Brain hypometabolic changes in 14 adolescent-adult patients with Niemann-Pick disease type C assessed by 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVE: Niemann Pick disease type C (NPC) is a rare progressive neurovisceral lysosomal disorder caused by autosomal recessive mutations in the NPC1 or NPC2 genes. 18F-fluorodeoxyglucose (FDG) is a positron-emitting glucose analogue for non-invasive imaging of brain metabolism. FDG PET is commonly used for dementia imaging but its specific application to NPC is rarely described. METHODS: This is a retrospective study of all baseline brain FDG PET performed for NPC patients. Images were assessed using a normal database statistical comparison of metabolic changes expressed in standard deviations and three-dimensional Stereotactic Surface Projection maps. Typical hypometabolic patterns in NPC were identified. We further investigated any correlation between the degree of regional brain hypometabolism and the Iturriaga clinical severity scale. RESULTS: Brain FDG PET images of 14 adolescent-adult NPC patients were analysed, with mean age of 35 years. We found significant frontal lobe hypometabolism in 12 patients (86%), thalamic hypometabolism in eight patients (57%) and variable parietal lobe hypometabolism in 13 patients (93%). Hypometabolic changes were usually bilateral and symmetric. Ten out of 13 ataxic patients showed cerebellar or thalamic hypometabolism (sensitivity 77%, specificity 100%). Linear regression analysis showed frontal lobe hypometabolism to have the best correlation with the Iturriaga clinical scale (R2 = 0.439; p = 0.01). CONCLUSIONS: We found bilateral symmetric hypometabolism of the frontal lobes, thalami and parietal lobes (especially posterior cingulate gyrus) to be typical of adolescent-adult NPC. Ataxia was commonly associated with cerebellar or thalamic hypometabolism. Frontal lobe hypometabolism showed the best inverse correlation with clinical severity.

Head-to-head comparison of cerebral blood flow single-photon emission computed tomography and 18 F-fluoro-2-deoxyglucose positron emission tomography in the diagnosis of Alzheimer disease.

BACKGROUND: Clinical diagnosis of Alzheimer disease (AD) is only 70% accurate. Reduced cerebral blood flow (CBF) and metabolism in parieto-temporal and posterior cingulate cortex may assist diagnosis. While widely accepted that 18 F-fluoro-2-deoxyglucose positron emission tomography (18 F-FDG PET) has superior accuracy to CBF-SPECT for AD, there are very limited head-to-head data from clinically relevant populations and these studies relied on clinical diagnosis as the reference standard. AIMS: To compare directly the accuracy of CBF-SPECT and 18 F-FDG PET in patients referred for diagnostic studies in detecting ß-amyloid PET confirmed AD. METHODS: A total of 126 patients, 56% with mild cognitive impairment and 44% with dementia, completed both CBF-SPECT and 18 F-FDG PET as part of their diagnostic assessment, and subsequently underwent ß-amyloid PET for research purposes. Transaxial slices and Neurostat 3D-SSP analyses of 18 F-FDG PET and CBF-SPECT scans were independently reviewed by five nuclear medicine clinicians blinded to all other data. Operators selected the most likely diagnosis and their diagnostic confidence. Accuracy analysis used final diagnosis incorporating ß-amyloid PET as the reference standard. RESULTS: Clinicians reported high diagnostic confidence in 83% of 18 F-FDG PET compared to 67% for CBF-SPECT (P = 0.001). All reviewers showed individually higher accuracy using 18 F-FDG PET. Based on majority read, the combined area under the receiver operating characteristic curve in diagnosing AD was 0.71 for 18 F-FDG PET and 0.61 for CBF-SPECT (P = 0.02). The sensitivity of 18 F-FDG PET and CBF-SPECT was 76% versus 43% (P < 0.001), while specificity was 74% versus 83% (P = 0.45). CONCLUSIONS: 18 F-FDG PET is superior to CBF-SPECT in detecting AD among patients referred for the assessment of cognitive impairment.

Carboplatin dosing in the era of IDMS-creatinine; the Cockroft-Gault formula no longer provides a sufficiently accurate estimate of glomerular filtration rate for routine use in clinical care.

