Parents' experiences with sequencing of all known pediatric cancer predisposition genes in children with cancer.

PURPOSE: Germline DNA sequencing is increasingly used within pediatric oncology, yet parental experiences remain underexplored. METHODS: Parents of children undergoing cancer predisposition gene panel sequencing (143 genes) were surveyed before and after disclosure of results. Questionnaires assessed knowledge, expectations, worries, satisfaction, and regret. Next to descriptives, linear mixed models and generalized mixed models were utilized to explore factors associated with knowledge and worries. RESULTS: Out of 325 eligible families, 310 parents (176 mothers and 128 fathers of 188 families) completed all after-consent questionnaires whereas 260 parents (150 mothers and 110 fathers of 181 families) completed all after disclosure questionnaires. Most parents hoped their participation would benefit others, although individual hopes were also common. Sequencing-related worries were common, particularly concerning whether their child would get cancer again, cancer risks for family members and psychosocial implications of testing. Parental satisfaction after disclosure was high and regret scores were low. Lower education was associated with lower knowledge levels, whereas foreign-born parents were at increased risk of experiencing worries. CONCLUSION: Germline sequencing of children with cancer is generally well received by their parents. However, careful genetic counseling is essential to ensure that parents are adequately informed and supported throughout the process.

Outcomes of ulna shortening osteotomy: a cohort analysis of 106 patients.

BACKGROUND: Ulna shortening osteotomy (USO) for ulnar impaction syndrome (UIS) aims to improve pain and function by unloading the ulnar carpus. Previous studies often lack validated patient-reported outcomes or have small sample sizes. The primary objective of this study was to investigate patient-reported pain and hand function at 12 months after USO for UIS. Secondary objectives were to investigate the active range of motion, grip strength, complications, and whether outcomes differed based on etiology. MATERIALS AND METHODS: We report on 106 patients with UIS who received USO between 2012 and 2019. In 44 of these patients, USO was performed secondary to distal radius fracture. Pain and function were measured with the Patient Rated Wrist/Hand Evaluation (PRWHE) before surgery and at 3 and 12 months after surgery. Active range of motion and grip strength were measured before surgery and at 3 and 12 months after surgery. Complications were scored using the International Consortium for Health Outcome Measurement Complications in Hand and Wrist conditions (ICHAW) tool. RESULTS: The PRWHE total score improved from a mean of 64 (SD = 18) before surgery to 40 (22) at 3 months and 32 (23) at 12 months after surgery (P < 0.001; effect size Cohen's d = -1.4). There was no difference in the improvement in PRWHE total score (P = 0.99) based on etiology. Also, no clinically relevant changes in the active range of motion were measured. Independent of etiology, mean grip strength improved from 24 (11) before surgery to 30 (12) at 12 months (P = 0.001). Sixty-four percent of patients experienced at least one complication, ranging from minor to severe. Of the 80 complications in total, 50 patients (47%) had complaints of hardware irritation, of which 34 (32%) had their hardware removed. Six patients (6%) needed refixation because of nonunion. CONCLUSION: We found beneficial outcomes in patients with UIS that underwent USO, although there was a large variance in the outcome and a relatively high number of complications (which includes plate removals). Results of this study may be used in preoperative counseling and shared decision-making when considering USO. LEVEL OF EVIDENCE: Therapeutic III.

If it ain't broke don't fix it? Ethics of splinting deformed newborn ears.

