Brachytherapy quality assurance in the PORTEC-4a trial for molecular-integrated risk profile guided adjuvant treatment of endometrial cancer.

OBJECTIVE: The PORTEC-4a trial investigates molecular-integrated risk profile guided adjuvant treatment for endometrial cancer. The quality assurance programme included a dummy run for vaginal brachytherapy prior to site activation, and annual quality assurance to verify protocol adherence. Aims of this study were to evaluate vaginal brachytherapy quality and protocol adherence. METHODS: For the dummy run, institutes were invited to create a brachytherapy plan on a provided CT-scan with the applicator in situ. For annual quality assurance, institutes provided data of one randomly selected brachytherapy case. A brachytherapy panel reviewed and scored the brachytherapy plans according to a checklist. RESULTS: At the dummy run, 15 out of 21 (71.4%) institutes needed adjustments of delineation or planning. After adjustments, the mean dose at the vaginal apex (protocol: 100%; 7 Gy) decreased from 100.7% to 99.9% and range and standard deviation (SD) narrowed from 83.6-135.1 to 96.4-101.4 and 8.8 to 1.1, respectively. At annual quality assurance, 22 out of 27 (81.5%) cases had no or minor and 5 out of 27 (18.5%) major deviations. Most deviations were related to delineation, mean dose at the vaginal apex (98.0%, 74.7-114.2, SD 7.6) or reference volume length. CONCLUSIONS: Most feedback during the brachytherapy quality assurance procedure of the PORTEC-4a trial was related to delineation, dose at the vaginal apex and the reference volume length. Annual quality assurance is essential to promote protocol compliance, ensuring high quality vaginal brachytherapy in all participating institutes.

[Care contacts of elderly patients in the emergency care pathway: a retrospective cohort study]. / Zorgcontacten van ouderen in de acute-zorgketen.

OBJECTIVE: To gain insight into the differences in emergency care offered to elderly (65+ years) and younger patients (20-64 years). The emergency care pathway includes: out-of-hours general practitioner cooperatives, regional ambulance services, psychiatric emergency medical services, accident and emergency departments and acute cardiac care units. DESIGN: Retrospective cohort study. METHOD: We used data from all emergency care contacts from the Emergency Care Monitor of April 2015 and April 2016 from an emergency care region in the east of the Netherlands ('Acute Zorgregio Oost'); this involved 84,647 care contacts with 55,061 patients. We defined pathway emergency care contacts as multiple emergency care contacts with different healthcare providers within the emergency care pathway, and differentiated between single or repeated care contacts with a single emergency healthcare provider. We investigated differences in presenting symptoms, diagnoses, lead time, hospital admissions and mortality in the chain care. RESULTS: Emergency care contact was more often pathway contact in elderly than in younger patients (26% vs. 16%; p < 0.0001). Elderly patients more often received a diagnosis of CVA, pneumonia or exacerbation of COPD, while younger patients more often had simple contusions or abdominal symptoms. Pathway lead time was longer in elderly than in younger patients (median difference: 33 minutes; 95% CI: 25-40. Elderly patients were admitted to hospital more often (71% vs. 39%, p < 0.0001) and their mortality rate was higher (2.0% vs. 0.5%; p < 0.0001). CONCLUSION: Elderly patients in the emergency care pathway have more frequent and longer pathway contact and present themselves with a more complicated and life-threatening clinical picture than younger patients. New solutions should be explored to ensure that the emergency care pathway remains accessible and available and offers sufficient quality for the increasing number of elderly.

Effect of adjuvant chemotherapy on recurrence-free survival varies by neo-adjuvant treatment in patients with stage III rectal cancer.

