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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The spatially and temporally variable parameters and inputs to complex groundwater models typically result in long runtimes which hinder comprehensive calibration, sensitivity, and uncertainty ...analysis. Surrogate modeling aims to provide a simpler, and hence faster, model which emulates the specified output of a more complex model in function of its inputs and parameters. In this review paper, we summarize surrogate modeling techniques in three categories: data‐driven, projection, and hierarchical‐based approaches. Data‐driven surrogates approximate a groundwater model through an empirical model that captures the input‐output mapping of the original model. Projection‐based models reduce the dimensionality of the parameter space by projecting the governing equations onto a basis of orthonormal vectors. In hierarchical or multifidelity methods the surrogate is created by simplifying the representation of the physical system, such as by ignoring certain processes, or reducing the numerical resolution. In discussing the application to groundwater modeling of these methods, we note several imbalances in the existing literature: a large body of work on data‐driven approaches seemingly ignores major drawbacks to the methods; only a fraction of the literature focuses on creating surrogates to reproduce outputs of fully distributed groundwater models, despite these being ubiquitous in practice; and a number of the more advanced surrogate modeling methods are yet to be fully applied in a groundwater modeling context.
Key Points:
Three broad categories of surrogate model exist, each with their shortfalls
Most methods common in water resources aren't applicable for large numbers of parameters
A number of promising methods have not been applied to water resources models
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Context:
Menopause has been hypothesized to occur when the nongrowing follicle (NGF) number falls below a critical threshold. Age at natural menopause can be predicted using NGF numbers and this ...threshold. These predictions support the use of ovarian reserve tests, reflective of the ovarian follicle pool, in menopause forecasting.
Objective:
The objective of the study was to investigate the hypothesis that age-specific NGF numbers reflect age at natural menopause.
Design and Setting:
Histologically derived NGF numbers obtained from published literature (n = 218) and distribution of menopausal ages derived from the population-based Prospect-European Prospective Investigation into Cancer and Nutrition (Prospect-EPIC) cohort (n = 4037) were combined.
Participants:
NGF data were from single ovaries that had been obtained postnatally for various reasons, such as elective surgery or autopsy. From the Prospect-EPIC cohort, women aged 58 years and older with a known age at natural menopause were selected.
Interventions:
There were no interventions.
Main Outcome Measure(s):
Conformity between observed age at menopause in the Prospect-EPIC cohort and NGF-predicted age at menopause from a model for age-related NGF decline constructed using a robust regression analysis. A critical threshold for NGF number was estimated by comparing the probability distribution of the age at which the NGF numbers fall below this threshold with the observed distribution of age at natural menopause from the Prospect-EPIC cohort.
Results:
The distributions of observed age at natural menopause and predicted age at natural menopause showed close conformity.
Conclusion:
The close conformity observed between NGF-predicted and actual age at natural menopause supports the hypothesis that that the size of the primordial follicle pool is an important determinant for the length of the individual ovarian life span and supports the concept of menopause prediction using ovarian reserve tests, such as anti-Müllerian hormone and antral follicle count, as derivatives of the true ovarian reserve.
In the future, an increasing number of elderly people will be asked to accept care delivered through the Internet. For example, health-care professionals can provide treatment or support via ...telecare. But do elderly people intend to use such so-called e-Health applications? The objective of this study is to gain insight into the intention of older people, i.e. the elderly of the future, to use e-Health applications. Using elements of the Unified Theory of Acceptance and Use of Technology (UTAUT), we hypothesized that their intention is related to the belief that e-Health will help (performance expectancy), the perceived ease of use (effort expectancy), the beliefs of important others (social influence), and the self-efficacy concerning Internet usage.
A pre-structured questionnaire was completed by 1014 people aged between 57 and 77 (response 67%). The hypothesized relationships were tested using nested linear regression analyses.
