Verified quantum information scrambling.

Quantum scrambling is the dispersal of local information into many-body quantum entanglements and correlations distributed throughout an entire system. This concept accompanies the dynamics of thermalization in closed quantum systems, and has recently emerged as a powerful tool for characterizing chaos in black holes1-4. However, the direct experimental measurement of quantum scrambling is difficult, owing to the exponential complexity of ergodic many-body entangled states. One way to characterize quantum scrambling is to measure an out-of-time-ordered correlation function (OTOC); however, because scrambling leads to their decay, OTOCs do not generally discriminate between quantum scrambling and ordinary decoherence. Here we implement a quantum circuit that provides a positive test for the scrambling features of a given unitary process5,6. This approach conditionally teleports a quantum state through the circuit, providing an unambiguous test for whether scrambling has occurred, while simultaneously measuring an OTOC. We engineer quantum scrambling processes through a tunable three-qubit unitary operation as part of a seven-qubit circuit on an ion trap quantum computer. Measured teleportation fidelities are typically about 80 per cent, and enable us to experimentally bound the scrambling-induced decay of the corresponding OTOC measurement.

Real-time, large-depth holographic 3D head-up display: selected aspects.

Today's state-of-the-art automotive head-up displays (HUD) possess single- or double layer focal planes that limit the observers' eye focus to these planes when crucial information is shown. Other visual 3D cues such as motion parallax also suffer from this limitation. The resulting viewing experience contradicts the natural way of viewing during driving or interaction, when alerts and hints should appear at the correct projection depth where real objects of interest are located. Here we present a real-time holographic HUD with continuous depth that supports the intuitive and natural way of viewing and interacting with virtual environments outside and inside the car. We demonstrate full-color, 3D real-time encoding within a field-of-view of 5∘×3∘.

Ambulant health care utilisation among children of childhood cancer survivors in Germany.

PURPOSE: Within the framework of a questionnaire-based health survey in Germany, we examined ambulant health care utilisation among childhood cancer survivors' offspring compared to utilisation among children of the general population. METHODS: In total, 1299 former patients received a questionnaire for every known biological child in two cross-sectional surveys, 2013/14 (n = 393) and 2015/16 (n = 906). For investigation of health care utilisation, questions on frequencies and kind of ambulant medical services were chosen for bivariate and multivariate analyses. Correlations between utilisation and anxiety, diagnosis of the parent, pain or preterm birth of the child and social indicators were conducted. For comparison with the general population, data of 17,640 children and adolescents aged 0 to 17 years were used for matched-pair analysis. These data were available from the KIGGS baseline study on the health of children and adolescents in Germany, conducted by the Robert Koch Institute. RESULTS: Overall, 852 (65.6%) of the contacted 1299 survivors completed 1340 questionnaires on their children's health. Childhood cancer survivors' offspring showed a similar attendance of ambulant primary health care compared to the general population (paediatricians 83.1% vs. 82.1%). However, the majority of specialist physicians was visited significantly more often (e.g. dermatologist 10.5% vs. 6.2%) by childhood cancer survivors' offspring compared to children from the general population. Logistic regression showed that parental diagnosis and anxiety on children's health significantly influenced health care utilisation. CONCLUSIONS: Further improvement of after-care for childhood cancer survivors by including topics on offspring seems necessary. Offspring's paediatricians should implement counselling and providing of information considering the special family anamnesis.

Health-Related Behaviour Among Children of Childhood Cancer Survivors in Germany.

