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Introduction/Objective Platelet refractory (PR) patients do not achieve expected post-transfusion platelet counts. We investigate such patients with a post-transfusion platelet count, indirect Platelet Antibody Screen (ind-PAS), Class I HLA Antibody (HLA-Ab) testing, and platelet crossmatch (PXM). The following three cases highlight potential pitfalls of laboratory investigations for PR patients. Methods/Case Report Case #1 (57-year-old male with AML) revealed discrepant predicted and observed donor compatibility. Antibody testing demonstrated no platelet glycoprotein antibodies and HLA-ab to B13, corresponding to 4% calculated PRA (CPRA), indicating 96% predicted donor compatibility. However, PXM revealed that the patient was compatible with 11/14 (79%) screened donors. Communication with the reference laboratory revealed that two PXM incompatible units were ABO incompatible. Case #2 (27-year-old female with aplastic anemia) is a highly sensitized patient (99% CPRA). PXM revealed compatibility with 1/14 screened donors; however, she failed to respond to the compatible donor. To investigate this poor response, patient’s plasma was tested against HLA incompatible donors. Neat serum demonstrated compatibility with all donors, whereas 1:8 dilution resulted in positive crossmatches with half the donors. The false negative crossmatches are likely explained by prozone in the setting of high HLA-ab burden. Case #3 (79-year-old male with AML) demonstrated a discrepancy between the ind-PAS (PakPlus, Immucor), which was negative for HLA-ab, and HLA specificity testing (LABScreen, OneLambda), which revealed Class I antibodies, corresponding to 38% CPRA. Per the ind-PAS package insert, the sensitivity of the assay was 85%-91% compared to selected HLA-ab tests; other sources have demonstrated lower sensitivity of 68%. Results (if a Case Study enter NA) NA. Conclusion The three cases highlight the importance of investigating incongruent results. Cases #1 and #2 demonstrate pitfalls in the PXM: ABO incompatibility can result in positive PXM and false-negative PXM can occur in the setting of high HLA-ab burden. Case #3 reveals the importance of knowing a test’s limitation, especially sensitivity. Centers that only perform ind-PAS may miss HLA-ab detection.

Background: Alemtuzumab (CD52-specific humanized monoclonal antibody) was found to be an effective therapy for treatment-naive patients with relapsing-remitting multiple sclerosis. Objective: Evaluate alemtuzumab’s effects in patients with treatment-refractory relapsing-remitting multiple sclerosis. Methods: Forty-five relapsing-remitting multiple sclerosis patients who experienced ≥2 relapses during 2 years prior to the study entry whilst receiving interferon therapy were administered 24 mg IV alemtuzumab/day for 5 days at baseline and 3 days 12 months later. Patients received premedication with 1 g IV methylprednisolone on days 1–3 at both times. Results: After 2-year follow-up, the annualized relapse rate was reduced by 94% compared to pre-treatment levels, from 1.6 (2 years prior to treatment) to 0.17 for the 2 years following (P

Objective: To determine the safety and efficacy of roquinimex (linomide) in the management of relapsing-remitting and secondary progressive MS as monitored by MRI. Background: Preclinical studies and several short term randomized trials of linomide suggested clinical and MRI-measured benefits with acceptable risk for closely followed MS patients. Methods: The North American Linomide Trial formally screened 853 individuals for relapsing or secondary progressive, clinically definite MS; recent disease activity or progression; and an Expanded Disability Status Scale score at entry of 3.0 to 6.5 inclusive. MRI was obtained on 811 subjects at pre-enrollment, 718 cases at enrollment, and then at three monthly intervals until the trial was prematurely terminated for unacceptable toxicity. Results: Enhancement was found on 40.2% of 718 entry scans. Statistically robust correlations were found between clinical demographic data and several entry MRI measures including CSF volume, a reflection of brain atrophy. Assessment of the effect of treatment on MRI-measured disease was limited by early trial termination. However, active treatment for 3 months reduced the proportion of patients with one or more enhancements. An exploratory analysis suggested that 2.5 mg was the most active of three doses tested in limiting the total volume of enhanced tissue, the proportion of MRI-defined lesions designated as “black holes,” and by a novel MRI composite disease measure. Conclusions: The short term signature of the effect of linomide on MRI-measured aspects of the disease suggests that safer drugs of this class might be useful in the management of MS. The use of a composite index of the heterogeneous nature of the pathology of MS as captured by MRI may have merit as an outcome measure in clinical trials.

