Individualised dosimetry and safety of SIRT for intrahepatic cholangiocarcinoma.

BACKGROUND: The aim of this study was to investigate the safety and efficacy of selective internal radiation therapy (SIRT) with 90Y resin microspheres for the treatment of Intrahepatic Cholangiocarcinoma (ICC). A total of 23 SIRT procedures from 18 ICC subjects were analysed to determine a lesion-based dose/response relationship with absorbed dose measures from 90Y PET and metabolic response as measured on [18F]FDG PET. Average absorbed dose (Davg), minimum dose to 70% of the volume (D70), volume receiving at least 50 Gy (V50), biological effective dose (BED) and equivalent uniform dose (EUD), were compared to changes in metabolic volume, maximum standardised uptake value (SUVmax) and total lesion glycolysis (TLG). Dose to normal liver was assessed with changes in liver uptake rate as measured with [99mTc]mebrofenin scintigraphy for a cohort of 20 subjects with primary liver malignancy (12 ICC, 8 hepatocellular carcinoma (HCC)). RESULTS: Thirty-four lesions were included in the analysis. A relationship was found between metabolic response and both Davg and EUD similar to that seen previously in metastatic colorectal cancer (mCRC), albeit trending towards a lower response plateau. Both dose and SUV coefficient of variation within the lesion (CoVdose and CoVSUV), baseline TLG and EUD were found to be mildly significant predictors of response. No strong correlation was seen between normal liver dose and change in [99mTc]mebrofenin liver uptake rate; low baseline uptake rate was not indicative of declining function following SIRT, and no subjects dropped into the 'poor liver function' category. CONCLUSIONS: ICC lesions follow a similar dose-response trend as mCRC, however, despite high lesion doses a full metabolic response was rarely seen. The CoV of lesion dose may have a significant bearing on response, and EUD correlated more tightly with metabolic response compared to Davg. SIRT in primary liver malignancy appears safe in terms of not inducing a clinically significant decline in liver function, and poor baseline uptake rate is not predictive of a reduction in function post SIRT.

Overlooked potential of positrons in cancer therapy.

Positron (ß+) emitting radionuclides have been used for positron emission tomography (PET) imaging in diagnostic medicine since its development in the 1950s. Development of a fluorinated glucose analog, fluorodeoxyglucose, labelled with a ß+ emitter fluorine-18 (18F-FDG), made it possible to image cellular targets with high glycolytic metabolism. These targets include cancer cells based on increased aerobic metabolism due to the Warburg effect, and thus, 18F-FDG is a staple in nuclear medicine clinics globally. However, due to its attention in the diagnostic setting, the therapeutic potential of ß+ emitters have been overlooked in cancer medicine. Here we show the first in vitro evidence of ß+ emitter cytotoxicity on prostate cancer cell line LNCaP C4-2B when treated with 20 Gy of 18F. Monte Carlo simulation revealed thermalized positrons (sub-keV) traversing DNA can be lethal due to highly localized energy deposition during the thermalization and annihilation processes. The computed single and double strand breakages were ~ 55% and 117% respectively, when compared to electrons at 400 eV. Our in vitro and in silico data imply an unexplored therapeutic potential for ß+ emitters. These results may also have implications for emerging cancer theranostic strategies, where ß+ emitting radionuclides could be utilized as a therapeutic as well as a diagnostic agent once the challenges in radiation safety and protection after patient administration of a radioactive compound are overcome.

Performance evaluation of quantitative SPECT/CT using NEMA NU 2 PET methodology.

