German specialists treating testicular cancer follow different guidelines with resulting inconsistency in assessment of retroperitoneal lymph-node metastasis: clinical implications and possible corrective measures.

BACKGROUND: Testicular germ cell tumors (GCTs) are aggressive but highly curable tumors. To avoid over/undertreatment, reliable clinical staging of retroperitoneal lymph-node metastasis is necessary. Current clinical guidelines, in their different versions, lack specific recommendations on how to measure lymph-node metastasis. OBJECTIVE: We aimed to assess the practice patterns of German institutions frequently treating testicular cancer for measuring retroperitoneal lymph-node size. METHODS: An 8-item survey was distributed among German university hospitals and members of the German Testicular Cancer Study Group. RESULTS: In the group of urologists, 54.7% assessed retroperitoneal lymph nodes depending on their short-axis diameter (SAD) (33.3% in any plane, 21.4% in the axial plane), while 45.3% used long-axis diameter (LAD) for the assessment (42.9% in any plane, 2.4% in the axial plane). Moreover, the oncologists mainly assessed lymph-node size based on the SAD (71.4%). Specifically, 42.9% of oncologists assessed the SAD in any plane, while 28.5% measured this dimension in the axial plane. Only 28.6% of oncologists considered the LAD (14.3% in any plane, 14.3% in the axial plane). None of the oncologists and 11.9% of the urologists (n = 5) always performed an MRI for the initial assessment, while for follow-up imaging, the use increased to 36.5% of oncologists and 31% of urologists. Furthermore, only 17% of the urologists, and no oncologists, calculated lymph-node volume in their assessment (p = 0.224). CONCLUSION: Clear and consistent measurement instructions are urgently needed to be present in all guidelines across different specialistic fields involved in testicular cancer management.

Initial experience on abdominal photon-counting computed tomography in clinical routine: general image quality and dose exposure.

OBJECTIVES: Photon-counting computed tomography has lately found its way into clinical routine. The new technique could offer substantial improvements regarding general image quality, image noise, and radiation dose reduction. This study evaluated the first abdominal examinations in clinical routine and compared the results to conventional computed tomography. METHODS: In this single-center retrospective study, 66 patients underwent photon-counting and conventional abdominal CT. Four radiologists assessed general image quality, image noise, and image artifacts. Signal-to-noise ratio and dose properties of both techniques within the clinical application were compared. An ex vivo phantom study revealed the radiobiological impact by means of DNA double-strand break foci in peripheral blood cells by enumerating γ-H2AX+53BP1 foci. RESULTS: General image quality in accordance with the Likert scale was found superior for photon-counting CT (4.74 ± 0.46 vs. 4.25 ± 0.54; p < 0.001). Signal-to-noise ratio (p < 0.001) and also dose exposure were higher for photon-counting CT (DLP: 419.2 ± 162.2 vs. 372.3 ± 236.6 mGy*cm; p = 0.0435). CT exposure resulted in significantly increased DNA damage in comparison to sham control (p < 0.001). Investigation of the average foci per cell and radiation-induced foci numbers revealed significantly elevated numbers (p = 0.004 and p < 0.0001, respectively) after photon-counting CT. CONCLUSION: Photon-counting CT in abdominal examinations showed superior results regarding general image quality and signal-to-noise ratio in clinical routine. However, this seems to be traded for a significantly higher dose exposure and corresponding double-strand break frequency. Optimization of standard protocols in further clinical applications is required to find a compromise regarding picture quality and dose exposure. KEY POINTS: • Photon-counting computed tomography promises to enhance the diagnostic potential of medical imaging in clinical routine. • Retrospective single-center study showed superior general image quality accompanied by higher dose exposure in initial abdominal PCCT protocols compared to state-of-the-art conventional CT. • A simultaneous ex vivo phantom study revealed correspondingly increased frequencies of DNA double-strand breaks after PCCT.

Impact of medical imaging on the epigenome - low-dose exposure in the course of computed tomography does not induce detectable changes of DNA-methylation profiles in peripheral blood cells.

