Anodal Capture for Multisite Pacing with a Quadripolar Left Ventricular Lead: A Feasibility Study

Background: Up to 40% of patients are CRT non-responders. Multisite pacing, using a unique quadripolar lead, also called multipoint/multipole pacing (MPP), is a potential alternative. We sought to determine the feasibility of intentional anodal capture using a single LV quadripolar lead, to reproduce MPP without the need of a specific algorithm (so-called “pseudo MPP”). Methods: Consecutive patients implanted with a commercially available CRT device and a quadripolar LV lead in our department were prospectively included. The electric charge (Q, in Coulomb) of RV and LV pacing spikes were calculated for all available LV pacing configurations at the threshold. The best MPP was defined as the configuration with the lowest consumption (QRV + Qbest LV1 + Qbest LV2). The best “pseudo MPP” (QRV + QLV1–LV2 with anodal capture) and best BVp (QRV + Qbest LV) were also calculated. A theoretical longevity was estimated for each configuration at the threshold without a safety margin. Results: A total of 235 configurations were tested in 15 consecutive patients. “Pseudo-MPP” was feasible in 80% of patients with 3.1 ± 2.6 vectors available per-patient and LVproximal-LVdistal (most distant electrodes) vectors were available in 47% of patients. Each MPP pacing spike electrical charge was comparable to “pseudo-MPP” (18,428 ± 6863 µC and 20,528 ± 5509 µC, respectively, p = 0.15). Theoretical longevity was 6.2 years for MPP, 5.6 years for “pseudo-MPP” and 13.7 years for BVp. Conclusions: “Pseudo MPP” using intentional anodal capture with a quadripolar left ventricular lead, mimicking conventional multisite pacing, is feasible in most of CRT patients, with comparable energy consumption. Further studies on their potential clinical impact are needed.

Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

Melanoma is the deadliest form of skin cancer. Although targeted therapies and immunotherapies have revolutionized the treatment of metastatic melanoma, most patients are not cured. Therapy resistance remains a significant clinical challenge. Melanoma comprises phenotypically distinct subpopulations of cells, exhibiting distinct gene signatures leading to tumor heterogeneity and favoring therapeutic resistance. Cellular plasticity in melanoma is referred to as phenotype switching. Regardless of their genomic classification, melanomas switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and often therapy-resistant state. In this review we discuss potential mechanisms underpinning melanoma phenotype switching, how this cellular plasticity contributes to resistance to both targeted therapies and immunotherapies. Finally, we highlight novel strategies to target plasticity and their potential clinical impact in melanoma.

The definition of pulmonary hypertension: history, practical implications and current controversies

The definition of pulmonary hypertension (PH) is based on a growing body of evidence and represents the result of ongoing discussions within the PH community over the past 50 years. In 2018, the most recent World Symposium on Pulmonary Hypertension introduced significant changes in the definition of PH by lowering the mean pulmonary arterial pressure threshold to >20 mmHg and (re)introducing the pulmonary vascular resistance ≥3 WU cut-off for all forms of pre-capillary PH. These changes and their potential clinical impact have been the subject of lively discussions in the community and some important questions and controversies have been identified.In this review we aim to present the development of the definition of PH over the past decades and discuss the main arguments that led to relevant modifications. In addition, we address the practical implications of the most recent changes and controversies that still exist.Educational aimsTo review the historical development of the definition of pulmonary hypertension.To discuss practical implications and current controversies of the currently recommended definitions of pulmonary hypertension and pulmonary arterial hypertension.

Uninterpretable cerebrospinal fluid absorbance scans caused by antibiotic therapy

Background The revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage (UK) provide an objective means of assessing cerebrospinal fluid samples to determine the risk of subarachnoid haemorrhage. The guidelines are intended for general use, but samples rendered uninterpretable due to the presence of the antibiotic doxycycline have been described. Here, further cases of antibiotic-based interference, and their implications, are presented. Methods An archival search of cerebrospinal fluid spectra performed at Hallands County Hospital Halmstad was performed for the years 2011 and 2016–2019 in an attempt to locate instances of interference. Each case of suspected interference was further investigated with in vitro reproduction experiments as a means of confirmation and assessment of potential clinical impact. Results A total of 10 cases of cerebrospinal fluid curve interference were discovered: six due to doxycycline, three due to metronidazole and one due to tetracycline. Interference caused by the tetracycline class was revealed through in vitro experimentation to cause an apparent decrease in the sample’s net bilirubin absorbance; the presence of xanthochromia on visual inspection was, however, conserved. Conclusions The problem of cerebrospinal fluid absorbance curve interference might be more common than previously suspected. Due to the potential net bilirubin absorbance-lowering effect of tetracyclines, the author recommends visual examination of cerebrospinal fluid samples in every case.