INTRODUCTION: Adjuvant chemotherapy still is a controversial therapy for rectal cancer patients. The aim of this study was to analyze the effect of adjuvant chemotherapy on recurrence-free survival (RFS) for patients with stage III rectal cancer treated in clinical practice, taking into account which neo-adjuvant treatment patients received. METHODS: Patients from regions in the Netherlands diagnosed between 1996 and 2013 with pathological stage III rectal cancer who received short-course radiotherapy, chemoradiation or no neo-adjuvant treatment and who underwent surgery were included. After stratification by neo-adjuvant treatment, 5-year RFS according to adjuvant chemotherapy receipt was calculated using Kaplan-Meier curves. Cox regression was used to discriminate the independent effect of adjuvant chemotherapy on the risk of recurrence/death. RESULTS: The study population consisted of 829 patients, of whom 537 (65%) patients received short-course radiotherapy, 128 (15%) patients received chemoradiation and 164 (20%) patients received no neo-adjuvant treatment. Adjuvant chemotherapy was administered to 152 (18%) patients. Adjuvant chemotherapy was associated with improved 5-year RFS for patients who received short-course radiotherapy (61% vs. 46%, p = 0.005) and for patients who did not receive any neo-adjuvant treatment (70% vs. 28%, p < 0.0001). In multivariable analyses, adjuvant chemotherapy was associated with a reduced risk of recurrence/death for patients treated with short-course radiotherapy (HR 0.65, 95% CI 0.46-0.93) and for patients without neo-adjuvant treatment (HR 0.35, 95% CI 0.18-0.71), but not for patients treated with chemoradiation (HR 1.11, 95% CI 0.51-2.41). CONCLUSION: Among patients with stage III rectal cancer, the effect of adjuvant chemotherapy on RFS seems to vary by neo-adjuvant treatment.

Effect of preoperative treatment strategies on the outcome of patients with clinical T3, non-metastasized rectal cancer: A comparison between Dutch and Canadian expert centers.

AIM: High-dose-rate brachytherapy (HDRBT) appears to be associated with less treatment-related toxicity compared with external beam radiotherapy in patients with rectal cancer. The present study compared the effect of preoperative treatment strategies on overall survival, cancer-specific deaths, and local recurrences between a Dutch and Canadian expert center with different preoperative treatment strategies. PATIENTS AND METHODS: We included 145 Dutch and 141 Canadian patients with cT3, non-metastasized rectal cancer. All patients from Canada were preoperatively treated with HDRBT. The preoperative treatment strategy for Dutch patients consisted of either no preoperative treatment, short-course radiotherapy, or chemoradiotherapy. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CIs) comparing overall survival. We adjusted for age, cN stage, (y)pT stage, comorbidity, and type of surgery. Primary endpoint was overall survival. Secondary endpoints were cancer-specific deaths and local recurrences. RESULTS: Five-year overall survival was 70.9% (95% CI 62.6%-77.7%) in Dutch patients compared with 86.9% (80.1%-91.6%) in Canadian patients, resulting in an adjusted HR of 0.70 (95% CI 0.39-1.26; p = 0.233). Of 145 Dutch patients, 6.9% (95% CI 2.8%-11.0%) had a local recurrence and 17.9% (95% CI 11.7%-24.2%) patients died of rectal cancer, compared with 4.3% (95% CI 0.9%-7.5%) local recurrences and 10.6% (95% CI 5.5%-15.7%) rectal cancer deaths out of 141 Canadian patients. CONCLUSION: We did not detect statistically significant differences in overall survival between a Dutch and Canadian expert center with different treatment strategies. This finding needs to be further investigated in a randomized controlled trial.

Towards a computational reconstruction of the electrodynamics of premature and full term human labour.

We apply virtual tissue engineering to the full term human uterus with a view to reconstruction of the spatiotemporal patterns of electrical activity of the myometrium that control mechanical activity via intracellular calcium. The three-dimensional geometry of the gravid uterus has been reconstructed from segmented in vivo magnetic resonance imaging as well as ex vivo diffusion tensor magnetic resonance imaging to resolve fine scale tissue architecture. A late-pregnancy uterine smooth muscle cell model is constructed and bursting analysed using continuation algorithms. These cell models are incorporated into partial differential equation models for tissue synchronisation and propagation. The ultimate objective is to develop a quantitative and predictive understanding of the mechanisms that initiate and regulate labour.