BACKGROUND: Glomerular filtration rate (GFR) measured by Chromium-51-EDTA excretion (51Cr-GFR) is considered the gold standard of renal function assessment, but serum creatinine in the Cockcroft-Gault (CG) formula is routinely used to estimate GFR for carboplatin dosing. Serum creatinine measured by isotope-dilution-mass-spectrometry (IDMS) can generate spuriously high GFR estimates when used in the CG formula. We hypothesized that GFR calculated using IDMS-creatinine in the CG formula (CG-GFR) exposes patients to inaccurate carboplatin dosing. METHODS: This is a multicenter retrospective study of patients who had a 51Cr-GFR assessment for malignant or non-malignant indications, with a matched CG-GFR. Carboplatin dose based on 51Cr-GFR at AUC5 was used as the reference. RESULTS: 550 patients were analyzed, median age 62 (19-90), 64% female. Indication for GFR evaluation: malignancy (85%), assessment for live kidney donation (12%), other (3%). Median ratio of CG-GFR: 51Cr-GFR 1.04 (0.43-3.38); <0.8 in 72 patients (13%), >1.2 in 180 patients (33%). Despite capping of CG-GFR at 125 mL/min, dosing according to AUC6 would have resulted in 18% of patients being underdosed and 23% overdosed by >100 mg compared to 51Cr-GFR. Subgroup analysis identified BMI (>35, MPE 39%), gender (female MPE 15%), GFR indication (malignancy MPE 11%) as risk factors for overestimate of CG-GFR, and BMI < 20 for underestimate (MPE -3.5%). CONCLUSIONS: The convention of considering AUC5 carboplatin based on 51Cr-GFR, and AUC6 carboplatin based on CG-GFR as equivalent is invalid and should be abandoned. When 51Cr-GFR is unavailable, capping CG-GFR at 125 mL/min is recommended.

Utility of MAG3 scintigraphy with the use of a 2 min uptake parameter in the assessment of postsurgical renal transplant complications.

OBJECTIVE: Major complications including acute tubular necrosis or rejection may occur after renal transplantation. We use a semiquantitative parameter, 2 min uptake (2MU), as part of Tc mercaptoacetyltriglycine (MAG3) scintigraphy for transplant evaluation. The aim of this study were (a) to examine the utility of Tc MAG3 scintigraphy in the assessment of postsurgical complications using the renal biopsy as the gold standard and (b) examine for any correlation with 2MU with serum creatinine (sCr) at 3 and 12 months. MATERIALS AND METHODS: We retrospectively reviewed all Tc MAG3 studies at our institution between July 2015 and June 2016, alongside available renal ultrasound, biopsy, and sCr results. RESULTS: A total of 105 patients fulfilled the inclusion criteria. 30/105 patients underwent biopsy less than 7 days of the Tc MAG3 study. Within this 7 day cohort, the negative predictive value for rejection with normal perfusion on Tc MAG3 study was 79% and the positive predictive value for rejection with abnormal Tc MAG3 perfusion was 9%. There was a weak negative correlation between 2MU and 3-month sCr (R=-0.358, P<0.001), and 2MU and 12-month sCr (R=-0.348, P<0.001). CONCLUSION: Although normal perfusion on Tc MAG3 scintigraphy study has a reasonable negative predictive value for rejection, abnormal Tc MAG3 perfusion is not useful in the differentiation of rejection from moderate to severe acute tubular necrosis. The 2MU parameter showed no additional benefit in the identification of rejection, but appeared to have a weak negative correlation with the 3-month and 12-month sCr, and may thus play a role in the prediction of longer term graft function.

Dynamic CT for Parathyroid Adenoma Detection: How Does Radiation Dose Compare With Nuclear Medicine?

