Background
The added value of surgery in breast cancer patients with pathological complete response (pCR) after neoadjuvant systemic therapy (NST) is uncertain. The accuracy of imaging identifying ...pCR for omission of surgery, however, is insufficient. We investigated the accuracy of ultrasound-guided biopsies identifying breast pCR (ypT0) after NST in patients with radiological partial (rPR) or complete response (rCR) on MRI.
Methods
We performed a multicenter, prospective single-arm study in three Dutch hospitals. Patients with T1–4(N0 or N +) breast cancer with MRI rPR and enhancement ≤ 2.0 cm or MRI rCR after NST were enrolled. Eight ultrasound-guided 14-G core biopsies were obtained in the operating room before surgery close to the marker placed centrally in the tumor area at diagnosis (no attempt was made to remove the marker), and compared with the surgical specimen of the breast. Primary outcome was the false-negative rate (FNR).
Results
Between April 2016 and June 2019, 202 patients fulfilled eligibility criteria. Pre-surgical biopsies were obtained in 167 patients, of whom 136 had rCR and 31 had rPR on MRI. Forty-three (26%) tumors were hormone receptor (HR)-positive/HER2-negative, 64 (38%) were HER2-positive, and 60 (36%) were triple-negative. Eighty-nine patients had pCR (53%; 95% CI 45–61) and 78 had residual disease. Biopsies were false-negative in 29 (37%; 95% CI 27–49) of 78 patients. The multivariable associated with false-negative biopsies was rCR (FNR 47%; OR 9.81, 95% CI 1.72–55.89;
p
= 0.01); a trend was observed for HR-negative tumors (FNR 71% in HER2-positive and 55% in triple-negative tumors; OR 4.55, 95% CI 0.95–21.73;
p
= 0.058) and smaller pathological lesions (6 mm vs 15 mm; OR 0.93, 95% CI 0.87–1.00;
p
= 0.051).
Conclusion
The MICRA trial showed that ultrasound-guided core biopsies are not accurate enough to identify breast pCR in patients with good response on MRI after NST. Therefore, breast surgery cannot safely be omitted relying on the results of core biopsies in these patients.
In patients with operable early breast cancer, neoadjuvant systemic treatment (NST) is a standard approach. Indications have expanded from downstaging of locally advanced breast cancer to facilitate ...breast conservation, to in vivo drug-sensitivity testing. The pattern of response to NST is used to tailor systemic and locoregional treatment, that is, to escalate treatment in nonresponders and de-escalate treatment in responders. Here we discuss four questions that guide our current thinking about ‘response-adjusted’ surgery of the breast after NST. (i) What critical diagnostic outcome measures should be used when analyzing diagnostic tools to identify patients with pathologic complete response (pCR) after NST? (ii) How can we assess response with the least morbidity and best accuracy possible? (iii) What oncological consequences may ensue if we rely on a nonsurgical-generated diagnosis of, for example, minimally invasive biopsy proven pCR, knowing that we may miss minimal residual disease in some cases? (iv) How should we design clinical trials on de-escalation of surgical treatment after NST?
•Safe past de-escalation treatments.•Surgery after complete response might be overtreatment.•Biopsies might diagnose response.
Autoantibodies directed against cytosolic 5'-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between ...anticytosolic 5'-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis.
Data from various European inclusion body myositis registries were pooled. Anticytosolic 5'-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression.
Data from 311 patients were available for analysis; 102 (33%) had anticytosolic 5'-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients.
Differences were observed in clinical and histopathological features between anticytosolic 5'-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5'-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.
