Enhanced RBE of Particle Radiation Depends on Beam Size in the Micrometer Range.

High-linear energy transfer (LET) radiation, such as heavy ions is associated with a higher relative biological effectiveness (RBE) than low-LET radiation, such as photons. Irradiation with low- and high-LET particles differ in the interaction with the cellular matter and therefore in the spatial dose distribution. When a single high-LET particle interacts with matter, it results in doses of up to thousands of gray (Gy) locally concentrated around the ion trajectory, whereas the mean dose averaged over the target, such as a cell nucleus is only in the range of a Gy. DNA damage therefore accumulates in this small volume. In contrast, up to hundreds of low-LET particle hits are required to achieve the same mean dose, resulting in a quasi-homogeneous damage distribution throughout the cell nucleus. In this study, we investigated the dependence of RBE from different spatial dose depositions using different focused beam spot sizes of proton radiation with respect to the induction of chromosome aberrations and clonogenic cell survival. Human-hamster hybrid (AL) as well as Chinese hamster ovary cells (CHO-K1) were irradiated with focused low LET protons of 20 MeV (LET = 2.6 keV/µm) beam energy with a mean dose of 1.7 Gy in a quadratic matrix pattern with point spacing of 5.4 × 5.4 µm2 and 117 protons per matrix point at the ion microbeam SNAKE using different beam spot sizes between 0.8 µm and 2.8 µm (full width at half maximum). The dose-response curves of X-ray reference radiation were used to determine the RBE after a 1.7 Gy dose of radiation. The RBE for the induction of dicentric chromosomes and cell inactivation was increased after irradiation with the smallest beam spot diameter (0.8 µm for chromosome aberration experiments and 1.0 µm for cell survival experiments) compared to homogeneous proton radiation but was still below the RBE of a corresponding high LET single ion hit. By increasing the spot size to 1.6-1.8 µm, the RBE decreased but was still higher than for homogeneously distributed protons. By further increasing the spot size to 2.7-2.8 µm, the RBE was no longer different from the homogeneous radiation. Our experiments demonstrate that varying spot size of low-LET radiation gradually modifies the RBE. This underlines that a substantial fraction of enhanced RBE originates from inhomogeneous energy concentrations on the µm scale (mean intertrack distances of low-LET particles below 0.1 µm) and quantifies the link between such energy concentration and RBE. The missing fraction of RBE enhancement when comparing with high-LET ions is attributed to the high inner track energy deposition on the nanometer scale. The results are compared with model results of PARTRAC and LEM for chromosomal aberration and cell survival, respectively, which suggest mechanistic interpretations of the observed radiation effects.

[Minimally invasive techniques for traumatic injuries of the cervical spine]. / Minimal-invasive Techniken bei traumatischen Halswirbelsäulenverletzungen.

Nowadays, although minimally invasive procedures are the standard for the treatment of thoracolumbar spinal injuries, these techniques are not yet established for the cervical spine. This is due to anatomical and technical reasons and also due to the fact that the classical anterior decompression and fusion procedure already fulfils the criteria of minimally invasiveness and is suitable for the vast majority of injuries. The existing literature consists mainly of case reports and small comparative cohort studies, the results of which are presented. There is a minimally invasive variant for nearly all open procedures, mainly in the upper cervical spine but also in the lower cervical spine. The further development of these promising techniques is still pending.

On-scene treatment of spinal injuries in motor sports.

Because spinal cord injuries can have fatal consequences for injured race car drivers, prehospital treatment of spinal injuries is a major concern in motor sports. A structured procedure for assessing trauma patients and their treatment should follow established ABCDE principles. Only then, a stable patient could be further examined and appropriate measures can be undertaken. For patients in an acute life-threatening condition, rapid transport must be initiated and should not be delayed by measures that are not indicated. If a competitor must first be extricated from the racing vehicle, the correct method of extrication must be chosen. To avoid secondary injury to the spine after a racing accident, in-line extrication from the vehicle and immobilization of the patient are standard procedures in motor sports and have been used for decades. Since immobilization can be associated with disadvantages and complications, the need for immobilization of trauma patients outside of motor sports medicine has become the subject of an increasing number of reports in the scientific literature. Even in motor sports, where specific safety systems that offer spinal protection are present, the indications for spinal immobilization need to be carefully considered rather than being blindly adopted as a matter of course. The aim of this article is to use recent literature to present an overview about the treatment of spinal injuries in motor sports. Further, we present a new protocol for indications for immobilizing the spine in motor sports that is based on the ABCDE principles and takes into account the condition of the patient.