OBJECTIVE: Dynamic CT is increasingly used for preoperative localization of parathyroid adenomas, but concerns remain about the radiation effective dose of CT compared with that of 99mTc-sestamibi scintigraphy. The purpose of this study was to compare the radiation dose delivered by three-phase dynamic CT with that delivered by 99mTc-sestamibi SPECT/CT performed in accordance with our current protocols and to assess the possible reduction in effective dose achieved by decreasing the scan length (i.e., z-axis) of two phases of the dynamic CT protocol. MATERIALS AND METHODS: The effective dose of a 99mTc-sestamibi nuclear medicine parathyroid study performed with and without coregistration CT was calculated and compared with the effective dose of our current three-phase dynamic CT protocol as well as a proposed protocol involving CT with reduced scan length. RESULTS: The median effective dose for a 99mTc-sestamibi nuclear medicine study was 5.6 mSv. This increased to 12.4 mSv with the addition of coregistration CT, which is higher than the median effective dose of 9.3 mSv associated with the dynamic CT protocol. Reducing the scan length of two phases in the dynamic CT protocol could reduce the median effective dose to 6.1 mSv, which would be similar to that of the dose from the 99mTc-sestamibi study alone. CONCLUSION: Dynamic CT used for the detection of parathyroid adenoma can deliver a lower radiation dose than 99mTc-sestamibi SPECT/CT. It may be possible to reduce the dose further by decreasing the scan length of two of the phases, although whether this has an impact on accuracy of the localization needs further investigation.

Four-Dimensional Computed Tomography: Clinical Impact for Patients with Primary Hyperparathyroidism.

BACKGROUND: In recent years, four-dimensional computed tomography (4DCT) has emerged as a new localization study for primary hyperparathyroidism (pHPT). OBJECTIVE: We aimed to assess the added value of 4DCT in our institution in the first 4 years of use. METHODS: A retrospective cohort study was conducted from February 2004 to June 2015. Since 2011, patients over 50 years of age without concordant sestamibi-SPECT (SeS) and ultrasound (US) findings underwent 4DCT. Imaging results, surgical findings, histopathology, and postoperative biochemistry were collected. RESULTS: A total of 536 parathyroid operations in 510 patients were performed during the study period. The overall cure rate was 99.2% after reoperation in some patients, and the overall sensitivity for SeS was 76.0%, and 74.8% for US. Since 2011, 100 patients without concordant SeS/US findings have undergone 4DCT, with a sensitivity of 72.9%. This is in comparison to the sensitivities for SeS (48.3%) and US (52.3%). 4DCT was more sensitive in patients with persistent/recurrent disease (60.0% compared with SeS 43.8% and US 36.4%) and patients with multigland disease (67.4% compared with SeS 40.9% and US 42.1%). Comparison between outcomes in the pre- versus post-CT era demonstrated no difference in the initial cure rate (95.4 vs. 95.9%, p = 0.85) or the rate of minimally invasive parathyroidectomies (74.5 vs. 79.9%, p = 0.22). CONCLUSION: Parathyroid 4DCT can aid surgical planning in cases without concordant SeS/US findings; however, the introduction of 4DCT as a second-line test did not change our overall cure rate or rate of minimally invasive parathyroidectomy. The role of 4DCT as the primary localization study for pHPT merits further investigation.

Phase II trial of selective internal radiation therapy and systemic chemotherapy for liver-predominant metastases from pancreatic adenocarcinoma.

BACKGROUND: This prospective, open-label phase II study assessed the impact of liver-directed therapy with selective internal radiation therapy (SIRT) and systemic chemotherapy on progression-free survival (PFS) in liver-dominant metastatic pancreatic adenocarcinoma. METHODS: Patients received yttrium-90-labelled ((90)Y) resin microspheres (SIR-Spheres; Sirtex Medical Limited, Sydney, Australia) as a single procedure on day 2 of the first weekly cycle of 5-fluorouracil (5FU; 600 mg/m(2)) with the option to switch to gemcitabine (1000 mg/m(2)) after 8 weeks of 5FU. Statistical analysis was conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA). The primary endpoint of the study was PFS in the liver, with a median of ≥ 16 weeks defined as the threshold for clinical significance. PFS and overall survival (OS) were summarised by the Kaplan-Meier method using non-parametric estimates of the survivor function. RESULTS: Fourteen eligible patients were enrolled; ten had primary tumour in situ and eight had liver-only metastases. Patients received a median (90)Y activity of 1.1 GBq and 8 weekly doses of 5FU; seven patients received a median of two doses of gemcitabine. Disease control in the liver was 93% (two confirmed partial responses [PR], one unconfirmed PR, ten stable disease). Median reduction in cancer antigen 19-9 was 72%. Median PFS was 5.2 months in the liver, which met the primary endpoint of the study, and 4.4 months at any site. PFS was prolonged in those with a resected primary compared with patients with primary in situ (median 7.8 vs. 3.4 months; p = 0.017). Median OS was 5.5 months overall and 13.6 months in patients with a resected primary. Grade 3/4 adverse events occurred in eight (57%) patients during days 0-60. There was one sudden death and another patient who died from possible treatment-related liver failure 7.0 months after SIRT. CONCLUSIONS: SIRT and chemotherapy appears to be an effective treatment for liver metastases from pancreatic cancer, likely to be of most benefit in selected patients with a resected primary tumour and liver only disease. Significant toxicity was observed and the safety of this approach in patients with metastatic pancreatic cancer will need to be confirmed in subsequent studies. Further study is warranted with SIRT and modern chemotherapies. TRIAL REGISTRATION: ACTRN12606000015549.

