ASO Author Reflections: National Analysis of Breast Surgery Malpractice Cases: A Teachable Moment?

Annals of Surgical Oncology -     

Comparison of Plasma Protein Binding of Basic Drugs in Black and White Individuals

Interethnic difference in drug disposition is an important contributing factor to interindividual variation in drug response. Since interethnic differences in the protein binding of drugs may contribute to variation in drug disposition between ethnic groups, we conducted a study in 10 black Americans (A) and mean (plus minusSE) age 26 plus minus 6 years and weight 80 plus minus 9 kg matched against 10 white Americans (C) with a mean age of 28 plus minus 6 years and weight 81 plus minus 9 kg, all within 10% of ideal body weight. Serum alpha-1-acid glycoprotein (AGP) and albumin concentrations were measured using the auramine-O and bromcresol green methods, respectively. Verapamil, propranolol, lidocaine, disopyramide and diazepam binding in plasma were measured with the equilibrium-dialysis method, involving the determination of free and unbound drug concentrations. The unbound fraction of diazepam (A = 1.1 plus minus 0.1%; C = 1.1 plus minus 0.1%), verapamil (A = 9.5 plus minus 0.8%; C = 9.8 plus minus 0.4%), propranolol (A = 14.2 plus minus 1.0%; C = 12.6 plus minus 0.7%), lidocaine (A = 28.5 plus minus 2.1%; C = 25.7 plus minus 1.1%) and diphenhydramine (A = 42.9 plus minus 10.2; C = 30.4 plus minus 7.01%) showed no significant ethnic differences (unpaired t-test). Disopyramide measured at 7 different concentrations (1.0--20.0 &mgr;g/ml) was similar in both groups, as were the plasma concentrations of AGP (A = 100 plus minus 20 mg 100 ml; C = 120 plus minus 20 mg 100 ml) and albumin (A = 4.3 plus minus 0.1 g 100 ml; C = 4.5 plus minus 0.1 g 100 ml). It is therefore concluded that there are no interethnic differences in the protein binding of basic drugs between black Americans and white Americans and that it is not a major contributing factor to any possible interethnic variation in the disposition of responsiveness of these drugs.     

Relationship of Body Core Temperature and Warm-up to Knee Range of Motion

This study examined the effects of submaximal, treadmill exercise-induced body core temperature (BCT) increase on selected knee range of motion (ROM). Twenty males, 18-35 years old, were tested (randomized crossover) for ROM, BCT, and heart rate (HR), followed by either Treatment I (20 minutes of rest) or Treatment II (20 minutes of submaximal running). The two treatments were subsequently followed by a two-minute passive stretch. Range of motion was assessed before and after passive stretch treatment intervention. Treatment means differed for BCT and HR (p < 0.001) but not for ROM after exercise intervention. It was concluded that 20 minutes of exercise increased BCT (>1 degrees C) but had no effect on knee ROM. J Orthop Sports Phys Ther 1991;13(3):126-131.     

The muscular vascular index. Analysis of the vascularization of the muscles of the forearm]

The results of an anatomic study based on 50 fresh adult cadaver upper extremities are analysed. All the arterial pedicles of each forearm muscle were counted, and each muscle was weighed. Each forearm contained an average number of 264 muscular pedicles. The relative mass fraction of each muscle was calculated, as was its "muscular vascular index" or MVI (number of pedicles divided by the weight of the muscle in grams). Half of the forearm muscles had a significant statistical relationship between their weight and their number of vascular pedicles. The other half had no statistical relationship. These two statistical muscular groups (with and without a statistical relationship) did not clearly correspond to anatomic or functional groups. No muscular group based on the average of MVI was found. Each of the 20 forearm muscle had finally its own characteristics of weight, number of pedicles, and MVI. The average MVI was 0.9 (from 0.4 to 1.8). The global muscular vascular index (GMVI) is the division of the total number of muscular pedicles of a forearm by the total muscular weight of this forearm. The average GMVI was 0.8 (from 0.4 to 1.6). In spite of its theoretical and practical limits, the MVI concept approximately reflects the high vascular density of the forearm muscles.     