Although PET is routinely evaluated using NEMA NU2 as standard in the clinic, standard methodology for evaluating the performance of quantitative SPECT systems has not been established. In this study, the quantitative performance of the Symbia Intevo SPECT/CT was evaluated for two common isotopes (99mTc, 177Lu) and benchmarked against the performance of a PET/CT. A further aim was to demonstrate the utility of adapting NEMA NU2 PET measurements to SPECT. In addition, dead-time and resolution recovery were evaluated to provide more complete system evaluations. Spatial resolution of the SPECT system at 1 cm from the center in the transverse direction was 13.1 mm and 22.4 mm for 99mTc and 177Lu respectively, compared with 4.3 mm (18F) and 5.8 mm (68Ga) for PET. Sensitivity at the center of the FoV was 119 cps MBq-1 and 48 cps MBq-1 (99mTc, 177Lu) for SPECT and 9632 cps MBq-1 and 8216 cps MBq-1 (18F, 68Ga) for PET. Scatter fraction was 0.25 and 0.36 (99mTc, 77Lu) for SPECT and 0.32 and 0.29 (18F, 68Ga) for PET. Contrast recovery coefficient in the largest spheres was 0.79 and 0.65 (99mTc, 177Lu) for SPECT, 1.00 and 0.97 (18F, 68Ga) for PET and the background variability was 2.7%, 6.5% (99mTc, 177Lu), 1.5% and 1.6% (18F, 68Ga), respectively. Partial volume effect was evaluated using the NEMA IQ phantom with six sphere inserts (diameter: 37 mm, 28 mm, 22 mm, 17 mm, 13 mm and 10 mm). Full contrast recovery was reached with the 17 mm for 18F, while SPECT did not reach full recovery for any sphere. Count rate losses were 2% for 99mTc at 1 GBq and 11% for 177Lu at 8.5 GBq which are well below the typical activities for clinical applications. We concluded NEMA NU2 methodology can be easily adapted to SPECT/CT as a routine quality assurance procedure in the clinic.

SPECT V/Q in Lung Cancer Radiotherapy Planning.

Curative-intent lung cancer radiation therapy either alone (RT) or combined with immuno-chemotherapy is associated with potential risk of serious radiation-induced lung injury. This review provides a summary of the role of SPECT ventilation perfusion (V/Q) imaging as an emerging adjunct to lung cancer RT planning and treatment dosimetry. Denoted "functional lung avoidance RT" it is hypothesized that preferential dosimetric avoidance of physiologically functional lung may reduce the frequency of radiation-induced lung injury. SPECT V/Q imaging datasets available during the planning process allows the prioritization (or "personalization') of RT dose to minimize the volume of functional lung probabilistically exposed to injurious radiation dose. Selective escalation of target dose and adaptive planning and replanning is also enabled. The emergent importance of the tumor-lung microenvironment and its biologic relationship to local immune effectors in lung cancer provides further incentive to individualize RT planning and delivery. This review examines important normal tissue dosimetric constraints that are part of current standards-of-care and the new dosimetric parameters associated with functional lung avoidance RT. SPECT V/Q has been a valuable tool in investigating the feasibility and efficacy of functional lung avoidance RT but is yet to become main stream due to the lack of large clinical trials. It is encouraging however that functional lung avoidance is feasible in RT dose-target delineation and some of the more promising studies are discussed.

CT ventilation imaging derived from breath hold CT exhibits good regional accuracy with Galligas PET.

BACKGROUND AND PURPOSE: CT ventilation imaging (CTVI) derived from four dimensional CT (4DCT) has shown only moderate spatial accuracy in humans due to 4DCT image artefacts. Here we assess the accuracy of an improved CTVI using high quality exhale/inhale breath-hold CT (BHCT). MATERIALS AND METHODS: Eighteen lung cancer patients underwent exhale/inhale BHCT, 4DCT and Galligas PET ventilation scans in a single imaging session. For each BHCT and 4DCT scan, we performed deformable image registration (DIR) between the inhale and exhale phase images to quantify ventilation using three published metrics: (i) breathing induced lung density change, CTVIDIR-HU (ii) breathing induced volume change CTVIDIR-Jac and (iii) the regional air-tissue product, CTVIHU Spatial accuracy was reported as the voxel-wise Spearman correlation r between CTVI and Galligas PET. RESULTS: For BHCT-based CTVIs (N = 16), the CTVIDIR-HU, CTVIDIR-Jac and CTVIHU methods yielded mean (range) r values of 0.67 (0.52-0.87), 0.57 (0.18-0.77) and 0.49 (0.14-0.75) respectively. By comparison the 4DCT-based CTVIs (n = 14) had values of 0.32 (-0.04 to 0.51), 0.16 (-0.31 to 44) and 0.49 (0.20-0.77) respectively. CONCLUSIONS: High quality CT imaging is a key requirement for accurate CT ventilation imaging. The use of exhale/inhale BHCT can improve the accuracy of CTVI for human subjects.

