Myeloablative 131I-tositumomab radioimmunotherapy in treating non-Hodgkin's lymphoma: comparison of dosimetry based on whole-body retention and dose to critical organ receiving the highest dose.

Myeloablative radioimmunotherapy using (131)I-tositumomab (anti-CD20) monoclonal antibodies is an effective therapy for B-cell non-Hodgkin's lymphoma. The amount of radioactivity for radioimmunotherapy may be determined by several methods, including those based on whole-body retention and on dose to a limiting normal organ. The goal of each approach is to deliver maximal myeloablative amounts of radioactivity within the tolerance of critical normal organs. METHODS: Records of 100 consecutive patients who underwent biodistribution and dosimetry evaluation after tracer infusion of (131)I-tositumomab before radioimmunotherapy were reviewed. We assessed organ and tissue activities over time by serial gamma-camera imaging to calculate radiation-absorbed doses. Organ volumes were determined from CT scans for organ-specific dosimetry. These dose estimates helped us to determine therapy on the basis of projected dose to the critical normal organ receiving a maximum tolerable radiation dose. We compared organ-specific dosimetry for treatment planning with the whole-body dose-assessment method by retrospectively analyzing the differences in projected organ-absorbed doses and their ratios. RESULTS: Mean organ doses per unit of administered activity (mGy/MBq) estimated by both methods were 0.33 for liver and 0.33 for lungs by the whole-body method and 1.52 for liver and 1.74 for lungs by the organ-specific method (P=0.0001). The median differences between methods were 0.92 mGy/MBq (range, 0.36-2.2 mGy/MBq) for lungs, 0.82 mGy/MBq (range, 0.28-1.67 mGy/MBq) for liver, and -0.01 mGy/MBq (range, -0.18-0.16 mGy/MBq) for whole body. The median ratios of the treatment activities based on limiting normal-organ dose were 5.12 (range, 2.33-10.01) for lungs, 4.14 (range, 2.16-6.67) for liver, and 0.94 (range, 0.79-1.22) for whole body. We found substantial differences between the dose estimated by the 2 methods for liver and lungs (P=0.0001). CONCLUSION: Dosimetry based on whole-body retention will underestimate the organ doses, and a preferable approach is to evaluate organ-specific doses by accounting for actual radionuclide biodistribution. Myeloablative treatments based on the latter approach allow administration of the maximum amount of radioactivity while minimizing toxicity.     

The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies.

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.     

Arthroscopic Coracoclavicular Ligament Reconstruction Using Biologic and Suture Fixation

Presented in this report is a modified arthroscopic approach to acromioclavicular joint reconstruction via suture and allograft fixation. An arthroscopic approach is used to expose the base of the coracoid by use of electrocautery. After an open distal clavicle excision is performed, clavicular and coracoid tunnels are created under arthroscopic visualization as previously described by Wolf and Pennington. The myotendinous end of a semitendinosus allograft is sutured to a Spider plate (Kinetikos Medical, San Diego, CA). The tendinous end of the graft is prepared with a running baseball stitch. A Nitinol wire with a loop end (Arthrex, Naples, FL) is used to pass 2 free FiberTape sutures (Arthrex) and the leading sutures from the tendinous end of the graft through the clavicular and coracoid tunnels, exiting out the anterior portal. One of the FiberTape sutures is retrieved with a grasper and passed over the anterior aspect of the distal clavicle. The second FiberTape suture and the allograft are passed over the distal end of the resected clavicle. While the acromioclavicular joint is held reduced, the FiberTape sutures are tied to the plate and the allograft is tensioned medially until the plate is embedded against the superior surface of the clavicle. The tendinous end of the graft is secured to the superior surface of the clavicle with a Bio-tenodesis screw (Arthrex) medial to the clavicular tunnel.     

Self-Warming Lidocaine/Tetracaine Patch Effectively and Safely Induces Local Anesthesia during Minor Dermatologic Procedures

BACKGROUND Dermatologic procedures often cause some degree of pain. A self-warming patch containing lidocaine and tetracaine (L/T) was developed to provide topical local anesthesia prior to painful procedures.
OBJECTIVES To evaluate the safety and efficacy of a self-warming L/T patch to provide anesthesia in adult patients undergoing minor dermatologic procedures.
METHODS An active or placebo study drug was placed on adults 30 minutes prior to minor dermatologic surgical procedures in a prospectively randomized, double-blinded manner. Subcutaneous lidocaine injection was available during the procedure as a rescue medication if requested by the subject. Immediately following the procedure, the subjects, the investigator, and an independent observer rated pain intensity and adverse events were recorded.
RESULTS Patient-reported pain intensity was significantly lower in the L/T patch group (   p < .001  ). Investigators and an independent observer rated the pain in the L/T patch group to be less than in the placebo patch group (   p = .004  and   p < .001  , respectively). Forty-nine percent of patients in the placebo group required rescue subcutaneous lidocaine compared with 22% in the L/T patch study group (   p = .008  ). One patient in the L/T patch group reported a transient moderate burning sensation.
CONCLUSION The self-warming L/T patch was effective in providing clinically useful local anesthesia for minor dermatologic procedures in adult patients.
ZARS, INC., PROVIDED SUPPORT VIA A SPONSORED RESEARCH GRANT TO THE UNIVERSITY OF MIAMI.     

Public health capacity building in southeastern Europe: a partnership between the Open Society Institute and the US Centers for Disease Control and Prevention.