BACKGROUND: Computed tomography (CT) is a main contributor to artificial low-dose exposure. Understanding the biological effects induced by CT exposure and their dependency on the characteristics of photon spectra is essential for knowledge-driven risk assessment. In a previous gene expression study, we have identified upregulation of AEN, BAX, DDB2, EDA2R and FDXR after ex vivo exposure with single-energy CT and dual-energy CT (DECT). In this study, we focused on CT-induced changes of DNA methylation. This epigenetic modification of DNA is a central regulator of gene expression and instrumental in preserving genome integrity. Previous studies reported focal hypermethylation and global hypomethylation after exposure with doses above 100 mSv, however, the effect of low dose exposure on DNA methylation is hardly explored. MATERIALS AND METHODS: DNA was isolated from peripheral blood of three healthy individuals 6 h after ex vivo exposition to single-energy (80 kV and 150 kV) and DECT (80 kV/Sn150 kV) with a calculated effective dose of 7.0 ± 0.08 mSv. The experimental setting was identical to the one used in our previous gene expression study enabling a direct comparison of gene expression results with changes of DNA methylation identified in this study. DNA methylation was analyzed by high-throughput sequencing of bisulfite-treated DNA targeted methylation sequencing. RESULTS: Unsupervised hierarchical clustering based on DNA methylation profiles of all samples created three distinct clusters. Formation of these three clusters was solely determined by the origin of samples, indicating the absence of prominent irradiation-associated changes of DNA methylation. In line with this observation, inter-individual comparison of non-irradiated samples revealed 1163, 1224 and 4550 significant differentially methylated regions (DMRs), respectively, whereas the pairwise comparison of irradiated and non-irradiated samples failed to identify irradiation-induced DMRs in any of the three probands. This even applied to the genomic regions harboring AEN, BAX, DDB2, EDA2R and FDXR, the five genes known to be upregulated by CT exposure. CONCLUSIONS: CT exposure with various photon spectra did not result in detectable changes of DNA methylation. However, minor effects in a subpopulation of irradiated cells cannot be ruled out. Thus, future studies with extended observation intervals are needed to investigate DNA methylation changes that are induced by indirect effects at later points of time or become detectable by clonal expansion of affected cells. Moreover, our data suggest that DNA methylation analysis is less sensitive in detecting immediate effects of low-dose irradiation when compared to gene expression analysis.

Gene expression changes and DNA damage after ex vivo exposure of peripheral blood cells to various CT photon spectra.

Dual-energy CT provides enhanced diagnostic power with similar or even reduced radiation dose as compared to single-energy CT. Its principle is based on the distinct physical properties of low and high energetic photons, which, however, may also affect the biological effectiveness and hence the extent of CT-induced cellular damage. Therefore, a comparative analysis of biological effectiveness of dual- and single-energy CT scans with focus on early gene regulation and frequency of radiation-induced DNA double strand breaks (DSBs) was performed. Blood samples from three healthy individuals were irradiated ex vivo with single-energy (80 kV and 150 kV) and dual-energy tube voltages (80 kV/Sn150kV) employing a modern dual source CT scanner resulting in Volume Computed Tomography Dose Index (CTDIvol) of 15.79-18.26 mGy and dose length product (DLP) of 606.7-613.8 mGy*cm. Non-irradiated samples served as a control. Differential gene expression in peripheral blood mononuclear cells was analyzed 6 h after irradiation using whole transcriptome sequencing. DSB frequency was studied by 53BP1 + γH2AX co-immunostaining and microscopic evaluation of their focal accumulation at DSBs. Neither the analysis of gene expression nor DSB frequency provided any evidence for significantly increased biological effectiveness of dual-energy CT in comparison to samples irradiated with particular single-energy CT spectra. Relative to control, irradiated samples were characterized by a significantly higher rate of DSBs (p < 0.001) and the shared upregulation of five genes, AEN, BAX, DDB2, FDXR and EDA2R, which have already been suggested as radiation-induced biomarkers in previous studies. Despite steadily decreasing doses, CT diagnostics remain a genotoxic stressor with impact on gene regulation and DNA integrity. However, no evidence was found that varying X-ray spectra of CT impact the extent of cellular damage.