(68)Ga PET Ventilation and Perfusion Lung Imaging-Current Status and Future Challenges.

Gallium-68 ((68)Ga) is a positron-emitting radionuclide suitable for positron emission tomography (PET) imaging that has a number of convenient features-it has a physical half life of 68 minutes, it is generator produced at the PET facility and needs no local cyclotron, and being a radiometal is able to be chelated to a number of useful molecules for diagnostic imaging with PET. (68)Ga has recently been investigated as a radiotracer for ventilation and perfusion (V/Q) lung imaging. It is relatively easy to produce both V/Q radiopharmaceuticals labeled with (68)Ga for PET studies, it offers higher spatial resolution than equivalent SPECT studies, the short half life allows for multiple (repeated) scans on the same day, and low amounts of radiotracer can be used thus limiting the radiation dose to the subject. In the usual clinical setting requiring a V/Q scan, that of suspected pulmonary embolism, the role of (68)Ga V/Q PET may be limited from a logistical perspective, however, in nonacute applications such as lung function evaluation, radiotherapy treatment planning, and respiratory physiology investigations it would appear to be an ideal modality to employ.

Measurement of preoperative lobar lung function with computed tomography ventilation imaging: progress towards rapid stratification of lung cancer lobectomy patients with abnormal lung function.

OBJECTIVES: In lung cancer preoperative evaluation, functional lung imaging is commonly used to assess lobar function. Computed tomography ventilation (CT-V) imaging is an emerging lung function imaging modality. We compared CT-V imaging assessment of lobar function and its prediction of postoperative lung function to that achieved by (i) positron emission tomography ventilation (PET-V) imaging and (ii) the standard anatomical segment counting (ASC) method. We hypothesized (i) that CT-V and PET-V have similar relative lobar function and (ii) that functional imaging and anatomic assessment (ASC) yield different predicted postoperative (ppo) lung function and therefore could change clinical management. METHODS: In this proof-of-concept study, 11 patients were subjected to pulmonary function tests, CT-V and PET-V imaging. The Bland-Altman plot, Pearson's correlation and linear regression analysis were used to assess the agreement between the CT-V-, PET-V- and ASC-based quantification of lobar function and in the ppo lung function. RESULTS: CT-V and PET-V imaging demonstrated strong correlations in quantifying relative lobar function (r = 0.96; P < 0.001). A Wilcoxon-signed rank test showed no significant difference in the lobar function estimates between the two imaging modalities (P = 0.83). The Bland-Altman plot also showed no significant differences. The correlation between ASC-based lobar function estimates with ventilation imaging was low, r < 0.45; however, the predictions of postoperative lung function correlated strongly between all three methods. CONCLUSIONS: The assessment of lobar function from CT-V imaging correlated strongly with PET-V imaging, but had low correlations with ASC. CT-V imaging may be a useful alternative method in preoperative evaluation for lung cancer patients.

Does a diet low in FODMAPs reduce symptoms associated with functional gastrointestinal disorders? A comprehensive systematic review and meta-analysis.

BACKGROUND: Functional gastrointestinal symptoms such as abdominal pain, bloating, distension, constipation, diarrhea and flatulence have been noted in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). The diversity of symptoms has meant that finding an effective treatment has been challenging with most treatments alleviating only the primary symptom. A novel treatment option for IBS and IBD currently generating much excitement is the low fermentable, oligo-, di-, mono-saccharides and polyol (FODMAP) diet. The aim of this meta-analysis was to determine the evidence of the efficacy of such a diet in the treatment of functional gastrointestinal symptoms. METHODS: Electronic databases were searched through to March 2015 to identify relevant studies. Pooled odds ratios (ORs) and 95 % confidence intervals were calculated for the effect of a low FODMAP diet on the reduction in IBS [Symptoms Severity Score (SSS)] score and increase in IBS quality of life (QOL) score for both randomized clinical trials (RCTs) and non-randomized interventions using a random-effects model. RESULTS: Six RCTs and 16 non-randomized interventions were included in the analysis. There was a significant decrease in IBS SSS scores for those individuals on a low FODMAP diet in both the RCTs (OR 0.44, 95 % CI 0.25-0.76; I (2) = 35.52, p = 0.00) and non-randomized interventions (OR 0.03, 95 % CI 0.01-0.2; I (2) = 69.1, p = 0.02). In addition, there was a significant improvement in the IBS-QOL score for RCTs (OR 1.84, 95 % CI 1.12-3.03; I (2) = 0.00, p = 0.39) and for non-randomized interventions (OR 3.18, 95 % CI 1.60-6.31; I (2) = 0.00, p = 0.89). Further, following a low FODMAP diet was found to significantly reduce symptom severity for abdominal pain (OR 1.81, 95 % CI 1.13-2.88; I (2) = 0.00, p = 0.56), bloating (OR 1.75, 95 % CI 1.07-2.87; I (2) = 0.00, p = 0.45) and overall symptoms (OR 1.81, 95 % CI 1.11-2.95; I (2) = 0.00, p = 0.4) in the RCTs. In the non-randomized interventions similar findings were observed. CONCLUSION: The present meta-analysis supports the efficacy of a low FODMAP diet in the treatment of functional gastrointestinal symptoms. Further research should ensure studies include dietary adherence, and more studies looking at greater number of patients and long-term adherence to a low FODMAP diet need to be conducted.

