A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas.

Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/ß and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/ß or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. Clinical Trial Number: NCT01782313.

A novel mutation in the GDAP1 gene is associated with autosomal recessive Charcot-Marie-Tooth disease in an Amish family.

Charcot-Marie-Tooth disease (CMT) constitutes a large group of genetically heterogeneous disorders of the peripheral nervous system. Autosomal recessive forms of CMT are less common in the general population but account for the vast majority of CMT phenotypes in communities with a high prevalence of consanguinity. At least 10 genetic loci cause autosomal recessive forms of CMT. Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are among the most frequent genetic causes of autosomal recessive forms of CMT. To date, 28 mutations in GDAP1 gene have been linked with the disease. Here, we report a novel GDAP1 mutation in an Old Order Amish family with CMT. To ascertain the Amish CMT locus, we performed a genome-wide single nucleotide polymorphism (SNP) analysis on one of three patients from a consanguineous pedigree. Assuming mutation homogeneity, the analysis sought large homozygous SNP blocks that also contained known CMT loci. The largest homozygous SNP block in the patient was localized to chromosome 8q13.1-21.3 and contained the GDAP1 gene. Sequence analysis revealed a novel homozygous mutation, c.692C>T, at codon 231 (p.P231L) in exon 5 of GDAP1 in all patients. Neither the unaffected individuals in the family nor the healthy control samples were homozygous for this mutation. Our findings suggested that this novel mutation in GDAP1 gene is associated with an autosomal recessive form of CMT in Ohio Old Order Amish community.

Isoelectric focusing of human antibodies directed against a high molecular weight antigen.

A simple technique has been developed to assess the spectrotypes of antigen-specific human autoantibodies. Following isoelectric focusing in 3 M urea at 1200 V for 2 h, immunoglobulins were fixed in polyacrylamide gels by precipitation with sheep anti-human immunoglobulin in the presence of sodium sulphate. Specific anti-thyroglobulin antibody bands were labelled by reaction with [125I]thyroglobulin, an antigen with a molecular weight of 660,000 daltons which is too large to enter the gel. The advantages of this method include increased sensitivity and reproducibility, and the ability to produce sharper bands and less non-specific binding than other methods.

Introduction of a rapid, simple radioimmunoassay and quality control scheme for thyroxine.

A simple radioimmunoassay has been developed for service purposes to determine serum total thyroxine levels. Only three additions are required, of standard or sample, labelled thyroxine and antibody in polyethylene glycol. After 2 hours' incubation at room temperature the antibody-bound and free fractions are separated by centrifugation. Serum total thyroxine levels were measured in 195 euthyroid subjects and it was established that normal values lay within the range 57 to 155 nmol/1. Serial blood samples taken over a 24-hour period, from 11 subjects, indicated that there was no circadian rhythm so that samples for total thyroxine assay can be taken at any time of the day. Similar results were obtained using serum or plasma. Satisfactory results were obtained for three quality control sera when measured by seven different laboratories using this method.

Stability of thyroxine and triiodothyronine in biological fluids.

The stability of thyroxine and triiodothyronine in serum has been investigated. Apparent levels of total thryroxine, as determined by two different protein-binding assays employing thyroxine-binding globulin as the binding protein, increased significantly in serum and plasma samples stored at room temperature and were signficantly lower in haemolysed samples. Values did not change significantly in samples stored at 4 degrees C, nor in samples stored at room temperature when determined by radioimmunoassay. Total triiodothyronine levels, as determined by radioimmunoassay, fell slightly on storage. Failure to appreciate the effect of storing samples at room temperature on apparent levels of total thyroxine, as determined by some protein-binding assays, could lead to an incorrect assessment of thyroid status.

Automated tests for the assessment of thyroid function.

Fully automated methods have been developed for the determination of thyroxine and triiodothyronine levels, antibodies to thyroglobulin and the assessment of thyroid hormone binding proteins in serum, using a continuous flow radioimmunoassay system. In addition the feasibility of a partially automated assay for thyrotrophin levels has been demonstrated. These employ Auto Analyzer modules and antibodies covalently linked to a magnetisable solid phase support. Separation of bound and free antigen is achieved by applying an external magnetic field. The system currently operates at a rate of 30 samples/h and requires only 10 minutes incubation since it is not necessary to reach equilibrium. The results are similar to those obtained by conventional manual techniques, however the precision is improved and operator error eliminated.

Solid-phase, magnetic particle radioimmunoassay.

