Mechanical instability secondary to vertebral metastases can lead to pathologic vertebral compression fracture (VCF) mechanical pain, neurological compromise, and the need for surgical stabilization. Stereotactic body radiation therapy (SBRT) as a treatment for spinal metastases is effective for pain and local tumor control, it has been associated with an increased risk of VCF. This study quantified computed tomography (CT) based stability measures in metastatic vertebrae with VCF treated with spine SBRT. It was hypothesized that semi-automated quantification of VCF based on CT metrics would be related to clinical outcomes. 128 SBRT treated spinal metastases patients were identified from a prospective database. Of these, 18 vertebral segments were identified with a VCF post-SBRT. A semi-automated system for quantifying VCF was developed based on CT imaging before and after SBRT. The system identified and segmented SBRT treated vertebral bodies, calculated stability metrics at single time points and changes over time. In the vertebrae that developed a new (n = 7) or progressive (n = 11) VCF following SBRT, the median time to VCF/VCF progression was 1.74 months (range 0.53–7.79 months). Fractured thoracolumbar vertebrae that went on to be stabilized (cemented and/or instrumented), had greater fractured vertebral body volume progression over time (12%) compared to those not stabilized (0.4%, p < 0.05). Neither the spinal instability neoplastic score (SINS) or any single timepoint stability metrics in post-hoc analyses correlated with future stabilization. This pilot study presents a quantitative semi-automated method assessing fractured thoracolumbar vertebrae based on CT. Increased fractured vertebral body volume progression post-SBRT was shown to predict those patients who were subsequently stabilized, motivating study of methods that assess temporal radiological changes toward augmenting existing clinical management in the metastatic spine.

PURPOSE:To evaluate standardized uptake value (SUV) stability on pretreatment and intratreatment 18-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in patients undergoing definitive CRT for head and neck cancer (HNC). METHODS:Primary tumor and nodal volumes of interest (VOIs) from HNC patients were contoured on the pretreatment and intratreatment PET-CT by two independent observers. SUV stability was measured with intersection calculations (DICE, overlap fraction, center to center) between the VOIs at threshold levels of 50%, 60%, 70%, 80%, and 90% of the SUV maximum. RESULTS:The mean calculated DICE of the 50%, 60%, 70%, 80%, 90% SUV threshold was 0.53, 0.48, 0.41, 0.28, and 0.12, respectively. The mean calculated overlap fraction was 0.71, 0.65, 0.58, 0.43, and 0.2, respectively. Center-center difference demonstrates spatial variability of 7.8, 8.2, 8.6, 9.5, and 11.2 mm for these SUV subvolumes of interest. CONCLUSIONS:HNC subvolumes defined by SUV thresholding technique in FDG PET-CT imaging do not remain physically stable during (chemo)RT. HIGHLIGHTS:All pretreatment and intratreatment SUV thresholds (50%-90%) overlap indexes are low during the course of (chemo)radiation. Pretreatment and intratreatment center to center variation further corroborates that all FDG threshold volumes do not remain stable during treatment. No difference in SUV threshold stability was seen between p16 positive and negative tumors.

We have developed a novel in vitro research platform that combines a human hair-bearing skin explant (that retains the normal cellular organization interactions of the skin) with immunostaining of transverse human frozen skin sections of the hair follicle (HF) and interfollicular epidermis (IE). Fresh skin obtained from abdominoplasty from 3 healthy individuals was placed in explant standard (control) media or in media containing 12-o-tetradecanoylphorbol-13-acetate (TPA) (48 nm), a compound with attributed pro-proliferative effects on melanocytes (MCs). Biopsies were evaluated by immunostaining using fluorescent markers to identify PMEL(+) MC and KI-67(+) proliferative cells that were quantified by microscopy and cell counting. We show that skin explants incubated with standard media for 7 days reproduced the features of control skin [that was collected and frozen on day (D)0 and was not incubated with media]; these reproduced features were preserved architecture and similar expression of PMEL and of its proliferative and non-proliferative phenotypes, in both HFs and IE. On the D7-treated explants, TPA treatment was associated with remarkably increased number of PMEL(+) cells (P=2.0E-02), and of PMEL non-proliferative phenotype (P=3.0E-02), and with slightly increased number of PMEL proliferative cells (P=8.0E-02) in contrast to the to D7 explants incubated in control media. The above phenotypes had a similar expression trend in the upper HF infundibulum, but no treatment changes have been observed on the overall-depth analysis of HFs (P>0.05 for all 3 phenotypes). In summary, TPA treatment impacted the proliferation of mature MCs in the IE, but not the proliferation of the HF MC precursors. Our results suggest that ex vivo explants represent a valuable platform to reproduce the pharmacologic response of the in vivo human skin and will be a useful tool for testing candidate gene functions. Our goal is to study the effects of agonists on pathways activated in the HF and IE of vitiligo skin.