The Nano-X Linear Accelerator: A Compact and Economical Cancer Radiotherapy System Incorporating Patient Rotation.

Rapid technological improvements in radiotherapy delivery results in improved outcomes to patients, yet current commercial systems with these technologies on board are costly. The aim of this study was to develop a state-of-the-art cancer radiotherapy system that is economical and space efficient fitting with current world demands. The Nano-X system is a compact design that is light weight combining a patient rotation system with a vertical 6 MV fixed beam. In this paper, we present the Nano-X system design configuration, an estimate of the system dimensions and its potential impact on shielding cost reductions. We provide an assessment of implementing such a radiotherapy system clinically, its advantages and disadvantages compared to a compact conventional gantry rotating linac. The Nano-X system has several differentiating features from current radiotherapy systems, it is [1] compact and therefore can fit into small vaults, [2] light weight, and [3] engineering efficient, i.e., it rotates a relatively light component and the main treatment delivery components are not under rotation (e.g., DMLCs). All these features can have an impact on reducing the costs of the system. In terms of shielding requirements, leakage radiation was found to be the dominant contributor to the Nano-X vault and as such no primary shielding was necessary. For a low leakage design, the Nano-X vault footprint and concrete volume required is 17 m2 and 35 m3 respectively, compared to 54 m2 and 102 m3 for a conventional compact linac vault, resulting in decreased costs in shielding. Key issues to be investigated in future work are the possible patient comfort concerns associated with the patient rotation system, as well as the magnitude of deformation and subsequent adaptation requirements.

A study of the native cell wall structures of the marine alga Ventricaria ventricosa (Siphonocladales, Chlorophyceae) using atomic force microscopy.

A substantial proportion of the architecture of the plant cell wall remains unknown with a few cell wall models being proposed. Moreover, even less is known about the green algal cell wall. Techniques that allow direct visualization of the cell wall in as near to its native state are of importance in unravelling the spatial arrangement of cell wall structures and hence in the development of cell wall models. Atomic force microscopy (AFM) was used to image the native cell wall of living cells of Ventricaria ventricosa (V. ventricosa) at high resolution under physiological conditions. The cell wall polymers were identified mainly qualitatively via their structural appearance. The cellulose microfibrils (CMFs) were easily recognizable and the imaging results indicate that the V. ventricosa cell wall has a cross-fibrillar structure throughout. We found the native wall to be abundant in matrix polysaccharides existing in different curing states. The soft phase matrix polysaccharides susceptible by the AFM scanning tip existed as a glutinous fibrillar meshwork, possibly incorporating both the pectic- and hemicellulosic-type substances. The hard phase matrix producing clearer images, revealed coiled fibrillar structures associated with CMFs, sometimes being resolved as globular structures by the AFM tip. The coiling fibrillar structures were also seen in the images of isolated cell wall fragments. The mucilaginous component of the wall was discernible from the gelatinous cell wall matrix as it formed microstructural domains over the surface. AFM has been successful in imaging the native cell wall and revealing novel findings such as the 'coiling fibrillar structures' and cell wall components which have previously not been seen, that is, the gelatinous matrix phase.