Scientific basis of personalised tomographic radiation planning for radioembolisation: A form of brachytherapy planning.

Today's tomographic imaging techniques such as catheter-directed CT and single photon emission computed tomography with integrated computed tomography may be used for pre-therapy radiation planning for radioembolisation based on prospective calculation of tissue radiation absorbed doses. We outline the scientific concepts that underlie modern personalised tomographic radiation planning for radioembolisation and highlight its similarities to brachytherapy planning.

Quantitative assessment of thyroid-to-background ratio improves the interobserver reliability of technetium-99m sestamibi thyroid scintigraphy for investigation of amiodarone-induced thyrotoxicosis.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is caused by excessive hormone synthesis and release (AIT I), a destructive thyroiditis (AIT II), or a combination of both (AIT Ind). Although no gold-standard diagnostic test is available, technetium-99m sestamibi thyroid scintigraphy (99mTc-STS) has been previously reported to be an accurate tool for differentiating subtypes with important therapeutic implications. However, the information to guide reporting of 99mTc-STS is qualitative and highly subjective. This study aims to compare the interobserver reliability of 99mTc-STS before and after the use of quantitative thyroid-to-background ratios (TBRs) displayed on a time-activity curve for differentiation of AIT subtypes. METHODS: A retrospective audit of Nuclear Medicine Departments at Royal Melbourne Hospital (Parkville, Victoria, Australia) and Cabrini Hospital (Malvern, Victoria, Australia) identified 15 consecutive 99mTc-STS studies performed for AIT. Four nuclear medicine physicians reported the studies according to previously established criteria (series 1). Quantitative TBR and estimated 'normal' range TBR were subsequently provided before the studies were reordered and reported again (series 2). Interobserver reliability was calculated using Fleiss' κ statistic for each assessment. RESULTS: The overall percentage of agreement (PoA) and κ statistics for use of conventional 99mTc-STS for diagnosis of AIT improved from 47 to 80% and from 0.30 to 0.67 following the use of quantitative TBR displayed on a time-activity curve with reference to a normal population. Interobserver reliability improved substantially under all diagnostic comparisons, particularly for differentiation of either AIT I (PoA 80% to 94%, κ: 0.48 to 0.84) or AIT Ind (PoA 47% to 82%, κ: -0.05 to 0.51) from other types of AIT. CONCLUSION: Use of quantitative TBR improves the interobserver reliability of reporting 99mTc-STS for investigation of different types of AIT. There is 'almost perfect' agreement upon differentiation of AIT I from AIT II and AIT Ind, with important implications for rationalizing the use of corticosteroid therapy. Prospective identification of AIT Ind is improved from 'poor' to a 'moderate' level of agreement to facilitate rational use of combination therapy at diagnosis.

Factors influencing radioiodine uptake after thyroid cancer surgery.

