Bleeding emergencies in neonatal and paediatric patients: improving the quality of care using simulation.

OBJECTIVES: Using a multidisciplinary approach and simulation, a massive transfusion process (MTP) was developed to care for patients in need of emergency transfusion. It was then assessed for effectiveness. BACKGROUND: After a series of sentinel emergency bleeding events, a reliable process for hospital staff to deliver appropriate blood products and obtain relevant laboratory tests to guide therapy for patients with emergency bleeding was needed. METHODS: To determine the feasibility of the new MTP, multidisciplinary teams participated in simulation events. Each simulation event helped refine the MTP. A special laboratory testing panel was devised. To judge the effectiveness and timeliness of the MTP, process measures and patient survival was retrospectively evaluated during the time period before and after MTP implementation. RESULTS: A new emergency bleeding panel of laboratory tests significantly decreased the turn-around time for fibrinogen, haematocrit, International normalised ratio (INR) and platelet count. The speed of commencing the first red blood cells transfusion was also improved (2:00 h vs 0:20 min, P = 0·001). Of 78 patients, there was no change in survival before (n = 31, 48·4%) and after (n = 47, 42·6%; P = 0·6478) MTP implementation. However, there was significant improvement in survival associated with MTP events on the weekdays. CONCLUSIONS: A reliable emergency transfusion process consists of an automatic chain of events that keeps decision-making to a minimum and leads to the fast procurement of blood products and salient test results. This work shows that a multidisciplinary iterative process using simulation increases the efficiency of clinical care delivery for bleeding paediatric and neonatal patients.

Pattern of Opioid Analgesic Prescription for Adults by Dentists in Nova Scotia, Canada.

Global consumption of prescription opioid analgesics has increased dramatically in the past 2 decades, outpacing that of illicit drugs in some countries. The increase has been partly ascribed to the widespread availability of prescription opioid analgesics and their subsequent nonmedical use, which may have contributed to the epidemic of opioid abuse, addiction, and overdose-related deaths. International studies report that dentists may be among the leading prescribers of opioid analgesics, thus adding to the societal impact of this epidemic. Between 2009 and 2011, dentists in the United States prescribed 8% to 12% of opioid analgesics dispensed. There is little information on the pattern of opioid analgesic prescription by dentists in Canada. The aim of this study was to examine the pattern of opioid analgesics prescription by dentists in Nova Scotia (NS), Canada. This retrospective observational study used the provincial prescription monitoring program's record of oral opioid analgesics and combinations dispensed to persons 16 y and older at community pharmacies that were prescribed by dentists from January 2011 to December 2015. During the study period, more than 70% of licensed dentists in NS wrote a prescription for dispensed opioid analgesics, comprising about 17% of all opioid analgesic prescribers. However, dentists were responsible for less than 4% of all prescriptions for dispensed opioid analgesics, prescribing less than 0.5% of the total morphine milligram equivalent (MMEq) of opioid analgesics dispensed over the 5 y. There was a significant downward trend in total MMEq of dispensed opioid analgesics prescribed by dentists from about 2.23 million MMEq in 2011 to 1.93 million MMEq in 2015 (r = -0.97; P = 0.006). Opioid prescription is common among dentists, but their contribution to the overall availability of opioid analgesics is low. Furthermore, there has been a downward trend in total dispensed MMEq of opioid analgesics prescribed by dentists. Knowledge Transfer Statement: This study will serve to inform dentists and policy makers on the types and dosage of opioid analgesics being prescribed by dentists. The study may prompt dentists to reflect on and adjust their practice of opioid analgesic prescription in view of the current opioid analgesic epidemic.

Factors Influencing Adoption of New Technologies into Dental Practice: A Qualitative Study.