Neonatal ear splinting is a proven and safe method to mold deformed ears into a more common shape. Based on our earlier studies, splinting is recommended only before the age of six weeks and preferably within the first week after birth. This can be done by initiating a system in which this intervention is actively proposed to parents. In this paper, we ethically evaluate such a system. By molding perfectly healthy newborn ears, we reach the boundary between treatment and enhancement. A key question is, therefore, whether we could classify neonatal ear splinting as a therapy. On the level of the individual, the advantages outweigh the drawbacks, but on the level of society, it is more complicated. Making ear deformities a part of official national screening programs fails to meet WHO criteria. Moreover, by systematically offering ear molding, professionals may be promoting guilt or fear of missing the opportunity. Additionally, it could affect societal attitudes toward cosmetic deformities. However, if we argue that on the individual level infants may benefit from ear splinting, then active detection of ear deformities allows parents to choose in a timely way from the full range of options, including splinting and a wait-and-see approach. We are inclined to optimally inform parents without setting up a full-blown public health program. The extent to which it is possible to timely offer splints to parents of newborns depends on the infrastructure of health care systems. The key will be for everyone involved, public or commercial, to responsibly educate and facilitate.

Transient thyroiditis after parathyroidectomy for tertiary hyperparathyroidism.

Thyrotoxicosis due to thyroiditis is predominantly caused by infection or autoimmune disease of the thyroid. Parathyroid surgery however, is a lesser known cause of thyroiditis, due to thyroid manipulation. We treated a patient who developed transient symptomatic thyroiditis following parathyroid surgery for tertiary hyperparathyroidism. Therefore, the differential diagnosis for patients with symptoms after parathyroid surgery should include transient thyroiditis.

Managing unsolicited findings in genomics: A qualitative interview study with cancer patients.

OBJECTIVE: Next-generation sequencing (NGS) is increasingly being employed in the context of personalized cancer treatment. Anticipating unsolicited findings that may arise during a NGS procedure is a key consideration; however, little is known about cancer patients' intentions, needs, and preferences concerning the return of unsolicited findings. METHODS: A qualitative design using individual semi-structured interviews with 24 cancer patients was utilized to explore patients' decisions on whether to receive unsolicited findings from NGS. These interviews were subsequently analyzed using the constant comparative method to develop codes and themes. RESULTS: We identified 4 interrelated themes that emerged in the context of the return of unsolicited findings. First, we describe how cancer patients expressed a strong need to control their lives. Second, we show the importance of family dynamics. Third, the NGS procedure regarding unsolicited findings is perceived as cognitively complex, and fourth, the procedure is also considered emotionally complex. CONCLUSIONS: The results of our study contribute to a better understanding of what cancer patients consider important and what may motivate and influence them when making decisions on the disclosure of unsolicited findings following NGS. We show how Joel Feinberg's classification of autonomy may help clinicians to better understand cancer patients' desire for autonomous decision making while also acknowledging the emotional and cognitive difficulties regarding the disclosure of unsolicited findings. These insights could be helpful for clinicians to guide patients through this complex process.

[Missed hyperinsulinaemia in a patient with an insulinoma]. / Gemiste hyperinsulinemie bij een patiënt met insulinoom.

In a 57-year-old man with symptomatic hypoglycaemias which gave cause to suspect an insulinoma, normal insulin levels were initially found. A repeated fasting assay at another hospital did, however, reveal the expected hyperinsulinaemia. Scans revealed an abnormality in the pancreas. After surgical removal of the insulin-producing tumour the patient made a quick recovery. The diagnosis of organic hyperinsulinaemia is established by demonstrating inappropriately high serum-insulin concentrations during fasting hypoglycaemia. The diagnostic normative values are based on the classic polyclonal method of determination. This new highly-specific insulin assay has no cross-reactivity with pro-insulin, which is often produced disproportionately more by an insulinoma. As a result of this false-normal insulin values are found. Therefore new normative values are needed for the newer insulin assays when diagnosing an insulin-producing islet cell tumour. Pro-insulin and C-peptide assays may play a useful role in this.

Protective effect of the bile salt hydrolase-active Lactobacillus reuteri against bile salt cytotoxicity.

