Interobserver variation in CD30 immunohistochemistry interpretation; consequences for patient selection for targeted treatment

AimsCD30 immunohistochemistry (IHC) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug-conjugate targeting the CD30 molecule. For reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD30 immunohistochemistry (IHC) staining is required. Methods and resultsWe conducted a three-round reproducibility assessment of CD30 scoring for categorised frequency and intensity, including a technical validation, a live polling' pre- and post-instruction scoring round and a web-based round including individual scoring with additional IHC information to mimic daily diagnostic practice. Agreement in all three scoring rounds was poor to fair ( = 0.12-0.35 for CD30-positive tumour cell percentage and = 0.16-0.41 for staining intensity), even when allowing for one category of freedom in percentage of tumour cell positivity ( = 0.30-0.61). The first round with CD30 staining performed in five independent laboratories showed objective differences in staining intensity. In the second round, approximately half the pathologists changed their opinion on CD30 frequency after a discussion on potential pitfalls, highlighting hesitancy in decision-making. Using fictional cut-off points for percentage of tumour cell positivity, agreement was still suboptimal ( = 0.35-0.60). ConclusionsLack of agreement in cases with heterogeneous expression is shown to influence patient eligibility for treatment with brentuximab vedotin, both in clinical practice and within the context of clinical trials, and limits the potential predictive value of the relative frequency of CD30-positive neoplastic cells for clinical response

Tumor immune escape in acute myeloid leukemia: Class II-associated invariant chain peptide expression as result of deficient antigen presentation

In this overview, we discuss the role of class II-associated invariant chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II. The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML

Haemodynamic and functional consequences of the iatrogenic atrial septal defect following Mitraclip therapy

Percutaneous MitraClip placement for treatment of severe mitral regurgitation in high surgical risk patients is a commonly performed procedure and requires a transseptal puncture to reach the left atrium. The resulting iatrogenic atrial septal defect (iASD) is not routinely closed, yet the haemodynamic and functional consequences of a persisting defect are not fully understood. Despite positive effects such as acute left atrial pressure relief, persisting iASDs are associated with negative consequences, namely significant bidirectional shunting and subsequent worse clinical outcome. Percutaneous closure of the iASD may therefore be desirable in selected cases. In this review we discuss the available literature on this matter

Sustained Delivery of Insulin-Like Growth Factor-1/Hepatocyte Growth Factor Stimulates Endogenous Cardiac Repair in the Chronic Infarcted Pig Heart

Activation of endogenous cardiac stem/progenitor cells (eCSCs) can improve cardiac repair after acute myocardial infarction. We studied whether the in situ activation of eCSCs by insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) could be increased using a newly developed hydrogel in chronic myocardial infarction (MI). One-month post-MI pigs underwent NOGA-guided intramyocardial injections of IGF-1/HGF (GF: both 0.5 μg/mL, n = 5) or IGF-1/HGF incorporated in UPy hydrogel (UPy-GF; both 0.5 μg/mL, n = 5). UPy hydrogel without added growth factors was administered to four control (CTRL) pigs. Left ventricular ejection fraction was increased in the UPy-GF and GF animals compared to CTRLs. UPy-GF delivery reduced pathological hypertrophy, led to the formation of new, small cardiomyocytes, and increased capillarization. The eCSC population was increased almost fourfold in the border zone of the UPy-GF-treated hearts compared to CTRL hearts. These results show that IGF-1/HGF therapy led to an improved cardiac function in chronic MI and that effect size could be further increased by using UPy hydrogel. Electronic supplementary material The online version of this article (doi:10.1007/s12265-013-9518-4) contains supplementary material, which is available to authorized users

Primary refractory follicular lymphoma: a poor outcome entity with high risk of transformation to aggressive B cell lymphoma

Background: Primary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome. Methods: Six thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation. Findings.: The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27–43), whilst it was 7.1% (95% CI: 6.0–8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0–4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28–39) for the PREF group, 57% (95% CI 54–61) in patients with PR, 51% (95% CI 43–58) in the SD group after first-line therapy and 63% (95% CI: 66–72) in patients with CR after initial treatment (p-value <0.001). The 5-year SAR for those patients with PREF who developed HT was 21% (95% CI: 12–31), clearly diminished when compared with those patients with PREF who did not experience HT (38% [95% CI: 31–44]) (p-value = 0.001). Interpretation.: Patients with PREF FL have a dismal outcome and an associated very high rate of HT that further worsens their poor prognosis