Indoleamine 2,3-dioxygenase-1 (IDO-1) is a cytosolic enzyme involved in the catabolism of tryptophan; IDO-1-related immune suppression is due to decreased tryptophan availability and to the generation of tryptophan metabolites, culminating in substantial suppression of T-lymphocytes. Here we investigate IDO-1 expression in a cohort of non-small-cell lung cancer (NSCLC) specimens, both in tumor cells and in immune infiltrate, with correlation of IDO-1 to PD-L1 expression, clinical patient demographics and outcomes. A cohort of 1.200 NSCLC samples were obtained from 437 patients who underwent surgical lung resections at Austin Health, Melbourne, Australia. IDO-1 expression was evaluated by immunohistochemistry. Correlations were assessed using Spearman and Kendall tests. A Cox proportional hazards (PH) model was used to assess if overall survival (OS) was associated with IDO-1 positivity in univariate and multivariable settings. Samples from 437 patients were analyzed for IDO-1 expression, with 111 (25.4%) determined as positive (H-Score ≥ 1) and 326 patients (74.6%) as negative (H-Score: 0). IDO-1 expression was determined to be greater in tumor immune infiltrate, with 406 patients (93.8%) determined as positive, while just 27 (6.2%) were IDO-1 negative. There was a significant positive correlation between IDO-1 positive tumor cells and immune cells (0.2167, p < 0.001). Both continuous and binary versions of tumor H-Score showed a significant positive correlation with the amount of tumor immune infiltrate (0.1806 and 0.1698, p < 0.0001, respectively). None of the analyzed variables (age, sex, histology, stage, EGFR, KRAS and PD-L1 status) were found to display a significant correlation with IDO-1 positivity in tumor and immune cells. IDO-1 positivity in tumor cells was found to be significantly associated with OS in the univariate setting and in the multivariable model where variables age, sex, histology, stage, EGFR, KRAS and PD-L1 status were included [P-value = 0.009 and 0.021, respectively; HR: 0.72 (95% CI: 0.55-0.95)]. IDO-1 positivity in immune cells was found to be significantly associated with OS in the univariate setting and was borderline significant in the multivariable model [P-value = 0.006 and 0.053, respectively; HR: 0.798 (95% CI: 0.635-1.003)]. To our knowledge, this is the most extensive analysis of IDO-1 expression in NSCLC patients reported in the literature. Our results suggest the possible prognostic role of IDO-1 expression in tumor and immune cells, highlighting the relevance of IDO-1 detection in tumor tissue. Since new compounds targeting IDO-1 are actually under investigation, the identification of potential prognostic and predictive biomarkers will be needed.

There has been no molecular studies of melanocyte (MC) precursors activation in the hair follicle (HF) bulge by NBUVB treatment in vitiligo. To better understand repigmentation process, we collected biopsies from untreated and NBUVB-treated vitiligo patients (n=6 unpaired samples). We performed laser capture microdissection of HF bulge MCs from both groups, isolated the RNA, and performed Whole Transcriptome RNA Sequencing followed by gene expression analysis. Using the Ingenuity Pathway Analysis tool and our list of differentially expressed genes (P<0.05), we identified the RHO-GTPase (RHO) pathway as the top canonical pathway modulated by NBUVB in the bulge MCs (P=1.2E-02; Activation Z-Score=2.4), and RHOJ (with role in melanoma migration) as the top RHO component (P=4.4E-03; fold change (FC)=12.7). Using qRT-PCR and new patient samples, we validated induction of RHOJ and VIM (P<0.05; FC≥2) by NBUVB, and found a similar expression trend for RELA, CDH3 and CDH11. To study functional phenotypes associated with RHOJ depletion, we used the PIG1 immortalized MC cell line, which we identified as good functional model for human bulge MCs. RHOJ knockdown by siRNA transient transfection caused: a. decreased PIG1 cell number and an abnormal, senescent phenotype; b. decreased PIG1 cell migration (≥45%; P≤3.6E-03) during the first 48h, as assessed by a scratch wound assay; c. decreased expression of cytoskeletal proteins (focal adhesions and actin stress fibers) (P≤5.0E-04), as analyzed by immunostaining. Our data suggest that RHOJ signaling impacts proliferation and migration of immature MCs, and is an important activator of these cells during NBUVB treatment.

Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC. A TMA of 527 resected NSCLC samples and 53 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from RandD Systems（AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 22C3 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used. HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was18.6%(77/415) and 45.3%(24/53) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, P=0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, P=0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p=0.706) and PD-L1 expression (median 45 vs 48 months, p=0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.232, p=0.002, Figure 1A) in patients with NSCLC and also have a negative correlation in NSCLC cell lines(r=-0.055, p=0.764,Figure 1B). HVEM was found to be overexpressed in patients of NSCLC with advanced disease or lymph node metastasis and has a negative co-relationship with PD-L1 expression, while, it did not have a prognostic role in patients with NSCLC.

The poliovirus receptor (PVR) is an immune checkpoint protein expressed on tumor cells. It has been reported to mediate activation of T cells via CD226 or inhibition through binding to T-cell Ig and ITIM domain (TIGIT). TIGIT competes with CD226 for binding to PVR, and exhibits stronger affinity for PVR. Recently we have found that PVR is highly expressed in SCLC cell lines. Characterizing the expression and significance of the PVR-TIGIT axis in SCLC will help us to better understand the immunology of SCLC and may lead to novel therapeutic strategies to combine checkpoint blocking agents for improved SCLC immunotherapy.

PURPOSE:The purpose of this educational report is to provide an overview of the present state-of-the-art PET auto-segmentation (PET-AS) algorithms and their respective validation, with an emphasis on providing the user with help in understanding the challenges and pitfalls associated with selecting and implementing a PET-AS algorithm for a particular application. APPROACH:A brief description of the different types of PET-AS algorithms is provided using a classification based on method complexity and type. The advantages and the limitations of the current PET-AS algorithms are highlighted based on current publications and existing comparison studies. A review of the available image datasets and contour evaluation metrics in terms of their applicability for establishing a standardized evaluation of PET-AS algorithms is provided. The performance requirements for the algorithms and their dependence on the application, the radiotracer used and the evaluation criteria are described and discussed. Finally, a procedure for algorithm acceptance and implementation, as well as the complementary role of manual and auto-segmentation are addressed. FINDINGS:A large number of PET-AS algorithms have been developed within the last 20 years. Many of the proposed algorithms are based on either fixed or adaptively selected thresholds. More recently, numerous papers have proposed the use of more advanced image analysis paradigms to perform semi-automated delineation of the PET images. However, the level of algorithm validation is variable and for most published algorithms is either insufficient or inconsistent which prevents recommending a single algorithm. This is compounded by the fact that realistic image configurations with low signal-to-noise ratios (SNR) and heterogeneous tracer distributions have rarely been used. Large variations in the evaluation methods used in the literature point to the need for a standardized evaluation protocol. CONCLUSIONS:Available comparison studies suggest that PET-AS algorithms relying on advanced image analysis paradigms provide generally more accurate segmentation than approaches based on PET activity thresholds, particularly for realistic configurations. However, this may not be the case for simple shape lesions in situations with a narrower range of parameters, where simpler methods may also perform well. Recent algorithms which employ some type of consensus or automatic selection between several PET-AS methods have potential to overcome the limitations of the individual methods when appropriately trained. In either case, accuracy evaluation is required for each different PET scanner and scanning and image reconstruction protocol. For the simpler, less robust approaches, adaptation to scanning conditions, tumor type, and tumor location by optimization of parameters is necessary. The results from the method evaluation stage can be used to estimate the contouring uncertainty. All PET-AS contours should be critically verified by a physician. A standard test, i.e., a benchmark dedicated to evaluating both existing and future PET-AS algorithms needs to be designed, to aid clinicians in evaluating and selecting PET-AS algorithms and to establish performance limits for their acceptance for clinical use. The initial steps toward designing and building such a standard are undertaken by the task group members.