A solid-phase radioimmunoassay system has been developed based on the use of antibodies covalently linked to polymer-coated iron oxide (EnzacrylR). An electro-magnet is employed both to mix the particles during incubation (by switching the field on and off) and to separate the antibody-bound and free fractions. This obviates the need for vertical rotation and for the time-consuming, multiple centrifugations required with conventional solid phase procedures. The system is universally applicable and methods have been established for the assay of thyroxine, human placental lactogen and digoxin. The thyroxine assay was employed as a model and it was shown that the results obtained for serum samples correlated closely with those using a routine liquid-phase radioimmunoassay. The applicability of employing a second antibody linked to the iron oxide particles was also studied.

Gender and the relationship between perceived fairness of pay or promotion and job satisfaction.

Brockner and Adsit (1986) found that satisfaction with an exchange relationship was more strongly related to perceptions of equity among men than women. Kahn (1972) reported that men were more likely than women to distribute outcomes to individuals in direct proportion to their input. We evaluated potential gender differences among 12,979 personnel in 30 different organizational systems in (a) correlations between fairness and job satisfaction scores and (b) standardized group differences in the perceived amounts of pay and promotion fairness and expressed levels of facet and global job satisfaction. The fairness-satisfaction relationship was not higher for men, and there were no practical differences in fairness perceptions and job satisfaction between men and women.

Some personality and aptitude characteristics of air traffic control specialist trainees.

This study examined the interrelations of personality traits, aptitude test scores, and job performance self-expectations as predictors of success in the FAA Academy screening program of prospective air traffic controllers. Based on the State-Trait Personality Inventory (STPI), men and women Air Traffic Control Specialist (ATCS) trainees exhibited less anxiety and anger than normative groups of college students and Navy recruits. ATCS pass rates for 1,284 entrants were lower within each aptitude test score level for the subjects with anxiety or anger scores above the normative levels. Analyses indicated significant relationships between self-expectations of future job performance and both anxiety and aptitude test scores. Personality factors were found to affect the predictive validity of the primary test used for determining a student's aptitude for learning air traffic control principles and procedures.

Relationships of anxiety scores to screening and training status of air traffic controllers.

The present study assessed the relationship between anxiety, as measured by the State-Trait Personality Inventory (STPI), and success of post-strike air traffic control specialist (ATCS) trainees at the FAA Academy and during field training. The STPI was administered to students who entered the FAA Academy between June 1984 and September 1985. Academy test scores were obtained for 1,790 students in the en route option. Criterion data included the field training status of the Academy graduates as of July 1988. Statistical analyses determined the relationships between ATCS student scores on the STPI measures and a) normative data and b) Academy screening and field training results. ATCS students reported significantly lower state (current level) and trait (proneness) levels of anxiety than did either college students or military recruits. Trainees who had relatively high scores (for ATCSs) on a combined index of the trait and state measures of anxiety exhibited significantly higher a) percentages of Academy failures/withdrawals, b) percentages of option switches in the field, and c) overall field attrition, than did trainees with low scores. Results support the operation of some personality-related self-selection among ATCS applicants regarding anxiety and the importance of this low anxiety characteristic for ATCS job success.

Office staff savvy: quality staff-patient communications as a loss prevention strategy.

Based on the prevalence of medical error that continues to make headlines, you would think that physicians are so busy defending medical malpractice lawsuits that they don't have time to practice medicine. Although many physicians may feel like this, in fact, it is not the case. Contrary to what the media would have you believing, it is not "the conspiracy of silence" that's keeping physicians out of court. It's good, old-fashioned effective communication: courtesy, empathy, friendliness, and professionalism. Because the complexity of health care delivery imposes ever-greater demands on physicians' time, medical office staff play a larger-than-ever role in defining the tenor of physician-patient relationships. It has become incumbent on staff to become the physicians' partners in effectuating patient relationships built on quality communications. This article will discuss ways in which office staff can utilize effective communications to improve physician-patient relationships, thereby reducing professional liability exposures.

An investigation of the clonality of human autoimmune thyroglobulin antibodies and their light chains.

Thyroglobulin antibodies in the sera from 31 patients with a variety of disorders were studied by isoelectric focusing. Only one gave a spectrotype indicative of a monoclonal response, the other 30 giving spectrotypes characteristic of polyclonal responses. There was evidence of clonal dominance in some of the sera and each gave a different spectrotype. Light chains were prepared from five thyroglobulin antibodies purified by affinity chromatography. There was no restriction in the spectrotypes when compared with light chains prepared from normal immunoglobulin.

The effect of portacaval anastomosis on oral carbohydrate tolerance and on plasma insulin levels.

In patients with portal hypertension, plasma insulin levels were raised both fasting and after oral glucose or intravenous tolbutamide. This supports previous suggestions that resistance to endogenous insulin plays a major role in producing the impaired glucose tolerance found in chronic hepatic dysfunction. The operation of portacaval anastomosis was followed by impaired oral fructose tolerance, but did not significantly change oral glucose tolerance. Plasma insulin levels were unchanged by the operation, either fasting or following the stimulus of an oral glucose load or intravenous tolbutamide. The insulin response after operation was only higher after intensive pancreatic beta cell stimulation by a combination of glucose, tolbutamide, and glucagon. These results indicate that, in patients with hepatic dysfunction, little insulin is being removed by the liver from the portal blood except when the insulin secretory rate is unusually high.

