Multidimensional Evaluation of Screening Brief Intervention and Referral to Treatment Training for Medical Students.

OBJECTIVE: Screening, Brief Intervention, and Referral to Treatment (SBIRT) is an evidence-based approach to identifying and addressing alcohol use in non-specialty settings. Many medical schools teach SBIRT, but most published evaluations of these efforts exclude rigorous skill assessments and teaching methods. METHODS: During the 2017-2018 academic year, 146 third-year medical students received classroom-based learning on SBIRT and motivational interviewing (MI) and at least two SBIRT practices with feedback as part of a 4-week psychiatry clerkship. The objective of this curriculum was to improve SBIRT knowledge, attitudes, and confidence and enable learners to skillfully deliver SBIRT. Outcomes evaluated included satisfaction, knowledge, attitudes and confidence, and clinical skill in delivering SBIRT to a standardized patient (rated by the actor, as well as an expert). RESULTS: Results indicated acceptable satisfaction at post-curriculum and significant improvements in attitudes and knowledge from pre- to post-curriculum. On the clinical skills exam, all students were rated as having mastered at least 80% of SBIRT elements by standardized patients and 91.8% were rated at this level by a faculty expert. Student attitudes and knowledge were unrelated to expert ratings, and standardized patient ratings had limited associations with expert ratings. CONCLUSIONS: These results suggest curriculum objectives were achieved and provide unique contributions to the SBIRT curricular outcome research for healthcare trainees. Other findings included that trainee knowledge and confidence may not relate to skill, and standardized patient feedback provides different information on SBIRT and MI skill than expert ratings.

Do Ultraviolet Air Disinfection Units Reduce Contamination by Particulates in Total Knee Replacement Procedures?

BACKGROUND: Prosthetic joint infections have become the leading cause of joint replacement failure. The primary sources of contamination are skin flora and bacteria from airborne particles. Portable ultraviolet air disinfection units are used in the Operating Room (OR) to prevent contamination from airborne particles; however, their effectiveness is not proven. The purpose of this study was to compare the rate of contamination of sites with and without Ultraviolet (UV) air disinfection units during active surgeries. METHODS: Sedimentation rates of viable particles were measured during 40 primary TKA procedures. Half of the procedures were performed with ultraviolet air disinfection units. Air-borne particles were collected on nitrocellulose membranes at 5 locations within the OR. After incubation, all microbial colonies were counted and the sedimentation rates were reported in CFUs/m2/hr. 10 additional trials were performed in an empty OR with no staff present. RESULTS: The average contamination rate of all sites was 22 ± 1.1 CFUs/m2/hr in the empty OR vs. 21.3 ± 4.6 CFUs/m2/hr with UV units and 20.3 ± 4.9 CFUs/m2/hr without (P = .03, P = .03, P = .964). Viable contaminates were found in the sterile field in 25% of UV cases vs 45% non-UV. These differences were not statistically significant. There were differences found however, according to the number of staff in the room (6 vs 7 staff: P = .036, 6 vs 8 staff: P = .004). CONCLUSION: There was no statistical difference in contamination rate with the usage or non-usage of UV units. These 40 cases shows that the largest variables affecting the contamination rate were the number of staff present and size of the OR.

Challenges of Assessing Resident Competency in Well-Being: Development of the Psychiatry Milestones 2.0 Well-Being Subcompetency.

Burnout and depression are major problems facing physicians, with 300-400 physicians dying by suicide each year. In an effort to address this issue, the Accreditation Council for Graduate Medical Education (ACGME) revised the Common Program Requirements for residency and fellowship programs to include a strong emphasis on well-being, and this revision has been extended to including a subcompetency on well-being in the Milestones 2.0. The Psychiatry Milestones 2.0 Work Group was convened to draft updated psychiatry milestones. As part of the open feedback period, the American Association of Directors of Psychiatric Residency Training submitted an organizational letter outlining several points to consider regarding the original draft of the well-being subcompetency. The ACGME was receptive to this feedback and allowed the Psychiatry Milestones 2.0 Work Group to revise the subcompetency. Current research indicates that burnout is largely driven by systemic factors, but well-being literature and initiatives often focus on individual factors and responsibility for burnout rather than systemic change. Program directors tasked with assessing resident well-being can additionally encounter several professionalism concerns, including how to (1) define a subcompetency within a competency that itself has not been well defined; (2) decide the appropriate balance between individual and systemic responsibility for well-being; (3) consider mental health as a parameter of well-being; (4) balance roles as physicians, psychiatrists, and training directors in thinking about the mental health of residents without overstepping boundaries and while maintaining privacy, confidentiality, and resident safety; and (5) measure well-being in a sociocultural context. This article describes how these considerations were incorporated into the revision of the Psychiatry Milestones 2.0 version of the well-being subcompetency, which has subsequently been made available to other specialty work groups for potential use as they develop their specialty-specific Milestones 2.0.