STING is a protein that promotes type I IFN production (IFNα/β) essential for activation of dendritic cells and antigen presentation and priming of T-cells. The cytoplasmic DNA sensor cGAS (cGAMP Synthase) is able to detect tumor DNA, and in response will synthesize cGAMP. cGAMP binds STING specifically, resulting in production of type I IFN. STING is therefore referred to as an adaptor protein essential for immune signaling following detection of tumor DNA. Analysis of the TCGA database indicates decreased survival in lung adenocarcinoma patients lacking STING expression. STING expression is decreased in tumor tissues and can be lost as the tumor progresses. One reported mechanism of loss of STING or cGAS in tumors is due to hypermethylation, a common occurrence in lung cancer. Agonists of STING show potent immune response and are currently in clinical trials. Importantly, recent studies show that expression of STING and cGAS proteins are essential for response to PD-1:PD-L1 blockade. Section not applicable. We analyzed 55 NSCLC and 39 SCLC cell lines, and 317 NSCLC and 78 SCLC tissues for STING and cGAS expression using immunohistochemistry. 14/55 (25.45%) NSCLC cell lines and 25/39 (64.10%) SCLC cell lines showed no STING expression. Separated in to adenocarcinoma (AC) and squamous cell carcinoma (SCC) subsets, STING expression in AC shows loss of STING as tumor stage increases (Positive: 70% Stage I, 65% Stage II, 52% Stage III, 40% Stage IV, 71% total; n=156) while STING expression is low at all stages of SCC (Positive: 29% Stage I, 18% Stage II, 36% Stage III, 13% Stage IV, 27% total; n=161). SCLC tissues stained showed widespread loss of STING (Positive: 40% Stage I, 27% Stage II, 31% Stage III, 100% Stage IV, 37.18% total, n=78). Expression of cGAS was higher in AC (94%) than SCC (75%) and showed no correlation with stage. TCGA analysis of STING methylation shows hypermethylation in AC (0.15- ± 0.13 tumor vs 0.05 ± 0.02 normal, n=422) and SCC (0.23 ± 0.16 tumor vs 0.04 ± 0.03 normal, n=359). cGAS shows slight methylation in AC (0.05 ± 0.07 tumor vs 0.05 ± 0.01 normal, n=422) but a large increase in SCC (0.19 ± 0.24 tumor vs 0.04 ± 0.01 normal, n=359). This study indicates drastic differences in STING and cGAS expression in AC, SCC, and SCLC. Differential expression of these proteins could impact the efficacy of STING agonists, radiation therapy, and immunotherapy in lung cancer.

White matter hyperintensities (WMH) are presumed to represent cerebral small vessel disease and they are associated with poorer processing speed and executive function, but their effect on verbal memory is more subtle. This study examines relationships between verbal memory and WMH, both as WMH occur alone and in the context of neurodegenerative disorders. In a cohort recruited to represent strata of WMH severity (patients recruited from transient ischemic attack, memory and cardiac rehabilitation clinics, and controls, all without cortical stroke visible on MRI), WMH volume and left temporal lobe brain parenchymal fraction were assessed using multimodal MRI. Verbal learning and recall were assessed using the California Verbal Learning Test, 2nd Edition. Serial mediation between these variables was tested in pathway analysis. A confirmatory analysis was conducted in a large independent cohort of consecutively recruited patients who presented with vascular cognitive impairment, Alzheimer’s disease (AD)/mild cognitive impairment (MCI), Parkinson’s/Lewey body disease and other/mixed neurodegenerative diagnoses, and controls (Sunnybrook Dementia Study; NCT01800214). In the stratified cohort (n=117), verbal recall was correlated with WMH volume (r=-.207, p=.024); however, this was due to an indirect pathway (mediation effect -4.05, 95% bootstrap CI [-8.97, -1.07]) wherein WMH predicted left temporal lobe brain parenchymal fraction, which predicted poorer verbal learning, leading to poorer verbal recall. This mediation effect was confirmed in a second cohort (n=702; effect -0.663, 95% bootstrap CI [-0.946, -0.403]). Adjusting for indirect effects, the direct effect between WMH and verbal recall was not significant in either cohort (B=1.166, p=.271 and B=.022, p=.892, respectively), nor were other indirect pathways. The indirect effect was significant in subgroups of the Sunnybrook Dementia Study with (n=363, effect -0.201, 95% CI [-0.381, -0.060]) and without (n=338, effect -0.707, 95% CI [-1.117, -0.384]) AD/MCI, and in a subgroup not diagnosed clinically with vascular cognitive impairment as a contributing cause (n=561, effect -0.680, 95% CI [-1.010, -0.332]). The effect of cerebral small vessel disease is more widespread than is likely to be clinically recognized; in diverse older populations, small vessel disease contributes indirectly to deficits in verbal recall, mediated in serial by left temporal lobe atrophy and verbal learning.