Review of remediation practices regarding cadmium-enriched farmland soil with particular reference to China.

Cadmium-enrichment of farmland soil greatly threatens the sustainable use of soil resources and the safe cultivation of grain. This review paper briefly introduces the status of farmland soil as well as grain, which are both often polluted by cadmium (Cd) in China, and illustrates the major sources of Cd contaminants in farmland soil. In order to meet soil environmental quality standards and farmland environmental quality evaluation standards for edible agricultural products, Cd-enriched farmland soil is frequently remediated with the following prevailing techniques: dig and fill, electro-kinetic remediation, chemical elution, stabilisation and solidification, phytoremediation, field management and combined remediation. Most remediation techniques are still at the stage of small-scale trial experiments in China and few techniques are assessed in field trials. After comparing the technical and economical applicability among different Cd-enriched farmland soil remediation techniques, a novel ecological and hydraulic remediation technique has been proposed, which integrated the advantages of chemical elution, solidification and stabilisation, phytoremediation and field management. The ecological and hydraulic remediation concept is based on existing irrigation and drainage facilities, ecological ditches (ponds) and agronomic measures, which mainly detoxify the Cd-enriched soil during the interim period of crop cultivation, and guarantee the grain safety during its growth period. This technique may shift the challenge from soil to water treatment, and thus greatly enhances the remediation efficiency and shortens the remediation duration. Moreover, the proposed ecological and hydraulic remediation method matches well with the practical choice of cultivation while remediation for Cd-enriched soil in China, which has negligible impacts on the normal crop cultivation process, and thus shows great potential for large area applications.

CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial).

BACKGROUND: To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. PATIENTS AND METHODS: CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. RESULTS: Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. CONCLUSION: In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. CLINICAL TRIALS NUMBER: NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.

[Evaluation of a Micro-Manipulator for Middle Ear Surgery: A Preclinical Trial]. / Evaluation eines Mikromanipulators für die Mittelohrchirurgie: Eine präklinische Studie.

BACKGROUND: Microsurgical preparation is limited by geometric and mechanical constraints. In preparation for clinical use, this study investigates performance, ease of handling and precision of a novel manipulator concept for microsurgery. MATERIAL AND METHODS: A group of 15 ENT experienced doctors, as well as a group of 17 medical students with low/non surgical experience participated in the study. Each of the subjects carried out 4 trials of simulated surgeries on a phantom with built-in force sensors. The task was to apply a defined force between 1.5 and 2 N using a Fisch micro perforator, 16 cm length, 0.4 mm (Storz) targeting holes with a diameter of 0.5 mm. For comparison, the Fisch micro perforator was moved manually or with the manipulator. RESULTS: Assessing the total number of errors proved a significantly lower error number (p<0.0001) and an improvement of the accuracy of 76% with the manipulator. The time requirement for the procedure with the micro manipulator is on average 2-3 times higher than with manual control (p<0.0001). But it is notable that this time requirement significantly decreases with training (p<0.0001). CONCLUSION: The study shows a significant reduction in the number of errors by using a new manipulator concept compared to the non-augmented human hand in an experimental setup. We observed a significant learning effect when subjects applied the micro manipulator, resulting in reduction of the time requirement while maintaining a constant number of errors.

Integration of a model-independent interface for RBE predictions in a treatment planning system for active particle beam scanning.

Especially for heavier ions such as carbon ions, treatment planning systems (TPSs) for ion radiotherapy depend on models predicting the relative biological effectiveness (RBE) of the particles involved. Such models are subject to intensive research and the choice of the optimal RBE model is a matter of debate. On the other hand TPSs are often strongly coupled to particular RBE models and transition even to extended models of the same family can be difficult. We present here a model-independent interface which allows the unbiased use of any RBE model capable of providing dose-effect curves (even sampled curves) for a TPS. The full decoupling between the RBE model and TPS is based on the beam-mixing model proposed by Lam which is, in contrast to the often-used Zaider-Rossi model, independent of the explicit form of the underlying dose-effect curves. This approach not only supports the refinement of RBE models without adaptations of the TPS--which we demonstrate by means of the local effect model (LEM)--but also allows the comparison of very different model approaches on a common basis. We exemplify this by a comparison between the LEM and a model from the literature for proton RBE prediction.