BACKGROUND: Total thyroidectomy followed by radioactive iodine (RAI) ablation is indicated for most patients with differentiated thyroid cancer. There have been no quantitative studies testing factors that affect uptake on post-ablation whole body scan. We hypothesized greater RAI uptake in patients who underwent two-stage total thyroidectomy (diagnostic hemithyroidectomy followed by completion thyroidectomy) compared to patients who underwent one-stage total thyroidectomy. METHODS: Medical records and whole body scan images of thyroid cancer patients were reviewed. Thyroid uptake as a percentage of Iodine-131 dose was calculated for each scan. RAI uptake was compared to procedure type, central lymph node dissection (CLND), extrathyroidal invasion, presence of thyroiditis and pre-operative diagnosis. RESULTS: One hundred six patients who underwent total thyroidectomy and RAI ablation for differentiated thyroid cancer were included. There was a trend to higher RAI uptake in patients who had undergone two-stage thyroidectomy compared to one-stage thyroidectomy (P = 0.06). CLND was associated significantly lower RAI uptake (P = 0.003). On multivariate analyses, CLND was the only variable that retained statistical significance (P = 0.023). CLND was performed more often in patients undergoing one-stage thyroidectomy (P = 0.001), as these patients' cancer diagnosis was known prior to surgery. CONCLUSION: RAI uptake appeared higher in two-stage thyroidectomy than one-stage thyroidectomy. This difference may be attributed to CLND being performed more often in one-stage thyroidectomy. These results add to the discussion about the role of CLND in surgery for differentiated thyroid cancer.

Myocardial perfusion imaging (MPI) is superior to the demonstration of distal collaterals in predicting cardiac events in chronic total occlusion (CTO).

BACKGROUND: In chronic total occlusion (CTO), the evidence for revascularization is less robust than for stable angina. A medical therapy strategy is common and often based on distal collateralization, regardless of the presence of ischemia. AIM: The aim of this study was to examine the correlation between distal collateralization, myocardial perfusion imaging (MPI), and hard cardiac events (HCE) in CTO. METHOD: Retrospective analysis of consecutive patients undergoing coronary angiography revealed 21 non-revascularized patients with CTO and MPI, over a 24-month period. Blinded review of patient charts, MPI, and angiography was undertaken. HCE of death, myocardial infarct, and unstable angina were assessed. Mean follow up was 23 months. RESULTS: Summed difference scores were calculated on a 17-segment model and collaterals graded on the Rentrop scale. 43% of patients had HCE, and 62% had collaterals. Ischemia on MPI accurately predicted HCE in CTO (60% vs 0%, P = .01). Distal collateralization failed to predict freedom from ischemia on MPI (31% vs 25%, P = .53) or HCE (31% vs 62%, P = .15). CONCLUSION: MPI in patients with CTO accurately predicted HCE. This allows for accurate triage of patients by MPI for consideration of revascularization. Patients without ischemia can be safely managed with optimal medical therapy. The presence of collateralization did not predict either ischemia or HCE.

Radioembolization in combination with systemic chemotherapy as first-line therapy for liver metastases from colorectal cancer.

PURPOSE: To report clinical experience with radioembolization (RE) plus systemic chemotherapy as a first-line treatment for liver metastases from colorectal cancer (CRC). MATERIALS AND METHODS: Clinical outcomes were evaluated retrospectively among 19 patients with unresectable liver metastases from CRC who had a good performance status and a low burden of extrahepatic disease (EHD) and were eligible for RE. Most (74%) had disease confined to the liver. Concurrent treatment with 5-fluorourail/leucovorin (n = 7) or 5-fluorourail/leucovorin/oxaliplatin (FOLFOX; n = 12) was started 3-4 days before single treatment with RE. RESULTS: Overall response rate according to the Response Evaluation Criteria in Solid Tumors was 84% (two complete responses and 14 partial responses). Median progression-free survival (PFS) time was 10.4 months and median overall survival (OS) time was 29.4 months. For patients with disease confined to the liver, PFS improved (10.7 mo vs 3.6 mo; P = .09), with significant prolongation of OS (median, 37.8 mo vs 13.4 mo; P = .03) compared with those who had EHD. Nine patients, including three long-term (> 3 y) survivors, remained alive after a median follow-up of 18.6 months. Serious treatment-related toxicities included febrile neutropenia with concurrent FOLFOX treatment, a perforated duodenal ulcer, and one death from hepatic toxicity. CONCLUSIONS: The present findings confirm the effectiveness of RE plus systemic chemotherapy for metastatic CRC. Patients with liver-confined disease derived the greatest benefit, with median survival times beyond 36 months. Larger datasets from ongoing phase III trials are needed to further define the safety and efficacy of RE in the first-line setting.