Greater influence of age than co-morbidity on primary treatment and complications of prostate cancer patients: an in-depth population-based study.

We investigated the influence of age and co-morbidity on treatment, the occurrence of serious non-urological complications of treatment and prognosis for prostate cancer patients diagnosed and treated in community hospitals. Additional information from a random sample of 505 prostate cancer patients (aged 40 years or older) from the Eindhoven Cancer Registry diagnosed between 1995 and 1999 was collected. In all, 43% of the prostate cancer patients aged 40-69 years and 64% of those aged 70 or older suffered from one or more serious concomitant disease that barely affected primary treatment choice. However, compared to patients without co-morbidity, patients with cardiovascular diseases underwent radical prostatectomy less often (P=0.01). In all, 38% of the patients undergoing radical prostatectomy suffered from complications during the first year after diagnosis versus about 20% of those receiving radiotherapy. The number of complications did not seem to be affected by co-morbidity. After adjustment for age, stage, grade, prostate-specific antigen level and treatment, the cumulative risk of death was almost two times higher for patients with two or more concomitant diseases than for patients without co-morbidity. After adjustment for age, prostate cancer patients with co-morbidity were not treated differently, did not suffer from more complications but had a worse prognosis, compared to those without co-morbidity.

Impact of comorbidity on treatment and prognosis of prostate cancer patients: a population-based study.

This study investigates the independent influence of serious comorbidity and age on treatment and survival of prostate cancer patients diagnosed between 1995 and 2002 in the southern part of the Netherlands. Eight percent of patients<60 years had two or more concomitant diseases versus 27% of those aged 80 years or older. The number of patients undergoing radical prostatectomy or curative radiotherapy decreased significantly with increasing age. The proportion of patients aged 60-69 years undergoing prostatectomy decreased significantly from 32% of patients without comorbidity to 17% of patients with two or more comorbid conditions and from 8% to 3%, respectively, of those aged 70-79 years. The risk of dying was significantly higher for patients with two or more comorbid conditions compared to patients without comorbidity. Serious comorbidity led to less aggressive treatment and negatively affected the prognosis of prostate cancer patients aged 60-79 years.

Quantifying the strength of ligand antagonism in TCR triggering.

Triggering of the T cell receptor (TCR) may be antagonized by ligands that are slight variants of the immunogenic peptide. This paper proposes a mathematical model to quantify the strength of the antagonistic effect. The model is based on the kinetics of association and dissociation of TCR and peptide/major histocompatibility (pMHC) molecules, and incorporates TCR triggering according to a kinetic proofreading mechanism. Model analysis indicates that while the average lifetime of the TCR/pMHC complex is the basic determinant of the contribution to TCR triggering made by the ligand, the affinity of the ligand and its MHC presentation level are also important. However, these contributions depend on the kinetic limitation regime. There is a continuum of limitation regimes, at the extremes of which are found TCR limitation and MHC limitation. Both ligand affinity and TCR and pMHC densities determine whether TCR triggering is TCR limited or MHC limited. The changing importance of affinity and antigen presentation level under various kinetic limitation regimes may explain the respective roles of antagonistic and agonistic self peptides in thymic selection. Moreover, TCR down-regulation under TCR-limited conditions may allow the T cell to differentiate between the average lifetime of the TCR/pMHC complex and the presentation level of the ligand. A method for experimental differentiation between passive and active antagonistic effects is proposed which exploits the differences between TCR and MHC limitation.

Ultrafast precessional magnetization reversal by picosecond magnetic field pulse shaping.

