Biological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors

We report cytogenetic findings in 19 c-Kit-positive gastrointestinal stromal tumors (GISTs) that represent a heterogenous group of mesenchymal neoplasms with respect to site, histology, and biologic behavior. All of the GISTs (5 low-risk, 11 high-risk, 3 recurrences) displayed clonal chromosomal aberrations; 15 were hypo- to near-diploid, and 4 were near-triploid and hypotetraploid. The most common abnormalities were loss of chromosomes 14 and/or 22, demonstrated in 14 GISTs irrespective of site or predominant phenotype. Ten cases (2 low-risk, 5 high-risk, 3 recurrences) were characterized by loss of both chromosomes 14 and 22, 2 cases (1 low-risk, 1 high- risk), by loss of chromosome 14; and 2 high-risk cases, by loss of chromosome 22. Additional chromosomal aberrations occurred preferentially in high-risk and recurrent GISTs, including loss of 9p and 1p in 8 cases each, loss of 15 in 6 cases, loss of 3p in 5 cases, loss of 13q and 10q in 4 cases each, loss of 19 in 3 cases, and complete or partial gains of chromosomes 5 and 4 in 2 cases each. More significantly, 5 of 6 patients with clinically aggressive GISTs, including 2 recurrences and 3 metastasing GISTs, were additionally characterized by loss of 9p; four of these had additional loss of chromosomes 1p and 15. The presented results herein indicate that loss of chromosome 14 and/or 22 is an early change in GIST tumorigenesis irrespective of site or differentiation, whereas malignant transformation and progression of GISTs appear to be associated with an increasing incidence of additional secondary aberrations.     

Cerebellar subjects show impaired coupling of reach and grasp movements

We examined how cerebellar deficits in isolated reaching or grasping movements contribute to abnormalities in a combined reach and grasp movement, and whether people with cerebellar damage show abnormalities in the spatiotemporal relationships of reach and grasp movements. We studied subjects with cerebellar damage and matched controls as they performed a combined reach and grasp, an isolated reach, and an isolated grasp. These movements were performed under slow-accurate and fast speed conditions. Subjects were also tested for their ability to correctly estimate the target size based on visual information. We measured the three-dimensional position of the index finger, thumb and wrist joint during all tasks. Results showed that cerebellar subjects overestimated the target size to a greater extent than did controls. During movement testing, cerebellar subjects were impaired on isolated reach and isolated grasp. However, they did not worsen parameters of reach or grasp movements during the combined reach and grasp. Instead there were distinct deficits in the coupling of the reach and grasp movement. Compared with controls, cerebellar subjects showed abnormalities in the sequence of the reach and grasp movement and highly variable timing of peak grip aperture. In the slow-accurate condition, cerebellar subjects decomposed the reach and grasp movement into separate reach then grasp components, and produced multiple peaks in grip aperture. In the fast condition, cerebellar subjects did not decompose, produced a single peak grip aperture, and dropped the target more often. These results indicate that cerebellar damage can cause a specific breakdown in the coupling of reach and grasp movements. The cerebellum may be involved in combining reach and grasp movements into a single motor program.     

Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas

Large congenital melanocytic nevi (CMN) are at an increased risk of developing melanoma. Several forms of secondary proliferations can arise in congenital nevi on rare occasions. Although some of these closely resemble melanoma both clinically and histologically, metastasis is rare. We used comparative genomic hybridization to analyze chromosomal aberrations in different types of proliferations arising in CMN and compared them to typical congenital nevi, clear-cut melanomas arising in congenital nevi, as well as primary cutaneous melanomas that were not associated with a CMN. Cases of CMN and CMN with secondary proliferations were assigned to six groups according to the predominant histological pattern: group I, bland congenital nevi (n = 6); group II, congenital nevi with foci of increased cellularity (n = 4); group III, CMN with a proliferation simulating superficial spreading melanoma in situ (n = 3); group IV, CMN with a proliferation simulating nodular melanoma (n = 9); group V, proliferating neurocristic hamartoma (n = 1); and group VI, melanoma arising in congenital nevus (n = 6). No aberrations were found in groups I to III, whereas seven of nine cases of group IV, and one of one case of group V, showed aberrations. In group IV six of seven cases with aberrations (86%) showed numerical aberrations of whole chromosomes exclusively. This pattern differed significantly from the findings in melanoma that arose within CMN (n = 6), group VI, or independent of CMN (n = 122) in which only 5% showed numerical changes only. The single case in group V showed aberrations similar to melanoma. The finding of frequent numerical chromosomal aberrations in atypical nodular proliferations arising in CMN identifies these as clonal neoplasms with a genomic instability consistent with a mitotic spindle checkpoint defect. This difference compared to the aberration pattern found in melanoma might explain their more benign clinical behavior and may be of diagnostic value in ambiguous cases.     

