Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma

Forty-nine patients were treated with either 3×75 MBq ⁸⁹Sr or saline as placebo. Analysis of results 1 to 3 years after therapy revealed the ineffectiveness of ⁸⁹Sr to relieve pain from metastases. Unexpectedly, a higher survival rate was found after Sr application (46% vs 4% after 2 years). Covariate analysis underlines the effect of ⁸⁹Sr therapy on life expectation.     

Max Brödel (1870–1941): his life and his role in the development of surgery

Summary. Max Br?del (1870–1941), from Leipzig, Germany, is often referred to in the USA as the father of modern medical illustration and mentioned in the same breath as Leonardo da Vinci or Andreas Vesal. After a classical formal art education in Leipzig he worked in Carl Ludwig's laboratory of physiology and anatomy, where he came in contact with American physicians. In 1894, the anatomist F. P. Mall convinced him to work for the recently inaugurated Johns Hopkins School of Medicine in Baltimore, where he collaborated with world-famous surgeons such as H. A. Kelly, W. S. Halsted, and H. Cushing. His illustrations were characterized by meticulous observation, both realistic and explanatory intention, technical superiority, and artistic merit. In 1911 he established the first “Department of Art as applied to Medicine”. Here, he proved to be an innovative artist, a creative scientist, and an inspiring and skillful instructor. By the time of Br?del's retirement in 1939, 160 students had graduated as medical illustrators. His pupils spread his principles and style throughout the USA and Canada, and several similar academic programs for medical illustration have been founded in these countries.      

Radioreceptor Assay of Metoprolol in Human Plasma: Comparison with an Enantiospecific High-Performance Liquid Chromatographic (HPLC) Procedure

Plasma concentrations of metoprolol after acute and repetitive administration of R/S-metoprolol to healthy volunteers were measured by a -adrenoceptor subtype-specific radioreceptor assay (RRA) and by an enantiospecific high-performance liquid chromatographic (HPLC) method. In the RRA, R/S-metoprolol showed a 20-fold ₁-subtype selectivity: the S-( – )-enantiomer was 35-fold more potent than the R-( + )-enantiomer. A comparison between S-( – )-metoprolol concentrations detected in the plasma samples by HPLC and those detected by RRA yielded a 1/1 relationship, indicating that active metabolites are not present to a significant extent. These results were independent of the widely scattering metabolic clearance of metoprolol (with the potential of differences in the rate and extent of formation of active metabolites) in the volunteers. In general, HPLC methods can be validated by comparison with RRA in order to clarify whether active metabolites are present and—on the basis of the K_i value from RRA—whether the detection limit of the physicochemical procedure is sufficient to cover the therapeutically relevant range.     

Procedures to Characterize In Vivo and In Vitro Enantioselective Glucuronidation Properly: Studies with Benoxaprofen Glucuronides

The diastereoisomeric glucuronic acid conjugates of R/S-benoxaprofen are the major benoxaprofen metabolites and are found in urine at high concentrations. The conjugates of R- and S-benoxaprofen can be separated directly on a C₁₈ reversed-phase column using a mixture of acetonitrile and tetrabutylammonium hydroxide buffer, pH 2.5 (28:72, v/v), as the mobile phase. The k values of S- and R-benoxaprofen glucuronides are 57.5 and 63.0, respectively. Diluted urine or deproteinized plasma samples were injected without further treatment. With fluorescence detection at 313/365 nm, quantifiable limits of 50 ng equiv./ml were found for the conjugates. The intra- and interday variability was below 12%. Utilizing this analytical procedure it is possible to characterize enantioselective glucuronidation both in vivo and in vitro. For in vitro procedures, apparent rates of formation and the R/S ratio may be substrate (benoxaprofen) and cosubstrate (UDPGA) dependent. Moreover, enantioselective cleavage of the formed benoxaprofen glucuronides by alkaline hydrolysis, hydrolytic enzymes, and acyl migration must be controlled for both in vitro and in vivo studies since R-benoxaprofen glucuronide is degraded faster than the S-diastereomer under certain conditions.     

