Advances in the implementation of helical tomotherapy–based total marrow irradiation with a novel field junction technique

Given the limitations in the travel ability of the helical tomotherapy (HT) couch, total marrow irradiation (TMI) has to be split in 2 segments, with the lower limbs treated with feet first orientation. The aim of this work is to present a planning technique useful to reduce the dose inhomogeneity resulting from the matching of the 2 helical dose distributions. Three HT plans were generated for each of the 18 patients enrolled. Upper TMI (UTMI) and lower TMI (LTMI) were planned onto the whole-body computed tomography (CT) and on the lower-limb CT, respectively. A twin lower TMI plan (tLTMI) was designed on the whole-body CT. Agreement between LTMI and tLTMI plans was assessed by computing for each dose-volume histogram (DVH) structure the γ index scored with 1% of dose and volume difference thresholds. UTMI and tLTMI plans were summed together on the whole-body CT, enabling the evaluation of dose inhomogeneity. Moreover, a couple of transition volumes were used to improve the dose uniformity in the abutment region. For every DVH, a number of points >99% passed the γ analysis, validating the method used to generate the twin plan. The planned dose inhomogeneity at the junction level resulted within ±10% of the prescribed dose. Median dose reduction to organs at risk ranged from 30–80% of the prescribed dose. Mean conformity index was 1.41 (range 1.36–1.44) for the whole-body target. The technique provided a “full helical” dose distribution for TMI treatments, which can be considered effective only if the dose agreement between LTMI and tLTMI plans is met. The planning of TMI with HT for the whole body with adequate dose homogeneity and conformity was shown to be feasible.     

Post‐irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review

Purpose: Events of the recent past have focused attention on the possibility of radiological (nuclear) terrorism and on the implications of such terrorist threats for radiation accident preparedness. This review discusses recent advances in the knowledge about how radiation injuries from such events might be treated pharmacologically, and the practical barriers to clinical utilization of these approaches.

Conclusions: A wide range of pharmacological approaches are being developed in the laboratory that could greatly expand the ability to treat acute and chronic radiation injuries. However, there are currently a variety of practical and legal barriers that would prevent the actual clinical use of most of the approaches. There are also the potential weaknesses in most of the current programmes for dealing with the consequences of radiation accidents or nuclear terrorism, including the absence of widespread radiation biodosimetry capabilities and the resulting inability to triage. If a major radiation accident or terrorist event occurs, the lack of biodosimetry and treatment capabilities will be compounded by widespread public fear of ‘radiation’.     

Can a comparison of clinical and deep space irradiation scenarios shed light on the radiation response of the brain?

Not surprisingly, our knowledge of the impact of radiation on the brain has evolved considerably. Decades of work have struggled with identifying the critical cellular targets in the brain, the latency of functional change and understanding how irradiation alters the balance between excitatory and inhibitory circuits. Radiation-induced cell kill following clinical fractionation paradigms pointed to both stromal and parenchymal targets but also defined an exquisite sensitivity of neurogenic populations of newly born cells in the brain. It became more and more apparent too, that acute (days) events transpiring after exposure were poorly prognostic of the late (months-years) waves of radiation injury believed to underlie neurocognitive deficits. Much of these gaps in knowledge persisted as NASA became interested in how exposure to much different radiation types, doses and dose rates that characterize the space radiation environment might impair central nervous system functionality, with possibly negative implications for deep space travel. Now emerging evidence from researchers engaged in clinical, translational and environmental radiation sciences have begun to fill these gaps and have uncovered some surprising similarities in the response of the brain to seemingly disparate exposure scenarios. This article highlights many of the commonalities between the vastly different irradiation paradigms that distinguish clinical treatments from occupational exposures in deep space.     

Effect of 211At α-particle irradiation on expression of selected radiation responsive genes in human lymphocytes

Purpose: Analysis of the relative expression of radiation responsive genes (previously shown to respond to γ-radiations) after exposure of human lymphocytes to ²¹¹At α-particles and the suitability of these genes as potential markers for α-biodosimetry.

Materials and methods: Lymphocytes isolated from the peripheral blood of two healthy human donors were exposed in triplicate for 30 min to different concentrations of Na²¹¹At at 37°C (absorbed doses: 0.05–1.6 Gy). Following an incubation period (2 h), the total RNA was isolated from the irradiated lymphocytes and the relative expression of the following 18 genes was tested for change using TaqMan? probes based upon the real-time quantitative polymerase chain reaction.

