Tumor infiltrating lymphocytes and change in tumor load on MRI to assess response and prognosis after neoadjuvant chemotherapy in breast cancer.

PURPOSE: In this study, we aimed to explore if the combination of tumor infiltrating lymphocytes (TILs) and change in tumor load on dynamic contrast-enhanced magnetic resonance imaging leads to better assessment of response to neoadjuvant chemotherapy (NAC) in patients with breast cancer, compared to either alone. METHODS: In 190 NAC treated patients, MRI scans were performed before and at the end of treatment. The percentage of stromal TILs (%TILs) was assessed in pre-NAC biopsies according to established criteria. Prediction models were developed with linear regression by least absolute shrinkage and selection operator and cross validation (CV), with residual cancer burden as the dependent variable. Discrimination for pathological complete response (pCR) was evaluated using area under the receiver operating characteristic curves (AUC). We used Cox regression analysis for exploring the association between %TILs and recurrence-free survival (RFS). RESULTS: Fifty-one patients reached pCR. In all patients, the %TILs model and change in MRI tumor load model had an estimated CV AUC of 0.69 (95% confidence interval (CI) 0.53-0.78) and 0.69 (95% CI 0.61-0.79), respectively, whereas a model combining the variables resulted in an estimated CV AUC of 0.75 (95% CI 0.66-0.83). In the group with tumors that were ER positive and HER2 negative (ER+/HER2-) and in the group with tumors that were either triple negative or HER2 positive (TN&HER2+) separately, the combined model reached an estimated CV AUC of 0.72 (95% CI 0.60-0.88) and 0.70(95% CI 0.59-0.82), respectively. A significant association was observed between pre-treatment %TILS and RFS (hazard ratio (HR) 0.72 (95% CI 0.53-0.98), for every standard deviation increase in %TILS, p = 0.038). CONCLUSION: The combination of TILs and MRI is informative of response to NAC in patients with both ER+/HER2- and TN&HER2+ tumors.

Does preoperative multidisciplinary team assessment of high-risk patients improve the safety and outcomes of patients undergoing surgery?

BACKGROUND: International guidelines recommend preoperative multidisciplinary team (MDT) assessment for high-risk surgical patients. Preoperative MDT meetings can help to improve surgical care, but there is little evidence on whether they improve patient outcomes. METHODS: This paper aims to share our experience of MDT meetings for high-risk surgical patients to underline their added value to the current standard of care. An observational study of a retrospective cohort of preoperative high-risk MDT meetings of a tertiary referral hospital between January 2015 and December 2020. For 249 patients the outcomes preoperative data, MDT decisions, and patient outcomes were collected from electronic health records. MAIN RESULTS: A total of 249 patients were discussed at high-risk MDT meetings. Most of the patients (97%) were assessed as having an American Society of Anesthesiology score ≥ 3, and 219 (88%) had a European Society of Cardiology and European Society of Anaesthesiology risk score of intermediate or high. After MDT assessment, 154 (62%) were directly approved for surgery, and 39 (16%) were considered ineligible for surgery. The remaining 56 (23%) patients underwent additional assessments before reconsideration at a high-risk MDT meeting. The main reason for patients being discussed at the high-risk MDT meeting was to assess the risk-benefit ratio of surgery. Ultimately, 184 (74%) patients underwent surgery. Of the operated patients, 122 (66%) did not have a major complication in the postoperative period, and 149 patients (81%) were alive after one year. CONCLUSIONS: This cohort study shows the vulnerability and complexity of high-risk patients but also shows that the use of an MDT assessment contributes too improved peri- and postoperative treatment strategies in high-risk patients. Most patients underwent surgery after careful risk assessment and, if deemed necessary, preoperative and perioperative treatment optimization to reduce their risk.

Good manufacturing practice production of CD34+ progenitor-derived NK cells for adoptive immunotherapy in acute myeloid leukemia.

