Hemophagocytic lymphohistiocytosis (HLH) is a devastating disorder of uncontrolled immune activation characterized by clinical and laboratory evidence of extreme inflammation. This syndrome can be ...caused by genetic mutations affecting cytotoxic function (familial HLH) or be secondary to infectious, rheumatologic, malignant, or metabolic conditions (acquired HLH). Prompt recognition is paramount and, without early treatment, this disorder is frequently fatal. Although HLH is well described in the pediatric population, less is known about the appropriate work-up and treatment in adults. Here, we review the clinical characteristics, diagnosis, and treatment of HLH in adults.
To cite this article: Schram ME, Spuls PI, Leeflang MMG, Lindeboom R, Bos JD, Schmitt J. EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important ...difference. Allergy 2012; 67: 99–106.
Background: Demonstration of adequate reliability and validity is sufficient for concluding that an instrument is applicable for descriptive and predictive purposes, but before we can confidently use an outcome measure in clinical trials, the responsiveness (synonymous with sensitivity to change) and minimal clinically important difference (MCID) should be known. With this study, we aimed to assess responsiveness and MCID of four outcome measures used in atopic eczema: the Severity Scoring of Atopic Dermatitis (SCORAD), the objective SCORAD, Eczema Area and Severity Index (EASI), and the Patient‐Oriented Eczema Measure (POEM).
Methods: Data of three randomized controlled trials were used. To demonstrate responsiveness, we plotted receiver operating characteristic (ROC) curves. MCID was estimated using mean change scores of patients that showed a relevant improvement. Bland and Altman methods were used to quantify the limits of agreement.
Results: Area under the ROC curve for the SCORAD was 0.70 95% confidence interval (CI): 0.61–0.78, for the objective SCORAD, 0.73 (95% CI: 0.70–0.77), for the EASI, 0.67 (95% CI: 0.60–0.76), and for the POEM, 0.67 (95% CI: 0.59–0.75). Scores above 0.70 represent a fair responsiveness. The MCID was 8.7 points for the SCORAD, 8.2 for the objective SCORAD, 6.6 for the EASI, and 3.4 for the POEM.
Conclusion: The objective SCORAD and SCORAD showed a fair responsiveness. The MCIDs are an important prerequisite for the interpretation of published eczema trials and for the planning/sample size estimation of future trials.
Kinase fusions are rare and poorly characterized in colorectal carcinoma, yet they present unique opportunities for targeted therapy. In this study, we characterized kinase fusions from patients with ...advanced colorectal carcinoma who had MSK-IMPACT testing of their tumors between January 2014 and June 2018. Patients were analyzed for the presence of fusions, microsatellite instability (MSI), and
mutations. Mismatch repair (MMR), IHC, and promoter hypermethylation status of MLH1 (MLH1ph) in microsatellite instability-high (MSI-H) colorectal carcinoma with fusions were investigated. Fusion transcripts were confirmed using a targeted RNA-seq panel assay. Of 2,314 colorectal carcinomas with MSK-IMPACT testing, 21 harbored kinase fusions. Overall 57% (12/21) of colorectal carcinoma fusions were MSI-H/MMR-D. Loss of MLH1 and MLH1ph was confirmed in all 12 and all 10 cases with available material, respectively. Fusions were present in 5% of MSI-H/MMR-D colorectal carcinoma compared with 0.4% of MSS/MMR-P colorectal carcinoma (
< 0.001) and 15% of MSI-H/MMR-D colorectal carcinoma with wild-type
. Of 24 total MLH1-deficient colorectal carcinomas with MLH1ph and wild-type
, 10 (42%) harbored kinase fusions. Kinase fusions in MSI-H colorectal carcinoma were associated with sporadic MLH1ph rather than with Lynch syndrome, and these patients may be eligible for kinase inhibitors, particularly following resistance or toxicity in response to immunotherapy. These findings identify a molecular subset of colorectal carcinoma with kinase fusions that may be responsive to kinase inhibitors.
A high frequency of targetable kinase fusions in
wild-type, MSI-H colorectal carcinoma offers a rationale for routine screening to identify patients with colorectal carcinoma with kinase fusions that may be responsive to kinase inhibitors.
.
TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition
. With the recent approval of the first selective TRK ...inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors
. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.
Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent
mutations or specific gene fusions, most commonly involving
. Comprehensive ...analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically.
A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT;
= 136) or hotspot 8-oncogene genotyping (
= 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS).
Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including
mutations (76%),
fusions (7%),
alterations (6%), and other less common events. In addition, WTS identified a novel
fusion (
-
). Overall, targetable gene fusions were identified in 51% of
wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with
-mutant IMAs,
-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (
< 0.0001).
This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of
-rearranged IMAs,
as the third most common alteration, and a novel
fusion in these tumors. Comprehensive molecular testing of
wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.
NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. ...Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity-enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion-positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion-positive metastatic cancer were treated with Zeno. Two patients with ATP1B1-NRG1-positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74-NRG1-positive non-small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion-positive cancers.
NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion-positive cancers and is thus an effective therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1171.