Method: BBC3 (B-cell lymphoma 2 binding component 3), CD69 (cluster of differentiation 69), CDKN1A (cyclin-dependent kinase inhibitor 1A), DUSP8 (dual specificity phosphatase 8) EGR1 (early growth response 1), EGR4 (early growth response 4), GADD45A (growth arrest and DNA-damage-inducible, alpha), GRAP (growth factor receptor-bound protein 2-related adaptor protein), LAP1B (TOR1AIP1; torsin A interacting protein 1), IFNG (interferon gamma), ISG20L1 (interferon-stimulated exonuclease gene 20kDa – like 1), c-JUN (jun oncogene), MDM2 (mouse double minute 2), PCNA (proliferating cell nuclear antigen), PLK2 (polo-like kinase 2), RND1 (rho family GTPase 1), TNFSF9 (tumour necrosis factor superfamily member 9) and TRAF4 (tumour necrosis factor receptor-associated factor 4).

Results: The expressions of the 18 genes, except GRAP, were up-regulated following exposure to α-radiation. A comparison of the results of two individuals tested here showed great variability. Dependence of gene expression upon α-dose was observed in certain dose intervals for BBC3 (R² = 0.61 [individual 1] / 0.81 [individual 2], significance 0.2–1.6 Gy [1] / 0.05–0.1 Gy [2]) and MDM2 (R² = 0.78/0.54; 0.8–1.6 Gy [1], 0.05–0.1 Gy [2]) genes in both individuals. Additionally, for individual 1 the dose dependence was found for the following genes: ISG20L1 (R² = 0.69, 0.05–0.1 Gy), PCNA (R² = 0.59, 0.8–1.6 Gy) and IFNG (R² = 0.74 up to 0.4 Gy, 0.05–0.1 Gy).

Conclusion: Candidate genes for a possible role in future early-phase (2 h) α-biodosimetry are BBC3, ISG20L1, MDM2, PCNA and IFNG.     

Treatment of malnutrition decreases complication rates and shortens the length of hospital stays in a radiation oncology department

Purpose

The nutritional status of inpatients influences the therapeutic outcome. Malnutrition is a common comorbidity in oncological patients. Both radio- and radiochemotherapy may contribute to the additional deterioration of the nutritional status. The aim of this study was to evaluate the impact of specialized treatment of malnutrition as a clinical routine.

Methods

The nutritional status of inpatients was assessed by the Nutritional risk screening (NRS-2002) on the day of admission to the University Department of Radiation Oncology. In case of significantly elevated NRS-2002 (NRS?≥?3), a guideline-compliant, individual nutritional treatment was initiated by a specialized nutrition support team. The influence of the nutritional status and nutritional treatment on length of stay and complication rate was assessed.

Results

Of 840 included patients, 344 patients (40.95%) were at risk for malnutrition. Malnutrition was a significant, independent risk factor for both prolonged hospital stay, represented by the deviation between the actual length of stay and the DRG-associated mean length of stay (dLOS at risk: 0.88 days, dLOS not at risk: ?0.88 days, p?=?0.0047), as well as for the occurrence of complications (OR: 1.758 CI: [1.286–2.402], p?=?0.0006). In the group of 337 (40.12%) rehospitalized patients the nutritional management was able to assimilate the values of length of stay as well as the complication rates to standard values.

Conclusions

The high risk for malnutrition and the negative consequences for patients and hospitals underline the urgent need for malnutrition screening on admission and treatment of malnutrition. A specialized, interdisciplinary nutrition support team positively influences patient outcome and should be established routinely in all oncological disciplines.

     

Cellular response of the rat brain to single doses of 137Cs γ rays does not predict its response to prolonged ‘biologically equivalent’ fractionated doses

Abstract

Purpose: To determine if the brain's response to single doses predicts its response to ‘biologically equivalent’ fractionated doses.

Methods: Young adult male Fischer 344 rats were whole-brain irradiated with either single 11, 14, or 16.5 Gy doses of ¹³⁷Cs γ rays or their ‘biologically equivalent’ 20, 30, or 40 Gy fractionated doses (fWBI) delivered in 5 Gy fractions, twice/week for 2, 3, or 4 weeks, respectively. At 2 months post-irradiation, cellular markers of inflammation (total, activated, and newborn microglia) and neurogenesis (newborn neurons) were measured in 40 μm sections of the dentate gyrus (DG).