Using e-cigarettes for smoking cessation: evaluation of a pilot project in the North West of England.

AIMS: E-cigarettes have been advocated as an effective smoking cessation intervention, with evidence indicating that they are substantially less harmful than conventional cigarettes. As a result, a pilot to encourage people to swap from conventional cigarettes to e-cigarettes was conducted in 2018 in a socially deprived area in the North West of England. This evaluation highlights the key findings from the pilot. METHODS: An analysis of secondary data at 4 weeks (n = 1022) was undertaken to predict those who used solely used e-cigarettes (i.e. had quit tobacco, as confirmed by a carbon monoxide test, CO < 10 ppm) from baseline characteristics, using chi-square tests and logistic regression. Baseline data were demographics, smoking levels and service provider type. RESULTS: Of the 1022 participants who engaged with the pilot 614 were still engaged at 4 weeks, of whom 62% had quit; quitting was more likely in younger participants (aged 18-24) and less likely in those who were sick and disabled. Of those who still smoked tobacco at week 4 (n = 226), smoking had reduced from a baseline of 19.1 cigarettes/day to 8.7. Overall, 37% (381) of those initially enrolled were confirmed to be using an e-cigarette on its own at follow-up. Successful quit was associated with occupation (unemployed, 33% vs intermediate, 47%, p = .023) and residing in the less deprived quintiles of deprivation (50% vs 34% in the most deprived quintile, p = .016). CONCLUSIONS: Making the conservative assumption that all those not in contact at 4 weeks were still smoking tobacco, for every five people entering the scheme, three people stayed on the programme and reduced their cigarette smoking and one person cut out tobacco altogether. E-cigarettes appear to be an effective nicotine replacement therapy; however, further research is required to determine whether e-cigarette users are more likely to reduce their overall nicotine consumption in the longer term.

Clinical relevance of the Humpty Dumpty Falls Scale in a pediatric specialty hospital.

The Joint Commission requires pediatric hospitals to implement fall prevention programs and evaluate the efficacy of such programs. The Humpty Dumpty Falls Scale (HDFS), a seven-item assessment scale used to document age, gender, diagnosis, cognitive impairments, environmental factors, response to surgery/sedation, and medication usage, is one of several instruments developed to assess fall risk in pediatric patients. To determine the specificity and sensitivity of the HDFS in predicting falls in children hospitalized for pediatric specialty care, a team at a pediatric specialty hospital conducted a nonexperimental retrospective study that used a matched case-control design and chart review analysis. The discoveries suggest that the HDFS lacks accuracy in pediatric specialty patients. Using the HDFS cut-off score of 12 and above to indicate a high risk for falls in these children yields a high false-positive rate. Investigators and staff at pediatric specialty hospitals need to continue their pursuit of valid instruments and tools that contribute to fall reduction.

Percutaneous autologous bone marrow injection in the treatment of distal meta-diaphyseal tibial nonunions and delayed unions.

OBJECTIVE: To report the outcomes of percutaneous autologous bone marrow injection for nonunion or delayed union of the distal tibial metaphysis in patients with prior plating. DESIGN: Consecutive case series. SETTING: Tertiary center. PATIENTS: Eleven consecutive patients (aged 24-51 years) were referred to us with a nonunion or delayed union of the distal tibial metaphysis after open reduction and internal fixation (plates and screws) at the time of fracture. The average time from initial injury to nonunion or delayed union and bone marrow treatment was 8 months (range, 3-20 months). INTERVENTION: A total of 40-80 mL of bone marrow aspirated from the posterior iliac crest and injected in and around the nonunion or delayed union site under fluoroscopic guidance. MEASUREMENTS: Healing at the injury site was evaluated using clinical and radiographic criteria, including computed tomography. Measures included American Academy of Orthopaedic Surgeons Lower Limb Core Scale (LLCS), Brief Pain Inventory, and Short Form 12 Physical Component Summary. RESULTS: Nine of the 11 patients attained bony union within 6 months of bone marrow injection. Six of these 9 patients who were followed-up an average of 4.4 years (range, 1.3-8.2 years) after the injection reported significant (P < 0.05) improvements in Lower Limb Core Scale (59.9-89.7), pain intensity (2.9-1.7), pain interference (4.6-2.3), and Short Form 12 Physical Component Summary (29.5-46.6) and 5.6 years improvement in quality-adjusted life years. CONCLUSIONS: Percutaneous autologous bone marrow injection is a minimally invasive, safe, and inexpensive treatment option for distal metaphyseal tibial nonunions or delayed unions after internal fixation and should be considered when the retained hardware seems to be intact and stable. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Marfan syndrome and vascular dissections during pregnancy.