Since the invention of the first magnetic memory disk in 1954, much effort has been put into enhancing the speed, bit density and reliability of magnetic memory devices. In the case of magnetic random access memory (MRAM) devices, fast coherent magnetization rotation by precession of the entire memory cell is desired, because reversal by domain-wall motion is much too slow. In principle, the fundamental limit of the switching speed via precession is given by half of the precession period. However, under-critically damped systems exhibit severe ringing and simulations show that, as a consequence, undesired back-switching of magnetic elements of an MRAM can easily be initiated by subsequent write pulses, threatening data integrity. We present a method to reverse the magnetization in under-critically damped systems by coherent rotation of the magnetization while avoiding any ringing. This is achieved by applying specifically shaped magnetic field pulses that match the intrinsic properties of the magnetic elements. We demonstrate, by probing all three magnetization components, that reliable precessional reversal in lithographically structured micrometre-sized elliptical permalloy elements is possible at switching times of about 200 ps, which is ten times faster than the natural damping time constant.

How microbes can achieve balanced growth in a fluctuating environment.

A microbial colony needs several essential nutrients in order to grow. Moreover, the colony requires these nutrients in fixed combinations, which are dictated by the chemical composition of its biomass. Unfortunately, ambient availabilities of the various nutrients vary all the time. This poses the question of how microbes can achieve balanced growth. The present solution to this problem is novel in that the allocation of molecular building blocks among assimilatory machineries within the cell is regarded as dynamic. This paper shows that allocation can be adapted so as to achieve balanced growth, nearly regardless of environmental conditions. Moreover, it is shown that a feedback mechanism, which monitors internal stores, is able to achieve this allocation.

A reliable and safe T cell repertoire based on low-affinity T cell receptors.

Antigens are presented to T cells as short peptides bound to MHC molecules on the surface of body cells. The binding between MHC/peptides and T cell receptors (TCRs) has a low affinity and is highly degenerate. Nevertheless, TCR-MHC/peptide recognition results in T cell activation of high specificity. Moreover, the immune system is able to mount a cellular response when only a small fraction of the MHC molecules on an antigen-presenting cell is occupied by foreign peptides, while autoimmunity remains relatively rare. We consider how to reconcile these seemingly contradictory facts using a quantitative model of TCR signalling and T cell activation. Taking into account the statistics of TCR recognition and antigen presentation, we show that thymic selection can produce a working T cell repertoire which will produce safe and effective responses, that is, recognizes foreign antigen presented at physiological levels while tolerating self. We introduce "activation curves" as a useful tool to study the repertoire's statistical activation properties.

Definition and validation of a reference target volume in early stage node-positive cervical carcinoma, based on lymphangiograms and CT-scans.

PURPOSE: To establish a reference planning target volume for postoperative radiotherapy in stage Ib and IIa N+ cervical carcinoma, based on 47 lymphangiograms and 15 CT-scans. METHODS: Radiation oncologists (n=17) from all radiotherapy institutes in The Netherlands were asked to define the clinical target volume (CTV) and planning target volume (PTV), and to delineate (on simulation films) the radiotherapy treatment portals following a radical hysterectomy with lymph node dissection for an early stage cervical carcinoma with positive iliac lymph nodes. A reference PTV was defined by using 47 normal lymphangiograms and CT-data of the pelvis from 15 patients who underwent surgery for cervical carcinoma. The simulation films were digitized and evaluated for adequacy in covering the PTV, previously individually determined by the radiation oncologists. Subsequently, the simulation films were also evaluated for adequacy in covering the reference PTV. RESULTS: Large variations were observed in the portals used and in treatment techniques. From the digitized films, it appeared that in 50% of the cases the defined PTV was not covered adequately. Furthermore, 71% of the treatment plans would not cover the lateral borders of the reference PTV sufficiently. CONCLUSIONS: There appears to be no consensus on the target volumes to be irradiated in postoperative radiotherapy of early stage cervical carcinoma. When a PTV defined on the basis of lymphangiograms and CT-data is taken as a reference, 71% of the treatment plans would not cover this PTV adequately. These findings indicate the need for a consensus in the design of standardized treatment volumes.

Three-dimensional treatment planning for postoperative radiotherapy in patients with node-positive cervical cancer. Comparison between a conventional and a conformal technique.