Results: Although the total number of microglia in the DG/hilus was not significantly different (p > 0.7) in unirradiated, single dose, and fWBI rats, single doses produced a significant (p < 0.003) increase in the percent-activated microglia; fWBI did not (p > 0.1). Additionally, single doses produced a significant (p < 0.002) dose-dependent increase in surviving newborn microglia; fWBI did not (p < 0.8). Although total proliferation in the DG was reduced equally by single and fWBI doses, single doses produced a significant dose-dependent (p < 0.02) decrease in surviving newborn neurons; fWBI did not (p > 0.6).

Conclusions: These data demonstrate that the rat brain's cellular response to single doses often does not predict its cellular response to ‘biologically equivalent’ fWBI doses.     

Protective effects of systemic dermatan sulfate treatment in a preclinical model of radiation-induced oral mucositis

Purpose

Oral mucositis is a frequent, dose-limiting side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is based on multiple tissue changes, which could offer targets for a biologically tailored treatment. The potential of dermatan sulfate (DS) to modulate radiation-induced oral mucositis was tested in an established preclinical mucositis model.

Methods

Irradiation was either applied alone or in combination with daily DS treatment (4?mg/kg, subcutaneously) over varying time intervals. Irradiation comprised single dose irradiation with graded doses to the lower tongue surface or daily fractionated irradiation of the whole tongue. Fractionation protocols (5?×?3?Gy/week) over one (days 0–4) or two weeks (days 0–4, 7–11) were terminated by an additional local single dose irradiation to a defined treatment field on the lower tongue surface to induce the mucosal radiation response. The additional single dose irradiation (top-up) on day 7 (after one week of fractionation) or day 14 (after 2 weeks of fractionation) comprised graded doses in order to generate full dose–effect curves. Ulceration of the epithelium of the lower tongue, corresponding to confluent mucositis, was analysed as clinically relevant endpoint. Additionally, the time course parameters, latent time and ulcer duration were analysed.

Results

DS treatment significantly reduced the incidence of ulcerations. DS application over longer time intervals resulted in a more pronounced reduction of ulcer frequency, increased latent times and reduced ulcer duration.

Conclusion

DS has a significant mucositis-ameliorating activity with pronounced effects on mucositis frequency as well as on time course parameters.

     

qPET – a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma

Background

Interim FDG-PET is used for treatment tailoring in lymphoma. Deauville response criteria consist of five ordinal categories based on visual comparison of residual tumor uptake to physiological reference uptakes. However, PET-response is a continuum and visual assessments can be distorted by optical illusions.

Objectives

With a novel semi-automatic quantification tool we eliminate optical illusions and extend the Deauville score to a continuous scale.

Patients and methods

SUV_peak of residual tumors and average uptake of the liver is measured with standardized volumes of interest. The qPET value is the quotient of these measurements. Deauville scores and qPET-values were determined in 898 pediatric Hodgkin’s lymphoma patients after two OEPA chemotherapy cycles.

Results

Deauville categories translate to thresholds on the qPET scale: Categories 3, 4, 5 correspond to qPET values of 0.95, 1.3 and 2.0, respectively. The distribution of qPET values is unimodal with a peak representing metabolically normal responses and a tail of clearly abnormal outliers. In our patients, the peak is at qPET = 0.95 coinciding with the border between Deauville 2 and 3. qPET cut values of 1.3 or 2 (determined by fitting mixture models) select abnormal metabolic responses with high sensitivity, respectively, specificity.

Conclusions

qPET methodology provides semi-automatic quantification for interim FDG-PET response in lymphoma extending ordinal Deauville scoring to a continuous scale. Deauville categories correspond to certain qPET cut values. Thresholds between normal and abnormal response can be derived from the qPET-distribution without need for follow-up data. In our patients, qPET < 1.3 excludes abnormal response with high sensitivity.     

Tolerance to proton irradiation in the eutardigrade Richtersius coronifer – a nuclear microprobe study

Purpose:?The tardigrade Richtersius coronifer has previously been shown to tolerate very high doses of low linear energy transfer (low-LET) radiation (gamma rays). The purpose of this study was to extend our knowledge on radiation tolerance in this species by investigating the dose-response to high-LET radiation in terms of protons.

Materials and methods:?Dehydrated tardigrades of the species R. coronifer were irradiated with 2.55 MeV (megaelectronvolts) protons at doses ranging from 500 gray (Gy) to 15,000 Gy, to investigate the dose-viability relationship. In addition, a focused proton microbeam was utilised to determine the areal mass distribution, using the ion beam analytical technique STIM (Scanning Transmission Ion Microscopy).