Covalent binding of isomeric benzo[a]pyrene diol-epoxides to DNA

We have compared the abilities of two diol-epoxide derivativesof benzo[a]pyrene (B[a]P) to bind covalently to DNA in a simplein vitro system. Purified DNA in aqueous solution was allowedto react with (±)-7, 8ß-dihydroxy-9ß,10ß-oxy-7,8,9,10-tetrahydroB[a]P (BPDE) or with (±)-9,10ß-dihydroxy-7,8-oxy-7,8,9,10-tetrahydroB[a]P (reverseBPDE) to completion. After repurification of the DNA, bindingwas detected by fluorescence spectroscopy or by absorbance spectroscopy.Both BPDE and reverse BPDE but not their hydrolysis productsexhibited binding which increased linearly with increasing diolepoxide concentration. When DNA modified by reverse BPDE wasenzymatically hydrolysed, two major fluorescent deoxyribonucleoside-adductswere detected by reverse phase h.p.l.c. These were separablefrom the major adduct obtained from BPDE-modified DNA and fromthe major products obtained by hydrolysis of reverse BPDE inthe absence of DNA. Absorbance and fluorescence spectroscopyof modified native DNA suggested that the pyrene nucleus ofreverse BPDE but not of BPDE was intercalated in the DNA doublehelix. This suggestion was supported by fluorescence-quenchingstudies. In the presence of increasing DNA concentrations, covalentbinding of both diol epoxides increased towards an apparentmaximum. Double reciprocal analysis of the data indicated amaximum binding level of 5% of the total dose for BPDE and 4%for reverse BPDE. This suggests that for both diol epoxidesthe ratio of the rate constants for covalent binding and forDNA-enhanced hydrolysis are nearly the same. Covalent bindingof reverse BPDE to DNA was effectively blocked by low concentrationsof Mg²⁺, suggesting that formation of a non-covalent intercalationcomplex may be a prerequisite for covalent reaction.     

Polilactofate microspheres for Paclitaxel delivery to central nervous system malignancies.

PURPOSE: The purpose of this study was to demonstrate that surgically implanted, controlled-release, biodegradable polilactofate microspheres (Paclimer) can be used safely to bypass the blood-brain barrier and deliver paclitaxel to malignant brain tumors. EXPERIMENTAL DESIGN: The rate of paclitaxel release from Paclimer microspheres submerged in PBS was measured in vitro by high-performance liquid chromatography. In vivo studies of Paclimer were performed as intracranial implants in Fischer 344 rats in the presence or absence of 9L gliosarcoma. Mantel-Cox statistics were used to assess the efficacy of Paclimer at extending survival of tumor-bearing animals compared with control implants. Paclimer implants tagged with [(3)H]paclitaxel were used to measure biodistribution of paclitaxel from the Paclimer implant. RESULTS: Paclimer released paclitaxel at a constant rate for up to 3 months in vitro. In vivo, Paclimer implants placed intracranially in rats released active drug for up to 30 days after implantation and doubled the median survival of rats bearing established 9L gliosarcomas (median survival of paclitaxel-treated animals = 35 days; median survival of control-treated animal = 16 days; P < 0.0001). Active drug was distributed throughout the rat brain based on liquid scintillation counting and TLC. Rats implanted with Paclimer demonstrated no overt signs of neurotoxicity and exhibited local cytopathological changes consistent with exposure to an antimicrotubule agent. CONCLUSIONS: Paclimer extends survival in a rodent model of glioma with minimal morbidity and optimal pharmacokinetics.     

Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial.

PURPOSE: To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). PATIENTS AND METHODS: From September 1996 to May 2002, 200 patients with CS I NSGCT were prospectively assigned to retroperitoneal lymph node dissection (RPLND), and risk factor assessment was performed within a multicenter protocol. One hundred sixty-five patients had an adequate minimum follow-up of 12 months (mean, 34.5 months) or had pathologic stage II. RESULTS: Pathologic stage II disease was found in 27.9% of patients. Only 0.6% of patients relapsed in the retroperitoneum after confirmation of pathologic stage I disease. With reference pathology, vascular invasion (VI) was most predictive of stage in multifactorial analysis (accuracy, 65.1%). However, the positive predictive value (PPV) of VI to predict patients who have metastatic disease or relapse during follow-up was only 52.7%. With absent VI, low-risk patients had a negative predictive value (NPV) of 76.9%. With a combination of several risk factors, the PPV increased to 63.6% and the negative predictive value increased to 86.5%. CONCLUSION: Even with an optimal combination of prognostic factors and reference pathology, more than one third of patients predicted to have pathologic stage II or relapse during follow-up will not harbor metastatic disease and, therefore, would be overtreated with adjuvant therapy. However, patients at low risk may be predicted at an 86.5% level, and thus, surveillance in highly compliant patients would be a valuable option. For high-risk patients, further reduction of adjuvant treatment is necessary.