SWI versus GRE-T2*: Assessing cortical superficial siderosis in advanced cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Cortical superficial siderosis (cSS) is a key neuroimaging marker of cerebral amyloid angiopathy (CAA) detected on blood-sensitive magnetic resonance imaging (MRI). We aimed to assess cSS in advanced CAA patients and explore differences in its evaluation between susceptibility weighted imaging (SWI) and gradient recalled echo-T2* (GRE-T2*). MATERIALS AND METHODS: Neuroimaging data gathered from a prospective cohort of CAA patients with probable or definite CAA were retrospectively analyzed by two independent raters. SWI and GRE-T2* were used to assess presence and severity (absent, focal [≤3 sulci] or disseminated [>3 sulci]) of cSS and number of foci. Ratings were compared between sequences and inter-rater agreement was determined. Post hoc analysis explored differences in cSS multifocality scores. RESULTS: We detected cSS in 38 patients with SWI and in 36 with GRE-T2* (70.4% versus 66.7%; P=0.5). The two raters agreed in detecting more disseminated cSS when using SWI: 16 focal (29.63%) and 20 disseminated (37.04%) cases of cSS seen on GRE-T2* and 11 (20.37%) focal and 27 (50%) disseminated cSS cases seen using SWI (P=0.008). Inter-rater agreement was equivalent for the two sequences (κpresence 0.7 versus 0.69; κseverity 0.74 versus 0.66) for assessing both presence and severity of cSS. Post hoc analysis showed higher multifocality scores from both raters' SWI evaluations, with agreement equivalent to that for T2* evaluations. CONCLUSIONS: Our findings suggest that SWI ratings could show more disseminated cSS and higher multifocality scores in advanced CAA patients with inter-rater reliability equivalent to that obtained using GRE-T2*, regardless of level of experience.

Apolipoprotein D: a potential biomarker for cerebral amyloid angiopathy.

AIMS: We investigated the potential of apolipoprotein D (apoD) as cerebrospinal fluid (CSF) biomarker for cerebral amyloid angiopathy (CAA) after confirmation of its association with CAA pathology in human brain tissue. METHODS: The association of apoD with CAA pathology was analysed in human occipital lobe tissue of CAA (n = 9), Alzheimer's disease (AD) (n = 11) and healthy control cases (n = 11). ApoD levels were quantified in an age- and sex-matched CSF cohort of CAA patients (n = 31), AD patients (n = 27) and non-neurological controls (n = 67). The effects of confounding factors (age, sex, serum levels) on apoD levels were studied using CSF of non-neurological controls (age range 16-85 years), and paired CSF and serum samples. RESULTS: ApoD was strongly associated with amyloid deposits in vessels, but not with parenchymal plaques in human brain tissue. CSF apoD levels correlated with age and were higher in men than women in subjects >50 years. The apoD CSF/serum ratio correlated with the albumin ratio. When controlling for confounding factors, CSF apoD levels were significantly lower in CAA patients compared with controls and compared with AD patients (P = 0.0008). CONCLUSIONS: Our data show that apoD is specifically associated with CAA pathology and may be a CSF biomarker for CAA, but clinical application is complicated due to dependency on age, sex and blood-CSF barrier integrity. Well-controlled follow-up studies are required to determine whether apoD can be used as reliable biomarker for CAA.

Response to omalizumab using patient enrichment criteria from trials of novel biologics in asthma.

BACKGROUND: Recent efficacy studies of asthma biologics have included highly enriched patient populations. Using a similar approach, we examined factors that predict response to omalizumab to facilitate selection of patients most likely to derive the greatest clinical benefit from therapy. METHODS: Data from two phase III clinical trials of omalizumab in patients with allergic asthma were examined. Differences in rates of asthma exacerbations between omalizumab and placebo groups during the 16-week inhaled corticosteroid (ICS) dose-stable phase were evaluated with respect to baseline blood eosinophil counts (eosinophils <300/µL [low] vs ≥300/µL [high]) and baseline markers of asthma severity (emergency asthma treatment in prior year, asthma hospitalization in prior year, forced expiratory volume in 1 second [FEV1 ; FEV1 <65% vs ≥65% predicted], inhaled beclomethasone dipropionate dose [<600 vs ≥600 µg/day], and long-acting beta-agonist [LABA] use [yes/no]). RESULTS: Adults/adolescents (N = 1071) were randomized to receive either omalizumab (n = 542) or placebo (n = 529). In the 16-week ICS dose-stable phase, rates of exacerbations requiring ≥3 days of systemic corticosteroid treatment were 0.066 and 0.147 with omalizumab and placebo, respectively, representing a relative rate reduction in omalizumab-treated patients of 55% (95% CI, 32%-70%; P = .002). For patients with eosinophils ≥300/µL or with more severe asthma, this rate reduction was significantly more pronounced. CONCLUSION: In patients with allergic asthma, baseline blood eosinophil levels and/or clinical markers of asthma severity predict response to omalizumab.

Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon ß in dermatomyositis.

BACKGROUND: Dermatomyositis (DM) is an autoimmune disease primarily affecting skin and muscle. OBJECTIVES: The purpose of this study was to determine whether an association exists between clinical skin disease activity as measured by the validated Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and type 1 interferon (IFN) pathway biomarkers in the blood of patients with DM. METHODS: Forty-two patients with DM and 25 healthy volunteers were prospectively enrolled. CDASI scores were obtained, and serum and blood RNA were isolated from all participants. Associations between CDASI activity and type 1 IFN-inducible gene signature were assessed cross-sectionally in all patient samples and longitudinally on 13 paired visits via transcriptional profiling analyses. RESULTS: By RNAseq analysis, type 1 IFN-inducible genes were the most highly differentially regulated. A CDASI activity threshold of 12 was correlated with an elevated type 1 IFN gene signature and with serum IFN-ß, but not with IFN-α protein. Expression analysis showed that all patients with mild disease activity had a low type 1 IFN gene signature, while 93% of patients with moderate-to-high disease activity had elevated gene signature. In longitudinal analysis, changes in CDASI activity showed nonsignificant trends with concordant directional changes in gene signature. CONCLUSIONS: A type 1 IFN pathway signature biomarker in blood is highly correlated with CDASI activity scores in DM, and may be a promising surrogate clinical trial end point. The correlation of serum IFN-ß, but not IFN-α, with both a gene signature and CDASI suggests that IFN-ß drives disease activity in DM.

Hyperinflation of the left anterior basal segment: a new sign of pectus excavatum severity on CT.

AIM: To describe a new finding in patients with pectus excavatum - left lower lobe anterior basal segment hyperinflation [LABSH]. A secondary objective is to determine the frequency of the new finding and association with pectus excavatum severity. MATERIAL AND METHODS: The study population included 52 children who underwent preoperative computed tomography (CT) for the evaluation of pectus excavatum. A control group of 50 children was obtained after evaluating 137 CT examinations performed for other reasons. Patient age in both groups ranged from 12 to 20 years. The Haller index was calculated for all patients. LABSH was evaluated by visual inspection of lung windows. The difference in mean radiodensity measurements in regions of interest in the left and right anterior basal segments [ΔHU] was calculated. Spirometry was performed in 44 of the patients and the results were compared to Haller index severity and the presence of LABSH. Echocardiography reports were available for 50 children in the pectus excavatum group. RESULTS: LABSH was identified by visual inspection in 15 patients [29%] and was significantly associated with a Haller index >4.0 (p=0.001). ΔHU for the patients with LABSH was 90.2 HU (standard deviation [SD]=37.7) and for the non-hyperinflated group -5.51 (SD=44.63), which was significant (p<0.0001). There was a significant association of LABSH with the pectus excavatum group as compared to the control group. The difference in mean Haller index for children with normal spirometry (4.4, SD=2.7) was not significantly different (p=0.9899) than for children with obstructive disease (4.5, SD=1). There was mild cardiac compression on two echocardiograms. CONCLUSION: LABSH is a new sign associated with pectus excavatum. The sign suggests segmental bronchial compression caused by chest deformity results in segmental air trapping.

Decoupling of structural and functional brain connectivity in older adults with white matter hyperintensities.

Age-related impairments in the default network (DN) have been related to disruptions in connecting white matter tracts. We hypothesized that the local correlation between DN structural and functional connectivity is negatively affected in the presence of global white matter injury. In 125 clinically normal older adults, we tested whether the relationship between structural connectivity (via diffusion imaging tractography) and functional connectivity (via resting-state functional MRI) of the posterior cingulate cortex (PCC) and medial prefrontal frontal cortex (MPFC) of the DN was altered in the presence of white matter hyperintensities (WMH). A significant correlation was observed between microstructural properties of the cingulum bundle and MPFC-PCC functional connectivity in individuals with low WMH load, but not with high WMH load. No correlation was observed between PCC-MPFC functional connectivity and microstructure of the inferior longitudinal fasciculus, a tract not passing through the PCC or MPFC. Decoupling of connectivity, measured as the absolute difference between structural and functional connectivity, in the high WMH group was related to poorer executive functioning and memory performance. These results suggest that such decoupling may reflect reorganization of functional networks in response to global white matter pathology and may provide an early marker of clinically relevant network alterations.

