63% 3-year actuarial disease-free survival [DFS]) and no patient relapsed. These results were compared to those of 38 historical controls with RA treated with cyclophosphamide and total body irradiation, of whom 22 are disease-free survivors and 1 relapsed. After correcting for significant variables between the two treatment groups, we found no statistically significant difference in outcome based on preparative regimen. Combining data from these 68 patients plus 2 additional patients with RA treated before 1993 with busulfan and cyclophosphamide, we identified four variables independently associated with improved survival: younger age, shorter disease duration, lower neutrophil count pretransplant, and lower hematocrit pretransplant. We also found that 15 patients 40 to 55 years of age had a 46% 3-year actuarial DFS and 26 patients receiving unrelated or mismatched related donor marrow had a 50% 3-year actuarial DFS. We conclude that there does not appear to be any significant difference in outcome based on preparative regimen in this patient population. In addition, allogeneic bone marrow transplantation may be a reasonable approach to therapy of RA early after diagnosis. However, whether early intervention with transplantation prolongs survival over that expected without transplantation cannot be ascertained with certainty from available data.

Actuarial Analysis↗
PubMed1996

The role of radioimmunotherapy in bone marrow transplantation.

Radioimmunotherapy offers an exciting new therapeutic modality for patients with recurrent hematologic malignancies and solid tumors resistant to conventional chemotherapy. In this review, a brief overview of tumor radiobiology as well as various obstacles to treatment is presented. Early radiolabeled antibody trials documented myelosuppression as the dose-limiting toxicity. Ongoing trials in solid tumors and hematologic malignancies are testing the hypothesis that myeloablative doses of radiation in conjunction with hematopoietic stem cell rescue will improve long-term survival. For solid tumors, there are many barriers to achieving this goal. The most encouraging trials in metastatic breast cancer have documented significant symptomatic relief and a 50% partial response in patients. In contrast, trials involving hematologic malignancies have produced more impressive results. With a median follow-up of 33 months, 67% of patients with recurrent acute myelogenous leukemia or myelodysplasia treated with radiolabeled antibodies, total-body irradiation, and high-dose chemotherapy remain disease free. Alone, myeloablative doses of radioimmunotherapy have documented a 41% complete response in patients with Hodgkin's disease. Seattle trials with recurrent non-Hodgkin's lymphoma have demonstrated objective responses in 90% of patients, complete responses in 85% of patients, a progression-free survival of 62%, and an overall survival of 93% with a median follow-up of 2 years.

Bone Marrow Transplantation↗
PubMed1996

Barriers to bone marrow transplantation for sickle cell anemia.

While allogeneic marrow transplantation is curative therapy for patients with sickle cell anemia, only a small fraction of patients in the United States receive this treatment. We surveyed participants in our multicenter study of marrow transplantation for sickle cell anemia to determine reasons for not proceeding to transplantation. Among the 4848 patients less than 16 years of age with sickle cell anemia that were followed in 22 collaborating centers, 315 (6.5%) patients were reported to meet protocol entry criteria for transplantation, although there was wide variation among the institutions (0.9-36%). Among the 315 patients eligible for transplantation, 128 (41%) had human leukocyte antigen (HLA) typing performed, and of these 44 (14% of those meeting entry criteria) had an HLA-identical sibling. Common reasons for not proceeding with HLA typing in the remaining 187 patients included lack of a candidate sibling donor (76 patients, 24% of those meeting criteria) and lack of financial or psychosocial support (33, 10.5%). Parental refusal (30, 9.5%), physician refusal (13, 4%), history of medical noncompliance (2, < 1%), and other reasons (33, 10.5%) were less frequently cited. To date, 25 patients have been transplanted. Of the remaining 19 patients with HLA-matched donors, seven did not proceed to transplantation because of parental refusal, while the others anticipate a future transplantation (6), have experienced symptomatic improvement (4), or have relocated abroad (2). We conclude that the major barrier to marrow transplantation for sickle cell anemia is lack of an HLA-identical donor. But since only 6.5% of all children with sickle cell disease were considered eligible for transplantation, it is possible that other significant obstacles remain to be identified. For patients reported to meet eligibility criteria, parental refusal and limited financial or psychosocial support were infrequent barriers to transplantation.

Anemia, Sickle Cell↗
PubMed1995

Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas.