This narrative review of the literature provides a summary and discussion of 25 years of research into the complex links between depression and diabetes. Systematic reviews have shown that depression ...occurs more frequently in people with type 1 or type 2 diabetes compared with people without diabetes. Currently, it remains unclear whether depression is also more common in people with impaired glucose metabolism or undiagnosed type 2 diabetes compared with people without diabetes. More prospective epidemiological research into the course of depression and an exploration of mechanisms in individuals with diabetes are needed. Depression in diabetes is associated with less optimal self‐care behaviours, suboptimal glycaemic control, impaired quality of life, incident micro‐ and macrovascular diseases, and elevated mortality rates. Randomized controlled trails concluded that depression in diabetes can be treated with antidepressant medication, cognitive–behavioural therapy (individual, group‐based or web‐based), mindfulness‐based cognitive therapy and stepped care. Although big strides forward have been made in the past 25 years, scientific evidence about depression in diabetes remains incomplete. Future studies should investigate mechanisms that link both conditions and test new diabetes‐specific web‐ or app‐based interventions for depression in diabetes. It is important to determine whether treatment or prevention of depression prevents future diabetes complications and lowers mortality rates.
What's new?
By 1995, a few epidemiological studies had concluded that depression was more common in people with diabetes than in those without. However, intervention studies were lacking and longitudinal studies were scarce.
Over the past 25 years, research has confirmed the bidirectional relationship between depression and type 2 diabetes.
Depression in diabetes impairs quality of life and is associated with less effective self‐management, a higher risk of diabetes complications and higher mortality rates.
Depression in diabetes can be treated effectively with psychological and pharmacological therapy.
Awareness of depression in people with diabetes should be raised and adequate mental health care should be available to treat depression.
Future studies should elucidate the biological and behavioural mechanisms that link depression and diabetes and test the long‐term effects of treatment.
Summary
Background Atopic dermatitis (AD) has a wide spectrum of dermatological manifestations and despite various validated sets of diagnostic criteria that have been developed over the past ...decades, there is disagreement about its definition. Nevertheless, clinical studies require valid diagnostic criteria for reliable and reproducible results.
Objective To summarize the evidence concerning the validity of diagnostic criteria for AD.
Methods All data sources were identified through searches on Medline, Embase and Cochrane databases. The Quality Assessment of Diagnostic Accuracy tool (QUADAS) was used. Results are presented in a receiver operating characteristic (ROC) plot.
Results Out of the 20 articles that met the criteria, 27 validation studies were identified. In two studies concerning Hanifin and Rajka diagnostic criteria sensitivity and specificity ranged from 87·9% to 96·0% and from 77·6% to 93·8%, respectively. Nineteen validation studies of the U.K. diagnostic criteria showed sensitivity and specificity ranging from 10% to 100% and 89·3% to 99·1%, respectively. Three validation studies concerning the Schultz‐Larsen criteria showed sensitivity from 88% to 94·4% and specificity from 77·6% to 95·9%. In one article concerning the criteria of Diepgen, the sensitivity ranged from 83·0% to 87·7% and the specificity from 83·9% to 87·0%. One article studied the Kang and Tian criteria and reported 95·5% sensitivity and 100% specificity. One article validating the International Study of Asthma and Allergies in Childhood (ISAAC) criteria showed a positive and negative predictive value of 48·8% and 91·1%, respectively.
Conclusion With this systematic review of the existing sets of diagnostic criteria for AD a varying number of validation studies with varying methodological quality was found. The U.K. diagnostic criteria are the most extensively validated. However, improvement of methodological design for validation studies and uniformity in well‐validated and applicable diagnostic criteria are needed to improve future intervention studies and to compare study results.
Summary
Background Eczema affects approximately 10% of all schoolchildren in the western world and has shown an increase over the past decades in ‘developing’ countries. Numerous factors have been ...suggested that might contribute to the increasing prevalence of eczema. A plausible explanation is the role of environmental factors. As part of the ‘hygiene hypothesis’ it has been thought that eczema is more common in urban than in rural communities, but such a notion has never been assessed systematically.
Objective Our aim was to assess whether there is a rural/urban gradient for the prevalence of eczema and, if so, to what extent.
Methods All data sources were identified through a search in MEDLINE and EMBASE. All primary studies comparing the prevalence rate of eczema between urban and rural populations were assessed for eligibility. Included articles were reviewed for methodological quality and a relative risk was calculated to indicate the risk of eczema in urban over rural areas.
Results Twenty‐six articles were included for analysis. Nineteen showed a higher risk for eczema in an urbanized area, of which 11 were significant. Six studies showed a lower risk of eczema in an urbanized area, of which one was statistically significant. One study had a relative risk of 1·00. Results were more homogeneous among studies of good methodological quality. A pooled relative risk could have been calculated but was not because of heterogeneity.
Conclusion There is some evidence of a higher risk for eczema in urban compared with rural areas, suggesting that place of residence may have a role in the pathogenesis of eczema. Future reviews on environmental circumstances should be carried out to reveal the factors associated with a higher prevalence of eczema in urban areas and the association with other allergic diseases.
Abstract Impaired microvascular dilatation from any cause and impaired insulin-mediated capillary recruitment in particular result in suboptimal delivery of glucose and insulin to skeletal muscle, ...and subsequently impairment of glucose disposal (insulin resistance). In addition, microvascular dysfunction, through functional and/or structural arteriolar and capillary drop-out, and arteriolar constriction, increases peripheral resistance and thus blood pressure. Microvascular dysfunction may thus constitute a pathway that links insulin resistance and hypertension. Overweight and obesity may be an important cause of microvascular dysfunction. Mechanisms linking overweight and obesity to microvascular dysfunction include changes in the secretion of adipokines leading to increased levels of free fatty acids and inflammatory mediators, and decreased levels of adiponectin all of which may impair endothelial insulin signaling. Microvascular dysfunction may thus constitute a new treatment target in the prevention of type 2 diabetes mellitus and hypertension.
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