Kt/V, nutritional parameters, serum cortisol, and insulin growth factor-1 levels and patient outcome in hemodialysis.

Despite many technical advances in dialysis care, morbidity and mortality in chronic hemodialysis patients in the United States remains high. In this study, we analyzed the effects of Kt/V, nutritional parameters (serum albumin level, triceps skin-fold thickness, mid-arm muscle circumference, and normalized protein catabolic rate), and predialysis serum cortisol and insulin growth factor-1 levels on predicting morbidity and mortality. The cohort studied consisted of 52 patients recruited from a single outpatient dialysis facility. Cox proportional hazards modeling indicated that only Kt/V predicted subsequent mortality (P = 0.02), while both predialysis cortisol levels (P = 0.03) and Kt/V (P = 0.03) predicted hospitalization. Kaplan-Meier analysis demonstrated that the ability of cortisol levels to predict hospitalization was largely confined to the group with values greater than 22 micrograms/dL predialysis. High serum cortisol levels were correlated with low serum albumin levels and a trend toward low triceps skin-fold thickness and higher normalized protein catabolic rate, suggesting a catabolic state. Both predialysis serum cortisol and insulin growth factor-1 levels were higher than those in age- and sex-matched normal human controls. These results demonstrate the importance role of Kt/V in predicting subsequent hospitalization rates and mortality, and that high predialysis serum cortisol levels correlate with a high hospitalization rate.

Multiple-dose pharmacokinetics of piperacillin and azlocillin in 12 healthy volunteers.

The pharmacokinetic profile of piperacillin and azlocillin after multiple-dose administration to healthy volunteers was studied. Twelve healthy volunteers received either piperacillin 4 g (as the sodium salt) or azlocillin 4 g (as the sodium salt) as a 20-minute infusion every six hours for five doses. After a one-week washout period, subjects received identical treatment with the alternate drug. Serum and urine concentrations of piperacillin and azlocillin were measured using a reversed-phase high-performance liquid chromatographic assay, and the pharmacokinetic analysis of serum concentration-versus-time data was performed using a computerized program. A standard open-model equation for i.v. infusions was used. Mean serum concentrations of piperacillin and azlocillin after dose 5 were 344 +/- 66 micrograms/mL and 414 +/- 86 micrograms/mL, respectively. The terminal elimination half-life of azlocillin (1.1 +/- 0.2 hr) was significantly longer than that of piperacillin (0.75 +/- 0.13 hr) (p less than 0.05). Total body clearance of azlocillin (125 +/- 25 mL/min) was significantly less than that of piperacillin (226 +/- 43 mL/min) after dose 5. Azlocillin showed accumulation between the first and fifth doses. Twelve hours after administration of dose 5, 75% of azlocillin and 57% of piperacillin were excreted unchanged into the urine. In healthy volunteers, azlocillin produced higher and more prolonged serum concentrations than piperacillin after administration of equivalent i.v. doses. Further studies are needed to determine the clinical importance of these observations.

A detailed investigation of circulating IgE levels in a normal population.

Total circulating IgE levels were measured in a carefully selected normal population, using a highly sensitive double antibody assay. The mean level of 36.3 u/ml found in this group is much lower than that reported in all previous studies. No circadian rhythm was evident, but IgE levels varied slightly from day-to-day. IgE levels in 100 serum samples were compared using the double antibody assay and the Phadebas test kit, based on a solid phase technique. A poor correlation was obtained with values below 100 u/ml, however, there was an excellent correlation for samples with IgE levels above this figure.

Restrictions in the response to autologous thyroglobulin in the human.

Fragments of thyroglobulin containing the autoreactive epitopes were prepared by an existing procedure, plus an ion-exchange chromatography step which increased their purity. Before purification, 39% of the fragmental material was bound by rabbit anti-human thyroglobulin whereas only 8% was bound by autoantibody, thus confirming earlier reports of more limited epitopes for human autoantibodies than heterologous antibody. Thyroglobulin autoantibodies in the globulin fractions from six human sera showed between 70 and 100% cross-reaction with one another, indicating that the majority of antibodies are directed against the same epitopes. The data are consistent with an estimated of two distinct major epitopic specificities with occasional sera having antibodies directed against a third site. Chemical modification of tyrosine residues by iodination did not inhibit the binding of thyroglobulin to either human autoantibodies or rabbit anti-human thyroglobulin; thus tyrosine residues do not contribute significantly to the epitopes for either auto- or heteroantibodies.