Tissue collection for correlative studies in childhood cancer clinical trials: ethical considerations and special imperatives.

Federal regulations prescribe distinct protections for children participating in research studies. Procedures for collecting tissue specimens from children solely for research purposes must pose no more than a minor increase over minimum risk, thereby limiting the approvable correlative biologic studies to evaluate molecularly targeted agents in children with cancer. Ethical issues arise when approvable correlative studies are a mandatory component of an early-phase pediatric clinical trial of new anticancer agents. The National Cancer Institute Cancer Therapy Evaluation Program sponsored a workshop in 2002 to discuss tissue collection for correlative biologic studies in early-phase childhood cancer clinical studies of molecularly targeted agents. Workshop participants recommended the following: (1) tissue specimens for correlative studies should provide vital clinical and scientific results to qualify for early-phase pediatric study consideration; (2) parents should receive a realistic appraisal of the risks, requirements, and potential for benefit of phase I protocol participation; (3) investigators should clearly distinguish clinically necessary procedures from research procedures of no benefit to the child to improve correlative study informed consent; and (4) participation in correlative research studies included in clinical trials generally should be voluntary. The need to acquire important biologic data regarding new molecular agents will challenge the ingenuity of pediatric cancer researchers, necessitating the application of highly sensitive laboratory assay methods, new imaging procedures, and preclinical models of childhood cancer. Such innovative methods can allow necessary scientific information to be obtained while simultaneously respecting the protections appropriately afforded to children participating in research studies and minimizing the burden of research participation for children with cancer and their families.     

Quantitative analysis of surface EMG activity of cranial and leg muscles across sleep stages in human.

OBJECTIVE: The aim of this study was to make a quantitative analysis of the changes in cranial and limb muscle activity from wakefulness to light and deep sleep stages and during rapid eye movement (REM) sleep of normal subjects. METHODS: Polysomnographic recordings were made of the sleep of 9 healthy human subjects, including electromyograms of the suprahyoid, temporalis and masseter cranial muscles and the anterior tibialis limb muscle. Quantitative assessments of EMG activity were carried out with root mean square (RMS) and frequency-spectral analysis (FSA) methods. RESULTS: From wakefulness to sleep, a significant reduction (-25.2 to -71.2%; P < 0.01) was observed in EMG activity (for both RMS and FSA) of the 3 cranial muscles using both methods of analysis. The EMG activity of suprahyoid muscle further decreased from non-REM to REM sleep (-17.8 to -43.0%; P < 0.01). In contrast, the EMG activity of the anterior tibialis muscle was only slightly reduced across sleep stages and did not further reduce during REM sleep. During REM sleep, all the 4 muscles maintained minimal activity. CONCLUSIONS: The maintenance of muscle activity during REM sleep suggests that a minimal level of activity is required to preserve physiological functions (e.g. airway patency, posture) related to homeostasis and bodily protection. SIGNIFICANCE: This study suggests that quantitative sleep EMG analysis is important for understanding the mechanisms of sleep-related movement disorders or when objective assessment of changes in EMG activity are needed for diagnostic purposes or for the assessment of drug efficiency.     

Kidney Disease After Heart and Lung Transplantation

Kidney disease is a commonly recognized complication of heart and lung transplantation and is associated with increased morbidity and mortality. While the spectrum of kidney disease in this population is wide-ranging, studies indicate that between 3% and 10% of these patients will ultimately develop end-stage renal disease (ESRD). This review examines the risk factors for both acute and chronic kidney injury, with a particular emphasis on the role of calcineurin inhibitor-mediated nephrotoxicity in both these settings. Against the background of current National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, we have further considered and recommended appropriate strategies for long-term management of kidney disease-related manifestations in heart and lung transplant recipients. Specific aspects addressed include retarding progressive renal injury and minimizing nephrotoxicity, as well as treatment of hypertension, hyperlipidemia and anemia. Finally, for patients in this population with advanced kidney disease, renal replacement therapy options are discussed. Based on the impact of chronic kidney disease on outcomes in both heart and lung recipients, we advocate early referral to a nephrologist for patients displaying evidence of significant renal dysfunction.     

Difficulties in localization and treatment of insulinomas in type 1 multiple endocrine adenomatosis (MEA).