Allogeneic natural killer (NK) cell-based immunotherapy is a promising, well-tolerated adjuvant therapeutic approach for acute myeloid leukemia (AML). For reproducible NK cell immunotherapy, a homogenous, pure and scalable NK cell product is preferred. Therefore, we developed a good manufacturing practice (GMP)-compliant, cytokine-based ex vivo manufacturing process for generating NK cells from CD34+ hematopoietic stem and progenitor cells (HSPC). This manufacturing process combines amongst others IL15 and IL12 and the aryl hydrocarbon receptor antagonist StemRegenin-1 (SR1) to generate a consistent and active NK cell product that fits the requirements for NK cell immunotherapy well. The cell culture protocol was first optimized to generate NK cells with required expansion and differentiation capacity in GMP-compliant closed system cell culture bags. In addition, phenotype, antitumor potency, proliferative and metabolic capacity were evaluated to characterize the HSPC-NK product. Subsequently, seven batches were manufactured for qualification of the process. All seven runs demonstrated consistent results for proliferation, differentiation and antitumor potency, and preliminary specifications for the investigational medicinal product for early clinical phase trials were set. This GMP-compliant manufacturing process for HSPC-NK cells (named RNK001 cells) is used to produce NK cell batches applied in the clinical trial 'Infusion of ex vivo-generated allogeneic natural killer cells in combination with subcutaneous IL2 in patients with acute myeloid leukemia' approved by the Dutch Ethics Committee (EudraCT 2019-001929-27).

Quantum simulation of a Fermi-Hubbard model using a semiconductor quantum dot array.

Interacting fermions on a lattice can develop strong quantum correlations, which are the cause of the classical intractability of many exotic phases of matter. Current efforts are directed towards the control of artificial quantum systems that can be made to emulate the underlying Fermi-Hubbard models. Electrostatically confined conduction-band electrons define interacting quantum coherent spin and charge degrees of freedom that allow all-electrical initialization of low-entropy states and readily adhere to the Fermi-Hubbard Hamiltonian. Until now, however, the substantial electrostatic disorder of the solid state has meant that only a few attempts at emulating Fermi-Hubbard physics on solid-state platforms have been made. Here we show that for gate-defined quantum dots this disorder can be suppressed in a controlled manner. Using a semi-automated and scalable set of experimental tools, we homogeneously and independently set up the electron filling and nearest-neighbour tunnel coupling in a semiconductor quantum dot array so as to simulate a Fermi-Hubbard system. With this set-up, we realize a detailed characterization of the collective Coulomb blockade transition, which is the finite-size analogue of the interaction-driven Mott metal-to-insulator transition. As automation and device fabrication of semiconductor quantum dots continue to improve, the ideas presented here will enable the investigation of the physics of ever more complex many-body states using quantum dots.

How to collaborate for health throughout the project timeline - a longitudinal study reflecting on implemented strategies in three projects for a healthy living environment.

BACKGROUND: When improving the health of local and regional populations, cross-sector collaboration between different policy domains, non-governmental organisations and citizens themselves is needed. Previously, enabling factors and strategies have been identified to improve cross-sector collaboration for health. However, few longitudinal studies have been conducted to understand how the implementation of strategies for cross-sector collaboration changes throughout the collaboration process. The aim of this study is therefore to learn more about the different strategies that were implemented throughout three cross-sector collaboration projects for a healthy living environment. METHODS: The realist evaluation approach was used to understand how the implemented strategies worked, in which context, why and with what outcomes. Project partners were asked to reflect on their implemented strategies at two different moments in the project timelines, and quarterly updates with project leaders were held. In addition two reference panels were organised for data triangulation. RESULTS: Three key insights for successful cross-sector collaboration throughout projects for a healthy living environment were identified, namely 1. Investing in trust among the partners and faith in the project has a positive influence on continuing the collaboration throughout the project; 2. Making stakeholders actively participate throughout the project requires additional strategies after the onset of the project, and 3. Defining roles, tasks, and other prerequisites at the start of the project helps in pursuing the project over time, but needs re-examination throughout the project. These key insights were based on multiple examples of implemented strategies, linked to context, mechanisms and outcomes. CONCLUSIONS: This study shows the different strategies that can be employed as the collaboration in projects for a healthy living environment progresses. We found that 'trust' does not merely include the relationships built between the partners, but at the onset of projects can also be based on faith in the project itself. In addition, as it can be difficult to foresee the right investments and strategies at the onset of the project, frequent reflection moments to choose fitting strategies might benefit regional partners in their cross-sector collaboration for health.

Factors related to patient-reported cosmetic outcome after breast-conserving therapy for breast cancer.