in British Columbia (BC), while controlling for physician case volume and rurality of patient residence. Methods and Materials:The BC Cancer Registry (BCCR), a population-based provincial database, was used to identify all patients in BC diagnosed for the first time with a primary nonthyroid HNC and treated with radiotherapy between 2006 and 2011.Patient demographics, pathology, stage, treatments, and death data were abstracted.Chart review of all patients was performed using the British Columbia Cancer Agency Information System (CAIS).Patients were categorized as residing in large, small and rural local health authorities (LHAs) using BC Stats and BC Ministry of Health information.Physician case frequency was defined as low (0-14 cases per year), medium (15-29 cases per year) and high (> 30 cases per year).We hypothesized that survival would not significantly differ among BC cancer centres after controlling for rurality, physician case frequency, IMRT use, and other patient and tumour characteristics.Results: 2330 HNC patients were included in our study.The fiveyear head and neck CSS (HNCSS) for the Abbotsford, Fraser Valley, Southern Interior, Vancouver and Vancouver Island centres was 72%, 71%, 73%, 75% and 68%, respectively (p = 0.54), while OS was 59%, 60%, 60%, 65% and 56%, respectively (p = 0.06).On multivariable analysis, after controlling for age, gender, cancer stage, anatomical site, treatment and physician case frequency, neither HNCSS (HR range = 0.92-1.03;p = 0.57-0.91)nor OS (HR range = 0.93-1.07;p = 0.47-0.92)was significantly different by treatment centre.OS was also not significantly different for patients treated by physicians with low case frequency (HR = 0.96; 0.77-1.19;p = 0.72) and middle case frequency (HR = 1.01; 0.83-1.23;p = 0.91) in reference to high case frequency.There was no significant difference in OS among patients living in rural LHAs (HR = 0.97; 0.85-1.11;p = 0.67) and small LHAs (HR = 1.13; 0.86-1.47;p = 0.38) in reference to large LHAs.Conclusions: There was no significant difference in survival among British Columbia Cancer Agency treatment centres after controlling for differences in rurality, physician case volume and other potential confounding variables.

Modern radiation therapy (RT) techniques offer precise delivery to the defined targets in head and neck cancer (HNC) while respecting surrounding critical organ tolerances. This is due in part to the enhanced ability to define the gross tumor volume (GTV) with supplemental imaging such as MRI and PET scans. As a standard, a high dose clinical target volume (CTV) of 5 mm is added to the GTV to further ensure complete coverage of gross disease. However, HN tumors often shrink during RT, which suggests that the high dose CTV margin during treatment may be greater than the original 5 mm, thus leading to overdosage of normal tissues. This study intends to quantify the potential gain of an adaptive technique that maintains the CTV to a changing gross tumor volumes in a series of HNC patients treated with chemoradiation therapy. A prospective study in 2009 enrolled advanced HNC patients undergoing curative IMRT to receive a dynamic pre-treatment FDG PET-CT simulator scan, which was also repeated intratreatment (IT) between the 10th and 15th fraction. 52 patients were evaluated. Two radiation oncologists separately contoured GTVs in the pre- and IT scans to account for inter-observer variability. Rigid fusion of the planning CT to pre- and IT PET-CT scans was performed. Margin expansions ranging from 1-25 mm were performed on the pre-treatment GTV to volumetrically match the original CTV (as defined by the treating radiation oncologist), based on optimal Dice Similarity Indices (DSI). An identical process took place with the IT PET CT scan, where the IT GTV margins were expanded to the original treatment CTV. 52 patients were evaluated with a total of 152 targets (50 primaries and 102 LNs).Volume matching given by DSI showed that the pre-treatment GTV needed an average 7.22 ± 4.75 mm expansion to optimally match the clinical CTV while the IT GTV required a margin of 8.27± 4.18 mm . On average, the radial size of the primary CTV decreased by 1.05 ± 3.59 mm between pre- and IT scans but 17 patients (32.7%) had a shrinkage over 5 mm and 6 patients (11.5%) had tumor growth of more than 5 mm. 19 patients had a paradoxical response between the primary and the LNs. On multivariate analysis, after controlling for smoking history, HPV status and stage, non-smokers only showed significant shrinkage in both primaries (mean = 2.34±0.64, P = 0.0004) and LNs (mean = 2.521±0.92, P = 0.008). In total, primaries and LNs had similar outcome with a mean of 1.14 ± 3.99 mm and 0.67 ± 3.63 mm respectively (P = 0.54). Our results show that HNC tumor shrinkage during RT is highly variable. A subset of patients is highly responsive to treatment where an adaptive approach to CTV margins CTV may reduce normal tissue toxicities and still provide safe coverage. Non-smokers respond better than smokers while HPV-positive patients do not appear statistically to have an early response at 2-3 weeks.