Bacterial bile salt hydrolysis is considered a risk factor for the development of colon cancer because of the risk of forming harmful secondary bile salts after an initial deconjugation step. In this study, the influence of enhanced bacterial bile salt transformation by the bile salt hydrolase-active Lactobacillus reuteri was studied in batch culture using the microbial suspension of the Simulator of the Human Intestinal Microbial Ecosystem; (SHIME), which was supplemented with oxgall at 5 g/l or 30 g/l. Changes in the fermentative capacity of the microbial ecosystem and the (geno)toxic properties of the SHIME supernatants were investigated. Increasing concentrations of oxgall inhibited the fermentation. Transient cell toxicity was observed for samples supplemented with 5 g oxgall/l, while samples with 30 g oxgall/l exhibited toxicity. The results of the haemolysis test suggest that the detrimental effects were probably due to the membrane-damaging effects of bile salts. In all cases, the adverse effects could be counteracted by the addition of 7.5 +/- 0.5 log10 CFU L. reuteri/ml. Plausible mechanisms for the protective properties of L. reuteri could involve a precipitation of the deconjugated bile salts and a physical binding of bile salts by the bacterium, thereby making the harmful bile salts less bioavailable.

Pitfall of the accessory spleen.

Two patients, one with insulinoma and one with Cushing's syndrome, are presented. Biochemical evaluation readily suggested the correct diagnosis. During radiologic imaging, the anatomic abnormality giving rise to these diseases, i.e. a pancreatic islet cell tumor, and an adrenal adenoma, at first were mistakenly interpreted as an accessory spleen on the basis of specific computed tomography and magnetic resonance imaging appearances. The insulinoma was identified as such during laparotomy, whereas additional jodo-cholesterol scintigraphy revealed the real nature of the lesion in the patient with Cushing's syndrome. Both patients were operated successfully.

Osteopenia and osteoporosis in Crohn's disease: prevalence in a Dutch population-based cohort.

Reduced bone mineral density (BMD) has been reported in 3-77% of patients with inflammatory bowel disease (IBD). The majority of these studies are cross-sectional and from tertiary referral centres. The aim of our study was to estimate the prevalence of metabolic bone disease and of symptomatic fractures in a population of patients with Crohn's disease (CD) living in a well-defined geographic area. Patients with CD living in three adjacent municipalities within the IBD South-Limburg study area were investigated. BMD was measured by dual X-ray absorptiometry (DXA) of the femoral neck, lumbar spine and total body. The population comprised of 181 CD patients, 23 of whom were excluded. One-hundred-and-nineteen (75%) of the 158 eligible patients (37 males, 82 females with a mean age of 42 years (17-78)) were investigated. Osteopenia of lumbar spine and/or femoral neck was found in 45% of patients. Osteoporosis was found in another 13% of patients. Mean BMD (T-score) of femoral neck was significantly lower than of lumbar spine (P < 0.001). Male CD patients and patients aged under 18 at diagnosis are more at risk of having a low bone mass at the lumbar spine (P < 0.001) and total body (P = 0.018). The prevalence of osteoporosis in postmenopausal CD patients (29%) was significantly higher than in premenopausal patients (3%) (odds ratio: 12). Twenty-nine of 119 (24%) patients had a history of symptomatic fractures. Osteopenia and osteoporosis are frequent in CD and should have the full attention of the treating physician.

Agonistic properties of alniditan, sumatriptan and dihydroergotamine on human 5-HT1B and 5-HT1D receptors expressed in various mammalian cell lines.