A simplified scheme for generating narrow-band mid-ultraviolet laser radiation.

We report on the development and characterization of continuous, narrow-band, and tunable laser systems that use direct second-harmonic generation from blue and green diode lasers with an output power level of up to 11.1 mW in the mid-ultraviolet. One of our laser systems was tuned to the mercury 6(1)S0 → 6(3)P1 intercombination line at 253.7 nm. We could perform Doppler-free saturation spectroscopy on this line and were able to lock our laser to the transition frequency on long time scales.

Sensitivity of the Giant LOop Binary LEsion (GLOBLE) cell survival model on parameters characterising dose rate effects.

The sensitivity of the Giant LOop Binary LEsion model for cell survival probabilities after arbitrary photon irradiation schedules on its parameters is presented. Since these parameters are closely linked to observable features of cell repair, the modelled influence of the parameters on cell survival gives indications about the relation between cell line-specific repair characteristics and the radiation response. To visualise the general findings about the impact of parameter changes on cell survival probabilities, survival curves for an exemplary cell line are shown. Furthermore, the relative change in the effect of radiation after a change in parameter values is investigated over the range of doses and dose rates usually applied in cell survival experiments.

Simulation of DSB yield for high LET radiation.

A simulation approach for the calculation of the LET-dependent yield of double-strand breaks (DSB) is presented. The model considers DSB formed as two close-lying single-strand breaks (SSB), whose formation is mediated by both intra-track processes (single electrons) or at local doses larger than about 1000 Gy in particle tracks also by electron inter-track processes (two independent electron tracks). A Monte Carlo algorithm and an analytical formula for the DSB yield are presented. The approach predicts that the DSB yield is enhanced after charged particle irradiation of high LET compared with X-ray or gamma radiation. It is used as an inherent part of the local effect model, which is applied to estimate the relative biological effectiveness of high LET radiation.

Impact of indication-shift of primary and adjuvant chemo radiation in advanced laryngeal and hypopharyngeal squamous cell carcinoma.

Based on level I evidence, postoperative platinum-based radiochemotherapy (PORCT) is the recommended standard of care in defined risk situations after resection of squamous cell carcinomas of the larynx and hypopharynx (LHSCC). The value of the addition of chemotherapy to adjuvant radiation in intermediate and high risk situations other than extracapsular spread or R1-/R2 resection is still debated. From 1993 to 2009, 555 patients (median follow-up: 24.4 months) with advanced LHSCC (UICC stages III-IVB) were treated in a curative intent. Patient data were continuously documented in the county of Leipzig cancer registry and were retrospectively analyzed as mono institutional survey. PORCT was introduced into the standard procedures in 2004, but also applied before in selected cases. Based on this paradigm shift, the patient population was divided into two comparative groups treated before and after 2004. 361 patients were treated before 2004. 43.8 % received primary surgery (OP) + postoperative radiotherapy (PORT) and 20.2 % OP + PORCT. 194 patients were treated after 2004: 21.1 % received OP + PORT and 35.6 % OP + PORCT. Regarding the PORCT groups, 20.6 % received cisplatin plus 5FU before 2004 which shifted to 59.4 % after 2004. The 3-year tumor-specific-survival rate of the whole cohort was improved from 47 to 60 % (p = 0.006). The subgroup treated with OP + PORT or PORCT improved from 56.1 to 68.5 % (p = 0.028). Localization proved to be a significant and independent factor. Only patients with advanced laryngeal cancer had significant improved survival (p < 0.01), while the improvement for hypopharyngeal cancer patients was not significant (p < 0.2). After 2004, there was a slight increase (+10.2 %) of primary radiochemotherapy (pRCT) due to stronger selection if R0 > 5 mm-resectability is unlikely. Standardised use of PORCT and pRCT considering clear indications showed to be significantly involved in improved survival in advanced LHSCC.

Fibrinogen is not a prognostic factor for response to HELP-apheresis in sudden sensorineural hearing loss (SSHL).