BACKGROUND: Multiple factors can affect cosmetic outcome after breast-conserving therapy. We investigated which combination of factors could optimally predict patient reported cosmetic outcome. METHODS AND MATERIALS: Dutch patients treated with BCT between 2008 and 2013 were retrospectively analysed. Demographics, tumour characteristics, and treatment-related factors were obtained from available digital medical records. Patients were asked to indicate their degree of cosmetic satisfaction using the Harvard scale. Both univariable and multivariable logistic regression analyses were performed to create a prediction model. RESULTS: The present study based on 220 patients shows that univariable analysis radiotherapy boost (OR 4.01 [1.85-8.70], p ≤ 0.001) and adjuvant chemotherapy (OR 2.67 [1.45-4.92], p = 0.002) were significantly associated with unsatisfactory cosmetic outcome. In multivariable analyses, only a radiotherapy boost remained significantly associated (OR 4.08 [1.76-9.49], p = 0.001) with poor cosmetic outcome, while adjuvant chemotherapy was no longer associated with it (OR 1.61 [0.81-3.24), p = 0.18). These two factors, together with tumour histology and lymph node staging, showed the highest predictive values, although the predictive property of the overall model was limited (AUC = 0.69). CONCLUSION: In the present study, a variety of factors is explored. However, a radiotherapy boost was the only factor that was independently associated with a poor cosmetic outcome after BCT. This finding can be used for counselling in daily clinical practice. Creation of a prediction model will require further investigation.

Role Of Ovarian Metastases In Colorectal Cancer (ROMIC): a Dutch study protocol to evaluate the effect of prophylactic salpingo-oophorectomy in postmenopausal women.

BACKGROUND: The mean incidence of ovarian metastases (OM) in patients with colorectal cancer (CRC) is 3.4%. The 5-year survival of these patients, even when operated with curative intent, is remarkably low. The lifetime risk of ovarian cancer is approximately 1.3%. Prophylactic salpingo-oophorectomy (PSO, or surgical removal of the ovaries and fallopian tubes) could reduce the number of CRC patients that develop OM after removal of the primary tumor, as well as preventing the occurrence of primary ovarian cancer. Recently, the care pathway for CRC has been changed in several hospitals in line with the updated Dutch guideline. The possibility of PSO is now discussed with postmenopausal CRC patients in these hospitals. The aims of the current study are firstly to estimate the incidence of OM and primary ovarian cancer in postmenopausal patients with CRC, and secondly to evaluate the effect of PSO in these patients. METHODS: An information bulletin and decision guide on this topic was implemented in several Dutch hospitals in 2020. Post-decision outcomes will be collected prospectively. The study population consists of postmenopausal (≥ 60 years of age) patients that are operated with curative intent for CRC. Based on their own preference, patients will be divided into two groups: those who choose to undergo PSO and those who do not. The main study parameters are the reduction in incidence of ovarian malignancies (metastatic or primary) following PSO, and the number needed to treat (NNT) by PSO to prevent one case of ovarian malignancy. DISCUSSION: This will be the first study to evaluate the effect of PSO in postmenopausal CRC patients that is facilitated by an altered CRC care pathway. The results of this study are expected to provide relevant information on whether PSO adds significant value to postmenopausal patients with CRC. TRIAL REGISTRATION: International Clinical Trials Registry Platform, NL7870. Registered on 2019 July 12. URL of trial registry record: https://trialsearch.who.int/Trial2.aspx?TrialID=NL7870 . PROTOCOL VERSION: 1.0, date 2021 June 8.

An economical and highly adaptable optogenetics system for individual and population-level manipulation of Caenorhabditis elegans.

BACKGROUND: Optogenetics allows the experimental manipulation of excitable cells by a light stimulus without the need for technically challenging and invasive procedures. The high degree of spatial, temporal, and intensity control that can be achieved with a light stimulus, combined with cell type-specific expression of light-sensitive ion channels, enables highly specific and precise stimulation of excitable cells. Optogenetic tools have therefore revolutionized the study of neuronal circuits in a number of models, including Caenorhabditis elegans. Despite the existence of several optogenetic systems that allow spatial and temporal photoactivation of light-sensitive actuators in C. elegans, their high costs and low flexibility have limited wide access to optogenetics. Here, we developed an inexpensive, easy-to-build, modular, and adjustable optogenetics device for use on different microscopes and worm trackers, which we called the OptoArm. RESULTS: The OptoArm allows for single- and multiple-worm illumination and is adaptable in terms of light intensity, lighting profiles, and light color. We demonstrate OptoArm's power in a population-based multi-parameter study on the contributions of motor circuit cells to age-related motility decline. We found that individual components of the neuromuscular system display different rates of age-dependent deterioration. The functional decline of cholinergic neurons mirrors motor decline, while GABAergic neurons and muscle cells are relatively age-resilient, suggesting that rate-limiting cells exist and determine neuronal circuit ageing. CONCLUSION: We have assembled an economical, reliable, and highly adaptable optogenetics system which can be deployed to address diverse biological questions. We provide a detailed description of the construction as well as technical and biological validation of our set-up. Importantly, use of the OptoArm is not limited to C. elegans and may benefit studies in multiple model organisms, making optogenetics more accessible to the broader research community.