Combined Mutational and Clonality Analyses Support the Existence of Intra-Tumor Heterogeneity in Papillary Thyroid Cancer

Despite its potential clinical impact, intra-tumor genetic heterogeneity (ITH) has been scantly investigated in papillary thyroid cancer (PTC). We studied ITH in PTC by combining, for the first time, data derived from the evaluation of the normalized allelic frequencies (NAF) of the mutation/s, using a customized MassARRAY panel, and those obtained by the HUMARA clonality assay. Among tumors with a single mutation, 80% of cases with NAF 50 ± 5% were clonal, consistent with the presence of a single mutated clone, while 20% of cases showed a polyclonal pattern, suggesting the presence of the same mutation in two or more clones. Differently, all cases with NAF < 45% were polyclonal. Among tumors with double mutation, cases with both mutations showing NAF 50 ± 5% were monoclonal, consistent with the presence of a single clone harboring both mutations. On the other hand, all cases with double mutation at NAF < 45% were polyclonal, indicating the presence of two clones with different mutations. Finally, no significant differences in the clinico-pathological characteristics were found between monoclonal and polyclonal tumors. In conclusion, the present study adds insights into the concept of ITH in PTC, which warrants attention because the occurrence of this phenomenon is likely to affect the response to targeted drugs.

EXPRESS: Uninterpretable cerebrospinal fluid absorbance scans caused by antibiotic therapy

Background The revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage (UK) provide an objective means of assessing cerebrospinal fluid (CSF) samples to determine risk of subarachnoid haemorrhage (SAH). The guidelines are intended for general use, but samples rendered uninterpretable due to the presence of the antibiotic doxycycline have been described. Here, further cases of antibiotic- based interference, and their implications, are presented. Methods An archival search of CSF spectra performed at Hallands County Hospital Halmstad was performed for the years 2011 and 2016- 2019 in an attempt to locate instances of interference. Each case of suspected interference was further investigated with in vitro reproduction experiments as a means of confirmation and assessment of potential clinical impact. Results A total of 10 cases of CSF curve interference were discovered: 6 due to doxycycline, 3 due to metronidazole and 1 due to tetracycline. Interference due to the tetracycline class was revealed through in vitro experimentation to cause an apparent decrease in the sample’s net bilirubin absorbance(NBA); the presence of xanthochromia on visual inspection was, however, conserved. Conclusions The problem of CSF absorbance curve interference might be more common than previously suspected. Due to the potential NBA- lowering effect of tetracyclines, the author recommends visual examination of CSF samples in every case.

Penetrance of breast cancer genes from the eMERGE III Network

We studied the penetrance and clinical outcomes of seven breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2 and PTEN) in almost 25,000 participants unselected for personal or family history of breast cancer. We identified 420 participants with pathogenic or likely pathogenic variants, and 147 were women who did not previously know their genetic results. Out of these 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 18-44%, depending on the gene. Within the first twelve months after genetic results disclosure, 42% of women had taken actions related to their genetic results and two new breast cancer cases were identified. Our study provides population-based penetrance estimates for the understudied genes, CHEK2, ATM, and PALB2, and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve healthcare through early diagnosis and preventative screening.

Artificial intelligence in radiology: 100 commercially available products and their scientific evidence

Objectives Map the current landscape of commercially available artificial intelligence (AI) software for radiology and review the availability of their scientific evidence. Methods We created an online overview of CE-marked AI software products for clinical radiology based on vendor-supplied product specifications (www.aiforradiology.com). Characteristics such as modality, subspeciality, main task, regulatory information, deployment, and pricing model were retrieved. We conducted an extensive literature search on the available scientific evidence of these products. Articles were classified according to a hierarchical model of efficacy. Results The overview included 100 CE-marked AI products from 54 different vendors. For 64/100 products, there was no peer-reviewed evidence of its efficacy. We observed a large heterogeneity in deployment methods, pricing models, and regulatory classes. The evidence of the remaining 36/100 products comprised 237 papers that predominantly (65%) focused on diagnostic accuracy (efficacy level 2). From the 100 products, 18 had evidence that regarded level 3 or higher, validating the (potential) impact on diagnostic thinking, patient outcome, or costs. Half of the available evidence (116/237) were independent and not (co-)funded or (co-)authored by the vendor. Conclusions Even though the commercial supply of AI software in radiology already holds 100 CE-marked products, we conclude that the sector is still in its infancy. For 64/100 products, peer-reviewed evidence on its efficacy is lacking. Only 18/100 AI products have demonstrated (potential) clinical impact. Key Points • Artificial intelligence in radiology is still in its infancy even though already 100 CE-marked AI products are commercially available. • Only 36 out of 100 products have peer-reviewed evidence of which most studies demonstrate lower levels of efficacy. • There is a wide variety in deployment strategies, pricing models, and CE marking class of AI products for radiology.