Cancro familiar - testes genéticos e estratégias

Acute liver failure is a rare disease with high mortality and liver transplantation is the only life saving therapy. Accurate prognosis of ALF is crucial for proper intervention.To identify and characterize newly developed prognostic models of mortality for ALF patients, assess study quality, identify important variables and provide recommendations for the development of improved models in the future.The online databases MEDLINE® (1950-2012) and EMBASE® (1980-2012) were searched for English-language articles that reported original data from clinical trials or observational studies on prognostic models in ALF patients. Studies were included if they developed a new model or modified existing prognostic models. The studies were evaluated based on an existing framework for scoring the methodological and reporting quality of prognostic models.Twenty studies were included, of which 18 reported on newly developed models, 1 on modification of the Kings College Criteria (KCC) and 1 on the Model for End-Stage Liver Disease (MELD). Ten studies compared the newly developed models to previously existing models (e.g. KCC); they all reported that the new models were superior. In the 12-point methodological quality score, only one study scored full points. On the 38-point reporting score, no study scored full points. There was a general lack of reporting on missing values. In addition, none of the studies used performance measures for calibration and accuracy (e.g. Hosmer-Lemeshow statistics, Brier score), and only 5 studies used the AUC as a measure of discrimination.There are many studies on prognostic models for ALF but they show methodological and reporting limitations. Future studies could be improved by better reporting and handling of missing data, the inclusion of model calibration aspects, use of absolute risk measures, explicit considerations for variable selection, the use of a more extensive set of reference models and more thorough validation

Appropriate use criteria for echocardiography in the Netherlands

Introduction Appropriate use criteria (AUC) for echocardiography based on clinical scenarios were previously published by an American Task Force. We determined whether members of the Dutch Working Group on Echocardiography (WGE) would rate these scenarios in a similar way. Methods All 32 members of the WGE were invited to judge clinical scenarios independently using a blanked version of the previously published American version of AUC for echocardiography. During a face-to-face meeting, consensus about the final rating was reached by open discussion for each indication. For reasons of simplicity, the scores were reduced from a 9-point scale to a 3-point scale (indicating an appropriate, uncertain or inappropriate echo indication, respectively). Results Nine cardiologist members of the WGE reported their judgment on the echo cases (n = 153). Seventy-one indications were rated as appropriate, 35 were rated as uncertain, and 47 were rated as inappropriate. In 5% of the cases the rating was opposite to that in the original (appropriate compared with inappropriate and vice versa), whereas in 20% judgements differed by 1 level of appropriateness. After the consensus meeting, the appropriateness of 7 (5%) cases was judged differently compared with the original paper. Conclusions Echocardiography was rated appropriate when it is applied for an initial diagnosis, a change in clinical status or a change in patient management. However, in about 5% of the listed clinical scenarios, members of the Dutch WGE rated the AUC for echocardiography differently as compared with their American counterparts. Further research is warranted to analyse this decreased external validity

Infective endocarditis in the Netherlands:current epidemiological profile and mortality An analysis based on partial ESC EORP collected data

Introduction: Infective endocarditis (IE) is associated with a high in-hospital and long term mortality. Although progress has been made in diagnostic approach and management of IE, morbidity and mortality of IE remain high. In the latest European guidelines, the importance of the multi-modality imaging in diagnosis and follow up of IE is emphasized. Aim: The aim was to provide information regarding mortality and adverse events of IE, to determine IE characteristics and to assess current use of imaging in the diagnostic workup of IE. Methods: This is a prospective observational cohort study. We used data from the EURO-ENDO registry. Seven hospitals in the Netherlands have participated and included patients with IE between April 2016 and April 2018. Results: A total of 139 IE patients were included. Prosthetic valve endocarditis constituted 32.4% of the cases, cardiac device related IE 7.2% and aortic root prosthesis IE 3.6%. In-hospital mortality was 14.4% (20 patients) and one-year mortality was 21.6% (30 patients). The incidence of embolic events under treatment was 16.5%, while congestive heart failure or cardiogenic shock occurred in 15.1% of the patients. Transthoracic and transoesophageal echocardiography were performed most frequently (97.8%; 81.3%) and within 3 days after IE suspicion, followed by 18F‑fluorodeoxyglucose positron emission tomography/computed tomography (45.3%) within 6 days and multi-slice computed tomography (42.4%) within 7 days. Conclusion: We observed a high percentage of prosthetic valve endocarditis, rapid and extensive use of imaging and a relatively low in-hospital and one-year mortality of IE in the Netherlands. Limitations include possible selection bias