Determining the normal aorta size in children.

PURPOSE: To establish effective aorta diameter standards at multiple levels of the thoracic aorta, abdominal aorta, and common iliac arteries by using computed tomographic (CT) data in healthy children (infants, children, adolescents) through young adults (hereafter referred to collectively as "children") of a wide range of sizes so that z scores may be calculated. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. The effective diameter, the average of aortic anteroposterior and lateral diameters, was independently measured at multiple levels of the aorta and common iliac arteries by two radiologists using 1-mm-collimation double-oblique reconstructions. Ordinary least squares regression methods were used to investigate models with various functional forms that related effective diameters at each level to patient body surface area (BSA) and sex. The best model was selected by using R(2), and formulas for deriving the expected diameter and estimates of the mean squared error (MSE) were generated. RESULTS: Results from 88 thoracic and 110 abdominal contrast material-enhanced CT examinations were analyzed in children without known cardiovascular disease who ranged in age from 0 to 20 years (mean, 9.9 years; standard deviation, 5.7), with BSA ranging from 0.19 to 2.52 m(2). Excellent interrater reliability was present (correlation coefficients ranged from 0.95 to 0.98). The best model was a polynomial regression model of the natural log transformation of the effective diameter that included linear, quadratic, and cubic BSA terms and a sex main effect as independent variables. The z scores were calculated by using the observed and expected effective diameters and the MSE. CONCLUSION: The range of normal effective diameters of the aorta at multiple levels and the common iliac arteries was determined for children of different sizes and both sexes. Measurements outside of the normal ranges are consistent with aneurysm or hypoplasia.

Sequential exposure to fibroblast growth factors (FGF) 2, 9 and 18 enhances hMSC chondrogenic differentiation.

OBJECTIVE: To test the effects of sequential exposure to FGF2, 9 and 18 on human Mesenchymal Stem Cells (hMSC) differentiation during in vitro chondrogenesis. DESIGN: Control and FGF2-expanded hMSC were cultured in aggregates in the presence of rhFGF9, rhFGF18 or rhFGFR3-specific signaling FGF variants, starting at different times during the chondroinductive program. Quantitative real time polymerase chain reaction (qRT-PCR) and immunocytochemistry were performed at different stages. The aggregate cultures were switched to a hypertrophy-inducing medium along with rhFGFs and neutralizing antibodies against FGFR1 and FGFR3. Histological/immunohistochemical/biochemical analyses were performed. RESULTS: FGF2-exposed hMSC during expansion up-regulated Sox9 suggesting an early activation of the chondrogenic machinery. FGF2, FGF9 and 18 modulated the expression profile of FGFR1 and FGFR3 in hMSC during expansion and chondrogenesis. In combination with transforming growth factor-beta (TGF-ß), FGF9 and FGF18 inhibited chondrogenesis when added at the beginning of the program (≤ d7), while exhibiting an anabolic effect when added later (≥d14), an effect mediated by FGFR3. Finally, FGFR3 signaling induced by either FGF9 or FGF18 delayed the appearance of spontaneous and induced hypertrophy-related changes. CONCLUSIONS: The stage of hMSC-dependent chondrogenesis at which the growth factors are added impacts the progression of the differentiation program: increased cell proliferation and priming (FGF2); stimulated early chondrogenic differentiation (TGF-ß, FGF9/FGF18) by shifting the chondrogenic program earlier; augmented extracellular matrix (ECM) production (FGF9/FGF18); and delayed terminal hypertrophy (FGF9/FGF18). Collectively, these factors could be used to optimize pre-implantation conditions of hMSC when used to engineer cartilage grafts.

Effect of ventilation on cerebral oxygenation in patients undergoing surgery in the beach chair position: a randomized controlled trial.