1. Alniditan, a novel migraine abortive agent, is a potent 5-HT1B/5-HT1D receptor agonist of nM affinity. We compared the agonistic properties of alniditan, sumatriptan and dihydroergotamine on the cloned human 5-HT1B receptor expressed at 200 fmol mg(-1) protein (Bmax) in non-induced L929sA cells, at 740 fmol mg(-1) protein in HEK 293 and at 2300 fmol mg(-1) protein in mIFNbeta-induced L929sA cells, and on the human cloned 5-HT1D receptor expressed in C6 glioma cells (Bmax 780 fmol mg(-1) protein). 2. Sodium butyrate treatment increased the expression level of human (h)5-HT1B receptors in HEK 293 cells and h5-HT1D receptors in C6 glioma cells approximately 3 fold, the binding affinities of [3H]-5-HT and [3H]-alniditan were unaffected. 3. Agonistic properties were evaluated based on inhibition of cyclic AMP accumulation in the cells after stimulation of adenylyl cyclase by forskolin or isoproterenol. Alniditan, sumatriptan and dihydroergotamine were full agonists at the hS-HT1B receptor (IC50 values were 1.7, 20 and 2 nM, respectively in HEK 293 cells) and hS-HT1D receptors (IC50 values of 1.3, 2.6 and 2.2 nM, respectively). At the h5-HT1B receptor the agonist potency of the compounds slightly increased with higher receptor density. The opposite was seen for antagonists (ocaperidone, risperidone and ritanserin). 4. This comparative study demonstrated that alniditan was 10 times more potent than sumatriptan at the h5-HT1B receptor, and twice as potent at the h5-HT1D receptor. Dihydroergotamine was more potent an agonist at the h5-HT1B receptor when expressed at high and low level in L929sA cells (but not in HEK 293 cells), and was less potent at the hS-HT1D receptor.

Cerebral relapse of sarcoidlike Whipple's disease.

Whipple's disease, an infection with the recently identified intracellular bacillus Tropheryma whippelii, is a systemic disorder that can be life threatening when untreated. In a few patients, the signs and symptoms of the disease are similar to those of sarcoidosis, and this illness is referred to as sarcoidlike Whipple's disease. This variant must be recognized because patients with sarcoidlike Whipple's disease must be treated with antibiotics instead of corticosteroids, which would be indicated for patients with true sarcoidosis. We describe a 53-year-old man who had sarcoidlike Whipple's diseases with polyvisceral granulomatous dissemination that was treated with procaine penicillin G and streptomycin followed by doxycycline. His condition initially improved. However, during his 4-month course of treatment he developed a cerebral relapse; this relapse was successfully treated with ceftriaxone and cefixime.

Alniditan, a new 5-hydroxytryptamine1D agonist and migraine-abortive agent: ligand-binding properties of human 5-hydroxytryptamine1D alpha, human 5-hydroxytryptamine1D beta, and calf 5-hydroxytryptamine1D receptors investigated with [3H]5-hydroxytryptamine and [3H]alniditan.

Alniditan is a new migraine-abortive agent. It is a benzopyran derivative and therefore structurally unrelated to sumatriptan and other indole-derivatives and to ergoline derivatives. The action of sumatriptan is thought to be mediated by 5-hydroxytryptamine (5-HT)1D-type receptors. We investigated the receptor-binding profile in vitro of alniditan compared with sumatriptan and dihydroergotamine for 28 neurotransmitter receptor subtypes, several receptors for peptides and lipid-derived factors, ion channel-binding sites, and monoamine transporters. Alniditan revealed nanomolar affinity for calf substantia nigra 5-HT1D and for cloned h5-HT1D alpha, h5-HT1D beta and h5-HT1A receptors (Ki = 0.8, 0.4, 1.1, and 3.8 nM, respectively). Alniditan was more potent than sumatriptan at 5-HT1D-type and 5-HT1A receptors. Alniditan showed moderate-to-low or no affinity for other investigated receptors; sumatriptan showed additional binding to 5-HT1F receptors. Dihydroergotamine had a much broader profile with high affinity for several 5-HT, adrenergic and dopaminergic receptors. In signal transduction assays using cells expressing recombinant h5-HT1D alpha, h5-HT1D beta, or h5-HT1A receptors, alniditan (like 5-HT) was a full agonist for inhibition of stimulated adenylyl cyclase (IC50 = 1.1, 1.3, and 74 nM, respectively, for alniditan). Therefore, in functional assays, the potency of alniditan was much higher at 5-HT1D receptors than at 5-HT1A receptors. We further compared the properties of [3H]alniditan, as a new radioligand for 5-HT1D-type receptors, with those of [3H]5-HT in membrane preparations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [3H]Alniditan revealed very rapid association and dissociation binding kinetics and showed slightly higher affinity (Kd = 1-2 nM) than [3H]5-HT. We investigated 25 compounds for inhibition of [3H]alniditan and [3H]5-HT binding in the three membrane preparations; Ki values of the radioligands were largely similar, although some subtle differences appeared. Most compounds did not differentiate between 5-HT1D alpha and 5-HT1D beta receptors, except methysergide, ritanserin, ocaperidone, risperidone, and ketanserin, which showed 10-60-fold higher affinity for the 5-HT1D alpha receptor. The Ki values of the compounds obtained with 5-HT1D receptors in calf substantia nigra indicated that these receptors are of the 5-HT1D beta-type. We demonstrated that alniditan is a potent agonist at h5-HT1D alpha and h5-HT1D beta receptors; its properties probably underlie its cranial vasoconstrictive and antimigraine properties.