25 patients with relapsed B-cell lymphomas were evaluated with trace labelled doses (2.5 mg/kg, 185-370 MBq [5-10 mCi]) of 131I-labelled anti-CD20 (B1) antibody in a phase II trial. 22 patients achieved 131I-B1 biodistributions delivering higher doses of radiation to tumour sites than to normal organs and 21 of these were treated with therapeutic infusions of 131I-B1 (12.765-29.045 GBq) followed by autologous haemopoietic stem cell reinfusion. 18 of the 21 treated patients had objective responses, including 16 complete remissions. One patient died of progressive lymphoma and one died of sepsis. Analysis of our phase I and II trials with 131I-labelled B1 reveal a progression-free survival of 62% and an overall survival of 93% with a median follow-up of 2 years. 131I-anti-CD20 (B1) antibody therapy produces complete responses of long duration in most patients with relapsed B-cell lymphomas when given at maximally tolerated doses with autologous stem cell rescue.

Adult↗
PubMed1995

Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation.

In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti-CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen-specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.

Adolescent↗
PubMed1995

The use of diagnostic tests to aid clinical diagnosis.

Clinical decision making in dentistry involves some uncertainty and error, but in the absence of good clinical research it is often more of an art than a science. This article demonstrates a way in which clinicians can consistently and effectively base the diagnostic process on scientific evidence. The authors examine the selection and utility of supplemental diagnostic tests, describe the properties of these tests, and explain how test results can be used to augment clinical opinion. To aid the dental clinician in the decision making process, a step-by-step strategy is presented for the detection of squamous cell carcinoma using toluidine blue dye.

Carcinoma, Squamous Cell↗
PubMed1994

Decision making in periodontics: a review of outcome measures.

Clinical decisions regarding selection of appropriate periodontal therapy is a multifactorial process involving the assimilation of information from clinical experiences, relevant research, and patient preferences for anticipated outcomes. In order to select the treatment which is most beneficial to patients, a rational, systematic approach to decision making is needed. Clinical experience is a key factor in decision making, but one not easily controlled for. Research to date has focused on clinical or proximate outcomes as a measurement of treatment efficacy, but few of these studies provide the highest level of evidence. While Quality of Life issues play an important role in treatment selection, patient-based outcomes have not been well researched in dentistry. This paper outlines a method clinicians can use to evaluate treatment efficacy studies. In addition, the evidence from longitudinal periodontal treatment efficacy studies is reviewed and the use of patient-based outcome measures is examined.

Clinical Trials as Topic↗
PubMed1993

Evaluating patient perceptions as short-term outcomes of periodontal treatment: a comparison of surgical and non-surgical therapy.

To quantify patient perceptions of periodontal therapy, we administered a self-report questionnaire employing a visual analog scale (VAS) to 162 patients following surgical and non-surgical treatments. The questionnaire tested for variables of pain, sensitivity, swelling, function, altered appearance, comparison of postoperative discomfort to restorative treatment (crown or filling), discomfort experienced during the procedure, and resultant disability days. Tests of reliability indicated that with the exception of thermal sensitivity, the variables were significantly reproducible (r > 0.45 for all tests, P < 0.002). Analyses of variance indicated that in contrast to non-surgical treatments, surgery produced significantly more postoperative "discomfort" (P < 0.05) for all variables except experience, sensitivity, altered speech, and comparison to crown preparation. When analyzed according to the type of procedure, soft tissue grafts and osseous surgery produced the most postoperative discomfort. Pearson correlation indicated statistically significant (P < .0001) relationships between pain-related measures (postoperative pain, number of postoperative analgesics, days of pain, days of work missed, and sensitivity). Duration of pain was also found to be related to a history of periodontal treatment (P < .02), but not to previous restorative treatment. These data indicate that patient perceptions of periodontal treatment can be reliably measured and may be used to address appropriateness of care issues.

Adolescent↗
PubMed1992

Selective radiation of hematolymphoid tissue delivered by anti-CD45 antibody.

The ability to deliver radiation selectively to lymphohematopoietic tissues may have utility in conditions treated by myeloablative regimens followed by bone marrow transplantation. Since the CD45 antigen is the most broadly expressed of hematopoietic antigens, we examined the biodistribution of radiolabeled anti-CD45 monoclonal antibodies in normal mice. Trace 125I or 131I-labeled monoclonal antibodies 30G12 (rat IgG2a), 30F11 (rat IgG2b), and F(ab')2 fragments of 30F11 were injected i.v. at doses of 5 to 1000 micrograms. For both intact antibodies, a higher percentage of injected dose/g (% ID/g tissue) in blood was achieved with higher antibody doses. However, as the dose of antibody was increased, the % ID/g in the target organs of spleen, marrow, and lymph nodes decreased. At doses between 5 and 10-micrograms, % ID/g in these tissues exceeded that in lung, the normal organ with the highest concentration of radiolabel. In contrast, thymus was the only hematopoietic organ in which the % ID/g increased with increasing antibody dose, although at high dose the % ID/g was still far below that achieved in the other hematopoietic organs. Antibody 30F11 F(ab')2 fragments were cleared more quickly than intact antibody from blood and from both target and nontarget organs, although the relationship between increasing antibody dose and decreasing % ID/g in spleen, marrow, and lymph nodes was observed. The time-activity curves for each dose of antibody were used to calculate estimates of radiation absorbed dose to each organ. At the 10-micrograms dose of 30G12, the spleen was estimated to receive a radiation dose that was 13 times more than lung, the lymph nodes 3 to 4 times more, and the bone marrow 3 times more than lung. For each antibody fragment dose, the radiation absorbed dose per MBq 131I administered was lower because the residence times of the fragments were shorter than those of the intact antibody. Thus these estimates suggested that the best "therapeutic ratio" of radiation delivered to target organ as compared to lung was achieved with lower doses of intact antibody. We have demonstrated that radiolabeled anti-CD45 monoclonal antibodies can deliver radiation to lymphohematopoietic tissues with relative selectivity and that the relative uptake and retention in different hematolymphoid tissues change with increasing antibody dose.