The objective of this study was to explore factors affecting decisions to adopt new technologies into dental practice using a colorimetric rinse test for detection of periodontal disease as a model. Focus groups with key informants in Canadian dentistry and dental hygiene were conducted. A deductive approach used Rogers's diffusion of innovation theory as a framework for organizing codes and subcodes. Two members of the research team independently reviewed and analyzed the data using NVivo 10. The attributes of the technology itself emerged as primary influencers. Perceived relative advantages of the diagnostic mouth rinse over existing methods were potential time efficiency, low implementation cost, and utility of the tool. Low complexity, compatibility with existing routines/beliefs, and the potential for reinvention-the use of a technology for other than its intended purpose (i.e., patient education, monitoring of disease, screening tool in nondental settings)-were other important features enhancing adoption. An overarching concern was that any new technology benefit the patient. Contextual factors also play a role. Numerous communication channels, including opinion leaders, patients, marketing, continuing education courses, and strength of evidence, influenced clinicians, with peer interaction being a stronger influence than marketing. Similar themes arose from specialist, general dentist, and dental hygienist focus groups. Adopter characteristics also came into play: participants ranged in their self-reported innovativeness with many considering themselves "early adopters" of new technology. Findings of this study suggest that the innovation adoption process is not straightforward, but attributes of the innovation, contextual factors, and adopter characteristics play important roles in the process. Knowledge Transfer Statement: Various factors affect the adoption of new tools into clinical dental practice. These include attributes of the test or tool itself, the context of the settings in which the tool is introduced to practitioners, and the characteristics of the clinicians themselves. A qualitative study of dentists and dental hygienists investigated these factors. Situations in which dentists and hygienists interact with their peers and colleagues-through social networks, continuing education courses, conventions, or personal contact-were a major driver in the decision to adopt new technologies. However, even among "early adopters," most were reluctant to use new tests or tools unless they perceived a benefit to their patients or practice.

Using interviews to construct and disseminate knowledge of oral health policy.

OBJECTIVES: Policymakers worldwide are challenged by the problem of oral health inequities. The goal of an interprovincial partnership in Canada was to guide policy aimed at improving the oral health of vulnerable populations. Insights regarding barriers and enablers to developing such policy in one province (Newfoundland & Labrador, Canada) were required to enhance collaboration between decision makers and researchers and to contribute to the evidence informing policy development. METHODS: Snowball technique identified fourteen key informants. Semistructured audio-recorded interviews were conducted in person or by telephone. Two researchers independently conducted the analyses of the transcribed interviews, one using NVivo software and the second, manual coding. Triangulation of the analyses confirmed the findings. RESULTS: Agreement between the two approaches showed that most key informants believed that oral health is an important policy issue; however, most felt it was not a high priority among the general public and most were unable to articulate the policy process. Barriers to oral health becoming a governmental priority were related to resource allocation and to poor communication among some groups including dentists and dental hygienists. Current government programmes and initiatives were praised but considered weak in health promotion strategies. Recommendations for enhancing oral health priority varied. CONCLUSIONS: Attention to the methodological considerations of qualitative research enhanced the credibility of the method and confidence in the findings. Leveraging of existing programmes and improving communication were recommended to contribute to raising the priority of oral health within the government, thereby increasing their commitment to address oral health care, particularly for vulnerable populations.

Designing a framework of intelligent information processing for dentistry administration data.

OBJECTIVES: This study was designed to test a cumulative view of current data in the clinical database at the Faculty of Dentistry, Dalhousie University. We planned to examine associations among demographic factors and treatments. METHODS: Three tables were selected from the database of the faculty: patient, treatment and procedures. All fields and record numbers in each table were documented. Data was explored using SQL server and Visual Basic and then cleaned by removing incongruent fields. After transformation, a data warehouse was created. This was imported to SQL analysis services manager to create an OLAP (Online Analytic Process) cube. RESULTS: The multidimensional model used for access to data was created using a star schema. Treatment count was the measurement variable. Five dimensions--date, postal code, gender, age group and treatment categories--were used to detect associations. Another data warehouse of 8 tables (international tooth code # 1-8) was created and imported to SAS enterprise miner to complete data mining. Association nodes were used for each table to find sequential associations and minimum criteria were set to 2% of cases. Findings of this study confirmed most assumptions of treatment planning procedures. There were some small unexpected patterns of clinical interest. Further developments are recommended to create predictive models. CONCLUSIONS: Recent improvements in information technology offer numerous advantages for conversion of raw data from faculty databases to information and subsequently to knowledge. This knowledge can be used by decision makers, managers, and researchers to answer clinical questions, affect policy change and determine future research needs.

Prevention of immunization to D+ red blood cells with red blood cell exchange and intravenous Rh immune globulin.