Inhibition of interleukin-6 synthesis in an animal model of septic shock by anti-C5a monoclonal antibodies

The complement activation fragment C5a was recently shown to induce interleukin (IL)-6 synthesis by peripheral blood mononuclear cells. To understand better the role of C5a in cytokine regulation in vivo, we investigated the effects of complement depletion by cobra venom factor (CVF) or of anti-C5a monoclonal antibodies (mAb) on IL-6 generation in an animal model of septic shock. Complement-depleted pigs which were subsequently challenged with Escherichia coli generated significantly (p < 0.05) less IL-6 during the 6-h observation period than complement-sufficient controls. To address specifically the role of C5a in IL-6 regulation, we produced a C5a(57–74) peptide-specific mAb (T13/9) which neutralizes the bioactivity of porcine C5a. The mAb T13/9 does not crossreact with the precursor protein C5. The pretreatment of pigs with anti-C5a mAb T13/9 prior to the induction of sepsis resulted in a decrease of over 75 % in serum IL-6 bioactivity compared to control animals (p < 0.0001). These results indicate a role for C5a in the modulation of IL-6 synthesis in Gram-negative bacteremia.     

A single-center pilot validation study of a new chronic GVHD skin scoring system.

The use of a quantifiable and reproducible measurement tool for skin manifestations of chronic graft-versus-host disease (cGVHD) is key for the successful assessment and documentation of therapeutic response. Skin scoring methods for use in clinical trials have not been validated for application in patients suffering from cGVHD. For this purpose we performed a prospective single-center pilot study to validate a skin-scoring tool developed at our institution for evaluating cutaneous involvement of cGVHD approximately 10 years ago. It combines percentage of involved body surface area (BSA) divided into 10 separate anatomic regions with manifestations of cGVHD coded from 0 (normal skin) to 4 (hidebound skin, unmovable sclerosis). Sixteen patients were examined separately by 4 trained physicians 3 times on 2 consecutive days for a total of 192 individual skin assessments; intraobserver and interobserver reliability were calculated. Good to excellent intraclass correlation coefficients (ICC) were obtained in almost all scores including erythematous lesions in areas with scores 3 and 4 for all observers. Moderate to good interrater reliability for observers 1 to 4 was seen in lesions with scores 0, 3, and 4, respectively. A marked improvement of interrater reliability in all scores and examinations was observed when ICCs were calculated only for the more experienced observers 1 to 3. This New Chronic GVHD Skin score is a reproducible, accurate, feasible, and inexpensive tool for use in selected clinical trials of chronic cutaneous GVHD. Further studies with larger patient numbers and validation of this new tool for assessment of treatment response are warranted.     

Running mass closure of abdominal wounds using absorbable looped suture

Three hundred patients undergoing celiotomies had fascial incisions closed using O-Maxon looped suture employing a knot-free running modification of the Smead Jones method. Two hundred ninety-three patients were evaluated prospectively to determine efficacy and safety of this technique. Seventy-two percent of patients underwent celiotomies for treatment of malignant diseases. A vertical incision was used in 79% and a transverse incision in 21% of patients. Mean fascial closure time was 8.4 minutes (range 3-32), without a significant difference between the vertical and transverse incisions. Overall suture handling was judged as excellent in 44% of the patients and good in 54%. Six weeks postoperatively, wounds were healed in 99% of patients, with less than 1% having residual infection or unclosed, granulating wounds. No herniation or fascial dehiscences occurred in this series. We conclude that Maxon looped suture employing a knot-free running Smead Jones technique appears to be a safe, efficient, and effective closure method in this group of patients. Further follow-up will be required to show whether this outcome is sustained.     

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Immunohistochemistry for c-myc and bcl-2 overexpression improves risk stratification in primary central nervous system lymphoma

Overexpression of bcl-2 and c-myc are defining features of double-expressor-lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c-myc and bcl-2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first-line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5-fold and 13-fold higher 5-year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN-IPI. DEL improved the discriminatory capability of the NCCN-IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN-IPI significantly improved the score's discriminatory potential both toward progression-free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple-to-use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN-IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.