Objective: To determine whether linomide (roquinimex) is better than placebo in slowing the time to confirmed clinical worsening in patients with relapsing–remitting (RR) and secondary progressive (SP) MS. Methods: In this 27-center, randomized, double-blind, placebo-controlled, multiple-dose, phase III trial, 715 patients with active RRMS (n = 90) or SPMS (n = 625) were randomized to receive either linomide (1.0, 2.5, or 7.5 mg orally daily) or placebo. Patients were evaluated at 3-month intervals clinically and with MRI. The planned primary outcome was the time to the development of “confirmed” clinical worsening (increase of ≥ 1.0 Expanded Disability Status Scale [EDSS] score for an enrollment EDSS score ≤ 5.0, or ≥ 0.5 point for an enrollment EDSS score of ≥ 5.5) not associated with an acute relapse. Results: The trial was terminated 1 month after it became fully enrolled due to unanticipated serious cardiopulmonary toxicities (pericarditis, pleural effusion, myocardial infarction, and possible pulmonary embolism), pancreatitis, and death. Notable arthralgia, myalgia, bursitis, and facial and peripheral edema were common adverse events. The high dose of linomide (7.5 mg) was not well tolerated. The trial was too brief to determine unequivocal clinical benefits. Trends suggested an unconfirmed early effect on change in EDSS score at 6 months for the medium dose (2.5 mg daily). Conclusion: MS patients may be more prone to develop important linomide treatment-related adverse events than other previously studied patients. However, linomide may be a potentially more toxic drug than was suspected from observations made in smaller studies for other indications. Phase III trials may identify infrequent and important toxicities that may not be anticipated by phase I and II trials.

To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon β-1a (IFNβ-1a) through extended follow-up (up to 60 months from baseline).Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNβ-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months.Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNβ-1a (both p0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNβ-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNβ-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNβ-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNβ-1a patients. Immune thrombocytopenia occurred in 3% of alemtuzumab patients and 0.9% of IFNβ-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab.Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNβ-1a, with a safety profile consistent with previous reports.This study provides Class III evidence that alemtuzumab is more effective than interferon β-1a in reducing relapses and disability in patients with RRMS in a long-term follow-up of a rater-blinded, randomized clinical trial with 59.5% of patients participating in the extended follow-up period.

Alemtuzumab (CD52-specific humanized monoclonal antibody) was found to be an effective therapy for treatment-naive patients with relapsing-remitting multiple sclerosis.Evaluate alemtuzumab's effects in patients with treatment-refractory relapsing-remitting multiple sclerosis.Forty-five relapsing-remitting multiple sclerosis patients who experienced ≥2 relapses during 2 years prior to the study entry whilst receiving interferon therapy were administered 24 mg i.v. alemtuzumab/day for 5 days at baseline and 3 days 12 months later. Patients received premedication with 1 g i.v. methylprednisolone on days 1-3 at both times.After 2-year follow-up, the annualized relapse rate was reduced by 94% compared to pre-treatment levels, from 1.6 (2 years prior to treatment) to 0.17 for the 2 years following (P0.0001). Moreover, 86% of patients showed stable or improved scores on the Expanded Disability Status Scale, and only 1 experienced an increase in disability lasting ≥6 months. The majority (70-88%) showed stable or improved leg, arm and cognitive function as measured by the Multiple Sclerosis Functional Composite. Serious adverse events observed in single patients were transient neutropenia and pneumonia, pulmonary emboli and deep vein thrombosis. Five patients developed clinical thyroid disorders but no opportunistic infections or cases of immune thrombocytopenic purpura were observed.Alemtuzumab effectively reduced relapse rates and improved clinical scores in patients with active relapsing-remitting multiple sclerosis not controlled by interferon therapy.