Purpose: Childhood cancer survivors fear that previous therapy could not only impair their own but also their children's health. We examined whether health-related behaviour in children of childhood cancer survivors differs from the general population. Methods: Our first nationwide survey wave (2013-2014) surveyed offspring health in 396 German childhood cancer survivors known to have a child of their own. Answers about health behaviour were analysed using descriptive statistics. Data were collected for 418 offspring and 394 could be integrated for matched-pair analyses with data from the German general population (KIGGS, n=17 641). Results: Teeth-cleaning routine, body-mass-index or subjective body image evaluation by parents were no different from children in the general population. Parents who included a cancer survivor smoked less in the presence of their children (p=0.01). During pregnancy, mothers in cancer survivor parent pairs abstained from drinking alcohol more often (p=0.01) and smoked less (p=0.05). While the calculated effect sizes (Phi) were generally low (0.135-0.247), children from cancer survivors played less outdoors than peers did (p=0.01). Boys participated in sports outside a club more often (p=0.05) and watched less TV on weekdays (p=0.01) and girls spent more time on the computer during weekdays than peers did (p=0.01). Conclusions: This study provides the first data for health-related behaviour in cancer survivors' offspring and sheds light on differences to parenting in the general population. Multivariate analyses in a larger study population are needed to relate these differences to fear issues in cancer survivors.

[True thymic hyperplasia : Differential diagnosis of thymic mass lesions in neonates and children]. / "Echte Thymushyperplasie" : Differenzialdiagnose der Thymusvergrößerung bei Säuglingen und Kindern.

Reactive and neoplastic thymic pathologies are the main considerations in the case of masses in the anterior and middle part of the mediastinum, while neurogenic tumors are predominant in the posterior mediastinum (which are not dealt with here). In neonates and infants, the commonest pathologies in the anterior mediastinum comprise germ cell tumors (mainly teratomas), congenital thymic cysts and true thymic hyperplasia (TTH). In toddlers, teratomas, yolk sac tumors and cysts predominate. In children over 5 years of age, lymphomas are the commonest mass lesions whereas thymomas and thymic carcinomas are rare. In addition, inflammation-linked hyperplasia in myasthenia gravis and rebound thymic hyperplasia after chemotherapy must be considered. Although rare at all ages, sarcomas must be considered in the differential diagnosis from birth onwards and throughout adolescence. Based on the report of a rare case of recurrent TTH, the differential diagnosis of this benign but potentially life-threatening condition is discussed.

[Time-dependent confounding in the estimation of treatment effects in randomised trials with multimodal therapies--an illustration of the problem of time-dependent confounding by causal graphs]. / Verzerrte Schätzung von Behandlungseffekten in randomisierten Studien mit multimodalem Behandlungsprozess--Darstellung des Problems zeitabhängiger Störvariablen anhand kausaler Graphen.

Biased effect estimates induced by unconsidered confounding variables are a known problem in observational studies. Selection bias, resulting from non-random sampling of study participants, is widely recognised as a problem in case-control and cross-sectional studies. In contrast, possible bias in randomised controlled trials (RCTs) is mostly ignored. This paper illustrates, by applying directed acyclic graphs (DAGs), possible bias in the effect estimates of first-line therapy, caused by subsequent changes in therapy (time-dependent confounding). Possible selection bias, induced by not only random loss to follow-up, will be explained as well using DAGs. Underlying assumptions of standard methods usually used to analyse RCTs (like intention-to-treat, per-protocol) are shown and it is explained why effect estimates may be biased in RCTs, if only these conventional methods are used. Adequate statistical methods (causal inference models as marginal structural models and structural nested models) exist. Higher documentary efforts, however, are necessary, because any changes in medication, loss to follow-up as well as reasons for such changes need to be documented in detail as required by these advanced statistical methods. Nevertheless, causal inference models should become standard along side the currently applied standard methods, especially in studies with high non-compliance due to changes in therapy and substantial loss to follow-up. Possible bias cannot be excluded if similar results are obtained from both methods. However, study results should be interpreted with caution if they differ between both approaches.

Combined SPECT/CT improves detection of initial bone invasion and determination of resection margins in squamous cell carcinoma of the head and neck compared to conventional imaging modalities.