Higher levels of fibrinogen or cholesterol were associated with improved hearing recovery in SSHL patients after treatment with HELP-apheresis (Heparin-induced extracorporeal LDL precipitation apheresis). The present trial was performed to demonstrate HELP-related effects on relevant metabolic and inflammatory parameters in the context of SSHL treatment. In the framework of a single arm non-controlled trial, we investigated the variation of metabolic and inflammatory parameters using HELP-apheresis for a defined group of 100 patients with SSHL. Based on cut off inclusion criteria (Serum LDL-cholesterol >1.6 g/l and/or fibrinogen >2.0 g/l, SSHL in minimum three frequencies more than 30 dB, time after event not longer than 6 days), the protocol followed a strict time line with one single shot HELP-apheresis and follow-up monitoring including laboratory parameters at six defined time points. If HELP-apheresis could not effect improvement of hearing on day 5, additional corticosteroid treatment was applied. Concentration of anti-inflammatory IL-10 increased while other proinflammatory parameters declined. Serum levels of all measured sterols and apolipoproteins decreased significantly. None of the investigated parameters were suitable to predict hearing improvement of the patients. Levels of fibrinogen and LDL-cholesterol were not prognostic for outcome after HELP-apheresis. A significant (p < 0.001) increase of anti-inflammatory IL-10 after apheresis was notable, while most of the proinflammatory parameters declined. Despite the limited validity of a single arm non-controlled trial, these alterations on immune modulating factors indicate possible secondary pleiotropic effects caused by HELP-apheresis.

Whole-genome assemblies of 56 burkholderia species.

Burkholderia is a genus of betaproteobacteria that includes three notable human pathogens: B. cepacia, B. pseudomallei, and B. mallei. While B. pseudomallei and B. mallei are considered potential biowarfare agents, B. cepacia infections are largely limited to cystic fibrosis patients. Here, we present 56 Burkholderia genomes from 8 distinct species.

Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression.

BACKGROUND: Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LNs) only. PATIENTS AND METHODS: A total of 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel 100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors. RESULTS: Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥ 20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18-0.82) for EC-Doc versus FEC (test for interaction; P = 0.01). CONCLUSION: EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1-3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy. CLINICAL TRIAL NUMBER: ClinicalTrials.gov, NCT02115204.

Efficacy of a new video-based training model in spinal surgery.

BACKGROUND: An important part of neurosurgical training is the improvement of surgical skills. Acquiring microsurgical skills follows a learning curve, influenced by specific exercises, feedback, and training. Aim of training should be rapid learning success. The study shows the way in which video-based training can influence the learning curve. METHODS: Over a period of 18 months (2011-2012) 12 residents were evaluated in spinal surgery (12 cases per resident) by a skilled evaluator based on different criteria. The evaluation criteria (exposition of important anatomy, intraoperative bleeding, efficacy of using bipolar cauterization) were weighted and added to a single quality-score. The participating residents were divided into two groups. Only one group (n = 5) received video-based training. RESULTS: Residents showed an individually different but explicit increase in microsurgical skills. The quality-score during the first surgery compared with the end point of the study demonstrated a faster improvement of surgical skills in the group with video-based training than in the group without special training. Considering all residents together, the video-training group displayed a steeper gradient of microsurgical success. Comparison of the single resident's microsurgical skills showed individual disparities. Various biases that influence the learning success are under examination. CONCLUSION: Video-based training can improve microsurgical skills, leading to an improved learning curve. An earlier entry of the learning curve plateau in the video-training group promotes a higher acquisition of surgical skills. Because of the positive effect, we plan to apply the video-based training model to other neurosurgical subspecialties, especially neurovascular and skull base surgery.

Sensitivity analysis of the relative biological effectiveness predicted by the local effect model.

The relative biological effectiveness (RBE) is a central quantity in particle radiobiology and depends on many physical and biological factors. The local effect model (LEM) allows one to predict the RBE for radiobiologic experiments and particle therapy. In this work the sensitivity of the RBE on its determining factors is elucidated based on monitoring the RBE dependence on the input parameters of the LEM. The relevance and meaning of all parameters are discussed within the formalism of the LEM. While most of the parameters are fixed by experimental constraints, one parameter, the threshold dose Dt, may remain free and is then regarded as a fit parameter to the high LET dose response curve. The influence of each parameter on the RBE is understood in terms of theoretic considerations. The sensitivity analysis has been systematically carried out for fictitious in vitro cell lines or tissues with α/ß = 2 Gy and 10 Gy, either irradiated under track segment conditions with a monoenergetic beam or within a spread out Bragg peak. For both irradiation conditions, a change of each of the parameters typically causes an approximately equal or smaller relative change of the predicted RBE values. These results may be used for the assessment of treatment plans and for general uncertainty estimations of the RBE.