Animals↗
PubMed1992

Localization of radiolabeled antimyeloid antibodies in a human acute leukemia xenograft tumor model.

Acute myeloid leukemia is an attractive disease to treat with radiolabeled antibodies because it is radiosensitive and antibody has ready access to the marrow cavity. In order to evaluate potentially useful radiolabeled antibodies against human acute myeloid leukemia, we have developed a nude mouse xenograft model using the human acute leukemia cell line, HEL. Mice with s.c. xenografts of HEL cells received infusions of radioiodinated anti-CD33 antibody. Examination of the biodistribution of the antibody showed that uptake in the s.c. tumor was maximal [16.9% injected dose (ID)/g at 1 h after infusion] following infusion of 1-10 micrograms of antibody and decreased following infusion of 100 micrograms (6.5% ID/g at 1 h) presumably as a result of saturation of antigen sites. The radiolabel was poorly retained in tumor (4.5-8.2% ID/g at 24 h after infusion). These results were consistent with in vitro studies demonstrating rapid internalization and catabolism of the anti-CD33 antibody. Uptake in tumor could be improved by using either a radiolabel that is retained intracellularly, 111In-DTPA (18.5% ID/g at 24 h), or by targeting a surface antigen that does not internalize upon antibody binding, CD45 (20.5% ID/g at 24 h). These results indicate that this model system will be useful in evaluating the interaction of radiolabeled antibodies with human acute myeloid leukemia cells in an in vivo setting.

Acute Disease↗
PubMed1992

Monoclonal antibodies in the study and therapy of hematopoietic cancers.

Recent advances utilizing monoclonal antibodies to phenotype acute leukemias have revealed no prognostic significance of the expression of lymphoid-associated antigens by acute myeloid leukemia blasts and conflicting results regarding 'biphenotypic' acute myeloid leukemia. Several studies treating patients with refractory lymphoma with immunotoxins reported encouraging results but significant production of anti-mouse or anti-toxin antibody. Radiolabeled antibodies that react with panhematopoietic antigens have delivered selective radiation to marrow, spleen and lymph nodes in animal models and are being used in Phase I studies of marrow transplantation for acute leukemia.

Antibodies, Monoclonal↗
PubMed1992

The use of radiolabeled anti-CD33 antibody to augment marrow irradiation prior to marrow transplantation for acute myelogenous leukemia.

Disease recurrence remains a major limitation to the use of marrow transplantation to treat leukemia. Previous transplant studies have demonstrated that higher doses of total-body irradiation result in less disease recurrence, but more toxicity. In this study, the possibility of delivering radiotherapy specifically to marrow using a radiolabeled anti-CD33 antibody (p67) was explored. Biodistribution studies were performed in nine patients using .05-.5 mg/kg p67 trace-labeled with 131I. In most patients initial specific uptake of 131I-p67 in the marrow was seen, but the half-life of the radiolabel in the marrow space was relatively brief, ranging from 9-41 hr, presumably due to modulation of the 131I-p67-CD33 complex with subsequent digestion and release of 131I from the marrow space. In four of nine patients these biodistribution studies demonstrated that with 131I-p67 marrow and spleen would receive more radiation than any normal nonhematopoietic organ, and therefore these four patients were treated with 110-330 mCi 131I conjugated to p67 followed by a standard transplant regimen of cyclophosphamide plus 12 Gy TBI. All four patients tolerated the procedure well and three of the four are alive in remission 195-477 days posttransplant. This study demonstrates the feasibility of using a radiolabeled antimyeloid antibody as part of a marrow transplant preparative regimen and also highlights a major limitation of using conventionally labeled anti-CD33--namely, the short residence time in marrow. Strategies to overcome this limitation include the use of alternative labeling techniques or the selection of cell surface stable antigens as targets.

Adolescent↗