BACKGROUND: Although young women who are D- occasionally receive unintentional transfusions with D+ red blood cells (RBCs), there are little data to assist with management of such an event. Two cases of D- girls transfused with D+ RBCs are reported. In an effort to prevent formation of anti-D, RBC exchange followed by administration of intravenous (IV) Rh immune globulin (RhIg) was used. CASE REPORTS: Patient 1, a 56-kg, 16-year-old D- girl, was involved in a motor vehicle crash. She received 4 units of Group O uncrossmatched D+ RBCs. Thirty-six hours after admission, she underwent RBC exchange with 10 units of D- RBCs, followed by a total of 2718 microg of IV RhIg over 32 hours. Six months later, her antibody screen was negative. Patient 2, a 39-kg, 10-year-old D- girl with aplastic anemia, received 1 unit of D+ RBCs. She underwent RBC exchange on the same day with 5 units of D- RBCs, followed by a total of 900 microg of IV RhIg over 8 hours. Six months later her antibody screen was negative. CONCLUSION: RBC exchange followed by a calculated dose of IV RhIg was successful in preventing allo-immunization to D. Several small studies suggest that both trauma and hematology patients may be less capable of becoming immunized with the transfusion of D+ blood components. Until these findings are more clearly defined, there will be times when prevention of immunization of any D- girl is desired. RBC exchange followed by RhIg appears to be one way to achieve this goal.

Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia.

Allogeneic bone marrow transplantation (BMT) may offer the only chance of cure for children with acute myeloid leukemia (AML) in second complete remission (CR2) or with relapsed disease, but the outcome of these patients has not been clearly defined. We conducted a retrospective study of 58 children, median age 7.4 years (range 0.8-17.3), who received matched related or unrelated BMT at our institution for AML in CR2 (n = 12), in untreated first relapse (n = 11) or with refractory disease (n = 35), to identify risk factors associated with disease-free survival (DFS). Life threatening to fatal regimen-related toxicity was observed in 22% of patients. Estimates of DFS at 5 years (95% confidence interval) for patients in CR2, with untreated first relapse and refractory disease were 58% (27-80%), 36% (11-63%) and 9% (2-21%), respectively. Non-relapse mortality estimates were 0%, 27% (0-54%) and 17% (5-30%), and relapse estimates were 42% (14-70%), 36% (8-65%) and 74% (60-89%), respectively. Advanced disease phase and cytogenetic abnormalities at the time of transplantation were each associated with decreased DFS and increased relapse in multivariable regression models. Survival for children transplanted in CR2 or untreated first relapse is higher than that previously reported, but relapse remains the major cause of treatment failure regardless of disease stage.

A placebo-controlled multi-centred evaluation of an anaesthetic gel (Oraqix) for periodontal therapy.

AIMS: Six Canadian dental schools investigated the ability of a thermosetting gel containing 25 mg/g prilocaine and 25 mg/g lidocaine as active agents to produce analgesia in periodontal pockets utilizing a randomized, double-blind, placebo-controlled study. MATERIALS AND METHODS: The study consisted of 130 patients, each of whom received the active or placebo gel in periodontal pockets in one quadrant of the mouth for 30 s prior to periodontal debridement (scaling and root planing). Pain was measured using both a 100-mm Visual Analogue Scale (VAS) and a Verbal Rating Scale (VRS). RESULTS: The median VAS pain score for the patients treated with the anaesthetic gel was 5 mm (range 0-85 mm) as opposed to 13 mm (range 0-79 mm) in the placebo-treated patients (P=0.015). There was no significant difference in the percentage of patients reporting no or mild pain (78% and 76% for the anaesthetic gel and placebo, respectively). No significant differences were seen in patient demographics, or mandible versus maxilla. CONCLUSIONS: The VAS pain scores showed that the anaesthetic gel 5% was statistically more effective than the placebo in reducing pain during periodontal debridement.

The use of radioimmunoconjugates in stem cell transplantation.

Radiolabeled monoclonal antibodies have been used with encouraging results in conjunction with stem cell transplantation for patients with hematologic malignancies targeting a variety of surface antigens including CD33, CD45 and CD66 for leukemias, CD20 and CD22 for non-Hodgkin's lymphomas, and ferritin for Hodgkin's disease. The results obtained targeting epithelial antigens on solid tumors, however, have generally been less encouraging, primarily due to the relative insensitivity of these malignancies to ionizing radiation. In this report we review clinical studies that have incorporated myeloablative doses of targeted radiation using radiolabeled antibodies in conjunction with stem cell transplant regimens.

Clinical practice guidelines in dentistry: Part II. By dentists, for dentists.

There is a growing interest in clinical practice guidelines (CPGs) for all health care providers. As discussed in the first paper of this 2-part series, there are many misperceptions about guidelines and their potential risks and benefits. The dental profession in Canada, cognizant of both the importance and the challenges of developing sound, credible and relevant guidelines for dentists, has created a unique, autonomous collaboration of multiple stakeholders, the Canadian Collaboration on CPGs in Dentistry (CCCD). This paper discusses the history, structure and processes of the CCCD and introduces the first guideline under development by and for Canadian dentists.