If offered an e-Health application in the future, 63.1% of the respondents would definitely or probably use it. In general, people with a lower level of education had less intention of using e-Health. The majority of respondents perceived e-Health as easy to use (60.8%) and easy to learn (68.4%), items that constitute the scale for effort expectancy. Items in the performance expectancy scale generally scored lower: 45.8% perceived e-Health as useful and 38.2% perceived it as a pleasant way to interact. The tested model showed that expected performance and effort were highly related to intention to use e-Health. In addition, self-efficacy was related to intention to use while social influence was not.
Acceptance of e-Health can be increased by informing people about the potential benefits of e-Health and letting them practice with the application. Special attention should be paid to people with less education and people who have not used the Internet before.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
To analyze the influence of hormone receptors (HR) and Human Epidermal growth factor Receptor-2 (HER2)-based molecular subtypes in stage III inflammatory breast cancer (IBC) on tumor ...characteristics, treatment, pathologic response to neoadjuvant chemotherapy (NACT), and overall survival (OS).
Methods
Patients with stage III IBC, diagnosed in the Netherlands between 2006 and 2015, were classified into four breast cancer subtypes: HR+/HER2− , HR+/HER2+ , HR−/HER2+ , and HR−/HER2− . Patient-, tumor- and treatment-related characteristics were compared. In case of NACT, pathologic complete response (pCR) was compared between subgroups. OS of the subtypes was compared using Kaplan–Meier curves and the log-rank test.
Results
1061 patients with stage III IBC were grouped into subtypes: HR+/HER2− (
N
= 453, 42.7%), HR−/HER2− (
N
= 258, 24.3%), HR−/HER2+ (
N
= 180,17.0%), and HR+/HER2+ (
N
= 170,16.0%). In total, 679 patients (85.0%) received NACT. In HR−/HER2+ tumors, pCR rate was highest (43%, (
p
< 0.001). In case of pCR, an improved survival was observed for all subtypes, especially for HR+/HER2+ and HR−/HER2+ tumor subtypes. Trimodality therapy (NACT, surgery, radiotherapy) improved 5-year OS as opposed to patients not receiving this regimen: HR+/HER2− (74.9 vs. 46.1%), HR+/HER2+ (80.4 vs. 52.6%), HR−/HER2+ (76.4 vs. 29.7%), HR−/HER2− (47.6 vs. 27.8%).
Conclusions
In stage III IBC, breast cancer subtypes based on the HR and HER2 receptor are important prognostic factors of response to NACT and OS. Patients with HR−/HER2− IBC were less likely to achieve pCR and had the worst OS, irrespective of receiving most optimal treatment regimen to date (trimodality therapy).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Breast cancer surgeons struggle with differentiating healthy tissue from cancer at the resection margin during surgery. We report on the feasibility of using diffuse reflectance spectroscopy (DRS) ...for real-time in vivo tissue characterization.
Evaluating feasibility of the technology requires a setting in which measurements, imaging and pathology have the best possible correlation. For this purpose an optical biopsy needle was used that had integrated optical fibers at the tip of the needle. This approach enabled the best possible correlation between optical measurement volume and tissue histology. With this optical biopsy needle we acquired real-time DRS data of normal tissue and tumor tissue in 27 patients that underwent an ultrasound guided breast biopsy procedure. Five additional patients were measured in continuous mode in which we obtained DRS measurements along the entire biopsy needle trajectory. We developed and compared three different support vector machine based classification models to classify the DRS measurements.
With DRS malignant tissue could be discriminated from healthy tissue. The classification model that was based on eight selected wavelengths had the highest accuracy and Matthews Correlation Coefficient (MCC) of 0.93 and 0.87, respectively. In three patients that were measured in continuous mode and had malignant tissue in their biopsy specimen, a clear transition was seen in the classified DRS measurements going from healthy tissue to tumor tissue. This transition was not seen in the other two continuously measured patients that had benign tissue in their biopsy specimen.