Burden of disease of type 2 diabetes mellitus: cost of illness and quality of life estimated using the Maastricht Study.

AIMS: To estimate the societal costs and quality of life of people with type 2 diabetes and to compare these results with those of people with normal glucose tolerance or prediabetes. METHODS: Data from 2915 individuals from the population-based Maastricht Study were included. Costs were assessed through a resource-use questionnaire completed by the participants; cost prices were based on Dutch costing guidelines. Quality of life was expressed in utilities using the Dutch EuroQol 5D-3L questionnaire and the SF-36 health survey. Based on normal fasting glucose and 2-h plasma glucose values, participants were classified into three groups: normal glucose tolerance (n = 1701); prediabetes (n = 446); or type 2 diabetes (n = 768). RESULTS: Participants with type 2 diabetes had on average 2.2 times higher societal costs than those with normal glucose tolerance (€3,006 and €1,377 per 6 months, respectively) and had lower utilities (0.77 and 0.81, respectively). No significant differences were found between participants with normal glucose tolerance and those with prediabetes. Subgroup analyses showed that higher age, being female and having two or more diabetes-related complications resulted in higher costs (P < 0.05) and lower utilities. CONCLUSIONS: This study showed that people with type 2 diabetes have substantially higher societal costs and lower quality of life than people with normal glucose tolerance. The results provide important input for future model-based economic evaluations and for policy decision-making.

Characterising the diffusion of biological nanoparticles on fluid and cross-linked membranes.

Tracing the motion of macromolecules, viruses, and nanoparticles adsorbed onto cell membranes is currently the most direct way of probing the complex dynamic interactions behind vital biological processes, including cell signalling, trafficking, and viral infection. The resulting trajectories are usually consistent with some type of anomalous diffusion, but the molecular origins behind the observed anomalous behaviour are usually not obvious. Here we use coarse-grained molecular dynamics simulations to help identify the physical mechanisms that can give rise to experimentally observed trajectories of nanoscopic objects moving on biological membranes. We find that diffusion on membranes of high fluidities typically results in normal diffusion of the adsorbed nanoparticle, irrespective of the concentration of receptors, receptor clustering, or multivalent interactions between the particle and membrane receptors. Gel-like membranes on the other hand result in anomalous diffusion of the particle, which becomes more pronounced at higher receptor concentrations. This anomalous diffusion is characterised by local particle trapping in the regions of high receptor concentrations and fast hopping between such regions. The normal diffusion is recovered in the limit where the gel membrane is saturated with receptors. We conclude that hindered receptor diffusivity can be a common reason behind the observed anomalous diffusion of viruses, vesicles, and nanoparticles adsorbed on cell and model membranes. Our results enable direct comparison with experiments and offer a new route for interpreting motility experiments on cell membranes.

Introduction of less invasive surfactant administration (LISA), impact on diagnostic and therapeutic procedures in early life: a historical cohort study.

BACKGROUND: In preterm infants with Respiratory Distress Syndrome (RDS), Less Invasive Surfactant Administration (LISA) has been established to reduce the need of mechanical ventilation and might improve survival rates without bronchopulmonary dysplasia. The aim of this study was to investigate whether NICU care has changed after introduction of less invasive surfactant administration (LISA), with regard to diagnostic and therapeutic procedures in the first week of life. METHODS: Infants with gestational age < 32 weeks who received surfactant by LISA (June 2014 - December 2017, n = 169) were retrospectively compared to infants who received surfactant after intubation (January 2012 - May 2014, n = 155). Local protocols on indication for surfactant, early onset sepsis, blood transfusions and enteral feeding did not change between both study periods. Besides, as secondary outcome complications of prematurity were compared. Data was collected from electronic patient files and compared by univariate analysis through Students T-test, Mann Whitney-U test, Pearson Chi-Square test or Linear by Linear Association. RESULTS: All baseline characteristics of both groups were comparable. Compared to controls, LISA patients received a higher total surfactant dose (208 vs.160 mg/kg; p < 0.001), required redosing more frequently (32.5% vs. 21.3%; p = 0.023), but needed less mechanical ventilation (35.5% vs. 76.8%; p < 0.001). After LISA, infants underwent fewer X-rays (1.0 vs. 3.0, p < 0.001), blood gas examinations (3.0 vs. 5.0, p < 0.001), less inotropic drugs (9.5% vs. 18.1%; p = 0.024), blood transfusions (24.9% vs. 41.9%, p = 0.003) and had shorter duration of antibiotic therapy for suspected early onset sepsis (3.0 vs. 5.0 days, p < 0.001). Moreover, enteral feeding was advanced faster (120 vs. 100 mL/kg/d, p = 0.048) at day seven. There were no differences in complications of prematurity. CONCLUSION: The introduction of LISA is associated with significantly fewer diagnostic and therapeutic procedures in the first week of life, which emphasizes the beneficial effects of LISA.