Background Syncope management is fraught with unnecessary tests and frequent failure to establish a diagnosis. We evaluated the potential of implementing the 2018 European Society of Cardiology (ESC) ...Syncope Guidelines regarding diagnostic yield, accuracy and costs. Methods A multicentre pre-post study in five Dutch hospitals comparing two groups of syncope patients visiting the emergency department: one before intervention (usual care; from March 2017 to February 2019) and one afterwards (from October 2017 to September 2019). The intervention consisted of the simultaneous implementation of the ESC Syncope Guidelines with quick referral routes to a syncope unit when indicated. The primary objective was to compare diagnostic accuracy using logistic regression analysis accounting for the study site. Secondary outcome measures included diagnostic yield, syncope-related healthcare and societal costs. One-year follow-up data were used to define a gold standard reference diagnosis by applying ESC criteria or, if not possible, evaluation by an expert committee. We determined the accuracy by comparing the treating physician's diagnosis with the reference diagnosis. Results We included 521 patients (usual care, n = 275; syncope guidelines intervention, n = 246). The syncope guidelines intervention resulted in a higher diagnostic accuracy in the syncope guidelines group than in the usual care group (86% vs.69%; risk ratio 1.15; 95% CI 1.07 to 1.23) and a higher diagnostic yield (89% vs. 76%, 95% CI of the difference 6 to 19%). Syncope-related healthcare costs did not differ between the groups, yet the syncope guideline implementation resulted in lower total syncope-related societal costs compared to usual care (saving euro908 per patient; 95% CI euro34 to euro1782). Conclusions ESC Syncope Guidelines implementation in the emergency department with quick referral routes to a syncope unit improved diagnostic yield and accuracy and lowered societal costs. Trial registration Netherlands Trial Register, NTR6268 Keywords: Transient loss of consciousness, Healthcare efficiency, Syncope, Epilepsy, Admission, Tilt table testing, QALY
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic ...levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance.
On April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19-specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 95% confidence interval (CI) 1.08 to 1.21), female sex (1.58 1.38 to 1.82), low educational level (primary education versus higher vocational/university 1.21 1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 1.80 to 2.22), unemployment (versus employed 2.29 1.54 to 3.39), smoking (1.34 1.08 to 1.65), concern about contracting COVID-19 (per level increase 1.28 1.19 to 1.38) and symptoms of depression (per point increase 1.13 1.11 to 1.14) and anxiety (per point increase 1.16 1.14 to 1.18). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population.
In this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was ...initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands.
Methods
Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments.
Results
Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28–84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%).
Conclusion
The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.
Purpose
The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of exercise on quality of life (QoL) ...and fatigue in inactive breast cancer survivors.
Methods
UMBRELLA Fit was conducted within the prospective UMBRELLA breast cancer cohort. Patients provided consent for future randomization at cohort entry. We randomized inactive patients 12–18 months after cohort enrollment. The intervention group (
n
= 130) was offered a 12-week supervised exercise intervention. The control group (
n
= 130) was not informed and received usual care. Six-month exercise effects on QoL and fatigue as measured in the cohort were analyzed with intention-to-treat (ITT), instrumental variable (IV), and propensity scores (PS) analyses.
Results
Fifty-two percent (
n
= 68) of inactive patients accepted the intervention. Physical activity increased in patients in the intervention group, but not in the control group. We found no benefit of exercise for dimensions of QoL (ITT difference global QoL: 0.8, 95% CI = − 2.2; 3.8) and fatigue, except for a small beneficial effect on physical fatigue (ITT difference: − 1.1, 95% CI = − 1.8; − 0.3; IV: − 1.9, 95% CI = − 3.3; − 0.5, PS: − 1.2, 95% CI = − 2.3; − 0.2).
Conclusion
TwiCs gave insight into exercise intervention acceptance: about half of inactive breast cancer survivors accepted the offer and increased physical activity levels. The offer resulted in no improvement on QoL, and a small beneficial effect on physical fatigue.
Trial registration
Netherlands Trial Register (NTR5482/NL.52062.041.15), date of registration: December 07, 2015.
Objective/Background Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease (PAD), and many patients with CLI are not eligible for conventional revascularization. In the ...last decade, cell based therapies have been explored as an alternative treatment option for CLI. A meta-analysis was conducted of randomized placebo controlled trials investigating bone marrow (BM) derived cell therapy in patients with CLI. Methods The MEDLINE, Embase, and the Cochrane Controlled Trials Register databases were systematically searched, and all included studies were critically appraised by two independent reviewers. The meta-analysis was performed using a random effects model. Results Ten studies, totaling 499 patients, were included in this meta-analysis. No significant differences were observed in major amputation rates (relative risk RR 0.91; 95% confidence interval CI 0.65–1.27), survival (RR 1.00; 95% CI 0.95–1.06), and amputation free survival (RR 1.03; 95% CI 0.86–1.23) between the cell treated and placebo treated patients. The ankle brachial index (mean difference 0.11; 95% CI 0.07–0.16), transcutaneous oxygen measurements (mean difference 11.88; 95% CI 2.73–21.02), and pain score (mean difference –0.72; 95% CI –1.37 to –0.07) were significantly better in the treatment group than in the placebo group. Conclusions This meta-analysis of placebo controlled trials showed no advantage of stem cell therapy on the primary outcome measures of amputation, survival, and amputation free survival in patients with CLI. The potential benefit of more sophisticated cell based strategies should be explored in future randomized placebo controlled trials.