Additional CTA-Subtraction Technique in Detection of Pulmonary Embolism-a Benefit for Patients or Only an Increase in Dose?

Latest advantages in computed tomography (CT) come with enhanced diagnostic imaging and also sophisticated dose reduction techniques. However, overall exposure to ionizing radiation of patients in Germany rises slightly, which is mainly based on the growing number of performed CT scans. Furthermore, new possibilities in modern imaging, including 4D scans or perfusion protocols, offer new medical insights but require additional scans.In this study, we reevaluated data sets from patients undergoing CT examinations because of suspected pulmonary embolism and compared doses and diagnostic results of the standard protocol to the additional modern CT subtraction technique. Two groups of single-blinded radiologists were provided with CT data sets from 50 patients. One group (G1) had access to full datasets including CT subtraction with perfusion map. The other group (G2) only evaluated conventional CT angiography. Results were compared to final clinical diagnosis. Dose length product (DLP) of CT angiography was compared to CT subtraction technique, which consists of an additional non-contrast-enhanced scan and perfusion map. Effective dose was calculated using a Monte Carlo simulation-based software tool (ImpactDose). Inter-rater agreement of both groups was strong in G1 with κ = .896 and minimal in G2 (κ = .307). Agreement to final diagnosis was strong in both groups (G1, κ = .848; G2, κ = .767). Doses applied using the CT subtraction technique were 34.8% higher than for CT angiography alone (G1 DLP 337.6 ± 171.3 mGy x cm; G2 DLP 220.2 ± 192.8 mGy x cm; p < .001). Calculated effective dose was therefore significantly higher for G1 (G1 4.82 ± 2.20 mSv; G2 3.04 ± 1.33 mSv; p < .001). Our results indicate a benefit of the CT subtraction technique for the detection of pulmonary embolisms in clinical routine, accompanied by an increase in the dose administered. Although CT protocols should always be applied carefully to specific clinical indications in order to maximize the potential for dose reduction and keep the administered dose as low as reasonably achievable, one should never lose sight of the diagnostic benefit, especially in vital clinical indications.

CT Irradiation-induced Changes of Gene Expression within Peripheral Blood Cells.

Computed tomography (CT) is a crucial element of medical imaging diagnostics. The widespread application of this technology has made CT one of the major contributors to medical radiation burden, despite the fact that doses per individual CT scan steadily decrease due to the advancement of technology. Epidemiological risk assessment of CT exposure is hampered by the fact that moderate adverse effects triggered by low doses of CT exposure are likely masked by statistical fluctuations. In light of these limitations, there is need of further insights into the biological processes induced by CT scans to complement the existing knowledge base of risk assessment. This prompted us to investigate the early transcriptomic response of ex vivo irradiated peripheral blood of three healthy individuals. Samples were irradiated employing a modern dual-source-CT-scanner with a tube voltage of 150 kV, resulting in an estimated effective dose of 9.6 mSv. RNA was isolated 1 h and 6 h after exposure, respectively, and subsequently analyzed by RNA deep sequencing. Differential gene expression analysis revealed shared upregulation of AEN, FDXR, and DDB2 6 h after exposure in all three probands. All three genes have previously been discussed as radiation responsive genes and have already been implicated in DNA damage response and cell cycle control after DNA damage. In summary, we substantiated the usefulness of AEN, FDXR, and DDB2 as RNA markers of low dose irradiation. Moreover, the upregulation of genes associated with DNA damage reminds one of the genotoxic nature of CT diagnostics even with the low doses currently applied.

Detection of Embedded Low-level Radioactive Shrapnel after the Explosion of a Radiological Dispersal Device in Radiological Emergency Imaging.