PURPOSE: Knowledge of the presence and extent of bone infiltration is crucial for planning the resection of potential bone-infiltrating squamous cell carcinomas of the head and neck (HNSCC). Routinely, plain-film radiography, multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) are used for preoperative staging, but they show relatively high rates of false-positive and false-negative findings. Scintigraphy with (99m)Tc-bisphosphonate has the ability to show increased metabolic bone activity. If combined with anatomical imaging (e.g. (SPECT)/CT), it facilitates the precise localization of malignant bone lesions. The aim of this study was to analyse the indications and advantages of SPECT/CT compared with standard imaging modalities and histology with regard to specificity and sensitivity METHODS: A longitudinally evaluated group of 30 patients with biopsy-proven HNSCC adjacent to the mandible underwent (99m)Tc-bisphosphonate SPECT/CT, MRI, MSCT and conventional radiography before partial or rim resection of the mandible was performed. Bone infiltration was first evaluated with plain films, MSCT and MRI. In a second reading, SPECT/CT data were taken into account. The results (region and certainty of bone invasion) were evaluated among the different imaging modalities and finally compared with histological specimens from surgical resection as the standard of reference. For a better evaluation of the hybrid property of SPECT/CT, a retrospectively evaluated group of 20 additional patients with tumour locations similar to those of the longitudinally examined SPECT/CT group underwent SPECT, MSCT and MRI. To assess the influence of dental foci on the specificity of the imaging modalities, all patients were separated into two subgroups depending on the presence or absence of teeth in the area of potential tumour-bone contact. RESULTS: Histologically proven bone infiltration was found in 17 patients (57 %) when analysed by conventional imaging modalities. SPECT/CT data revealed bone infiltration in two additional patients (7 %), who both showed discrete cortical bone erosion not visible by MSCT or MRI. There were no false-positive or false-negative findings on SPECT/CT. The quality criteria for detecting bone involvement in HNSCC by SPECT/CT were as follows: sensitivity 100 % (lower 95 % confidence interval limit 80 %), specificity 100 % (75 %), positive predictive value 100 % (80 %) and negative predictive value 100 % (75 %). Corresponding data for MRI were 95 % (76 %), 94 % (73 %), 95 % (76 %) and 94 % (73 %), and for MSCT were 89 % (71 %), 100 % (85 %), 100 % (86 %) and 88 % (69 %). In the retrospective evaluation SPECT showed results similar to SPECT/CT. CONCLUSION: Hybrid SPECT/CT has a high specificity as it can provide additional information about the existence and local extent of malignant bone infiltration of the mandible. Although the sensitivity of conventional SPECT is similar to that of SPECT/CT, the latter provides a much better delineation of the local tumour-bone contact area. Based on this information, surgical intervention of the rim versus partial resection can be planned and performed more precisely. Patient outcome can be improved by avoiding undertreatment and unnecessary or overextended bone resections.

Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers.

BACKGROUND: Genomic rearrangements at the fragile site FRA1E may disrupt the dihydropyrimidine dehydrogenase gene (DPYD) which is involved in 5-fluorouracil (5-FU) catabolism. In triple-negative breast cancer (TNBC), a subtype of breast cancer frequently deficient in DNA repair, we have investigated the susceptibility to acquire copy number variations (CNVs) in DPYD and evaluated their impact on standard adjuvant treatment. METHODS: DPYD CNVs were analysed in 106 TNBC tumour specimens using multiplex ligation-dependent probe amplification (MLPA) analysis. Dihydropyrimidine dehydrogenase (DPD) expression was determined by immunohistochemistry in 146 tumour tissues. RESULTS: In TNBC, we detected 43 (41%) tumour specimens with genomic deletions and/or duplications within DPYD which were associated with higher histological grade (P=0.006) and with rearrangements in the DNA repair gene BRCA1 (P=0.007). Immunohistochemical analysis revealed low, moderate and high DPD expression in 64%, 29% and 7% of all TNBCs, and in 40%, 53% and 7% of TNBCs with DPYD CNVs, respectively. Irrespective of DPD protein levels, the presence of CNVs was significantly related to longer time to progression in patients who had received 5-FU- and/or anthracycline-based polychemotherapy (hazard ratio=0.26 (95% CI: 0.07-0.91), log-rank P=0.023; adjusted for tumour stage: P=0.037). CONCLUSION: Genomic rearrangements in DPYD, rather than aberrant DPD protein levels, reflect a distinct tumour profile associated with prolonged time to progression upon first-line chemotherapy in TNBC.

Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy.

BACKGROUND: The aim of this study was to evaluate the impact of pathologic complete response (pCR) on outcome in patients with gastric or esophagogastric junction (EGJ) adenocarcinoma after neoadjuvant docetaxel/platin/fluoropyrimidine-based chemotherapy. PATIENTS AND METHODS: Patients received at least one cycle of chemotherapy for potentially operable disease. Pretreatment clinicopathologic factors and pCR were investigated. Disease-free survival (DFS), overall survival (OS) and tumor-related death were correlated with pCR. RESULTS: One hundred twenty patients were included in this analysis. Eighteen patients (15%) achieved a pCR. Tumor localization in the EGJ was identified as the only significant predictor of pCR (P = 0.019). Median follow-up was 41.1 months. Median DFS and OS for all patients were 24.1 and 48.6 months, respectively. Median DFS for patients with a pCR was not reached versus 22.1 months non-pCR patients (hazard ratio, HR 0.38; 3-year DFS: 71.8% and 37.7%, respectively, P = 0.018). While OS was not significantly different, the risk for tumor-related death was significantly lower for pCR patients compared with non-pCR patients (3-year cumulative incidences of 6.4% and 45.4%, respectively, P = 0.009). CONCLUSION: A pCR following preoperative docetaxel/platin/fluoropyrimidine indicates favorable outcome in patients with gastric or EGJ adenocarcinoma. Tumor location in the EGJ is associated with a higher pCR rate.

Advanced techniques in neoadjuvant radiotherapy allow dose escalation without increased dose to the organs at risk : Planning study in esophageal carcinoma.

PURPOSE: The goal of this work was to investigate the potential of advanced radiation techniques in dose escalation in the radiotherapy (RT) for the treatment of esophageal carcinoma. METHODS: A total of 15 locally advanced esophageal cancer (LAEC) patients were selected for the present study. For all 15 patients, we created a 3D conformal RT plan (3D-45) with 45 Gy in fractions of 1.8 Gy to the planning target volume (PTV1), which we usually use to employ in the neoadjuvant treatment of LAEC. Additionally, a 3D boost (as in the primary RT of LAEC) was calculated with 9 Gy in fractions of 1.8 Gy to the boost volume (PTV2) (Dmean) to a total dose of 54 Gy (3D-54 Gy), which we routinely use for the definitive treatment of LAEC. Three plans with a simultaneous integrated boost (SIB) were then calculated for each patient: sliding window intensity-modulated radiotherapy (IMRT-SIB), volumetric modulated arc therapy (VMAT-SIB), and helical tomotherapy (HT-SIB). For the SIB plans, the requirement was that 95 % of the PTV1 receive ≥ 100 % of the prescription dose (45 Gy in fractions of 1.8 Gy, D95) and the PTV2 was dose escalated to 52.5 Gy in fractions of 2.1 Gy (D95). RESULTS: The median PTV2 dose for 3D-45, 3D-54, HT-SIB, VMAT-SIB, and IMRT-SIB was 45, 55, 54, 56, and 55 Gy, respectively. Therefore, the dose to PTV2 in the SIB plans was comparable to the 3D-54 plan. The lung dose in the SIB plans was in the range of the standard 3D-45, which is applied for neoadjuvant radiotherapy. The mean lung dose for the same plans was 13, 15, 12, 12, and 13 Gy, respectively. The V5 lung volumes were 71, 74, 79, 75, and 73 %, respectively. The V20 lung volumes were 20, 25, 16, 18, and 19 %, respectively. CONCLUSION: New treatment planning techniques enable higher doses to be delivered for neoadjuvant radiotherapy of LAEC without a significant increase in the delivered dose to the organs at risk. Clinical investigations are warranted to study the clinical safety and feasibility of applying higher doses through advanced techniques in the neoadjuvant treatment of LAEC.

Chronic adverse events and quality of life after radiochemotherapy in anal cancer patients. A single institution experience and review of the literature.