Long-term effects of infant rearing condition on the acquisition of dominance rank in juvenile and adult rhesus macaques (Macaca mulatta)

We examined the effects of early rearing experience on the development of dominance status in 53 juvenile (age 3) and then in 38 adult (ages 5-8) rhesus macaques. Based on previous research investigating the behavioral outcomes of nursery-rearing, we predicted that mother-reared (MR) monkeys would outrank peer-only reared (PR) monkeys, which would in turn outrank surrogate/peer-reared (SPR) subjects. Juvenile MR and PR subjects did not differ in ranks, but monkeys from both rearing backgrounds outranked SPR cage-mates at age 3. Independent of rearing condition, high-ranking juveniles gained the most weight between ages 1-3, suggesting that low status may be associated with decreases in early weight gain. Adult MR subjects outranked both PR and SPR subjects, with PR animals occupying intermediate ranks. These results indicate that impoverished early experiences, such as adult absence and limited social interaction, are useful predictors of future social success in rhesus macaques.     

Characterization of a reduced peptide bond analogue of a promiscuous CD4 T cell epitope derived from the Plasmodium falciparum malaria vaccine candidate merozoite surface protein 1

Use of synthetic peptides as vaccine components is hampered by their susceptibility to enzymatic degradation and rapid clearance from biological fluids. Introduction of non-natural structural modifications can render peptides more resistant to enzymatic degradation, encouraging attempts to profile such non-natural ligands as components of synthetic sub-unit vaccines. We have compared the antigenic and immunogenic properties of a series of non-natural peptide analogues derived from a promiscuous T cell epitope of the major Plasmodium falciparum malaria vaccine candidate merozoite surface protein 1 (MSP-1). A series of HLA class II restricted MSP-1(38-58)-specific TCC established from three volunteers were characterized for their minimal epitope and fine specificity. T cell stimulatory activities of a series of pseudo-peptide analogues with single reduced peptide bond Psi-[CH2-NH] modifications were compared with those of single d-amino acid replacement analogues. Compared to reduced peptide bond analogues the single d-amino acid replacement analogues turned out to be less suitable for stimulation of TCC. In particular, the reduced peptide analogue carrying a Psi-[CH2-NH] backbone modification between positions V52 and L53 of MSP-1(38-58) demonstrated properties that would make it a more suitable vaccine component than the unmodified parent peptide. First, the pseudo-peptide stimulated a number of TCC restricted by a range of HLA class II alleles. Second, trypsin treatment in combination with T cell stimulation assays provided evidence for increased resistance to proteolytic digestion. Third, the parasite-binding anti-MSP-1 mAb 7.27 recognized best this particular pseudo-peptide in competition ELISA experiments and its immunogenicity in out-bred Aotus monkeys was superior to that of the parent peptide eliciting antibodies cross-reactive with native MSP-1.     

Relative contributions of balance and voluntary leg-coordination deficits to cerebellar gait ataxia

Different cerebellar regions participate in balance control and voluntary limb coordination, both of which might be important for normal bipedal walking. We wanted to determine the relative contributions of balance versus leg-coordination deficits to cerebellar gait ataxia in humans. We studied 20 subjects with cerebellar damage and 20 control subjects performing three tasks: a lateral weight-shifting task to measure balance, a visually guided stepping task to measure leg- coordination, and walking. We recorded three-dimensional joint position data during all tasks and center of pressure coordinates during weight-shifting. Each cerebellar subject was categorized as having no detectable deficits, a balance deficit only, a leg-placement deficit only, or both deficits. We then determined the walking abnormalities associated with each of these categories. Five of 10 measures of gait ataxia were abnormal in cerebellar subjects with a balance deficit, but only 1 was abnormal in cerebellar subjects with a leg-placement deficit. Furthermore, subjects with a balance deficit performed worse than subjects with a leg-placement deficit on 9 of the 10 gait measures. Finally, performance on the balance task, but not the leg-placement task, explained a significant proportion of the variance in walking speed for the entire cerebellar group. We conclude that balance deficits are more closely related to cerebellar gait ataxia than leg-placement deficits. Our findings are consistent with animal literature, which has suggested that cerebellar control of balance and gait are interrelated, and dissociable from cerebellar control of voluntary, visually guided limb movements.     