Summary Background An important goal of stem cell research in orthopaedics is to develop clinically relevant techniques that could be applied to heal cartilage or joint pathology. Stem cell treatment ...in orthopaedics for joint pathology is promising since these cells have the ability to modulate different processes in the various tissues of the joint simultaneously. The non life-threatening nature of musculoskeletal system disorders makes safety of stem cell therapy a necessary prerequisite. Objective To systematically review the literature and provide an overview of reported adverse events (AEs) of intra-articular treatment with culture-expanded stem cells in humans. Design A systematic literature search was performed in Pubmed, EMBASE, Web of Science and CINAHL in February 2013. AEs were reported into three categories: local/systemic, serious adverse event or AE (SAE/AE), related/unrelated. Results 3039 Potentially eligible articles were identified of which eventually eight fulfilled our inclusion criteria. In total, 844 procedures with a mean follow-up of 21 months were analysed. Autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) were used for cartilage repair and osteoarthritis treatment in all included studies. Four SAEs were reported by the authors. One infection following bone marrow aspiration (BMA) was reported as probably related and resolved with antibiotics. One pulmonary embolism occurred 2 weeks after BMA and was reported as possibly related. Two tumours, both not at the site of injection, were reported as unrelated. Twenty-two other cases of possible procedure-related and seven of possible stem cell-product related adverse events (AEs) were documented. The main AEs related to the procedure were increased pain/swelling and dehydration after BMA. Increased pain and swelling was the only AE reported as related to the stem cell-product. Conclusions Based on current literature review we conclude that application of cultured stem cells in joints appears to be safe. We believe that with continuous caution for potential side effects, it is reasonable to continue with the development of articular stem cell therapies.
Several individual clinical and preclinical studies have shown the possibility of evaluating tumor hypoxia by using noninvasive positron emission tomography (PET). The current study compared 3 ...hypoxia PET tracers frequently used in the clinic, 18FFMISO, 18FFAZA, and 18FHX4, in a preclinical tumor model. Tracer uptake was evaluated for the optimal time point for imaging, tumor-to-blood ratios (TBR), spatial reproducibility, and sensitivity to oxygen modification.
PET/computed tomography (CT) images of rhabdomyosarcoma R1-bearing WAG/Rij rats were acquired at multiple time points post injection (p.i.) with one of the hypoxia tracers. TBR values were calculated, and reproducibility was investigated by voxel-to-voxel analysis, represented as correlation coefficients (R) or Dice similarity coefficient of the high-uptake volume. Tumor oxygen modifications were induced by exposure to either carbogen/nicotinamide treatment or 7% oxygen breathing.
TBR was stabilized and maximal at 2 hours p.i. for 18FFAZA (4.0 ± 0.5) and at 3 hours p.i. for 18FHX4 (7.2 ± 0.7), whereas 18FFMISO showed a constant increasing TBR (9.0 ± 0.8 at 6 hours p.i.). High spatial reproducibility was observed by voxel-to-voxel comparisons and Dice similarity coefficient calculations on the 30% highest uptake volume for both 18FFMISO (R = 0.86; Dice coefficient = 0.76) and 18FHX4 (R = 0.76; Dice coefficient = 0.70), whereas 18FFAZA was less reproducible (R = 0.52; Dice coefficient = 0.49). Modifying the hypoxic fraction resulted in enhanced mean standardized uptake values for both 18FHX4 and 18FFAZA upon 7% oxygen breathing. Only 18FFMISO uptake was found to be reversible upon exposure to nicotinamide and carbogen.
This study indicates that each tracer has its own strengths and, depending on the question to be answered, a different tracer can be put forward.
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