PURPOSE: To report on chronic adverse events (CAE) and quality of life (QOL) after radiochemotherapy (RCT) in patients with anal cancer (AC). PATIENTS AND METHODS: Of 83 patients who had received RCT at our department between 1988 and 2011, 51 accepted the invitation to participate in this QOL study. CAE were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 and QOL was assessed with the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire. RESULTS: CAE could be evaluated in 49 patients. There was a tendency toward a higher rate of grade 3 CAE in female patients, i.e. 18 out of 37 (49 %) vs. 2 out of 12 (17 %) male patients (p = 0.089). The most common grade 3 CAE were dyspareunia and vaginal symptoms (itching, burning and dryness) in 35 and 22 % of female patients, respectively, followed by stool incontinence in 13 % of all patients (6 out of 49). Both FACT-C and CAE information were available for 42 patients, allowing evaluation of the impact of CAE on QOL. The median total FACT-C score was 110 (40-132) out of a possible maximum of 136. The absence of grade 3 CAE (115 vs. 94, p = 0.001); an interval of ≥ 67 months after the end of the treatment (111 vs. 107, p = 0.010), no stool incontinence vs. grade 3 stool incontinence (111 vs. 74, p = 0.009), higher education (114 vs. 107, p = 0.013) and no dyspareunia vs. grade 3 dyspareunia (116 vs. 93, p = 0.012) were significantly associated with a higher median FACT-C score. CONCLUSION: The majority of AC patients treated with RCT have acceptable overall QOL scores, which are comparable to those of the normal population. Patients with grade 3 CAE-particularly dyspareunia and fecal incontinence-have a poorer QOL compared to patients without CAE. In order to improve long-term QOL, future strategies might aim at a reduction in dose to the genitalia and more intensive patient support measures.

Localization and quantification of the delivered dose to the spinal cord. Predicting actual delivered dose during daily MVCT image-guided tomotherapy.

PURPOSE: The goal of the present work was to localize and quantify the actual delivered dose to the cervical spinal cord (SC) during head and neck cancer (H&N) treatment. MATERIALS AND METHODS: A total of 20 H&N patients treated with bilateral nodal irradiation with helical tomotherapy (HT) were analyzed. Daily MVCTs were performed for image guidance. On every second MVCT, the SC was recontoured and the delivered dose for the given treatment fraction (12 fractions per patient) was recalculated. The magnitude and localization (CT slice, spinal cord quadrant) of the Dmax to the SC on the planning CT (PLAN-Dmax) and of the actual delivered Dmax (a-Dmax) were analyzed. RESULTS: A systematic deviation from the PLAN-Dmax was observed in 15 out of 20 patients. Large interpatient variability of the a-Dmax in the spinal cord was noted (4.5±4%). Intrapatient variability in a-Dmax was, generally, minimal (1.8±2.7%). Throughout the treatment course, the higher dose was located in the same CT slices and in the same quadrants (anterior right and anterior left) for the same patient. CONCLUSION: Exact localization and quantification of the change of the a-Dmax can be made for most patients by recalculating the dose on the daily IGRT-MVCTs. This could be helpful in assessing whether replanning is necessary in patients with doses close to the known tolerance doses of the spinal cord.

Motional coherence of fermions immersed in a Bose gas.

We prepare a superposition of two motional states by addressing lithium atoms immersed in a Bose-Einstein condensate of sodium with a species-selective potential. The evolution of the superposition state is characterized by the populations of the constituent states as well as their coherence. The latter we extract employing a novel scheme analogous to the spin-echo technique. Comparing the results directly to measurements on freely evolving fermions allows us to isolate the decoherence effects induced by the bath. In our system, the decoherence time is close to the maximal possible value since the decoherence is dominated by population relaxation processes. The measured data are in good agreement with a theoretical model based on Fermi's golden rule.

Oxidative stress after a carbohydrate meal contributes to the deterioration of diastolic cardiac function in nonhypertensive insulin-treated patients with moderately well controlled type 2 diabetes.