The political disintegration of former Yugoslavia inaugurated in 1991 resulted in the decentralization of health systems in the federation's successor nation-states. Efforts by the Open Society Institute improved public health planning and management needs consequent to health sector changes. Beginning in Croatia in 2001, the Institute developed ongoing collaborations between Andrija Stampar School of Public Health and the US Centers for Disease Control and Prevention. In 2003 and 2004, it expanded its project to include the republics of Macedonia and of Serbia and Montenegro.     

Infectious bronchitis virus S1 gene sequence comparison is a better predictor of challenge of immunity in chickens than serotyping by virus neutralization.

Five strains of infectious bronchitis virus isolated from commercial chickens from the state of Pennsylvania, USA during the years 1998 and 1999 were studied. The strains were selected for cross-challenge in specific pathogen free chickens and virus neutralization in chick embryos on the basis of partial S1 sequence amino acid identity values. The partial sequences analysed spanned the hypervariable amino terminus region of S1 from amino acid residues 48 to 219, based on the Beaudette strain. Using their S1 identity values, the strains represented a continuum of genetic, and thus antigenic, relationships. When compared with strain PA/5083/99, strain PA/Wolgemuth/98 had high sequence identity (96%) followed by PA/171/99 (85%), PA/5344/98 (70%) and PA/1220/98 (34%). The method of Archetti and Horsfall was used for calculating antigenic relatedness values of virus neutralization tests. The same formula was also applied to the percentage protection values of cross-challenge tests to derive protective relatedness values among the strains. The antigenic relatedness values, protective relatedness values, and the partial S1 sequence identity values were then analysed. The findings indicated partial S1 sequence identity values were more strongly correlated with protective relatedness values and than antigenic relatedness values.     

Radiopacity of dental materials using a digital X-ray system.

OBJECTIVES: Radiopacity is a desirable property for most intra-oral materials. There are established ISO and ANSI/ADA protocols for determining radiopacity using film-based radiography. However, these methods are not always followed by researchers. This study aims to adapt those procedures by using digital radiography, a simplified stepwedge, and examine the effects of target distance and exposure time choice. METHODS: One millimetre thick samples of three dental materials were prepared by placing the materials into a 1.00 mm thick washer sandwiched between two glass slides. The samples were digitally radiographed alongside a stepwedge of aluminum alloy 1100 with an X-ray unit at 70 kVp using five different target distance/exposure time combinations. For each combination, the grey scale values of various thicknesses of the stepwedge were converted into absorbencies and plotted against their thickness. These plots were then linearly regressed in order to correlate absorbance with a thickness of aluminum for each target distance/exposure time combination. The absorbencies of each sample were then converted into radiopacities using these correlations. RESULTS: The correlations between the absorbance of the stepwedge and its thickness were highly linear. This linearity allows the correlation to be accurately deduced from fewer data points than required by the ISO and ANSI/ADA protocols. Varying exposure time did not significantly affect the mean radiopacity measured at a target distance of 30 cm. Varying the target distance did not significantly affect the measured radiopacity as long as the samples were properly exposed. SIGNIFICANCE: A simplified, consistent digital method for determining radiopacity is presented.     

Can Electrocardiographic Criteria Predict Adverse Cardiac Events and Positive Cardiac Markers?

OBJECTIVES: To determine electrocardiogram (ECG) predictors of positive cardiac markers and short-term adverse cardiac events in an undifferentiated chest pain population presenting to emergency departments (EDs). The authors hypothesized that specific ECG findings, other than those previously identified in higher-risk populations, would be predictive of cardiac outcomes and positive cardiac markers. METHODS: This study used data from a prospectively collected, retrospectively analyzed Internet-based data registry of undifferentiated chest pain patients (i*trACS). Logistic regression modeling was performed to determine the ECG findings that were predictive of 1) positive cardiac markers and 2) short-term adverse cardiac events. RESULTS: ST-segment elevation (STE), ST-segment depression (STD), pathological Q-waves (PQW), and T-wave inversion were associated with increased odds of percutaneous coronary intervention or catheterization, myocardial infarction, or coronary artery bypass grafting. The odds of creatine kinase-MB (CK-MB) measuring positive were increased if STE, STD, or PQW were present [odds ratio (OR) 2.495, 2.582, and 1.295, respectively]. A right bundle branch block tended to decrease the odds of CK-MB measuring positive (OR 0.658). A similar pattern of results was observed for troponin I (OR 3.608 for STE, 3.72 for STD, 1.538 for PQW). Troponin T showed an increased odds of measuring positive if any of STE, STD, left bundle branch block, or T-wave inversion were evident (OR 2.313, 2.816, 1.80, and 1.449, respectively). CONCLUSIONS: Initial ECG criteria can be used to predict short-term cardiac outcomes and positive cardiac markers. These findings can be important aids in the risk-stratification and aggressive treatment regimens of chest pain patients presenting to EDs.     

A novel mutation in the last exon of ATRX in a patient with α-thalassemia myelodysplastic syndrome

Abstract:  We describe a patient with acquired alpha-thalassemia myelodysplastic syndrome (ATMDS). A previously healthy 66-year-old man presented with hemoglobin of 9.3 g/dL, mean corpuscular volume 59 fL, and a bone marrow aspirate with increased erythroid precursors and hypolobulated megakaryocytes. Hemoglobin H inclusions were seen in most red cells after 1% brilliant cresyl blue supravital stain of the peripheral blood. At the molecular level, we identified of a novel mutation in the most 3' exon of the ATRX gene ( C GA→ T GA substitution in codon 2407) resulting in a premature termination codon (p.R2407X). This case provides further evidence for a link between ATRX mutations and ATMDS, and suggests a possible role for the conserved Q-box element in ATRX function.