Pregnancy in a patient with Marfan syndrome may pose significant maternal and fetal risks, and pregnancy outcome is most impacted by the extent of cardiovascular involvement present at conception. This review addresses principles to guide preconception counseling of a Marfan patient, in addition to antepartum and intrapartum management considerations. Multidisciplinary care is recommended during pregnancy, given the potential for multiorgan involvement and various complications which may occur. Mode of delivery planning is guided by the degree of aortic root dilatation. Dissection of a dilated aortic root can present a surgical emergency during pregnancy, and principles for cardiopulmonary bypass in a pregnant patient are reviewed.

The treatment of run-off from a fertiliser plant for nitrification, denitrification and phosphorus removal by use of constructed wetlands: a demonstration study.

The paper describes an evaluation carried out on demonstration scale to show that it was possible to use a Hybrid Reed Bed System comprising a Horizontal flow and a Vertical Flow Bed for treating the high strength run-off from a fertiliser packaging plant. The site is located close to an estuary which is sensitive to nutrients. The environmental regulators were therefore concerned that excessive mass flows of nitrate, ammoniacal nitrogen and phosphate, potentially arising from the site run-off, were not discharged into the estuary. The fertiliser manufacturing company required a simple, low maintenance system for removing nitrogen and phosphorus. A series of experimental runs were carried out to characterise the performance of the Hybrid System, establishing the effluent quality that could be achieved and the mass removal rate which was appropriate for acceptable treatment. These tests showed that it was possible to achieve a reduction of 79% in Total N whilst using molasses as a carbon source for denitrification. When using a 4:1 recycle ratio this produced an effluent with concentrations of 14 mg NH(4)-N/litre and 18 mg NO(3)-N/litre from treating site run-off containing concentrations in the order of 75 mg/litre of both NH(3)N and NO(3)-N. Chemical dosing with an iron salt brought the P concentration down to around 0.5 mg PO(4)-P/litre.

Immunization of Macaca fascicularis against experimental periodontitis using a vaccine containing cysteine proteases purified from Porphyromonas gingivalis.

INTRODUCTION: Periodontitis is a common infectious disease to which Porphyromonas gingivalis has been closely linked, in which the attachment tissues of the teeth and their alveolar bone housing are destroyed. We conducted a study to determine if immunization using a purified antigen could alter the onset and progression of the disease. METHODS: Using the ligature-induced model of periodontitis in Macaca fascicularis, we immunized five animals with cysteine protease purified from P. gingivalis and used an additional five animals as controls. Alveolar bone loss was measured by digital subtraction radiography. RESULTS: Immunization induced high titers of specific immunoglobuin G serum antibodies that were opsonic. Total bacterial load, levels of P. gingivalis in subgingival plaque and levels of prostaglandin E(2) in gingival crevicular fluid were significantly reduced. Onset and progression of alveolar bone loss was inhibited by approximately 50%. No manifestations of toxicity were observed. CONCLUSIONS: Immunization using a purified protein antigen from P. gingivalis inhibits alveolar bone destruction in a ligature-induced periodontitis model in M. fascicularis.

Avidity-mediated enhancement of in vivo tumor targeting by single-chain Fv dimers.