The prevalence and prognostic importance of diastolic dysfunction in type 2 diabetes has only recently been appreciated. We tested the hypothesis that in insulin treated type 2 diabetes (D), carbohydrate consumption induces oxidative stress resulting in further impairment of diastolic function beyond structural myocardial stiffness. The effects of a pure carbohydrate breakfast (48 g) on oxidative stress and cardiac function were studied in the fasting and postmeal states in subjects without hypertension or overt cardiac disease (moderately well controlled D, n=21 and controls without D, n=20). Studied variables included systolic and early diastolic (E') myocardial velocities, traditional metabolic and hemodynamic parameters, serum nitrotyrosine, and sVCAM-1. In D compared to control subjects, the postmeal increase (∆) in glucose (1.44±2.78 vs. 0.11±0.72 mmol/l, p=0.04) and ∆nitrotyrosine (0.34±0.37 vs. -0.23±0.47 nM/l, p<0.001) were significantly higher. sVCAM-1 was higher in fasting and postmeal (p=0.02). E' was significantly lower in postmeal (7.3±1.3 vs. 9.6±1.3 cm/s, p<0.001) and fasting (p<0.001) whereas the rate pressure product was significantly higher (9 420±1 118 vs. 7 705±1 871 mm Hg/min, p<0.001). Multivariable regression models of the pooled data demonstrated that independent predictors for postmeal E' were ∆nitrotyrosine and septal thickness (R² 0.466) and for fasting E' age, ∆nitrotyrosine, and septal thickness (R² 0.400). In insulin requiring type 2 diabetes, carbohydrate consumption may induce oxidative stress that is associated with worsening diastolic function, indicating that this metabolic factor is an important determinant of diastolic dysfunction in the diabetic heart beyond the increase in structural myocardial stiffness.

Children and adolescents with ureteropelvic junction obstruction: is an additional voiding cystourethrogram necessary? Results of a multicenter study.

PURPOSE: The incidence of ureteropelvic junction obstruction (UPJO) and concomitant vesicoureteral reflux (VUR) ranges from 14 to 18 %. Therefore, different guidelines recommend a voiding cystourethrogram (VCUG) to identify cases of VUR early in the diagnostic process. Aim of this multicenter study was to reassess the incidence of concomitant VUR and the need for additional VCUG in a large cohort of patients with UPJO. Furthermore, we asked for clinical objectives that defined the need for VCUG with the intention of minimizing radiation exposure and the need for invasive diagnostic procedures. METHODS: Medical records for 266 patients (69 girls, 197 boys) with UPJO were analyzed retrospectively. Data were obtained on gender, clinical symptoms, results of pre- and postnatal ultrasound, VCUG and 99(m)Technetium-MAG3 (MAG3) scan. They were correlated with the incidence of concomitant VUR. RESULTS: One hundred and seventy-eight patients (67 %) underwent VCUG. Concomitant VUR was detected in 13 patients. Dilating VUR (dVUR) was observed in 11 patients. In our study, the overall incidence of a concomitant VUR was 7.3 %. In cases of proven VUR, we observed a positive predictive value for female gender, ureteral dilatation, renal insufficiency, and recurrent urinary tract infections (UTI). But there was no correlation between concomitant VUR and the severity of hydronephrosis. CONCLUSIONS: Our data suggest that the low incidence of concomitant VUR in cases of UPJO does not justify the routine use of VCUG as a routine diagnostic tool. Especially, ureteral dilatation and recurrent UTI have a positive predictive value for concomitant VUR.

[What medical students want - evaluation of medical recruitment ads by future physicians]. / Was Medizinstudierende wollen - Einschätzung ärztlicher Stellenanzeigen durch angehende Ärztinnen und Ärzte der Humanmedizin.