BACKGROUND: Surgery in the beach chair position (BCP) may reduce cerebral blood flow and oxygenation, resulting in neurological injuries. The authors tested the hypothesis that a ventilation strategy designed to achieve end-tidal carbon dioxide (E'(CO2)) values of 40-42 mm Hg would increase cerebral oxygenation (Sct(O2)) during BCP shoulder surgery compared with a ventilation strategy designed to achieve E'(CO2) values of 30-32 mm Hg. METHODS: Seventy patients undergoing shoulder surgery in the BCP with general anaesthesia were enrolled in this randomized controlled trial. Mechanical ventilation was adjusted to maintain an E'(CO2) of 30-32 mm Hg in the control group and an E'(CO2) of 40-42 mm Hg in the study group. Cerebral oxygenation was monitored continuously in the operating theatre using near-infrared spectroscopy. Baseline haemodynamics and Sct(O2) were obtained before induction of anaesthesia, and these values were then measured and recorded continuously from induction of anaesthesia until tracheal extubation. The number of cerebral desaturation events (CDEs) (defined as a ≥20% reduction in Sct(O2) from baseline values) was recorded. RESULTS: No significant differences between the groups were observed in haemodynamic variables or phenylephrine interventions during the surgical procedure. Sct(O2) values were significantly higher in the study 40-42 group throughout the intraoperative period (P<0.01). In addition, the incidence of CDEs was lower in the study 40-42 group (8.8%) compared with the control 30-32 group (55.6%, P<0.0001). CONCLUSIONS: Cerebral oxygenation is significantly improved during BCP surgery when ventilation is adjusted to maintain E'(CO2) at 40-42 mm Hg compared with 30-32 mm Hg. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01546636.

Optimizing image quality for pediatric torso computed tomography: the use of advanced iterative reconstruction and wide-detector scanning techniques.

OBJECTIVES: To compare radiation exposure and image quality in children undergoing torso helical acquisition computed tomography (CT) using filtered back projection (FBP) or adaptive iterative dose reduction (AIDR) 3D reconstruction algorithms. A secondary purpose is to compare radiation exposure and image quality in children undergoing torso CT acquired with helical or wide-detector techniques reconstructed with AIDR 3D. METHODS: The study was approved by the institutional review board. Phase 1 included 200 helical torso CT studies: 100 using FBP and 100 using AIDR 3D. The size-specific dose estimate (SSDE) was calculated for each study. Region of interest (ROI) noise measurements were recorded in the thorax, abdomen, and pelvis for each study. Unpaired t tests compared SSDE and image noise for each group. Phase 2 included 100 wide-detector CT torso studies using AIDR 3D. Size-specific dose estimate and ROI noise measurements were calculated. Unpaired t tests compared helical and wide-detector SSDE and ROI. Additional t tests looked for age- and weight-specific differences in the helical and wide-detector groups. RESULTS: Phase 1: AIDR 3D showed significant reduction in SSDE (P = 0.0001) and significant improvement in image quality. Phase 2: no significant difference in SSDE was observed. Children younger than 6 years had a significant reduction in SSDE with wide-detector technique (P = 0.0445) with no loss in image quality. CONCLUSIONS: Adaptive iterative dose reduction 3D produces significant reduction in radiation dose without degradation to image quality compared with FBP. Significant dose reduction without loss of image quality can also be obtained in younger, smaller children using wide-detector technique.

Inappropriate and cloned clinical histories on radiology request forms for sick children.

BACKGROUND: An appropriate clinical history improves the perception and interpretation of radiographic examinations in children and adults. However, clinical history provided on radiology request has not been studied for its appropriateness and frequency of cloned clinical history. OBJECTIVE: The purpose of this study was to determine the frequency of inappropriate histories and cloned histories at a tertiary-care children's hospital. MATERIALS AND METHODS: We analyzed radiology request forms of 388 outpatient and inpatient radiographic examinations obtained on 3 days during the same month at a tertiary-care children's hospital. Appropriateness of the clinical history was judged by its relevance to the examination ordered and appropriate associated billable ICD-9 code. Cloning was defined as identical clinical histories appearing on the radiology request on three consecutive days. Cloned histories were further subdivided as being appropriate or inappropriate. RESULTS: A total of 18% (70/388) of the requests for clinical history were either inappropriate, cloned or both. Neonatal intensive care unit (NICU) referrals constituted the majority (82%, 9/11) of combined inappropriate history and cloning. NICU referrals accounted for 52% (28/54) of all inappropriate clinical histories, a significantly higher percentage than other inpatient locations (P = 0.006). The cardiovascular intensive care unit (CVICU) was the second most common patient location for inappropriate clinical histories (11%, 6/54). About one-third of the radiographic requests from the NICU had inappropriate histories (35%, 28/79). Among the outpatient referrals, 50% (4/8) of the inappropriate histories were from the emergency department. The most common cloned histories included "hypoplastic left heart syndrome" (15%, 4/27), "endotracheal tube placement" (11%, 3/27) and "evaluate lung fields and bowel" (11%, 3/27). The most commonly cloned clinical history was seen on referrals from the NICU at 63% (17/27), a significantly higher percentage than other inpatient locations (P = 0.006). The CVICU unit accounted for the second most common patient location for cloned clinical histories (26%, 7/27). The cloned clinical history on the referral request for radiography was unjustified in 48% (13/27) of the cases. NICU referrals had 85% (11/13) of the unjustified cloned histories. CONCLUSION: Inpatient units, particularly the NICU, were most likely to have inappropriate histories and cloning. Cloning was clinically justified in about half of the cases of cloning. The patterns of inappropriate histories and cloning suggest possible corrective measures.