Comparison and modelling of pegylated or unpegylated G-CSF schedules in CHOP-14 regimen of elderly patients with aggressive B-cell lymphoma.

Bi-weekly (R)-CHOP therapy is one of the standard treatmentS for elderly patients with aggressive B-cell lymphoma, but it is only feasible with supportive G-CSF treatment. In the trials of the DSHNHL, either unpegylated G-CSF was given daily over 7 or 10 days or pegylated G-CSF was applied at day 4 of each cycle. These schedules were planned on the basis of simulations of a biomathematical pharmacokinetic/pharmacodynamic model. By analysing the observed data, we investigated whether our model predictions were correct and whether even better schedules can be proposed. We used data on 249 matched patients of two prospective trials, RICOVER-60 and PEGFILGRASTIM. The three G-CSF-schedules showed similar outcomes regarding leukocytopenia, infections and days in hospital, with pegylated G-CSF having slightly but not significantly better scores in all three endpoints. Regarding pegylated G-CSF, the best timing is predicted to be any day between days 4 and 7. With respect to unpegylated G-CSF, the starting day is less important, but it should be continued until the end of each cycle.The three G-CSF-schedules are interchangeable in (R)-CHOP-14 for elderly patients with aggressive B-cell lymphoma. Our model correctly predicts time courses of leukocytes. Further model predictions are presented, which can be tested in subsequent clinical trials.

Puerperal development of ewes following dystocia: a retrospective analysis of two approaches to caesarean section.

The objective of this study was to retrospectively analyse the puerperal development of ewes referred to a veterinary teaching hospital following caesarean section in comparison with assisted parturition. Laparotomy was performed either via left flank incision (group 1, n=86) or ventral mid-line approach (group 2, n=33). Both groups were compared with ewes following non-surgical intervention (group 3, n=73). The overall fetal death rate was 41 per cent. There was no significant difference in fetal deaths between groups 1 and 2, but assisted delivery led to a higher number of liveborn lambs compared with caesarean section (P<0.05). Seven ewes (3.6 per cent) died or were euthanased on welfare grounds during caesarean surgery, and the overall maternal mortality rate following dystocia in the postpartum period was 10.9 per cent. While there was no significant difference between groups 1 and 2 in the percentage of ewes developing healing disorders, the complications that occurred were more severe after the left flank approach (P=0.04), and the mean hospitalisation period was significantly longer in group 1 than in group 2 (P<0.05), leading to the conclusion that ventral mid-line laparotomy has some advantages over a left flank approach.

The vacuum phenomenon in intervertebral disc disease of dogs based on computed tomography images.

OBJECTIVES: Vacuum phenomenon is suspected to be indicative of disc degeneration and subsequent herniation. The objective of this study was to assess the reliability of vacuum phenomenon for identification of herniated discs causing neurological signs. Prevalence of vacuum phenomenon and influencing factors in dogs with disc herniation were determined. METHODS: Retrospective review of computed tomography scans from dogs with suspected disc herniation for the presence of gas within intervertebral disc space with subsequent comparison of vacuum phenomenon and herniated disc as confirmed by surgery. Subgroups were created (chondrodystrophic, non-chondrodystrophic and unknown classification) to analyse prevalence and influencing factors (age, breed and gender) for vacuum phenomenon and agreement with herniated disc. RESULTS: Prevalence of vacuum phenomenon in all dogs, chondrodystrophic, non-chondrodystrophic dogs and those with unknown classification was 19·8, 14·9, 35·7 and 24·5%, respectively. Corresponding correlation rate between vacuum phenomenon and herniated disc was 64, 67, 40 and 82%. Prevalence of vacuum phenomenon was significantly higher in nonchondrodystrophic dogs (P=0·04). Age was the only factor influencing prevalence of vacuum phenomenon (P=0·04). CLINICAL SIGNIFICANCE: In dogs with intervertebral disc disease, vacuum phenomenon is a frequent but inconsistent finding. Although helpful to identify degenerated discs, it is not suitable to identify currently herniated disc with sufficient accuracy.