Biodistribution of canine leucocytes labelled with technetium-99m stannous fluoride colloid in whole blood and their ability to localise to sites of induced inflammation.

This study assessed the biodistribution of autologous leucocytes radiolabelled with technetium-99m stannous fluoride colloid (99mTcSnC) for detection of foci of induced inflammation in dogs. Venous blood was collected from seven healthy dogs and incubated with 99mTcSnC for 1h at room temperature. Radiolabelled samples were injected intravenously (IV) and the dogs were scanned using a gamma camera. Another seven healthy dogs were injected intradermally with tumour necrosis factor alpha and then IV with 99mTcSnC radiolabelled autologous blood 3h later before being scanned. The radiolabelled leucocytes localised to sites of inflammation by 30 min post-injection. IV injection of autologous leucocytes radiolabelled with 99mTcSnC appears to be a sensitive method for localisation of induced foci of inflammation in dogs.

Fixed defect on rest/stress Tc-99m sestamibi study underestimates myocardial ischemia: comparison with 24-hour thallium-201 study for short- and intermediate-term follow-up.

PURPOSE: We assessed whether a same day rest/stress gated Tc-99m sestamibi (MIBI) SPECT myocardial study underestimates reversible ischemia in patients with fixed perfusion defects compared with a 24-hour thallium-201 (Tl-201) study. The short- and intermediate-term outcome with or without Tl-201 reversibility was assessed. METHODS: Forty-nine consecutive patients with fixed MIBI defects received an additional Tl-201 study and were evaluated. Tl-201 was given to patients with a high clinical suspicion of underestimation of reversibility. Images were interpreted semiquantitatively by 3 nuclear medicine physicians using a 17-segment, 5-point model. A summed stress score (SSS) from stress MIBI images, a summed rest score (SRS) from Tl images, and a summed difference (SDS = SSS - SRS) score were calculated. SDS >3 indicated significant Tl-201 redistribution. Composite end points included acute myocardial infarction, unstable angina needing admission, cardiac death, or revascularization within 3 and 6 months. RESULTS: Fifteen of 49 patients showed no Tl-201 redistribution. Thirty-four of 49 (69%) patients had significant Tl-201 redistribution, and these patients had significantly higher cardiac events (CE) at 3 months (29% vs. 7%; P = 0.039), and higher at 6 months (32% vs. 7%; P = 0.027). These patients with CE had a larger amount of Tl-201 redistribution, mean SDS 8.6 vs. 5.3 (P = 0.047). Patients with significant Tl-201 redistribution had a lower left ventricular ejection fraction (mean 37%; P = 0.001). CONCLUSION: With short- and intermediate-term follow-up, our study shows a significant association towards fixed defects on the rest/stress MIBI study underestimating CE risk when compared with a delayed Tl-201 study, especially in patients with a large amount of Tl-201 redistribution. Hence, the addition of a Tl-201 study may be useful in the management of patients with large fixed MIBI defects, especially with a depressed left ventricular ejection fraction.

Results of strontium-89 therapy in patients with prostate cancer resistant to chemotherapy.

PURPOSE: Strontium-89 (Sr-89) chloride is an effective palliative treatment of the bone metastases of prostate cancer. Chemotherapy has also been shown to have a palliative benefit in this disease. We aimed to determine the benefits and complications of Sr-89 therapy in patients with prostate cancer who had become refractory to chemotherapy. We conducted a retrospective review of 14 treatments administered to 13 patients with chemotherapy-resistant and hormone-resistant prostate cancer. RESULTS: Of the 14 administered treatments, 8 (57%) resulted in improved pain control, with 2 patients able to stop analgesia. The median duration of response was 56 days. No prostate-specific antigen response was seen in the 8 patients tested. There was significant and prolonged bone marrow toxicity, with 6 patients requiring red blood cell transfusion. Prolonged thrombocytopenia was seen, with platelet counts remaining below baseline levels after treatment in all but one patient. Leukopenia was generally mild and not associated with infection. CONCLUSIONS: Sr-89 is an effective treatment of patients with chemotherapy-refractory prostate cancer, but careful and prolonged monitoring of hematologic parameters after therapy is required.