Sternitis and mediastinitis after coronary artery bypass grafting. Analysis of risk factors.

As part of a quality control program, we analyzed possible risk factors in the development of sternitis and mediastinitis after coronary artery bypass grafting. From 1 January 1990 through 31 December 1991, 1,368 consecutive coronary artery bypass grafting procedures were performed at our institution, either alone or in combination with other procedures. Twenty-three patients (1.7%) developed sternitis and/or mediastinitis; 7 (30.4%) of these patients died in an early postoperative phase. Univariate analysis revealed the following statistically significant (p < or = 0.05) risk factors: perfusion time, length of stay in operating room of longer than 5 hours 30 minutes, presence at the operation of a certain surgical resident, revision for bleeding, and postoperative mechanical ventilation lasting longer than 72 hours. After multivariate analysis, statistically significant independent risk factors were: diabetes mellitus, recent cigarette-smoking, reoperation, presence of a certain surgical resident at the operation, revision for bleeding, and length of mechanical ventilation of longer than 72 hours. The use of both internal thoracic arteries was not, in this study, shown to be an independent risk factor. We conclude that although the technique of using both internal thoracic arteries for myocardial revascularization carries no extra risk by itself in the development of sternitis or mediastinitis, associated factors such as prolonged stay in the operating room and reoperation could be responsible for a higher frequency of sternitis-mediastinitis in patients who have undergone this procedure. Therefore, it is advisable to use this technique selectively in high-risk patients. Close surveillance and reporting of wound infections is mandatory to detect risk factor related to the surgical staff (such as Staphylococcus aureus dissemination).

On the maturation order of AML cells: a distinction on the basis of self-renewal properties and immunologic phenotypes.

To investigate the heterogeneous cellular structure of human acute myeloid leukemia (AML), subpopulations of cells were distinguished by two combined criteria: proliferation and differentiation. Purified blast cells were fractionated from blood or bone marrow of patients with newly diagnosed AML and colonies and clusters grown in phytohemagglutinin (PHA)-leukocyte feeder cultures. Large colonies, small colonies, macroclusters, and microclusters were recloned separately to assess the replicative capacities as a function of clone size. Large colonies showed higher proliferative capacities than did small ones, etc. Anti-Ia and an antigranulocyte (B4.3) monoclonal antibody (MoAb) were then employed to evaluate the stage of differentiation of AML cells in two patients before and following colony culture. Alterations of the immunologic phenotypes appeared during colony formation. This suggested differentiation of cells to more mature B4.3 granulocyte antigen-positive stages. MoAb-dependent cell lysis with the two antibodies was subsequently performed to assess the phenotypes of the precursors of the colonies and clusters. Leukemic colony-forming cells were Ia-positive and B4.3-negative and different from cluster-forming cells, which were largely Ia-negative and B4.3-negative. These data suggest that the cell organization of AML fits a maturation scheme containing immature cells with relatively high proliferative capacities, intermediate cells with low proliferative capacities, and end cells that are nonreplicative, and each with specific phenotypes.