Clinical practice guidelines in dentistry: Part I. Navigating new waters.

Clinical Practice Guidelines (CPGs) are tools, developed by and for practitioners, to assist in clinical decision making. They are designed to enhance, not replace, clinical judgement and expertise. Well-developed guidelines use the evidence-based approach. The research evidence related to a topic is assembled in a systematic, comprehensive and unbiased manner. Recommendations are made based on the evidence and practitioner feedback is sought prior to formulating the final practice guideline. There are many misperceptions about CPGs and some dentists are wary about their development and use. In this paper, we explore some of the reasons for these misperceptions, review the benefits of sound guidelines, and discuss some of the challenges for guideline development in dentistry in Canada

Immunosuppressive effects of (131)I-anti-CD45 antibody in unsensitized and donor antigen-presensitized H2-matched, minor antigen-mismatched murine transplant models.

Iodine-131-labeled anti-CD45 antibody has been added to conventional hematopoietic stem cell transplant preparative regimens to deliver targeted radiation to hematopoietic tissues, with the goal of decreasing relapse rates without increasing toxicity. However, higher radiation doses could be delivered to leukemia cells by antibody if the systemic therapy were decreased or eliminated. To examine the ability of (131)I-anti-CD45 antibody to provide sufficient immunosuppression for transplantation across allogeneic barriers, T-cell-depleted BALB.B marrow was transplanted into H2-compatible B6-Ly5(a) mice after (131)I-30F11 (rat antimurine CD45) antibody with or without varying dose levels of total body irradiation (TBI). Groups of five or six recipient mice per (131)I or TBI dose level per experiment were given tail vein injections of 100 microg of (131)I-labeled 30F11 antibody 4 days before marrow infusion, with or without TBI on day 0. Engraftment, defined as > or =50% donor B cells at 3 months posttransplant, was determined by two-color flow cytometric analysis of peripheral blood granulocytes, T cells, and B cells using antibodies specific for donor and host CD45 allotypes and for CD3. Donor engraftment of > or =80% recipient mice was achieved with either 8 Gy of TBI or 0.75 mCi of (131)I-30F11 antibody, which delivers an estimated 26 Gy to bone marrow. Subsequent experiments determined the dose of TBI alone or TBI plus 0.75 mCi of (131)I-30F11 antibody necessary for engraftment in recipient mice that had been presensitized to donor antigens before transplant, a setting requiring more stringent immunosuppression. Engraftment was seen in > or =80% of presensitized recipients surviving after 14-16 Gy of TBI or 12-14 Gy of TBI and 0.75 mCi of (131)I-30F11 antibody. However, only 28 of 69 (41%) presensitized mice receiving 10-16 Gy of TBI alone survived, presumably because of rejection of donor marrow and ablation of host hematopoiesis. In contrast, 29 of 35 (83%) presensitized mice receiving (131)I-30F11 antibody and 10-14 Gy of TBI survived, presumably because the additional immunosuppression provided by estimated radiation doses of 53 Gy to lymph nodes and 81 Gy to spleen from 0.75 mCi of (131)I-30F11 antibody permitted engraftment of donor marrow. These results suggest that targeted radiation delivered by (131)I-anti-CD45 antibody provides sufficient immunosuppression to replace an appreciable portion of the TBI dose used in matched sibling hematopoietic stem cell transplant.

Tooth loss in periodontal patients.