OBJECTIVE: Three-quarters of all hospitals in Germany are now struggling to fill open positions for doctors. The medical job ad is a vital tool for human resources marketing and an important image factor. The present study examines the importance of information and offers in medical recruitment ads on application decisions by medical students. METHOD: A total of 184 future physicians from clinical semesters participated voluntarily in an anonymous cross-sectional survey. Using a standardised questionnaire, the importance of 49 -individual items extracted from medical recruitment ads were rated with the help of a 4-point Likert Scale. Finally, the study participants prioritised their reasons for an application as a physician. RESULTS: Primary influence on the application decision on medical recruitment ads by medical students had offers/information in relation to education and training aspects and work-life balance. Payment rates for physicians and work load played an important role for the application motivation. Additional earnings for, e. g., emergency calls, providing of medical expertise and assistance with housing, relocation and reimbursement of interview expenses were less crucial. In prioritising key reasons for selecting a prospective employer "regular working hours," an "individual training concept" and an "attractive work-life balance" scored the highest priority. The "opportunity for scientific work" was assigned only a small significance. CONCLUSION: High importance for the application decision by future physicians on medical recruitment ads is placed on jobs with an opportunity for personal development and aspects that contribute to work-life balance.

Specific activity of cyclin-dependent kinase I is a new potential predictor of tumour recurrence in stage II colon cancer.

BACKGROUND: There are no established biomarkers to identify tumour recurrence in stage II colon cancer. As shown previously, the enzymatic activity of the cyclin-dependent kinases 1 and 2 (CDK1 and CDK2) predicts outcome in breast cancer. Therefore, we investigated whether CDK activity identifies tumour recurrence in colon cancer. METHODS: In all, 254 patients with completely resected (R0) UICC stage II colon cancer were analysed retrospectively from two independent cohorts from Munich (Germany) and Leiden (Netherlands). None of the patients received adjuvant treatment. Development of distant metastasis was observed in 27 patients (median follow-up: 86 months). Protein expression and activity of CDKs were measured on fresh-frozen tumour samples. RESULTS: Specific activity (SA) of CDK1 (CDK1SA), but not CDK2, significantly predicted distant metastasis (concordance index=0.69, 95% confidence interval (CI): 0.55-0.79, P=0.036). Cutoff derivation by maximum log-rank statistics yielded a threshold of CDK1SA at 11 (SA units, P=0.029). Accordingly, 59% of patients were classified as high-risk (CDK1SA ≥11). Cox proportional hazard analysis revealed CDK1SA as independent prognostic variable (hazard ratio=6.2, 95% CI: 1.44-26.9, P=0.012). Moreover, CKD1SA was significantly elevated in microsatellite-stable tumours. CONCLUSION: Specific activity of CDK1 is a promising biomarker for metastasis risk in stage II colon cancer.

Erythropoietin in the prevention of experimental burn progression.

BACKGROUND: Damage control is essential in first aid of burn lesions. The aim of the present study was to investigate whether systemic erythropoietin (EPO) administration could prevent secondary burn progression in an experimental model. METHODS: The burn comb model creates four rectangular burn surfaces intercalated by three unburned zones prone to progression. Twenty-one Wistar rats were randomized to a control group or to receive intraperitoneal EPO (500 units per kg) once a day for 5 days starting 45 min (EPO45min) or 6 h (EPO6h) after burn injury. Histological analyses assessing burn depth, inflammation and neoangiogenesis, planimetric evaluation of burn progression, and laser Doppler flowmetry to assess perfusion were performed after 1, 4 and 7 days. Final scarring time and contracture rate were assessed once a week. RESULTS: Burn progression was decreased significantly with EPO45min but not EPO6h; progression of burn depth stopped in the intermediate dermis (mean(s.e.m.) burn depth score 3·3(0·6) for EPO45min versus 4·7(0·3) and 5·0(0·0) for EPO6h and control respectively on day 7; P = 0·026) and the surface extension was significantly reduced (45(8), 65(4) and 78(4) respectively on day 7; P = 0·017). This was paralleled by faster re-establishment of perfusion with EPO45min (114(5) per cent on day 4 versus 85(6) and 91(3) per cent for EPO6h and control respectively; P = 0·096). The reduction in progression resulted in a decreased healing time (7·3(0·7) weeks for EPO45min versus 11·5(1·0) and 10·8(0·5) weeks for EPO6h and control; P = 0·020) and contracture rate (P = 0·024). CONCLUSION: Early EPO prevented burn progression, mainly by improved vascular perfusion.