Banded Roux-en-Y gastric bypass in patients with super morbid obesity (BRandY-study): protocol of a cohort study with 10 year follow-up.

BACKGROUND: Weight loss outcomes after bariatric surgery are less favorable in super morbidly obese patients (BMI ≥50 kg/m2). Non-response, either defined as insufficient weight loss or weight regain after initial successful weight loss, is a matter of serious concern in these patients. The primary banded Roux-en-Y gastric bypass has shown promising results regarding weight loss in the bariatric population. However, up to now, long-term comparative data about the banded and non-banded bypass in superobese patients is lacking. The aim of this study is to assess the added value of the banded Roux-en-Y gastric bypass in superobese patients on long-term weight loss outcomes. METHODS: This single center study will evaluate superobese patients who receive a non-banded Roux-en-Y gastric bypass (NB-RYGB) and a banded Roux-en-Y gastric bypass (B-RYGB). Data from the NB-RYGB group will be collected in retrospect, while data from the B-RYGB group will be collected prospectively. When performing a B-RYGB, a 7.0-8.0 cm silastic ring (MiniMizer®) will be placed proximal to the gastrojejunostomy. The main outcomes of this study are weight loss and non-response during a 10 year follow-up period. Secondary outcomes are reduction of obesity related comorbidities and medication, (ring-related) morbidity and mortality, complications, re-operations, patient satisfaction and health-related quality of life. A total of 142 patients will be included in this study. DISCUSSION: This study will help establish the clinical utility of the B-RYGB in superobese patients. TRIAL REGISTER: NL8093. Registered 15 October 2019 - Retrospectively registered on the Dutch Registry of Clinical trials, www.trialregister.nl.

Truly selective primary IgM deficiency is probably very rare.

Isolated decreased serum-immunoglobulin (Ig)M has been associated with severe and/or recurrent infections, atopy and autoimmunity. However, the reported high prevalence of clinical problems in IgM-deficient patients may reflect the skewed tertiary centre population studied so far. Also, many papers on IgM deficiency have included patients with more abnormalities than simply IgM-deficiency. We studied truly selective primary IgM deficiency according to the diagnostic criteria of the European Society for Immunodeficiencies (ESID) (true sIgMdef) by reviewing the literature (261 patients with primary decreased serum-IgM in 46 papers) and analysing retrospectively all patients with decreased serum-IgM in a large teaching hospital in 's-Hertogenbosch, the Netherlands [1 July 2005-23 March 2016; n = 8049 IgM < 0·4 g/l; n = 2064 solitary (IgG+IgA normal/IgM < age-matched reference)]. A total of 359 of 2064 (17%) cases from our cohort had primary isolated decreased serum-IgM, proven persistent in 45 of 359 (13%) cases; their medical charts were reviewed. Our main finding is that true sIgMdef is probably very rare. Only six of 261 (2%) literature cases and three of 45 (7%) cases from our cohort fulfilled the ESID criteria completely; 63 of 261 (24%) literature cases also had other immunological abnormalities and fulfilled the criteria for unclassified antibody deficiencies (unPAD) instead. The diagnosis was often uncertain (possible sIgMdef): data on IgG subclasses and/or vaccination responses were lacking in 192 of 261 (74%) literature cases and 42 of 45 (93%) cases from our cohort. Our results also illustrate the clinical challenge of determining the relevance of a serum sample with decreased IgM; a larger cohort of true sIgMdef patients is needed to explore fully its clinical consequences. The ESID online Registry would be a useful tool for this.