Concern about the threat of a terrorist attack with a Radiological Dispersal Device has increased considerably over the last few years, and this comes along with an immense challenge, especially regarding medical treatment of combined injuries with incorporated radioactive fragments. In such scenarios, the identification and surgical exploration of radioactive fragments is a major issue to prevent further radiation-induced effects like wound healing disorders, onset of acute radiation syndrome, and as a late-effect cancer. However, in a usual emergency setting, it is unclear how this task can be achieved. Within this study, we evaluated the feasibility of different radiological methods to identify and locate an incorporated radioactive fragment. We placed two different Cs sources and several non-radioactive fragments representing sham control samples within a human spine phantom. Standard emergency imaging procedures were performed, including plane radiography and different CT scans (64 row, 384 row dual energy, 320 row without iterative metal artifact reduction), respectively. Eight radiologists were blinded toward the results and asked to identify the radioactive fragments within the provided images. For both sources, correct identification was rather low (15.63%). Furthermore, none of the questioned radiologists (N = 0) stated that they were able to identify the radioactive shrapnel distinctly. Positive predictive value was accordingly low (15.63%). Most participants recommended a scintigraphy-based technique for identification (26.67%) rather than radiographic procedures (6.67%). Identification and location of incorporated small radioactive fragments with low energies by standard radiological procedures prior to surgical exploration is not promising. Nevertheless, procedures that can achieve this aim are needed direly in the case of a terrorist attack with a radiological dispersal device and should be available in an emergency department.

Health Risks and Interventions in Exertional Heat Stress.

BACKGROUND: With climate change, heat waves are expected to become more frequent in the near future. Already, on average more than 25 000 "heat deaths" are estimated to occur in Europe every year. However, heat stress and heat illnesses arise not just when ambient temperatures are high. Physical exertion increases heat production within the organism many times over; if not enough heat is lost, there is a risk of exertional heat stress. This review article discusses contributing factors, at-risk groups, and the diagnosis and treatment of heat illnesses. METHODS: A selective literature search was carried out on PubMed. Current guidelines and expert recommendations were also included. RESULTS: Apart from muscular heat production (>70% of converted energy), there are other factors that singly or in combination can give rise to heat stress: clothing, climate/acclimatization, and individual factors. Through its insulating properties, clothing reduces the evaporation of sweat (the most effective physiological cooling mechanism). A sudden heat wave, or changing the climate zone (as with air travel), increases the risk of a heat-related health event. Overweight, low fitness level, acute infections, illness, dehydration, and other factors also reduce heat tolerance. In addition to children, older people are particularly at risk because of their reduced physiological adaptability, (multi-)morbidity, and intake of prescription drugs. A heat illness can progress suddenly to life-threatening heat stroke. Successful treatment depends on rapid diagnosis and cooling the body down as quickly as possible. The aim is to reduce core body temperature to <40 °C within 30 minutes. CONCLUSION: Immediately effective cooling interventions are the only causal treatment for heat stroke. Time once lost cannot be made up. Prevention (acclimatization, reduced exposure, etc.) and terminating the heat stress in good time (e.g., stopping work) are better than any cure.

Index Finger Muscle Fatigue and Pistol Firing Failure.

