Background Folliculotropic mycosis fungoides (FMF) is a distinct variant of mycosis fungoides. Recent studies recognized indolent and aggressive subgroups of FMF, but there is controversy how... Show moreBackground Folliculotropic mycosis fungoides (FMF) is a distinct variant of mycosis fungoides. Recent studies recognized indolent and aggressive subgroups of FMF, but there is controversy how patients presenting with plaques should be classified. The present study describes the histopathologic features of 40 FMF plaques. The aim of the study was to identify risk factors for disease progression and poor outcome in this group. Methods Clinical, histopathological, and immunophenotypical data from 40 patients with plaque stage FMF were reviewed and analysed for risk factors for disease progression and survival. Results After a median follow-up of 80 months, disease progression occurred in 20 of 40 patients. Percentage of atypical cells, cell size, percentage of Ki-67+ cells, and co-existent interfollicular epidermotropism, but not the extent of perifollicular infiltrates, were associated with disease progression and reduced survival, while extensive follicular mucinosis was associated with increased survival. Conclusions This study underlines that FMF patients presenting with plaques represent a heterogeneous group and that a subgroup of these patients may have an indolent clinical course. It further shows that histological examination is a valuable tool to differentiate between indolent and aggressive disease. Show less
Objective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive... Show moreObjective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH +). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC) +). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases.Materials and methods: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH.Results: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC + /FISH +) and 16 discordant (ALK IHC + /FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR = 4.5; 95% CI = 1.2-15.9; p = 0.010.Conclusion: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines. Show less
Dilated cardiomyopathy (DCM) is defined by the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery... Show moreDilated cardiomyopathy (DCM) is defined by the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to explain these changes. This is a heterogeneous disease frequently having a genetic background. Imaging is important for the diagnosis, the prognostic assessment and for guiding therapy. A multimodality imaging approach provides a comprehensive evaluation of all the issues related to this disease. The present document aims to provide recommendations for the use of multimodality imaging according to the clinical question. Selection of one or another imaging technique should be based on the clinical condition and context. Techniques are presented with the aim to underscore what is 'clinically relevant' and what are the tools that 'can be used'. There remain some gaps in evidence on the impact of multimodality imaging on the management and the treatment of DCM patients where ongoing research is important. Show less
Dietz, M.F.; Prihadi, E.A.; Bijl, P. van der; Goedemans, L.; Mertens, B.J.A.; Gursoy, E.; ... ; Bax, J.J. 2019
Objective: To investigate the effects of different types of surgery on breast cancer prognosis in germline BRCA1/BRCA2 mutation carriers compared with noncarriers.Summary of Background Data:... Show moreObjective: To investigate the effects of different types of surgery on breast cancer prognosis in germline BRCA1/BRCA2 mutation carriers compared with noncarriers.Summary of Background Data: Although breast-conserving therapy (breast-conserving surgery followed by radiotherapy) has been associated with more local recurrences than mastectomy, no differences in overall survival have been found in randomized trials performed in the general breast cancer population. Whether breast-conservation can be safely offered to BRCA1/2 mutation carriers is debatable.Methods: The study comprised a cohort of women with invasive breast cancer diagnosed <50 years and treated between 1970 and 2003 in 10 Dutch centers. Germline DNA for BRCA1/2 testing of most-prevalent mutations covering similar to 61%) was mainly derived from paraffin-blocks. Survival analyses were performed taking into account competing risks.Results: In noncarriers (N = 5820), as well as in BRCA1 (N = 191) and BRCA2 (N = 70) mutation carriers, approximately half of the patients received breast-conserving therapy. Patients receiving mastectomy followed by radiotherapy had prognostically worse tumor characteristics and more often received systemic therapy. After adjustment for these potential confounders, patients who received breast-conserving therapy had a similar overall survival compared with patients who received mastectomy, both in noncarriers (hazard ratio [HR] = 0.95, confidence interval [CI] = 0.85-1.07, P = 0.41) and BRCA1 mutation carriers (HR = 0.80, CI = 0.42-1.51, P = 0.50). Numbers for BRCA2 were insufficient to draw conclusions. The rate of local recurrences after breast-conserving therapy did not differ between BRCA1 carriers (10-year risk = 7.3%) and noncarriers (10-year risk = 7.9%).Conclusion: Our results, together with the available literature, provide reassurance that breast-conserving therapy is a safe local treatment option to offer to BRCA1 mutation carriers with invasive breast cancer. Show less