Results:?The experiment suggests that R. coronifer is unaffected by doses of proton irradiation up to 10,000 Gy, but shows very little viability at higher doses. The STIM analysis revealed that the thickness of the dehydrated tardigrades exceeds 150 μm, and that a fraction of the protons may not be fully absorbed.

Conclusion:?Our results are in line with previous studies of exposure to high-LET radiation in tardigrades, indicating that these animals are equally or even more tolerant to high-LET compared to low-LET gamma radiation. The physiological background to this remarkable result is currently unknown, but deserves investigation.     

Investigating the prediction value of multiparametric magnetic resonance imaging at 3 T in response to neoadjuvant chemotherapy in breast cancer

Objective

To explore the predictive value of parameters derived from diffusion-weighted imaging (DWI) and contrast-enhanced (CE)-MRI at different time-points during neoadjuvant chemotherapy (NACT) in breast cancer.

Methods

Institutional review board approval and written, informed consent from 42 breast cancer patients were obtained. The patients were investigated before and at three different time-points during neoadjuvant chemotherapy (NACT) using tumour diameter and volume from CE-MRI and ADC values obtained from drawn 2D and segmented 3D regions of interest. Prediction of pathologic complete response (pCR) was evaluated using the area under the curve (AUC) of receiver operating characteristic analysis.

Results

There was no significant difference between pathologic complete response and non-pCR in baseline size measures (p?>?0.39). Diameter change was significantly different in pCR (p?<?0.02) before the mid-therapy point. The best predictor was lesion diameter change observed before mid-therapy (AUC?=?0.93). Segmented volume was not able to differentiate between pCR and non-pCR at any time-point. The ADC values from 3D-ROI were not significantly different from 2D data (p?=?0.06). The best AUC (0.79) for pCR prediction using DWI was median ADC measured before mid-therapy of NACT.

Conclusions

The results of this study should be considered in NACT monitoring planning, especially in MRI protocol designing and time point selection.

Key Points

? Mid-therapy diameter changes are the best predictors of pCR in neoadjuvant chemotherapy. ? Volumetric measures are not strictly superior in therapy monitoring to lesion diameter. ? Size measures perform as a better predictor than ADC values.

     

Survival of human lung epithelial cells following in vitro α-particle irradiation with absolute determination of the number of alpha-particle traversals of individual cells

Purpose : To throw light on human exposure to domestic radon and radon progeny, the effects of low doses of alpha-particle irradiation on normal human lung epithelial cells has been studied. At such low exposure levels the concept of dose is inadequate due to the stochastic variation in the number of α -particle traversals per cell. The objective of the current study was to establish an accurate survival curve for human lung epithelial cells with absolute determination of the exact number of α -particle traversals of individual cells. Materials and methods : Irradiation of L132 cells growing in tracketch detector-based cell dishes, was performed using a collimated alpha-particle beam from a 210 Po source. The number of α -particle traversals through each individual cell was scored by using a technique of retrospective track-etch dosimetry. This technique is based upon image matching and mapping of corresponding cell and α -particle track images. The spatial resolution of the hit determination procedure was ±0.9 μ m. Results : Surviving fractions of cells (SF) showed strict dependence on the number of nuclear traversals (n) , with SF (n) = a exp (-bn) , a =0.957 (±0.046), b =0.587 (±0.059), R 2 = 98.8%. No significant dependence on the number of nuclear membrane traversals (m) or the number of cytoplasm traversals (c) was observed.     

Changes in the expression of somatostatin receptor imaging following Y-90 lanreotide therapy for carcinoid tumor: a flare response?

A 53-year-old man with In-111 octreotide-positive metastatic hepatic carcinoid was referred for Y-90 lanreotide therapy. A diagnostic In-111 lanreotide scan, performed to assess suitability for therapy, showed less uptake in lesions compared with In-111 octreotide. After 3 therapy doses of Y-90 lanreotide, a repeat In-111 lanreotide scan showed intense uptake in old lesions, appearance of new lesions, and uptake in the spleen. This was associated with improvement in flushing and regression of liver size. Computed tomography scan showed stable disease. Increased expression of somatostatin receptors has been observed with In-111 octreotide but not with In-111 lanreotide. If this is a flare response, then pretreatment with "cold" lanreotide may be beneficial before Y-90 lanreotide therapy.