OBJECTIVE: The aim of this study was to analyze finger strength and effects of muscle fatigue on the ability to shoot. BACKGROUND: The finger and hand muscles of soldiers are subject to high loads. For example, the trigger pull of military pistols can amount up to 58 N (≈6 kg) and could cause muscle fatigue in the trigger finger. For soldiers, however, maintaining the ability to shoot is essential for self-defense and survival. METHOD: The marksmanship training of 30 German soldiers (15 female) ages 18 to 40 years was evaluated. Three consecutive exercises with a total of 60 rounds were fired from target ranges of 5 and 10 m, equally using a single-action and double-action trigger mode. Maximum voluntary isometric contraction of the index finger (MVCIF) was measured before and after each of the three firing exercises. RESULTS: Shooting reduced MVCIF in female (88.2 ± 15.8 N to 67.3 ± 17.7 N, p < .001) and male soldiers (145.8 ± 21.7 N to 112.7 ± 26.6 N, p < .001). Of the 30 subjects, 23 were unable to shoot due to fatigue, including 15 of 15 female soldiers. The higher MVCIF was at rest, the less commonly (r = .73, p < .001) and the later (r = 0.82, p < .001) task failure occurred. Two intermissions of approximately 6 min did not suffice for a significant recovery. CONCLUSION: Excessive trigger pull weight causes muscle fatigue of the index finger and can ultimately lead to task failure during pistol marksmanship training. Short breaks are insufficient for the recovery of finger muscles. APPLICATION: This study presents a new perspective on ideal trigger pull weight, which should be carefully considered by manufacturers to allow repetitive firing and simultaneously ensure safe handling.

Diagnostic accuracy of third-generation dual-source dual-energy CT: a prospective trial and protocol for clinical implementation.

PURPOSE: Uric acid (UA) calculi can be referred to chemolitholysis rather than invasive treatment. Dual-energy computed tomography (DECT) may be able to distinguish between UA and non-UA (NUA) calculi. The aim of this study was to evaluate the validity of third-generation DECT for the first time and to investigate whether combining DECT with clinical parameters can increase its predictive accuracy. MATERIALS AND METHODS: All patients who presented to our emergency department between January 2015 and March 2017 with urinary stones were prospectively included in this observational study and underwent DECT with subsequent interventional stone removal. Stone composition was analyzed using infrared spectrometry as the gold standard. Predictive accuracy of DECT and clinical covariates was computed by assessing univariate and multivariate areas under the curve (AUCs). RESULTS: Of 84 patients with 144 urinary stones, 10 (11.9%) patients had UA stones according to infrared spectrometry, and the remaining stones were NUA or mixed stones. DECT had a positive predictive value of 100% and a negative predictive value of 98.5% for UA stones. The AUC for urine pH alone was 0.71 and 0.97 for DECT plus urine pH. No UA stones were found in patients with a urine pH above > 5.5. Mean DLP was 225.15 ± 128.60 mGy*cm and mean effective dose was 3.38 ± 1.93 mSv. CONCLUSIONS: DECT is a safe method for assigning patients to oral chemolitholysis. Clinical preselection of patients based on urinary pH (< 6.0) leads to a more liable use of DECT. Third-generation DECT needs significant lower radiation doses compared to previous generations.

Gene expression changes in human iPSC-derived cardiomyocytes after X-ray irradiation.

Purpose: Radiation-induced heart disease caused by cardiac exposure to ionizing radiation comprises a variety of cardiovascular effects. Research in this field has been hampered by limited availability of clinical samples and appropriate test models. In this study, we wanted to elucidate the molecular mechanisms underlying electrophysiological changes, which we have observed in a previous study. Materials and methods: We employed RNA deep-sequencing of human-induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) 48 h after 5 Gy X-ray irradiation. By comparison to public data from hiPSC-CMs and human myocardium, we verified the expression of cardiac-specific genes in hiPSC-CMs. Results were validated by qRT-PCR. Results: Differentially gene expression analysis identified 39 and 481 significantly up- and down-regulated genes after irradiation, respectively. Besides, a large fraction of genes associated with cell cycle processes, we identified genes implicated in cardiac calcium homeostasis (PDE3B), oxidative stress response (FDXR and SPATA18) and the etiology of cardiomyopathy (SGCD, BBC3 and GDF15). Conclusions: Notably, observed gene expression characteristics specific to hiPSC-CMs might be relevant regarding further investigations of the response to external stressors like radiation. The genes and biological processes highlighted in our study present promising starting points for functional follow-up studies for which hiPSC-CMs could pose an appropriate cell model when cell type specific peculiarities are taken into account.

Papillary Thyroid Cancer and Coexisting Autoimmune Thyroiditis.