To determine whether linomide (roquinimex) is better than placebo in slowing the time to confirmed clinical worsening in patients with relapsing-remitting (RR) and secondary progressive (SP) MS.In this 27-center, randomized, double-blind, placebo-controlled, multiple-dose, phase III trial, 715 patients with active RRMS (n = 90) or SPMS (n = 625) were randomized to receive either linomide (1.0, 2.5, or 7.5 mg orally daily) or placebo. Patients were evaluated at 3-month intervals clinically and with MRI. The planned primary outcome was the time to the development of "confirmed" clinical worsening (increase of/= 1.0 Expanded Disability Status Scale [EDSS] score for an enrollment EDSS score/= 5.0, or/= 0.5 point for an enrollment EDSS score of/= 5.5) not associated with an acute relapse.The trial was terminated 1 month after it became fully enrolled due to unanticipated serious cardiopulmonary toxicities (pericarditis, pleural effusion, myocardial infarction, and possible pulmonary embolism), pancreatitis, and death. Notable arthralgia, myalgia, bursitis, and facial and peripheral edema were common adverse events. The high dose of linomide (7.5 mg) was not well tolerated. The trial was too brief to determine unequivocal clinical benefits. Trends suggested an unconfirmed early effect on change in EDSS score at 6 months for the medium dose (2.5 mg daily).MS patients may be more prone to develop important linomide treatment-related adverse events than other previously studied patients. However, linomide may be a potentially more toxic drug than was suspected from observations made in smaller studies for other indications. Phase III trials may identify infrequent and important toxicities that may not be anticipated by phase I and II trials.

This article reviews the diagnosis and management of pseudotumor cerebri. Signs and symptoms of the syndrome are reviewed along with current recommended treatment. If the diagnosis is made early in the clinical course of patients with the disorder, minimal morbidity is incurred.

Safety related problems encountered in the production and handling of materials using monomers in water based polymerization reactions are covered. It must be noted that the author's experience is specifically in acrylic monomers.

Parameterization and the Davidon-Fletcher-Powell method are used to study the characteristics of optimal shuttle entry trajectories. Two problems of thermal protective system weight minimization are considered: roll modulation and roll plus an angle-of-attack modulation. Both problems are targeted for the edges of the entry footprint. Results consistent with constraints on loads and control bounds are particularly well-behaved and strongly support 'energy' approximation results obtained for the case of symmetric flight by Kelley and Sullivan (1973). Furthermore, results indicate that optimal shuttle entry trajectories should be easy to duplicate and to analyze by using simple techniques.

The remarkable ability of the periodontium to repair once the long-term etiologic factors have been eliminated is now belatedly being recognized as a key consideration in periodontal therapy. This will force many practitioners interested in comprehensive periodontal treatment to reconsider the classic resective approach to pocket elimination. Resective techniques have been and will probably remain the foundation of periodontal therapy for some time to come. However, the knowledge that is now available concerning the reparative potential of the periodontium opens new treatment avenues for selected patients. In addition, as more research and clinical information becomes available, we can anticipate that the philosophy of repair will play an ever-increasing role in the therapeutic approach to periodontal treatment. This fact should not make the practitioner who is secure with his present treatment philosophy uncomfortable, since the required therapeutic modifications can easily be incorporated into the office routine without confusion. If the clinician then completes each step of the treatment plan with close attention to detail, regeneration will occur in many cases. It should be reiterated that many of the concepts introduced in this paper are based on the authors' clinical observations and are applicable only to select patients. Admittedly, basic research on this subject is sparse, however, the efficacy of this treatment modality has been well substantiated clinically by many therapists. The authors estimate that regenerative therapy is utilized in 10 to 20 per cent of their patients. They believe it is the therapeutic program of choice in many cases showing extensive periodontal destruction, since an innovative and skilled therapist treating a well motivated patient can utilize regenerative periodontal therapy in conjunction with sophisticated restorative dentistry in order to avoid complete dentures.