It was concluded that DRS is feasible for integration in a surgical tool that could assist the breast surgeon in detecting positive resection margins during breast surgery. Trail registration NIH US National Library of Medicine-clinicaltrails.gov, NCT01730365. Registered: 10/04/2012 https://clinicaltrials.gov/ct2/show/study/NCT01730365.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Although psychotherapies for depression produce equivalent outcomes, individual patients respond differently to different therapies. Predictors of outcome have been identified in the context of ...randomized trials, but this information has not been used to predict which treatment works best for the depressed individual. In this paper, we aim to replicate a recently developed treatment selection method, using data from an RCT comparing the effects of cognitive therapy (CT) and interpersonal psychotherapy (IPT).
134 depressed patients completed the pre- and post-treatment BDI-II assessment. First, we identified baseline predictors and moderators. Second, individual treatment recommendations were generated by combining the identified predictors and moderators in an algorithm that produces the Personalized Advantage Index (PAI), a measure of the predicted advantage in one therapy compared to the other, using standard regression analyses and the leave-one-out cross-validation approach.
We found five predictors (gender, employment status, anxiety, personality disorder and quality of life) and six moderators (somatic complaints, cognitive problems, paranoid symptoms, interpersonal self-sacrificing, attributional style and number of life events) of treatment outcome. The mean average PAI value was 8.9 BDI points, and 63% of the sample was predicted to have a clinically meaningful advantage in one of the therapies. Those who were randomized to their predicted optimal treatment (either CT or IPT) had an observed mean end-BDI of 11.8, while those who received their predicted non-optimal treatment had an end-BDI of 17.8 (effect size for the difference = 0.51).
Depressed patients who were randomized to their predicted optimal treatment fared much better than those randomized to their predicted non-optimal treatment. The PAI provides a great opportunity for formal decision-making to improve individual patient outcomes in depression. Although the utility of the PAI approach will need to be evaluated in prospective research, this study promotes the development of a treatment selection approach that can be used in regular mental health care, advancing the goals of personalized medicine.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Case series suggest that laparoscopic peritoneal lavage might be a promising alternative to sigmoidectomy in patients with perforated diverticulitis. We aimed to assess the ...superiority of laparoscopic lavage compared with sigmoidectomy in patients with purulent perforated diverticulitis, with respect to overall long-term morbidity and mortality. Methods We did a multicentre, parallel-group, randomised, open-label trial in 34 teaching hospitals and eight academic hospitals in Belgium, Italy, and the Netherlands (the Ladies trial). The Ladies trial is split into two groups: the LOLA group comparing laparoscopic lavage with sigmoidectomy and the DIVA group comparing Hartmann's procedure with sigmoidectomy plus primary anastomosis. The DIVA section of this trial is still underway but here we report the results of the LOLA section. Patients with purulent perforated diverticulitis were enrolled for LOLA, excluding patients with faecal peritonitis, aged older than 85 years, with high-dose steroid use (≥20 mg daily), and haemodynamic instability. Patients were randomly assigned (2:1:1; stratified by age <60 years vs ≥60 years) using secure online computer randomisation to laparoscopic lavage, Hartmann's procedure, or primary anastomosis in a parallel design after diagnostic laparoscopy. Patients were analysed according to a modified intention-to-treat principle and were followed up after the index operation at least once in the outpatient setting and after sigmoidoscopy and stoma reversal, according to local protocols. The primary endpoint was a composite endpoint of major morbidity and mortality within 12 months. This trial is registered with ClinicalTrials.gov , number NCT01317485. Findings Between July 1, 2010, and Feb 22, 2013, 90 patients were randomly assigned in the LOLA section of the Ladies trial when the study was terminated by the data and safety monitoring board because of an increased event rate in the lavage group. Two patients were excluded for protocol violations. The primary endpoint occurred in 30 (67%) of 45 patients in the lavage group and 25 (60%) of 42 patients in the sigmoidectomy group (odds ratio 1·28, 95% CI 0·54–3·03, p=0·58). By 12 months, four patients had died after lavage and six patients had died after sigmoidectomy (p=0·43). Interpretation Laparoscopic lavage is not superior to sigmoidectomy for the treatment of purulent perforated diverticulitis. Funding Netherlands Organisation for Health Research and Development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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