Histological findings often display an association between papillary thyroid carcinomas (PTC) and autoimmune thyroiditis (AIT) and so differ significantly from follicular thyroid carcinomas (FTC). The aim of this interdisciplinary, retrospective study was to evaluate the association of AIT in patients with PTC and FTC and a control group of benign nodular goiters. One hundred thyroidectomies with histologically confirmed differentiated thyroid carcinomas, 67 with PTC and 33 with FTC, were submitted for examination. The two control groups consisted of 60 patients with euthyroid nodular goiter, displaying no signs for malignancy (no surgery) and 100 patients (second control group) with surgery of a benign nodular goiter. Controls were collected to obtain data about the incidence of significantly increased TPOAbs in the first group and of lymphocytic infiltrates (LI) in the second group. High TPOAbs were found in 35% (23/67) of patients with PTC. LI were detected by histology in 48% (32/67) of PTC. Ten patients (10/32) of this group showed the clinical and histological manifestation of a classic AIT with diffuse dense LI as well as diffuse hypoechogeneity in ultrasonography. In 7/32 cases, the histological report described focal dense LI (fAIT) and in 15/32 cases scant scattered LI. AIT and fAIT, together 25% of all PTC (17/67), showed germinal centers and can therefore be characterized as chronic autoimmune thyroiditis. In this group, high TPOAb could be detected in 94% (16/17). Scan scattered LI without germinal centers (15/32) do not represent a fAIT, although TPOAb are high in 47% (7/15). The younger age group (<45 years) showed significantly more often high TPOAbs (p<0.023) in comparison with the age-group older than 60 years. In contrast to PTC, only 4/33 (12%) patients with FTC had high TPOAb levels. We conclude that in contrast to benign euthyroid goiters and to FTC, different degrees of LI are often associated with high TPOAb levels and seem to be significantly increased in PTC, particularly prominent in younger age. There is a high coincidence between LI and high TPOAb levels. In the presence of hypoechoic thyroid nodule, signs of thyroid autoimmunity such as the presence of high TPOAbs, lymphocytic infiltration in cytology, and/or characteristic ultrasonic features, are arguments that might favor the decision for surgery if a cytologically indeterminate thyroid nodule is found and focal autonomy is excluded by szintiscan.

Strength Training for Women as a Vehicle for Health Promotion at Work.

BACKGROUND: Women, on average, have less muscle strength than men. This anthropometric-physiological trait may make them more vulnerable to ex - cessive physical strain, injury, and inability to work. Strength training is used for preventive health maintenance and to lessen musculoskeletal symptoms. In this context, we studied whether the degree of muscle strength has any effect on women's health in everyday working life, and also the effects of strength training for women on their health in the workplace. METHODS: We systematically searched the PubMed/MEDLINE, Embase, CINAHL, Web of Science, CENTRAL, and SPOLIT databases for pertinent publications, in accordance with the PRISMA criteria for literature searches. We analyzed all of the retrieved randomized controlled trials conducted on women aged 18 to 65 to determine the effects of training on muscle strength, physical performance ability, and health-related parameters including body composition, musculo - skeletal pain, and subjective well-being. RESULTS: We did not find any studies that provided answers to the first question. As for the second question, the selection criteria were met by 12 of the 4969 retrieved studies, which dealt with the effect of strength training on health in the occupational environment and involved a total of 1365 female subjects. These studies were carried out in heterogeneous subject groups, with a variety of overlapping interventions consisting of both strength and endurance training. Significantly increased strength was found in all studies, as was a reduction of pain in all of the studies where this question was asked. Inconsistent results were obtained with respect to body weight, body composition, and subjective well-being. CONCLUSION: The interventions that were conducted in these studies succeeded in increasing strength and reducing pain, even when the training was brief and of low intensity. This was true not only for women working in occupations requiring unusual physical strength, but also for those in sedentary occupations. The small number of studies performed on this subject to date is surprising in view of the high prevalence of musculoskeletal symptoms in women.