Lecanemab: Appropriate Use Recommendations.

Lecanemab (Leqembi®) is approved in the United States for the treatment of Alzheimer's disease (AD) to be initiated in early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) with confirmed brain amyloid pathology. Appropriate Use Recommendations (AURs) are intended to help guide the introduction of new therapies into real-world clinical practice. Community dwelling patients with AD differ from those participating in clinical trials. Administration of lecanemab at clinical trial sites by individuals experienced with monoclonal antibody therapy also differs from the community clinic-based administration of lecanemab. These AURs use clinical trial data as well as research and care information regarding AD to help clinicians administer lecanemab with optimal safety and opportunity for effectiveness. Safety and efficacy of lecanemab are known only for patients like those participating in the phase 2 and phase 3 lecanemab trials, and these AURs adhere closely to the inclusion and exclusion criteria of the trials. Adverse events may occur with lecanemab including amyloid related imaging abnormalities (ARIA) and infusion reactions. Monitoring guidelines for these events are detailed in this AUR. Most ARIA with lecanemab is asymptomatic, but a few cases are serious or, very rarely, fatal. Microhemorrhages and rare macrohemorrhages may occur in patients receiving lecanemab. Anticoagulation increases the risk of hemorrhage, and the AUR recommends that patients requiring anticoagulants not receive lecanemab until more data regarding this interaction are available. Patients who are apolipoprotein E ε4 (APOE4) gene carriers, especially APOE4 homozygotes, are at higher risk for ARIA, and the AUR recommends APOE genotyping to better inform risk discussions with patients who are lecanemab candidates. Clinician and institutional preparedness are mandatory for use of lecanemab, and protocols for management of serious events should be developed and implemented. Communication between clinicians and therapy candidates or those on therapy is a key element of good clinical practice for the use of lecanemab. Patients and their care partners must understand the potential benefits, the potential harms, and the monitoring requirements for treatment with this agent. Culture-specific communication and building of trust between clinicians and patients are the foundation for successful use of lecanemab.

Relationship between disease activity and type 1 interferon- and other cytokine-inducible gene expression in blood in dermatomyositis and polymyositis.

The objective of this study was to evaluate the relationship between blood mRNA, disease activity and treatment effects in a longitudinal study of patients with dermatomyositis (DM) or polymyositis (PM). In all, 24 patients with DM or PM were followed for up to 6 years (mean of 1.9 years) at 2-7 follow-up visits while receiving standard clinical care. Clinical data and blood samples collected at 80 patient visits were used for the analysis of cytokine-induced gene expression for the signaling pathways of type 1 interferon (IFN), tumor necrosis factor-α, IL-1ß, granulocyte-monocyte colony-stimulating factor, IL-10 and IL-13. A type 1 IFN signature score, but not other cytokine signature scores in the blood of patients with DM or PM, correlated highly with disease activity, decreased significantly with immunomodulatory therapies and showed concordant changes with major changes in disease activity. Type 1 IFN signature score in the blood correlates with disease activity in longitudinal follow-up of individual patients with DM or PM. The type 1 IFN-inducible gene transcripts in the blood have potential utility for monitoring disease activity in patients with DM or PM.

Dynamic pulmonary CT of children.