A limited-sampling method for evaluation of the area under the curve of ultrafilterable carboplatin in children

Carboplatin is a widely used cytotoxic agent in numerous solid tumors of children. Since there is a large degree of interpatient variability in the area under the curve of free carboplatin for a given dose of the drug, the current tendency is to adjust the carboplatin dose so as to reach a target area under the curve rather than to determine a carboplatin dose on the basis of the body surface area. A limited-sampling method was developed for estimation of the ultrafilterable carboplatin area under the curve and for adjustment of the carboplatin dose on subsequent treatments. Population parameters were obtained from 16 children (reference group). We used the maximum a posteriori (MAP) Bayesian approach on 15 children with complete carboplatin pharmacokinetic data (test group). Two blood samples were sufficient to obtain reliable prediction of the area under the curve. The best sampling times were: (a) 30 min after the end of the infusion and (b) 5 h after the end of the infusion. On the basis of these data it is possible to prescribe prospectively a target area under the curve for free carboplatin given in a fractionated daily infusion and to adapt the carboplatin dose directly to ultrafilterable carboplatin measurements. Received: 8 June 1997 / Accepted: 9 January 1998     

Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial

Background: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity.Patients and methods: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined.Results: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent.Conclusions: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase I trials of S9788 infused over six hours precluded the further clinical development of S9788.     

Tuberculosis notifications in Australia, 2003.

The National Notifiable Disease Surveillance System (NNDSS) received 982 tuberculosis (TB) notifications in 2003, of which 947 were new cases, 33 were relapses and two were cases with unknown history. The incidence of TB in Australia has remained at a stable rate since 1985 and was 4.9 cases per 100,000 population in 2003. The high-incidence groups remain people born overseas and Indigenous Australians at 19.9 and 8.7 cases per 100,000 population, respectively. By contrast the incidence in non-Indigenous Australians was 0.9 per 100,000. Comparison of the 2003 TB notification data against the performance indicators set by National Tuberculosis Advisory Committee highlights that enhanced TB control measures should be considered among these high-risk groups.     

Assessment of Left Ventricular Size and Function during Cardiac Surgery. An Intraoperative Evaluation of Six Two‐Dimensional Echocardiographic Methods with Real Time Three‐Dimensional Echocardiography as a Reference

Transesophageal echocardiography is recommended to monitor left ventricular (LV) size and function in various operations. Generally, two‐dimensional (2D) methods are applied intraoperatively. The aim of this study was to compare the accuracy and feasibility of 6 commonly used 2D methods to assess LV function during surgery. LV function in 120 consecutive patients was evaluated. Real time three‐dimensional transesophageal echocardiograpy (3DTEE) served as reference. End‐diastolic and end‐systolic volumes and ejection fraction (EF) were analyzed with Simpson's method of discs (monoplane [MP] and biplane [BP]), eyeball method, Teichholz' method, and speckle tracking (ST) methods. Furthermore, fractional area change (FAC) and peak systolic pressure rise (dP/dt) were determined. Each 2D method was evaluated regarding correlation and agreement with 3DE, intra‐ and interobserver variability and the time required for evaluation. Simpson BP showed the strongest correlation and best agreement with 3DE for EF (limits of agreement 3.7 ± 11.6%) and volumes. Simpson MP showed similar agreement with 3DE compared to ST (2.8 ± 14.5% vs. 2.0 ± 15.3% and 3.8 ± 14.4% vs. 1.9 ± 15.6%, respectively). Both the eyeball method and Teichholz' method showed wide limits of agreement (?1.5 ± 18.2% and 5.2 ± 22.1%, respectively). DP/dt did not correlate with 3DE. FAC and ST FAC showed similar agreement. Application of 3DE (429 ± 108 seconds) took the longest time, and the eyeball method took the shortest time (8 ± 5 seconds) for analysis. Simpson BP is the most accurate intraoperative 2D method to evaluate LV function, followed by long‐axis MP evaluations. Short‐axis views were less accurate but may be suited for monitoring. We do not recommend using dP/dt.