Performance of BRCA1/2 mutation prediction models in male breast cancer patients.

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

Systematic review of the diagnostic value of laryngeal stroboscopy in excluding early glottic carcinoma.

OBJECTIVE: Laryngeal stroboscopy is an important diagnostic tool in the work-up of patients with phoniatric complaints. The aim of this article was to evaluate the diagnostic value of laryngeal stroboscopy in excluding glottic carcinoma in patients with suspected glottic carcinoma. DATA SOURCES: PubMed, Embase and the Cochrane Library. REVIEW METHODS: A systematic literature search was performed in PubMed, Embase and the Cochrane Library. Studies reporting original study data were included. Studies were selected based on predefined inclusion and exclusion criteria and were consequently systematically assessed for their relevance and risk of bias. Studies with low relevance, high risk of bias or both were excluded from analysis. The prevalences, sensitivities, specificities and post-test probabilities of laryngeal stroboscopy for detecting glottic carcinoma were extracted or calculated with data supplied in the articles. RESULTS: Seven studies, with high relevance and moderate risk of bias, were selected for data extraction. The baseline risk of glottic carcinoma was 25-49% in the included studies. Sensitivity ranged between 80% and 100% and specificity between 25% and 100%. Post-test probabilities of malignancy in case of an abnormal stroboscopy ranged between 35% and 100%. Post-test probabilities of malignancy in case of a normal stroboscopy ranged between 0% and 29%. CONCLUSION: A normal laryngeal stroboscopic result predicts the absence of invasive carcinoma. Laryngeal stroboscopy can therefore be suggested as a useful supplemental examination in the standard diagnostic work-up for all patients with suspected glottic carcinoma.

Off-site primary percutaneous coronary intervention in a new centre is safe: comparing clinical outcomes with a hospital with surgical backup.

OBJECTIVES: To evaluate the procedural and clinical outcomes of a new primary percutaneous coronary intervention (PPCI) centre without surgical back-up (off-site PCI) and to investigate whether these results are comparable with a high volume on-site PCI centre in the Netherlands. BACKGROUND: Controversy remains about the safety and efficacy of PPCI in off-site PCI centres. METHODS: We retrospectively analysed clinical and procedural data as well as 6­month follow-up of 226 patients diagnosed with ST-elevated myocardial infarction (STEMI) who underwent PPCI at VieCuri Medical Centre Venlo and 115 STEMI patients who underwent PPCI at Catharina Hospital Eindhoven. RESULTS: PPCI patients in VieCuri Medical Centre had similar procedural and clinical outcomes to those in Catharina Hospital. Overall there were no significant differences. The occurrence of procedural complications was low in both groups (8.4 % VieCuri vs. 12.3 % Catharina Hospital). In the VieCuri group there was one procedural-related death. No patients in either group needed emergency surgery. At 30 days, 17 (7.9 %) patients in the VieCuri group and 9 (8.1 %) in the Catharina Hospital group had a major adverse cardiac event. CONCLUSION: Performing PPCI in an off-site PCI centre is safe and effective. The study results show that the procedural and clinical outcomes of an off-site PPCI centre are comparable with an on-site high-volume PPCI centre.

Cardiovascular response to exercise training in the systemic right ventricle of adults with transposition of the great arteries.