OBJECTIVE: To compare tooth loss between patients who received surgical therapy for chronic periodontitis and those who received nonsurgical therapy alone. METHODS: A retrospective chart study was conducted at Dalhousie University. All patients who had periodontal treatment and were active cases for at least 10 years were included (n = 335). The sample consisted of 120 males (35.8%) and 215 females (64.2%). Ages ranged from 16 to 77 (mean = 46.1 +/- 12.0 years). All patients received nonsurgical therapy; 44.8% received periodontal surgery as well. Variables recorded were demographics, initial attachment loss, treatment type, recall frequency, patient compliance and history of extracted teeth. Independent t-tests or chi-squared tests were used to compare these for surgical and nonsurgical patients. ANOVA was used to test for interactions between initial attachment loss, age, gender, compliance and type of therapy a patient received as reasons for tooth loss. RESULTS: 521 teeth were lost in 69 patients (20.6% of sample). Of teeth lost, 61.8% were due to periodontal disease; 24.8% to caries; 13.2% to other reasons. Patients initially diagnosed with early attachment loss lost an average of 0.37 (+/- 1.33) teeth. Patients diagnosed with moderate attachment loss lost an average of 1.50 (+/- 2.54) teeth and those diagnosed with advanced attachment loss lost an average of 3.11 (+/- 3.01) teeth. Those who received surgical therapy lost more teeth (mean = 1.31 +/- 2.36) than those who received nonsurgical treatment (mean = 0.68 +/- 1.87; p = 0.001). However, initial attachment loss was the only factor that could predict tooth loss. The type of therapy (surgical or nonsurgical) was not statistically significant. CONCLUSIONS: Most periodontal patients (79.4%) who received treatment at this dental school clinic did not lose any teeth due to periodontal disease over at least 10 years. Although patients who had surgical therapy lost more teeth than those who had nonsurgical therapy alone, this was not an important predictor of tooth loss.

Factors affecting patients' and potential patients' choices among anaesthetics for periodontal recall visits.

OBJECTIVES: Dentinal hypersensitivity and recurrent disease may necessitate the use of anaesthetic during periodontal recall visits. However, an aversion to injections may affect patient compliance. The objectives of this study were to determine choices patients and 'potential' patients make when provided with information on the risks and benefits of alternative anaesthetic choices for root planing during periodontal recalls and to examine which factors influence these choices. METHODS: Using an interactive computer tool, scenarios described the risks and benefits of root planing during periodontal maintenance and the anaesthetic alternatives (no anaesthetic, an experimental thermosetting gel anaesthetic and traditional local infiltration anaesthesia). Compliant patients for whom anaesthesia was recommended during recall cleanings were recruited from private periodontal practices (n=97). General population subjects (potential patients) were recruited by random digit dialing (n=196) RESULTS: As dental insurance was one of the inclusion criteria, the sample was representative of a working population. Most subjects reported tooth sensitivity (recall 84.5%, general 59.9%). The majority of patients wanted some form of anaesthetic, either gel (recall 82.5%, general 81.0%) or local infiltration (recall 10.3%, general 16.4%). Fifty-five percent of subjects reported moderate or severe pain from their previous dental injection(s). Asked if they were to have a dental needle tomorrow, 52.5% would be somewhat or very anxious. Of those who chose gel, 63.47% would be more or much more willing to return for recall visits if the gel were available. Using multivariate logistic regression, concern about pain and anxiety associated with needles were the only statistically significant characteristics associated with anaesthetic preference. CONCLUSIONS: Concern about pain and anxiety associated with needles dominates preferences for dental anaesthesia. The overwhelming preference for a non-injectable anaesthetic reveals a strong clinical need for such alternatives.

Periodontal medicine: a new paradigm.

Recent evidence indicates that we need to change how we think about the etiology and pathogenesis of periodontal disease. Although bacteria are a necessary factor in the equation, the reaction of the host's immuno-inflammatory system is responsible for most of the destruction found in periodontal disease. Thus, it makes sense that a number of environmental and acquired factors may modify a patient's risk of developing periodontal disease. This paper reviews the scientific evidence for a number of these risk factors including age, genetics, smoking, diabetes mellitus, stress and osteoporosis.

Current uses of monoclonal antibodies in the treatment of acute leukemia.

Advances in the treatment of acute leukemia have been limited by both disease resistance and toxicity. Monoclonal antibodies have been used as a means of targeting therapy to malignant cells in the form of antibody-mediated cellular toxicity, radiation, or other cytotoxic agents. Anti-CD33 and anti-CD45 antibodies have been most extensively studied. Antibodies conjugated with either radioisotopes or cytotoxic moieties have been used as part of stem cell transplant regimens or as induction therapy in patients with relapsed acute myelogenous leukemia (AML), and have demonstrated antileukemic activity with acceptable toxicities.

A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.

Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 ((131)I)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg (131)I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of (131)I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of (131)I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.

The clinical impact of increased sensitivity PT and APTT coagulation assays.