BACKGROUND In severe aortic stenosis (AS), patients often show extra-aortic valvular injury. Recently, a new staging system for severe AS has been proposed on the basis of the extent of cardiac... Show moreBACKGROUND In severe aortic stenosis (AS), patients often show extra-aortic valvular injury. Recently, a new staging system for severe AS has been proposed on the basis of the extent of cardiac damage.OBJECTIVES The present study evaluated the prevalence and prognostic impact of these different stages of cardiac damage in a large, real-world, multicenter cohort of symptomatic severe AS patients.METHODS From the ongoing registries from 2 academic institutions, a total of 1,189 symptomatic severe AS patients were selected and retrospectively analyzed. According to the extent of cardiac damage on echocardiography, patients were classified as Stage 0 (no cardiac damage), Stage 1 (left ventricular damage), Stage 2 (mitral valve or left atrial damage), Stage 3 (tricuspid valve or pulmonary artery vasculature damage), or Stage 4 (right ventricular damage). Patients were followed for all-cause mortality and combined endpoint (all-cause mortality, stroke, and cardiac-related hospitalization).RESULTS On the basis of the proposed classification, 8% of patients were classified as Stage 0, 24% as Stage 1, 49% as Stage 2, 7% as Stage 3, and 12% as Stage 4. On multivariable analysis, cardiac damage was independently associated with all-cause mortality and combined outcome, although this was mainly determined by Stages 3 and 4.CONCLUSIONS In this large multicenter cohort of symptomatic severe AS patients, stage of cardiac injury as classified by a novel staging system was independently associated with all-cause mortality and combined endpoint, although this seemed to be predominantly driven by tricuspid valve or pulmonary artery vasculature damage (Stage 3) and right ventricular dysfunction (Stage 4). (C) 2019 by the American College of Cardiology Foundation. Show less
Lijfering, W.M.; Timp, J.F.; Cannegieter, S.C. 2019
An important clinical problem in the management of venous thrombosis is to determine whether a patient can safely cease anticoagulant therapy. In this Forum article, we summarize the predictive... Show moreAn important clinical problem in the management of venous thrombosis is to determine whether a patient can safely cease anticoagulant therapy. In this Forum article, we summarize the predictive performance of several prediction models for recurrent thrombosis, as well as for bleeding while using anticoagulants. Patients with provoked first thrombosis (considered "low risk") are now denied long-term treatment, although a strong gradient in risk can be found in this group. We furthermore discuss the problem of an unclear definition of "(un)provoked" and show that this affects the yield of currently available prediction scores plus the limitations of a "one-size-fits-all" strategy. Better prediction tools are urgently needed. We propose a strategy for future studies for which the following should be considered: (a) reporting of absolute risks next to C-statistics, (b) model applicable to all patients, (c) no discontinuation of anticoagulation for measurement of predictors. Show less
Aims The present study aimed at investigating the association between left ventricular (LV) mechanical dispersion measured with speckle tracking echocardiography and severity of aortic stenosis (AS... Show moreAims The present study aimed at investigating the association between left ventricular (LV) mechanical dispersion measured with speckle tracking echocardiography and severity of aortic stenosis (AS) and its impact on prognosis.Methods and results This retrospective study included 630 patients [age 72 (62-78) years, 61.4% men] with various grades of AS (mild AS, 19.8%; moderate AS, 37.0%; severe AS, 43.2%). LV mechanical dispersion (defined as standard deviation of time from Q/R on electrocardiogram to peak longitudinal strain in 17 LV segments) was assessed by speckle tracking echocardiography. Clinical, electrocardiographic, and echocardiographic determinants of increased LV mechanical dispersion were evaluated. During a follow-up of 107 (43-133) months, the independent association between LV mechanical dispersion and all-cause mortality (n = 302, 48%) was evaluated including aortic valve replacement as time-dependent co-variate. LV mechanical dispersion increased significantly with increasing severity of AS (mild AS, 54.5 +/- 17.2 ms; moderate AS, 56.7 +/- 19.3 ms; severe AS, 70.9 +/- 24.3 ms; P < 0.001). Independent determinants of increased mechanical dispersion included older age (beta = 0.28; P = 0.003), lower LV ejection fraction (beta = -0.24; P = 0.020), smaller aortic valve area (beta = -8.55; P = 0.001), larger LV mass index (beta = 0.20; P < 0.001), and longer QRS duration (beta = 1.12 per each 10 ms increase; P = 0.012). LV mechanical dispersion showed incremental prognostic value for all-cause mortality (hazard ratio 1.10 per each 10 ms increase, 95% confidence interval 1.04-1.15; P < 0.001).Conclusion LV mechanical dispersion assessed by speckle tracking echocardiography increases significantly with severity of AS and is significantly associated with all-cause mortality. Show less
BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of... Show moreBACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators. Show less
Background: The potential survival benefits of adding radiotherapy to systemic therapy for esophageal cancer patients with oligometastases are unknown.Methods: In this retrospective analysis,... Show moreBackground: The potential survival benefits of adding radiotherapy to systemic therapy for esophageal cancer patients with oligometastases are unknown.Methods: In this retrospective analysis, patients with stage IV esophageal cancer (according to the American Joint Committee on Cancer Seventh edition staging system) with <= 3 metastases who underwent chemotherapy with cisplatin/paclitaxel between 2012 and 2015 were identified. Patients received chemotherapy (CT) alone vs. concurrent chemoradiotherapy (CCRT) to all metastases.Results: Of 461 patients, 97% had squamous cell cancer. One hundred and ninety-six patients (42.5%) received CCRT and 265 (57.5%) underwent CT alone. At week 8, there were 3 (1.5%) complete responses (CR) and 95 (48.5%) partial responses (PR) in the CCRT group, compared to 3 (1.1%) CR and 102 (38.5%) PR in the CT alone group. The overall rate of improvement in dysphagia score was noted in 78.5% of patients in the CCRT group versus 61.5% in the CT alone group (P=0.014). A statistically significant difference was demonstrated in disease control rate between the two groups (81.6% vs. 64.5%, P<0.001). Patients who underwent CCRT had superior median PFS and a trend toward longer median OS compared to those receiving CT alone (8.7 vs. 7.3 months, P=0.002 and 16.8 vs. 14.8 months, P=0.056, respectively). The median OS was 19.3 months in patients who achieved CR/PR, compared to 14.9 months and 9.6 months for patients who had stable disease and progressive disease, respectively (P<0.001).Conclusions: Compared to chemotherapy alone, chemoradiation to all sites in patients with esophageal cancer with <= 3 metastases may lead to a modest increase in PFS and a trend toward longer OS. Further investigation of optimal integration of radiotherapy and chemotherapy in these patients is warranted. Show less
Background-The predictive value of coronary artery calcium (CAC) has been widely studied; however, little is known about specific characteristics of CAC that are most predictive. We aimed to... Show moreBackground-The predictive value of coronary artery calcium (CAC) has been widely studied; however, little is known about specific characteristics of CAC that are most predictive. We aimed to determine the independent associations of Agatston score, CAC volume, CAC area, CAC mass, and CAC density score with major adverse cardiac events in patients with suspected coronary artery disease.Methods and Results-A total of 379 symptomatic participants, aged 45 to 85 years, referred for invasive coronary angiography, who underwent coronary calcium scanning and computed tomography angiography as part of the CORE320 (Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Detector Computed Tomography) study, were included. Agatston score, CAC volume, area, mass, and density were computed on noncontrast images. Stenosis measurements were made on contrast-enhanced images. The primary outcome of 2-year major adverse cardiac events (30 revascularizations [>182 days of index catheterization], 5 myocardial infarctions, 1 cardiac death, 9 hospitalizations, and 1 arrhythmia) occurred in 32 patients (8.4%). Associations were estimated using multivariable proportional means models. Median age was 62 (interquartile range, 56-68) years, 34% were women, and 56% were white. In separate models, the Agatston, volume, and density scores were all significantly associated with higher risk of major adverse cardiac events after adjustment for age, sex, race, and statin use; density was the strongest predictor in all CAC models. CAC density did not provide incremental value over Agatston score after adjustment for diameter stenosis, age, sex, and race.Conclusions-In symptomatic patients, CAC density was the strongest independent predictor of major adverse cardiac events among CAC scores, but it did not provide incremental value beyond the Agatston score after adjustment for diameter stenosis. Show less