A 15 year old girl with a family history of type 1 multiple endocrine adenomatosis presented with reversible neurological disturbances, hypoglycaemia and hyperinsulinaemia. Initial radiology was normal, but portal venous sampling suggested an insulinoma in the tail of the pancreas which was removed with conservation of the spleen. Hypoglycaemia persisted despite high doses of diazoxide and intravenous dextrose. A second laparotomy revealed a pancreatic endocrine tumour and sub-total pancreatectomy was performed. Histology revealed islet cell microadenomatosis. Hypoglycaemia persisted despite treatment with somatostatin analogues and 40% intravenous dextrose was required to maintain normoglycaemia. A possible lesion near the splenic hilum on computed tomographic scan was reported as a splenunculus although further peripheral, hepatic and portal venous sampling suggested hepatic or systemic lesions. A positron emission scan and selective visceral angiography suggested a lesion in the left upper quadrant. Acute lactic acidosis, rhabdomyolysis and renal failure supervened. Post mortem revealed the putative ''splenunculus'' to be a residual insulinoma, whilst the splenic vein was thrombosed, accounting in part for discrepant venous sampling data. Hyperinsulinaemia in type 1 multiple endocrine adenomatosis may require more aggressive surgical and hormonal intervention than when dealing with solitary insulinomas. Insulinomas may mimic developmental abnormalities on computed tomographic scanning.     

Inhibitory motor control in children with attention-deficit/hyperactivity disorder: event-related potentials in the stop-signal paradigm.

BACKGROUND: The aim of the study was to investigate the inhibitory control of an ongoing motor response and to identify underlying neural deficiencies, manifested in event-related potentials, that cause poorer inhibitory performance in children with attention-deficit/hyperactivity disorder. METHODS: A stop-signal paradigm with a primary visual task and auditory stop signal was used to compare performance in 13 children with attention-deficit/hyperactivity disorder and 13 control children, while event-related potentials were recorded simultaneously. RESULTS: Children with attention-deficit/hyperactivity disorder showed poorer inhibitory performance through a slower inhibitory process. Inhibitory processing of auditory stop signals was marked by a frontal N2 component that was reduced in the attention-deficit/hyperactivity disorder group relative to controls. A central positive component (P3) was associated with the success of inhibiting a response, but there were no group differences in its amplitude or latency. CONCLUSIONS: Findings support the hypothesis of deficient inhibitory control in children with attention-deficit/hyperactivity disorder. Slower inhibitory processing appears to be due to a specific neural deficiency that manifests in the processing of the stop signal as attenuated negativity in the N2 latency range.     

Sequence specificity of mutation induced by the anti-tumor drug cisplatin in the CHO aprt gene

Cis-diammine dichloroplatinum (cisplatin) is an effective anticancerdrug which forms adducts with DNA, in both bacterial and mammaliancells. It is suspected of producing tumors as well. To determinethe molecular nature of geneti alterations induced by cisplatin,we cloned and sequenced cisplatin-induced mutants in the adeninephosphoribosyl-transferase (aprt) gene of Cinese hamster ovary(CHO) cells. Mutation by cisplatin appears to be targeted asthe sites of mutation are consistent with the known bindingspecificity of cisplatin. Many mutations occur at or proximalto the sequence 5'-AGG-3' and 5'-GAG-3' and include transversions,transitions, frameshifts and short deletions and duplications.Several double changes were also observed. No major rearrangementswere recovered in our collection. At several locations, a numberof mutants were found to be clustered within a small targetregion, but unlike traditional hotspots, tese represent diversechanges occurring in a localized region of a few base pairs.     

Plasma cortisol and natural killer cell activity during bereavement

Natural killer cell (NK) activity, which is important in the defense against tumors and viral infections, is reduced in women undergoing conjugal bereavement. The relationship between NK activity and plasma cortisol was investigated in three groups of subjects: women who were anticipating the death of their husbands, women whose husbands had recently died, and controls. Bereaved women showed reduced NK activity and increased plasma cortisol levels as compared to controls. Anticipatory bereaved women also showed significant reductions in NK activity, but had levels of plasma cortisol comparable to those of controls. The reduction of NK activity during anticipatory and actual bereavement cannot be explained solely on the basis of increased cortisol secretion.     

In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain.

Metastasis (the spread of cancer from a primary tumor to secondary organs) is responsible for most cancer deaths. The ability to follow the fate of a population of tumor cells over time in an experimental animal would provide a powerful new way to monitor the metastatic process. Here we describe a magnetic resonance imaging (MRI) technique that permits the tracking of breast cancer cells in a mouse model of brain metastasis at the single-cell level. Cancer cells that were injected into the left ventricle of the mouse heart and then delivered to the brain were detectable on MR images. This allowed the visualization of the initial delivery and distribution of cells, as well as the growth of tumors from a subset of these cells within the whole intact brain volume. The ability to follow the metastatic process from the single-cell stage through metastatic growth, and to quantify and monitor the presence of solitary undivided cells will facilitate progress in understanding the mechanisms of brain metastasis and tumor dormancy, and the development of therapeutics to treat this disease.