PURPOSE: Reduction of irradiated small bowel volume, using a conformal three-dimensional treatment planning technique in postoperative radiotherapy of cervical cancer patients. PATIENTS AND METHODS: Large gynecological treatment fields including the para-aortic nodes were analyzed in 15 patients. A conventional treatment plan with anterior and posterior (AP-PA) parallel opposed fields and a 3D 4-field conformal radiotherapy plan with a central blocking of small bowel were compared for each patient. Dose-volume histograms and dose parameters were established. Because of the tolerance constraints of the small bowel, the cumulative dose applied to the target was 48.6 Gy. RESULTS: The mean Tumor Control Probability (TCP) values for both the conventional and the conformal technique were 0.60 and 0.61, respectively, with ranges of 0.56 to 0.67 and 0.57 to 0.66, respectively. The mean volume receiving 95% or more of the prescribed dose (V95) of the small bowel was 47.6% (32.5 to 66.3%) in the AP-PA technique and 14.9% (7.0 to 22.5%) in the conformal technique (p < 0.001), indicating a significant reduction in irradiated volume of small bowel in the higher dose range. The mean Normal Tissue Complication Probability (NTCP) decreased from 0.11 to 0.03 with the conformal plan. In patients who received a pedicled omentoplasty during surgery, the mean V95 for small bowel could be reduced to 8.5% (7.0 to 9.9%). The mean median dose to the kidneys was only slightly elevated in the conformal treatment. Especially the mean dose to the right kidney in conventional vs conformal treatment was 3.3 vs 7.9 Gy. The mean near-minimum dose (D95) to the rectosigmoid decreased from 48.4 to 30.1 Gy in the conformal plan compared to the conventional plan. CONCLUSION: The small bowel dose can be significantly reduced with 3D treatment planning, particularly if a pedicled omentoplasty is performed. This allows dose escalation to the tumor region without unacceptable toxicity for the small bowel.

Multiple nutrient limitation in unicellulars: reconstructing Liebig's law.

Liebig's law of the Minimum is reformulated in terms of biomass composition dynamics. The doctrine of the single limiting nutrient is shown to be invalid generally. The nutritional status of a unicellular organism is expressed in terms of state variables; one which represents the subsistence composition and a number of reserve surplus type variables. It is proposed that the property of being limiting should be defined in terms of the reserve surplus variables. On the basis of this definition, it can be decided whether a nutrient, or combination of nutrients, is limiting, both in transient and steady states. The concept of multiple limitation is shown to have two distinct meanings on these definitions. A non-interactive minimum model, based on a 'hard' minimum operator, is introduced. Smooth interactive models may be formulated which have this minimum model as a limiting case. One such model is described. Numerical simulations show how the behaviour of this smooth model can approximate that of the minimum model: apparently hard non-linearities can arise in the smooth model, through time-scale separation.

I1Legal measures in behalf of veterinary medicine and public health (author's transl). / Wettelijke maatregelen ten dienste van de diergeneeskunde en de volksgezondheid

The constantly growing world population and the altered consumption pattern have considerably increased the demand for more, and more refined, food, particularly that of animal origin. Altered methods of production, highly concentrated froms of animal husbandry but also the resulting increase of the need for the cheapest possible materials for the mixed feed industry, the more rapid and greater transport facilities, the markedly increased trade in animals and particuarly in products originating fromthese animals, they all involve an increased risk of the import and outbreak of animal disease. The increased use of animal drugs, production-increasing agents and pesticides involve the danger of injurious residues being left in products of animal origin as a result of the comulative factors in animals. Therefore, the entire chain of production, beginning at the earliest possible stage, should be closely supervised. Supervisotry programmes of the Chief Veterinary Inspectorate of the Ministry of Health and of the Veterinary Service are, in a manner of speaking, the search-lights which, thanks to the refined methods of analysis developed by research workers, are able to detect and point out failings and deficiencies. An anticipated amendment of the Livestock Breeding Act, an anticipated replacement of the Antibiotics Act and a regulation forming part of the Statutory Trade Organization are designed to make it possible to respond more promptly to these signals.