Radiolabeled single-chain Fv (sFv) molecules display highly specific tumor retention in the severe combined immunodeficient (SCID) mouse model; however, the absolute quantity of sFv retained in the tumors is diminished by the rapid renal elimination resulting from the small size of the sFv molecules (Mr 27,000) and by dissociation of the monovalent sFv from tumor-associated antigen. We previously reported significant improvement in tumor retention without a loss of targeting specificity on converting monovalent sFv into divalent [(sFv')2] dimers, linked by a disulfide bond between COOH-terminal cysteinyl peptides engineered into the sFv'. However, our data for enhanced dimer localization in tumors could not distinguish between the contributions of enhanced avidity and increased systemic retention associated with the larger size of 54 kDa [(sFv')2] dimers relative to 27-kDa sFv. In this investigation, we have compared tumor targeting of divalent anti-c-erbB-2/HER2/neu 741F8-1 (sFv')2 homodimers with monovalent 741F8/26-10 (sFv')2 heterodimers (Mr 54,000) and 741F8 sFv monomers (741F8 sFv has binding specificity for erbB-2/HER2/neu and 26-10 sFv specificity for digoxin and related cardiac glycosides). These studies allowed us to distinguish the dominant effect of valency over molecular weight in accounting for the superior tumor retention of 741F8-1 (sFv')2 homodimers. Each of the radioiodinated species was administered i.v. to SCID mice bearing SK-OV-3 human tumor xenografts and tumor localization at 24 hours post i.v. injection was determined for 125I-741F8-1 (sFv')2 (3.57 %ID/g), 125I-741F8/26-10 (sFv')2 (1.13 %ID/g), and 125I-741F8-1 sFv (1.25 %ID/g). These findings substantiate that the improved tumor retention of (sFv')2 homodimers over sFv monomers results from the availability of dual binding sites rather than from the slower systemic clearance of homodimers.

Functional characteristics of antibodies induced by Arg-gingipain (HRgpA) and Lys-gingipain (Kgp) from Porphyromonas gingivalis.

Arginine-specific gingipain (HRgpA) and lysine-specific gingipain (Kgp), enzymes produced by Porphyromonas gingivalis, may be candidates for an anti-P. gingivalis vaccine. The purpose of our study was to determine whether HRgpA and Kgp have opsonic target sites and whether these sites are available and accessible on intact P. gingivalis cells. Rabbits were used to generate polyclonal antibodies to both proteins. Animals were immunized and immunoglobulin G (IgG) fractions were isolated from preimmune and immune sera. Functional characteristics of the antibodies were assessed by determining antibody titers by enzyme-linked immunosorbent assay (ELISA), generating Western immunoblots, and measuring antibody enhancement of P. gingivalis opsonization, phagocytosis and killing by polymorphonuclear leukocytes (PMN) of intact cells of strains of P. gingivalis representative of the four serotypes. Strains studied included 33277 (serotype A), A7A1-28 (serotype B), W50 (serotype C) and 381 (serotype D). Both HRgpA and Kgp induced high titers of IgG antibody. Anti-HRgpA and anti-Kgp bound to both HRgpA and Kgp demonstrating a large proportion of shared antigenic epitopes. The two antibodies bound equally well to all four P. gingivalis serotypes with titers ranging from 77 to 205 ELISA units when compared to preimmune IgG set at 1 ELISA unit. The immunoblot patterns of binding of the two antibodies to HRgpA and Kgp and to sonicates of the four P. gingivalis serotypes were virtually identical. Both antibodies detected components in HRgpA at 27, 35 and 45 kDa and in Kgp at 27, 32, 35, 40 and 55 kDa. The antibodies also detected components at or near these same positions in addition to multiple high molecular mass components in the cell sonicates of P. gingivalis. Both proteins induced antibodies that significantly enhanced opsonization as assessed by chemiluminescence, with values ranging from 130 mV to 375 mV for anti-HRgpA IgG and from 240 mV to 475 mV for anti-Kgp IgG. Both antibodies significantly enhanced PMN-mediated bacterial killing of the four P. gingivalis serotypes, although the percentage of killing varied among the serotypes (24-81% for anti-HRgpA and 37-89% for anti-Kgp). Thus, both HRgpA and Kgp express opsonic target sites and induce high titers of antibodies that opsonize and enhance killing of all four serotypes of P. gingivalis. These two proteins appear to be potential candidate antigens for an anti-P. gingivalis vaccine.

Serum antibody titers to Bacteroides forsythus in elderly subjects with gingivitis or periodontitis.