To determine how more-sensitive prothrombin time (PT) and activated partial thromboplastin time (aPTT) reagents affected the number and distribution of abnormal test results and whether the increased sensitivity for deficiencies resulted in improved diagnosis of clinically significant coagulopathies, we retrospectively compared preoperative coagulation screening data for 140 children undergoing open heart surgery after the reagent change with a similar group of 135 before the change. The more sensitive reagents resulted in a higher rate of abnormal values, but no increase in the identification of clinically significant hemostatic abnormalities. Of 67 patients with abnormal aPTTs in the group screened with more sensitive reagents, 63 had no further workup. No patients in either group were diagnosed subsequently with a coagulopathy because of unexpected bleeding. An abnormal test result did not predict the need for perioperative blood products. We hypothesize that the high frequency of abnormal aPTTs led to physician "desensitization" about the merit of coagulation screening. Therefore, we question the usefulness of preoperative coagulation screening of the pediatric cardiac surgery patient, particularly since lasting changes in physician perception regarding the clinical significance of abnormal values may lead to missed diagnoses in other settings.

Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome.

Delivery of targeted hematopoietic irradiation using radiolabeled monoclonal antibody may improve the outcome of marrow transplantation for advanced acute leukemia by decreasing relapse without increasing toxicity. We conducted a phase I study that examined the biodistribution of (131)I-labeled anti-CD45 antibody and determined the toxicity of escalating doses of targeted radiation combined with 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI) followed by HLA-matched related allogeneic or autologous transplant. Forty-four patients with advanced acute leukemia or myelodysplasia received a biodistribution dose of 0.5 mg/kg (131)I-BC8 (murine anti-CD45) antibody. The mean +/- SEM estimated radiation absorbed dose (centigray per millicurie of (131)I) delivered to bone marrow and spleen was 6.5 +/- 0.5 and 13.5 +/- 1.3, respectively, with liver, lung, kidney, and total body receiving lower amounts of 2.8 +/- 0.2, 1.8 +/- 0.1, 0.6 +/- 0.04, and 0.4 +/- 0.02, respectively. Thirty-seven patients (84%) had favorable biodistribution of antibody, with a higher estimated radiation absorbed dose to marrow and spleen than to normal organs. Thirty-four patients received a therapeutic dose of (131)I-antibody labeled with 76 to 612 mCi (131)I to deliver estimated radiation absorbed doses to liver (normal organ receiving the highest dose) of 3.5 Gy (level 1) to 12.25 Gy (level 6) in addition to CY and TBI. The maximum tolerated dose was level 5 (delivering 10.5 Gy to liver), with grade III/IV mucositis in 2 of 2 patients treated at level 6. Of 25 treated patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), 7 survive disease-free 15 to 89 months (median, 65 months) posttransplant. Of 9 treated patients with acute lymphoblastic leukemia (ALL), 3 survive disease-free 19, 54, and 66 months posttransplant. We conclude that (131)I-anti-CD45 antibody can safely deliver substantial supplemental doses of radiation to bone marrow (approximately 24 Gy) and spleen (approximately 50 Gy) when combined with conventional CY/TBI.

Marrow ablative and immunosuppressive effects of 131I-anti-CD45 antibody in congenic and H2-mismatched murine transplant models.

Targeted hematopoietic irradiation delivered by 131I-anti-CD45 antibody has been combined with conventional marrow transplant preparative regimens in an effort to decrease relapse. Before increasing the proportion of therapy delivered by radiolabeled antibody, the myeloablative and immunosuppressive effects of such low dose rate irradiation must be quantitated. We have examined the ability of 131I-anti-CD45 antibody to facilitate engraftment in Ly5-congenic and H2-mismatched murine marrow transplant models. Recipient B6-Ly5(a) mice were treated with 30F11 antibody labeled with 0.1 to 1.5 mCi 131I and/or total body irradiation (TBI), followed by T-cell-depleted marrow from Ly5(b)-congenic (C57BL/6) or H2-mismatched (BALB/c) donors. Engraftment was achieved readily in the Ly5-congenic setting, with greater than 80% donor granulocytes and T cells after 0.5 mCi 131I (estimated 17 Gy to marrow) or 8 Gy TBI. A higher TBI dose (14 Gy) was required to achieve engraftment of H2-mismatched marrow, and engraftment occurred in only 3 of 11 mice receiving 1.5 mCi 131I delivered by anti-CD45 antibody. Engraftment of H2-mismatched marrow was achieved in 22 of 23 animals receiving 0.75 mCi 131I delivered by anti-CD45 antibody combined with 8 Gy TBI. Thus, targeted radiation delivered via 131I-anti-CD45 antibody can enable engraftment of congenic marrow and can partially replace TBI when transplanting T-cell-depleted H2-mismatched marrow.