PURPOSE:To develop a practical method to localize bones in magnetic resonance (MR) images, to create "computed tomography-like" MR images (ctMRI) that could be used for radiation therapy verification, and to generate MR-based digitally reconstructed radiographs (DRR). METHODS AND MATERIALS:Using T1-weighted MR images, an air mask was derived from the manual contouring of all airways within the head and neck region using axial images at 6 anatomic levels. Compact bone, spongy bone, and soft tissue masks were then automatically generated using the statistical data derived from MR intensities and the air mask. ctMRI were then generated by mapping the MR intensities of the voxels within these masks into the CT number ranges of corresponding tissues. MR-based DRRs created from ctMRI were quantitatively evaluated using the co-registered MR and CT head images of 20 stereotactic radiosurgery patients. Ten anatomical points, positioned on the skull segmented using a threshold of 300 HU, in CT and ctMRI, were used to determine the differences in distance between MR-based DRRs and CT-based DRRs, and to evaluate the geometric accuracy of ctMRI and MR-based DRRs. RESULTS:The bony structures were identified on ctMRI and were visible in the MR-based DRRs. From the 20 patient cases, the mean geometric difference and standard deviation between the 10 anatomical points on MR-based and CT-based DRRs was -0.05 ± 0.85 mm, respectively. This included uncertainty in image fusion. The maximum distance difference was 1.88 mm. CONCLUSIONS:A practical method was developed to segment bone from MR images. The ctMRI created can be used for radiation treatment verification when MR-only simulation is performed. MR-based DRRs can be used in place of CT-based DRRs.

Dementia with Lewy bodies (DLB) and Corticobasal Syndrome (CBS) are atypical parkinsonian disorders with fronto-subcortical and posterior cognitive dysfunction as common features. While visual hallucinations are a good predictor of Lewy body pathology and are rare in CBS, they are not exhibited in all cases of DLB. Given the clinical overlap between these disorders, neuropsychological and imaging markers may aid in distinguishing these entities.

The purpose of this study was to assess the accuracy and practicality of well counter– and thyroid probe–based methods, commonly available in nuclear medicine facilities, for measuring the concentration of 18F-FDG in blood samples. The degree to which the accuracy of such methods influences quantitative analysis of dynamic PET scans was also assessed. Methods: Thirty-five patients with cancer of the head and neck underwent dynamic PET imaging as part of a study intended to evaluate the utility of quantitative, image-based metrics for assessment of early treatment response. The activity in blood samples from the patients, necessary to provide an estimate of the input function for quantitative analysis, was measured both using a thyroid probe and using a well counter. Three calibration techniques were compared: single-point calibration using a standard solution for the thyroid probe (ProbePoint technique), single-point calibration using a standard solution for the well counter (WellPoint technique), and multiple-point calibration over the full range of expected blood activities for the well counter (WellCurve technique). The WellCurve method was assumed to provide the most accurate estimate of blood activity. The precision of measuring blood volume using a micropipette was also evaluated by obtaining multiple blood samples. Simplified-kinetic-analysis multiple-time-point (SKA-M) uptake rates for the primary tumor were calculated for all 35 patients using PET images and each of the 3 methods for assessing blood concentration. Results: Errors in blood activity measurements ranging from −9.5% to 7.6% were found using the ProbePoint method, whereas the error range was much less (from −1.3% to 0.9%) for the WellPoint method. The precision in blood volume measurements ranged from −6% to 12% in the 10 patients assessed. The errors in blood activity and volume measurements were reflected in the SKA-M measurements in the same range. Conclusion: The WellPoint method provides a compromise between accuracy and clinical practicality. Random errors in both blood activity and volume measurements accumulate and may compromise parameters—such as the SKA-M estimate of tumor uptake rate—that depend not only on images but also on blood concentration data.