Adaptive radiotherapy for soft tissue changes during helical tomotherapy for head and neck cancer.

PURPOSE: The goal of the present study was to assess the frequency and impact of replanning triggered solely by soft tissue changes observed on the daily setup mega-voltage CT (MVCT) in head and neck cancer (H&N) helical tomotherapy (HT). MATERIAL AND METHODS: A total of 11 patients underwent adaptive radiotherapy (ART) using MVCT. Preconditions were a soft tissue change > 0.5 cm and a tight mask. The dose­volume histograms (DVHs) derived from the initial planning kVCT (inPlan), the recalculated DVHs of the fraction (fx) when replanning was decided (actSit) and the DVHs of the new plan (adaptPlan) were compared. Assessed were the following: maximum dose (Dmax), minimum dose (Dmin), and mean dose (Dmean) to the planning target volume (PTV) normalized to the prescribed dose; the Dmean/fx to the parotid glands (PG), oral cavity (OC), and larynx (Lx); and the Dmax/fx to the spinal cord (SC) in Gy/fx. RESULTS: No patient had palpable soft tissue changes. The median weight loss at the moment of replanning was 2.3 kg. The median PTV Dmean was 100% for inPlan, 103% for actSit, and 100% for adaptPlan. The PTV was always covered by the prescribed dose. A statistically significant increase was noted for all organs at risk (OAR) in the actSit. The Dmean to the Lx, the Dmean to the OC and the Dmax to the SC were statistically better in the adaptPlan. No statistically significant improvement was achieved by ART for the PGs. No significant correlations between weight and volume loss or between the volume changes of the organs to each other were observed, except a strong positive correlation of the shrinkage of the PGs (ρ = + 0.77, p = 0.005). CONCLUSION: Soft tissue shrinkage without clinical palpable changes will not affect the coverage of the PTV, but translates into a higher delivered dose to the PTV itself and the normal tissue outside the PTV. The gain by ART in individual patients­especially in patients who receive doses close to the tolerance doses of the OAR­could be substantial.

Salvage radiotherapy in patients with recurrent esophageal carcinoma.

PURPOSE: The feasibility and effectiveness of radiotherapy in the management of recurrent esophageal carcinoma (REC) is reported. PATIENTS AND METHODS: A consecutive cohort of 54 patients with rcT1-4, rcN0-1, or cM0 recurrent esophageal carcinoma (69% squamous cell carcinoma, 31% adenocarcinoma) was treated between 1988 and 2010. The initial treatment for these patients was definitive radiochemotherapy, surgery alone, or neoadjuvant radiochemotherapy + surgical resection in 8 (15%), 33 (61%), and 13 (24%) patients, respectively. The median time to recurrence from initial treatment was 19 months (range 4-79 months). The site of the recurrence was anastomotic or local, nodal, or both in 63%, 30%, and 7% of patients, respectively. Salvage radio(chemo)therapy was carried out with a median dose of 45 Gy (range 30-68 Gy). RESULTS: Median follow-up time for surviving patients from the start of R(C)T was 38 months (range 10-105 months). Relief of symptoms was achieved in 19 of 28 symptomatic patients (68%). The median survival time was 12 months (95% confidence interval (CI) 7-17 months) and the median recurrence-free interval was 8 months (95% CI 4-12 months). The survival rates at 1, 2, and 3 years were 55 ± 7%, 29 ± 6%, and 19 ± 5%, respectively. The recurrence-free survival rates at 1, 2, and 3 years were 44 ± 7%, 22 ± 6%, and 15 ± 5%, respectively. A radiation dose ≥ 45 Gy and conformal RT were associated with a better prognosis. CONCLUSION: RT is feasible and effective in the management of recurrent esophageal carcinoma, especially for relief of symptoms. Toxicity is in an acceptable range. The outcome of REC is poor; however, long-term survival of patients with recurrent esophageal carcinoma after radiochemotherapy might be possible, even with a previous history of radiotherapy in the initial treatment. If re-irradiation of esophageal carcinoma is contemplated, three-dimensional conformal techniques and a minimum total dose of 45 Gy are recommended.