BACKGROUND: The risks for periodontal disease appear to increase with age. STUDY PURPOSE: To determine associations between clinical findings, the presence of specific bacteria in periodontal pockets, and serum antibody titers. 10 older subjects (mean age=73.0 years SD+/-4.9) with confirmed gingivitis only (gingivitis group) and 10 subjects with periodontitis (mean age: 76.1 years, SD+/-10.4) (periodontitis group) were studied. RESULTS: The mean group differences for probing depth and clinical attachment levels were 4.1 mm and 5.6 mm, respectively, and were significantly different (p<0.001). Both groups had high plaque scores (>60% surfaces with plaque). DNA probes demonstrated that B. forsythus was present in 8/10 samples from the periodontitis group and in 7/10 samples from the gingivitis group. The B. forsythus isolates studied were found in four of the subjects with periodontitis and from 2 of the subjects with gingivitis. Serum antibody titers to 6 ribotypes of B. forsythus were studied. Western blots, gradient gels, and pulsed field gel electrophoresis concurrently demonstrated that the B. forsythus isolates were genotypically, and phenotypically unique for each subject. Antibody titers to two selected B. forsythus isolates were significantly higher in the periodontitis group (p<0.01, Mann-Whitney test). The study confirmed that antibody serum titers to the six different ribotypes of B. forsythus varied greatly between older individuals with gingivitis or periodontitis. Not all strains of B. forsythus elicited higher titers in periodontitis affected subjects. CONCLUSIONS: The results of the present study suggest genotype variation of B. forsythus that is unique to the individual and that serotype variation can be expected. It is possible that B. forsythus under specific host conditions can modulate surface antigen factors to evade the host immune response.

Humoral immunity host factors in subjects with failing or successful titanium dental implants.

BACKGROUND: Treatment with titanium dental implants is in general successful. However, an unknown number of implants do not integrate and are removed either by exfoliation or at the time of second stage surgery. It would be of importance to identify subjects at risk and predict early implant failure. METHODS: In a retrospective study serum IgG antibody titers and avidity in sera from 40 subjects who had experienced titanium dental implant treatments with non-osseo-integration as the outcome (NOTI) and in sera from 40 age and gender matched control subjects who had received successful titanium dental implants (SOTI) were studied. Serum IgG titers to whole cell Actinomyces viscosus, Bacteroides forsythus, Porphyromonas gingivalis, Staphylococcus aureus, and Streptococcus intermedius sonicated antigen preparations were studied by ELISA. RESULTS: Serum IgG antibody titers to S. aureus were significantly higher in subjects with SOTI than in NOTI (p<0.001) suggesting that higher titers indicate protection against implant failure as a result of S. aureus infection. Statistically significant higher serum IgG antibody avidity to P. gingivalis and B. forsythus were found in subjects with SOTI than in subjects with NOTI (p<0.01 and p<0.001, respectively). Statistical analysis failed to demonstrate antibody titer or avidity differences to the other pathogens studied. The likelihood that SOTI was associated with a high OD reading for S. aureus was 13.1:1 (p<0.001). Whether subjects were edentulous or not, or if they had lost teeth because of periodontitis or caries did not seem to matter. CONCLUSION: Serum IgG antibodies relative to B. forsythus, P. gingivalis and S. aureus may be associated with the outcome of implant procedures and explain why early implant failures occur.

Function of anti-Porphyromonas gingivalis immunoglobulin classes in immunized Macaca fascicularis.

We previously reported that Macaca fascicularis immunized with formalin-killed Porphyromonas gingivalis were protected against the bone loss of periodontitis. To examine mechanisms of protection, we determined specific immunoglobulin G (IgG), IgM and IgA titers and opsonic capacities of sera from immunized and control animals. Serum IgG and IgA titers to P. gingivalis appeared early and persisted throughout the 36-week observation period. IgM titers were elevated until 6 to 12 weeks and then decreased through week 36. A significant association was observed between peak IgM titers prior to ligature placement and protection against bone loss (measured at week 30). In control monkeys, no significant IgG, IgA or IgM titers were seen. In sera from immunized animals, significant opsonic capacity was seen by 6-12 weeks and persisted throughout the study. In contrast, control sera showed only low opsonization capacity. Anti P. gingivalis antibody titers in purified IgG, IgA and IgM fractions were determined by enzyme-linked immunosorbent assay, and opsonic activity was demonstrated only in the IgG fraction.

Targeting tumor cells via EGF receptors: selective toxicity of an HBEGF-toxin fusion protein.