A primary goal of nuclear medicine facility design is to keep public and worker radiation doses As Low As Reasonably Achievable (ALARA). To estimate dose and shielding requirements, one needs to know both the dose equivalent rate constants for soft tissue and barrier transmission factors (TFs) for all radionuclides of interest. Dose equivalent rate constants are most commonly calculated using published air kerma or exposure rate constants, while transmission factors are most commonly calculated using published tenth-value layers (TVLs). Values can be calculated more accurately using the radionuclide's photon emission spectrum and the physical properties of lead, concrete, and/or tissue at these energies. These calculations may be non-trivial due to the polyenergetic nature of the radionuclides used in nuclear medicine. In this paper, the effects of dose equivalent rate constant and transmission factor on nuclear medicine dose and shielding calculations are investigated, and new values based on up-to-date nuclear data and thresholds specific to nuclear medicine are proposed. To facilitate practical use, transmission curves were fitted to the three-parameter Archer equation. Finally, the results of this work were applied to the design of a sample nuclear medicine facility and compared to doses calculated using common methods to investigate the effects of these values on dose estimates and shielding decisions. Dose equivalent rate constants generally agreed well with those derived from the literature with the exception of those from NCRP 124. Depending on the situation, Archer fit TFs could be significantly more accurate than TVL-based TFs. These results were reflected in the sample shielding problem, with unshielded dose estimates agreeing well, with the exception of those based on NCRP 124, and Archer fit TFs providing a more accurate alternative to TVL TFs and a simpler alternative to full spectral-based calculations. The data provided by this paper should assist in improving the accuracy and tractability of dose and shielding calculations for nuclear medicine facility design.

The safety, pharmacokinetics, biodistribution and radiation dosimetry of (111)In-DTPA-hEGF, an Auger electron-emitting radiopharmaceutical, were evaluated in a first-in-human trial. Dose escalation was performed in patients with EGFR-positive metastatic breast cancer who had received ≥2 prior courses of systemic treatment. (111)In-DTPA-hEGF (0.25 mg) was administered once intravenously (i.v.). Blood was collected for biochemistry/hematology testing and pharmacokinetic and immunogenicity analyses at selected times post injection (p.i.). Whole body planar images were acquired at 1, 4-6, 24 and 72 h p.i. and SPECT images at 24 and/or 72 h p.i. Macrodosimetry (MIRD) for the whole body and organs was estimated using OLINDA. Correlative radiological imaging was obtained at baseline, 1 and 3 months and then 6 monthly. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE)v2.0. Sixteen patients, median age 47 yr (range, 35-59), received (111)In-DTPA-hEGF as follows: 357-434 MBq (7), 754-805 MBq (3), 1,241-1,527 MBq (3) and 2,030-2,290 MBq (3). Fifteen were evaluable for toxicity. The commonest adverse events (AE) were flushing, chills, nausea, and vomiting occurring during or immediately p.i. One patient experienced Grade 3 thrombocytopenia (attributed to bone marrow infiltration by cancer). There were no other Grade 3 or 4 AEs. Maximum tolerated dose was not reached. Clear accumulation of radiopharmaceutical in at least one known site of disease was observed in 47% of patients. (111)In-DTPA-hEGF was cleared biexponentially from the blood with α-phase T½ of 0.16 ± 0.03 h and β-phase T½ of 9.41 ± 1.93 h. (111)In-DTPA-hEGF was not immunogenic. The mean radiation dose estimates in mGy/MBq for whole body, liver, kidneys, spleen and thyroid were 0.08, 0.86, 0.74, 0.37 and 0.30, respectively. No objective antitumor responses were observed at the doses studied. In summary, administered amounts of up to 2,290 MBq (0.25 mg) of (111)In-DTPA-hEGF were well tolerated as a single i.v. injection.