OBJECTIVE: Wide-detector CT allows simultaneous imaging of the entire airway and lungs in small children. Images acquired in multiple phases by continuous scanning during respiration are viewed dynamically, allowing more complete airway and pulmonary evaluation than possible with static protocols. The purpose of this study was to evaluate whether low-dose techniques can be applied to dynamic pulmonary CT of small children. MATERIALS AND METHODS: The study included 24 infants and small children with persistent respiratory difficulty who underwent dynamic pulmonary CT (11 with IV contrast administration, 13 without contrast administration). No significant difference in patient age was present in the two groups. Continuous-mode wide-detector scans were obtained at 350-millisecond gantry rotation for a total of 1.4 seconds at 80 kVp. Some contrast-enhanced studies for simultaneous vascular and airway evaluation were performed at slightly greater tube current. The effective dose for each patient was calculated, and the Student t test was performed to compare effective dose measurements. RESULTS: All studies were of diagnostic quality, frequently yielding critical information not available with other diagnostic tests. The mean effective dose for all patients was 1.7 (SD, 1.1) mSv. In the group who received contrast material, the mean effective dose was greater (1.9 [SD, 1.4] mSv) than in the group who did not receive contrast material (1.5 [SD, 0.7] mSv), but the difference was not significant (p = 0.4). CONCLUSION: Wide-detector dynamic CT is ideal for evaluation of the airway and lungs in infants and small children with persistent respiratory distress. Effective doses are low, typically less than 2 mSv.

MR imaging and CT evaluation of congenital pulmonary vein abnormalities in neonates and infants.

Magnetic resonance (MR) imaging and computed tomography (CT) are increasingly being used in diagnosis and follow-up of congenital pulmonary vein anomalies in neonates and infants. Such anomalies include total or partial anomalous pulmonary venous return, sinus venosus defect, malposition of the septum primum, cor triatriatum, pulmonary vein atresia or stenosis, and abnormal number or course of the pulmonary veins. MR imaging provides a wealth of anatomic and functional data that are valuable in case management and planning intervention. Gadolinium-enhanced MR angiography is the mainstay of anatomic evaluation. Ventricular volumetry with two-dimensional steady-state free-precession sequences and flow analysis with cine phase-contrast imaging provide physiologic information that may be used to calculate the degree of right heart enlargement and the shunt fraction, allowing the cardiologist to determine the functional importance of the lesion. CT provides superior spatial resolution and short imaging times but at the expense of exposure to ionizing radiation.

Discrepancies between tumor genomic profiling and germline genetic testing.

BACKGROUND: Tumor genomic profiling (TGP) often incidentally identifies germline pathogenic variants (PVs) associated with cancer predisposition syndromes. Methods used by somatic testing laboratories, including germline analysis, differ from designated germline laboratories that have optimized the identification of germline PVs. This study evaluated discrepancies between somatic and germline testing results, and their impact on patients. PATIENTS AND METHODS: Chart reviews were carried out at a single institution for patients who had both somatic and designated germline genetic testing. Cases with discrepant results in which germline PVs were not detected by the somatic laboratory or in which variant classification differed are summarized. RESULTS: TGP was carried out on 2811 cancer patients, 600 of whom also underwent designated germline genetic testing. Germline PVs were identified for 109 individuals. Discrepancies between germline genetic testing and tumor profiling reports were identified in 20 cases, including 14 PVs identified by designated germline genetic testing laboratories that were not reported by somatic testing laboratories and six variants with discrepant classifications between the designated germline and somatic testing laboratories. Three PVs identified by designated germline laboratories are targets for poly adenosine diphosphate-ribose polymerase (PARP) inhibitors and resulted in different treatment options. Of the PVs identified by designated germline laboratories, 60% (n = 12) were in genes with established associations to the patients' cancer, and 40% of the PVs were incidental. The majority (90%) of all discrepant findings, both contributory and incidental, changed management recommendations for these patients, highlighting the importance of comprehensive germline assessment. CONCLUSIONS: Methods used by somatic laboratories, regardless of the inclusion of germline analysis, differ from those of designated germline laboratories for identifying germline PVs. Unrecognized germline PVs may harm patients by missing hereditary syndromes and targeted therapy opportunities (e.g. anti-programmed cell death protein 1 immunotherapy, PARP inhibitors). Clinicians should refer patients who meet the criteria for genetic evaluation regardless of somatic testing outcomes.

Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study.