Over-expression of the epidermal growth factor receptor (EGFR) is a hallmark of numerous solid tumors, thus providing a means of selectively targeting therapeutic agents. Heparin-binding epidermal growth factor (HBEGF) binds to EGFRs with high affinity and to heparan sulfate proteoglycans, resulting in increased mitogenic potential compared to other EGF family members. We have investigated the feasibility of using HBEGF to selectively deliver a cytotoxic protein into EGFR-expressing tumor cells. Recombinant fusion proteins consisting of mature human HBEGF fused to the plant ribosome-inactivating protein saporin (SAP) were expressed in Escherichia coli. Purified HBEGF-SAP chimeras inhibited protein synthesis in a cell-free assay and competed with EGF for binding to receptors on intact cells. A construct with a 22-amino-acid flexible linker (L22) between the HBEGF and SAP moieties exhibited an affinity for the EGFR that was comparable to that of HBEGF. The sensitivity to HBEGF-L22-SAP was determined for a variety of human tumor cell lines, including the 60 cell lines comprising the National Cancer Institute Anticancer Drug Screen. HBEGF-L22-SAP was cytotoxic in vitro to a variety of EGFR-bearing cell lines and inhibited growth of EGFR-over-expressing human breast carcinoma cells in vivo. In contrast, the fusion protein had no effect on small-cell lung carcinoma cells, which are EGFR-deficient. Our results demonstrate that fusion proteins composed of HBEGF and SAP exhibit targeting specificity and cytotoxicity that may be of therapeutic value in treating a variety of EGFR-bearing malignancies.

Demystifying acid-base regulation.

Acid-base imbalances may have serious clinical implications for all patients. The maintenance of homeostasis within the body is intimately linked to the balance of acids and bases within the body. Any disturbance in this balance will adversely effect all cellular metabolism and ultimately the functioning of vital body systems. Figure 3 may help you to understand the integration of the mechanisms which regulate acid-base balance in the body.

Establishment of epitope-defined monoclonal antibodies with specificity for fibroblast growth factor receptor types 1 and 2.

The development of specific antibody probes for characterizing the expression of the family of 4 fibroblast growth factor receptor (FGFR) types has been difficult because of their close homology to each other and high degree of evolutionary conservation. Of the existing anti-FGFR monoclonal antibodies (MAbs), there are few that are useful for staining paraffin-embedded tissues. We have raised MAbs against human FGFR1 and FGFR2 in both rats and mice using bacterial recombinant receptor fusion proteins as immunogens. We used peptide epitope mapping to characterize the immune sera and the selected MAbs. Immunized animals were selected that displayed the broadest reactivity against epitopes unique to the immunizing receptor type. We produced FGFR1 specific MAbs that bind epitopes in immunoglobulin domain I (Ig-I) and FGFR2 specific MAbs that bind epitopes in Ig-I, Ig-II, and the acid box. The specificity of the antibodies was demonstrated by ELISA and immunoblot analysis of purified recombinant FGFR1 and FGFR2 extracellular domains produced both in E. coli and in eucaryotic cells. Based on the lack of epitope homology, these MAbs would not be expected to cross-react with FGFR3 or FGFR4. We isolated MAbs that bound to paraffin embedded tissue and immunoblots of recombinant receptor. These epitope-defined MAbs can distinguish between members of the FGF receptor family and should be useful as tools for assessing FGF receptor expression in a variety of normal and diseased tissues.

Intraventricular immunotoxin therapy for leptomeningeal neoplasia.

OBJECTIVE: The goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity. METHODS: We performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454A12-rRA is a conjugate of a monoclonal antibody against the human transferrin receptor and recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. Patients were treated with single doses of 454A12-rRA ranging from 1.2 to 1200 micrograms. RESULTS: The early phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (CSF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than the clearance of coinjected technetium-99m-diethylenetriamine penta-acetic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degradation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling the concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 micrograms of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 micrograms caused a CSF inflammatory response that was associated with transient headache, vomiting, and altered mental status. This acute syndrome was responsive to steroids and CSF drainage. No systemic toxicity was detected. In four of the eight patients, a greater than 50% reduction of tumor cell counts in the lumbar CSF occurred within 5 to 7 days after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance imaging evidence of tumor progression was demonstrated in seven of the eight patients after treatment. CONCLUSION: Tumoricidal concentrations of the immunotoxin 454A12-rRA can be attained safely in the CSF of patients with leptomeningeal tumor spread.