KEY POINTS: Patients with transposition of the great arteries (TGA) and systemic right ventricles have premature congestive heart failure; there is also a growing concern that athletes who perform extraordinary endurance exercise may injure the right ventricle. Therefore we felt it essential to determine whether exercise training might injure a systemic right ventricle which is loaded with every heartbeat. Previous studies have shown that short term exercise training is feasible in TGA patients, but its effect on ventricular function is unclear. We demonstrate that systemic right ventricular function is preserved (and may be improved) in TGA patients with exercise training programmes that are typical of recreational and sports participation, with no evidence of injury on biomarker assessment. Stroke volume reserve during exercise correlates with exercise training response in our TGA patients, identifying this as a marker of a systemic right ventricle (SRV) that may most tolerate (and possibly even be improved by) exercise training. ABSTRACT: We aimed to assess the haemodynamic effects of exercise training in transposition of the great arteries (TGA) patients with systemic right ventricles (SRVs). TGA patients have limited exercise tolerance and early mortality due to systemic (right) ventricular failure. Whether exercise training enhances or injures the SRV is unclear. Fourteen asymptomatic patients (34 ± 10 years) with TGA and SRV were enrolled in a 12 week exercise training programme (moderate and high-intensity workouts). Controls were matched on age, gender, BMI and physical activity. Exercise testing pre- and post- training included: (a) submaximal and peak; (b) prolonged (60 min) submaximal endurance and (c) high-intensity intervals. Oxygen uptake (V̇O2; Douglas bag technique), cardiac output (Q̇c, foreign-gas rebreathing), ventricular function (echocardiography and cardiac MRI) and serum biomarkers were assessed. TGA patients had lower peak V̇O2, Q̇c, and stroke volume (SV), a blunted Q̇c/V̇O2 slope, and diminished SV response to exercise (SV increase from rest: TGA = 15.2%, controls = 68.9%, P < 0.001) compared with controls. After training, TGA patients increased peak V̇O2 by 6 ± 8.5%, similar to controls (interaction P = 0.24). The magnitude of SV reserve on initial testing correlated with Q̇c training response (r = 0.58, P = 0.047), though overall, no change in peak Q̇c was observed. High-sensitivity troponin T (hs-TnT) and N-terminal prohormone of brain naturetic peptide (NT pro-BNP) were low and did not change with acute exercise or after training. Our data show that TGA patients with SRVs in this study safely participated in exercise training and improved peak V̇O2. Neither prolonged submaximal exercise, nor high-intensity intervals, nor short-term exercise training seem to injure the systemic right ventricle.

Thyroid function alters during neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01).

This side study investigated the effect of chemotherapy on thyroid function and the extent to which it can predict pathological complete response (pCR) in patients with early breast cancer taking part in NEOZOTAC phase III trial, randomizing between neoadjuvant chemotherapy with or without additional zoledronic acid. Moreover, we examined the impact of thyroid function on toxicity. Serum samples of 38 patients were available for analyses. Free thyroxin (fT4) and thyroid stimulating hormone (TSH) levels were compared between baseline and before the 6th cycle and between subjects with and without pCR. The relation between toxicity and the variation in fT4 and TSH levels during chemotherapy was tested. Samples at baseline and before the 6th cycle were available for 31 and 21 patients, respectively. The mean baseline fT4 level was 16.0 pmol/L and TSH level 1.11 mU/L, and these did not differ between both arms at each time point. During six cycles of chemotherapy, fT4 levels decreased (p = 0.0001), and TSH levels increased significantly (p = 0.019). Interestingly, the decrease of fT4 was significantly greater in patients without nausea, vomiting, or neuropathy, than in patients with those side effects (p = 0.037, p = 0.043, and p = 0.050, respectively). Baseline TSH levels tended to be higher in patients with pCR (p = 0.035 univariate analysis and p = 0.074 multivariate analysis). Chemotherapy blunts thyroid function, which was associated with less side effects. These data urge further evaluation of the effects of thyroid function on toxicity and outcome of breast cancer therapy.

Does the Use of Diagnostic Imaging Reduce the Rate of Negative Appendectomy?

BACKGROUND: In February 2010, the Dutch Society of Surgeons introduced a guideline for diagnosis and treatment of acute appendicitis. This guideline suggests that, with the standardized use of imaging (ultrasound and computed tomography), the percentage of negative appendectomies can be reduced. With this study we evaluated the effect of the implementation of this guideline. Primary outcome is the percentage of negative appendectomies. Diagnostic imaging might result in a delay of surgery and a higher rate of perforated appendices. Therefore, our secondary outcome is the perforation rate. METHODS: Retrospectively all pathology results in our hospital were studied, which were classified as "appendicitis acuta" or "appendix sana" from January 2007 until October 2012. To evaluate the perforation rate in acute appendicitis, surgery reports of all patients included in the study were studied. Both percentages of negative appendectomies and perforation rate were compared for the periods before and after the introduction of the new guideline (i.e. 2007-2009 vs. 2010-2012). RESULTS: A significant decline in the percentage of negative appendectomies was found from an average of 18.0% before implementation of the guideline towards an average of 9.2% after implementation of the guideline (p<0.001). The percentage of patients with appendicitis in which the appendix perforated remained about the same; 20.9% before implementation of the guideline compared to 19.2% after implementation of the guideline (p=0.527). CONCLUSIONS: Our data show a significant decline in negative appendectomies without an increase of perforation rate after introduction of the new diagnostic guideline for acute appendicitis.