BACKGROUND: Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy. OBJECTIVE: To report in detail the safety findings from the 96-week, phase III, double-blind CLARITY study, which evaluated treatment with cladribine tablets in relapsing-remitting MS. METHODS: A total of 1,326 patients were randomized 1:1:1 to two short-course regimens of cladribine tablets (3.5 or 5.25 mg/kg cumulative dose over 96 weeks) or placebo. Safety assessments included monitoring for adverse events (AEs), routine physical and neurologic examinations and frequent laboratory parameter assessments. RESULTS: Of the randomized patients, 88.6% completed treatment with cladribine tablets versus 86.3% with placebo. Lymphopenia was the most commonly reported AE in patients treated with cladribine tablets and was anticipated based on the mechanism of action. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-to-moderate by investigators. Herpes zoster infections developed in 20 (2.3%) cladribine-treated patients; all cases were dermatomal. There were no herpes zoster infections in the placebo group. Nine (1.0%) patients experienced events related to uterine leiomyomas in the cladribine tablets groups versus one (0.2%) with placebo. Three isolated cases of malignancy were reported in cladribine-treated patients during the study; a fourth was reported during post-study surveillance. A pre-malignant cervical carcinoma in situ was also reported. The incidence of malignancies during the study did not exceed the expected rate in a population standardized for country, gender and age. CONCLUSION: The safety and tolerability profile observed in the CLARITY study together with the reported efficacy support the potential for cladribine tablets as an MS therapy.

A double-blind, randomized, placebo-controlled trial of topical tacrolimus 0·1% vs. clobetasol propionate 0·05% in childhood vitiligo.

BACKGROUND: Both clobetasol propionate 0·05% (CP 0·05%) and tacrolimus 0·1% (T 0·1%) ointments have been shown to be efficacious and safe in treating vitiligo in the paediatric population. OBJECTIVES: To assess efficacy and safety of these two therapies compared with each other and with placebo. METHODS: In this prospective study, children aged 2-16 years with vitiligo, stratified into 'facial' (n = 55) and 'nonfacial' (n = 45) groups, were randomized into three arms: CP 0·05% ointment (n = 30), T 0·1% ointment (n = 31) and placebo (n = 29) for 6 months. Successful repigmentation, defined as > 50% improvement, was evaluated by comparing photographs taken at baseline and at 2, 4 and 6 months. RESULTS: In the facial group, 58% of the CP 0·05% group responded successfully compared with 58% of the T 0·1% group, and in the nonfacial group, 39% of the CP 0·05% group responded compared with 23% of the T 0·1% group (P > 0·05). There was a significant difference in response between the CP 0·05% group vs. placebo (P < 0·0001) and the T 0·1% group vs. placebo (P = 0·0004). Spontaneous repigmentation was evaluated as 2·4%. No significant clinical adverse events were noted in any group. CONCLUSIONS: Both CP 0·05% and T 0·1% ointments offer similar benefit in paediatric vitiligo, both facial and nonfacial. The facial lesions responded faster than the nonfacial ones.

Optimal frequency of parathyroid hormone monitoring in chronic hemodialysis patients.

BACKGROUND: Secondary hyperparathyroidism is a common manifestation of chronic kidney disease (CKD). Serum parathyroid hormone (PTH) level is widely used as a marker for hyperparathyroidism. Currently, there is limited data to guide the frequency of PTH monitoring in CKD patients. The present study was undertaken to determine the optimal frequency of monitoring PTH in patients on maintenance hemodialysis. METHODS: A cohort of 154 patients on maintenance dialysis at a single outpatient hemodialysis center was included in this retrospective study. In Phase I of the study, PTH was measured every 3 months as per Kidney Disease Outcomes Quality Initiative (KDOQI) recommendations. In Phase II, PTH was measured monthly. In both phases, dietary education and optimization of medications including phosphate binders, vitamin D analogues and calcimimetics were implemented using standard protocols Data from the two phases was compared with each other and with their respective national norms. RESULTS: The percentage of patients with PTH in target range of 150 - 300 pg/ml increased significantly from Phase I to Phase II of the study (25.4 - 40.3%, p < 0.01). There was a significant reduction in the percentage of patients with PTH levels > 300 pg/ml in Phase II compared with national averages (37% vs. 47%, p < 0.02). There was no significant difference in calcium and phosphorus levels or their product. There was a significant increase in the usage of calcimimetics and vitamin D analogues. CONCLUSION: We observed that increasing the frequency of monitoring PTH from quarterly to monthly was associated with a significant increase in the percentage of patients reaching KDOQI target PTH values.