[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial.

BACKGROUND: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT. METHODS: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete. FINDINGS: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1). INTERPRETATION: These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease. FUNDING: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.

Delineation and agreement of FET PET biological volumes in glioblastoma: results of the nuclear medicine credentialing program from the prospective, multi-centre trial evaluating FET PET In Glioblastoma (FIG) study-TROG 18.06.

PURPOSE: The O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in Glioblastoma (FIG) trial is an Australian prospective, multi-centre study evaluating FET PET for glioblastoma patient management. FET PET imaging timepoints are pre-chemoradiotherapy (FET1), 1-month post-chemoradiotherapy (FET2), and at suspected progression (FET3). Before participant recruitment, site nuclear medicine physicians (NMPs) underwent credentialing of FET PET delineation and image interpretation. METHODS: Sites were required to complete contouring and dynamic analysis by ≥ 2 NMPs on benchmarking cases (n = 6) assessing biological tumour volume (BTV) delineation (3 × FET1) and image interpretation (3 × FET3). Data was reviewed by experts and violations noted. BTV definition includes tumour-to-background ratio (TBR) threshold of 1.6 with crescent-shaped background contour in the contralateral normal brain. Recurrence/pseudoprogression interpretation (FET3) required assessment of maximum TBR (TBRmax), dynamic analysis (time activity curve [TAC] type, time to peak), and qualitative assessment. Intraclass correlation coefficient (ICC) assessed volume agreement, coefficient of variation (CoV) compared maximum/mean TBR (TBRmax/TBRmean) across cases, and pairwise analysis assessed spatial (Dice similarity coefficient [DSC]) and boundary agreement (Hausdorff distance [HD], mean absolute surface distance [MASD]). RESULTS: Data was accrued from 21 NMPs (10 centres, n ≥ 2 each) and 20 underwent review. The initial pass rate was 93/119 (78.2%) and 27/30 requested resubmissions were completed. Violations were found in 25/72 (34.7%; 13/12 minor/major) of FET1 and 22/74 (29.7%; 14/8 minor/major) of FET3 reports. The primary reasons for resubmission were as follows: BTV over-contour (15/30, 50.0%), background placement (8/30, 26.7%), TAC classification (9/30, 30.0%), and image interpretation (7/30, 23.3%). CoV median and range for BTV, TBRmax, and TBRmean were 21.53% (12.00-30.10%), 5.89% (5.01-6.68%), and 5.01% (3.37-6.34%), respectively. BTV agreement was moderate to excellent (ICC = 0.82; 95% CI, 0.63-0.97) with good spatial (DSC = 0.84 ± 0.09) and boundary (HD = 15.78 ± 8.30 mm; MASD = 1.47 ± 1.36 mm) agreement. CONCLUSION: The FIG study credentialing program has increased expertise across study sites. TBRmax and TBRmean were robust, with considerable variability in BTV delineation and image interpretation observed.

[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial.

BACKGROUND: Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers ß radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. METHODS: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. FINDINGS: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. INTERPRETATION: [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.

BACKGROUND: Conventional imaging using CT and bone scan has insufficient sensitivity when staging men with high-risk localised prostate cancer. We aimed to investigate whether novel imaging using prostate-specific membrane antigen (PSMA) PET-CT might improve accuracy and affect management. METHODS: In this multicentre, two-arm, randomised study, we recruited men with biopsy-proven prostate cancer and high-risk features at ten hospitals in Australia. Patients were randomly assigned to conventional imaging with CT and bone scanning or gallium-68 PSMA-11 PET-CT. First-line imaging was done within 21 days following randomisation. Patients crossed over unless three or more distant metastases were identified. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant-metastatic disease defined by the receiver-operating curve using a predefined reference-standard including histopathology, imaging, and biochemistry at 6-month follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry, ANZCTR12617000005358. FINDINGS: From March 22, 2017 to Nov 02, 2018, 339 men were assessed for eligibility and 302 men were randomly assigned. 152 (50%) men were randomly assigned to conventional imaging and 150 (50%) to PSMA PET-CT. Of 295 (98%) men with follow-up, 87 (30%) had pelvic nodal or distant metastatic disease. PSMA PET-CT had a 27% (95% CI 23-31) greater accuracy than that of conventional imaging (92% [88-95] vs 65% [60-69]; p<0·0001). We found a lower sensitivity (38% [24-52] vs 85% [74-96]) and specificity (91% [85-97] vs 98% [95-100]) for conventional imaging compared with PSMA PET-CT. Subgroup analyses also showed the superiority of PSMA PET-CT (area under the curve of the receiver operating characteristic curve 91% vs 59% [32% absolute difference; 28-35] for patients with pelvic nodal metastases, and 95% vs 74% [22% absolute difference; 18-26] for patients with distant metastases). First-line conventional imaging conferred management change less frequently (23 [15%] men [10-22] vs 41 [28%] men [21-36]; p=0·008) and had more equivocal findings (23% [17-31] vs 7% [4-13]) than PSMA PET-CT did. Radiation exposure was 10·9 mSv (95% CI 9·8-12·0) higher for conventional imaging than for PSMA PET-CT (19·2 mSv vs 8·4 mSv; p<0·001). We found high reporter agreement for PSMA PET-CT (κ=0·87 for nodal and κ=0·88 for distant metastases). In patients who underwent second-line image, management change occurred in seven (5%) of 136 patients following conventional imaging, and in 39 (27%) of 146 following PSMA PET-CT. INTERPRETATION: PSMA PET-CT is a suitable replacement for conventional imaging, providing superior accuracy, to the combined findings of CT and bone scanning. FUNDING: Movember and Prostate Cancer Foundation of Australia. VIDEO ABSTRACT.

Comparison of glomerular filtration rates determined using two- and single-blood sample methods with a three-blood sample technique for 2922 paediatric studies.

OBJECTIVE: Several different methods for measuring glomerular filtration rates (GFRs) have been developed in search of a more accurate and simplified technique. Currently, the main methods used are the slope-intercept and distribution volume techniques. In this work, 2922 GFR studies have been retrospectively reanalysed as two- and single-blood sample methods and compared with the three-blood sample data. PATIENTS AND METHODS: Paediatric GFR data from 1/1/1993 to 4/12/2018 using the three-blood sample technique have been reanalysed as two- and single-blood sample methods. The timing of blood sampling was also reviewed. RESULTS: Both the two- and the single-sample methods provide accurate estimates of GFR in children for all levels of renal function provided that the blood samples are collected at the appropriate times post administration of the tracer. For the highest accuracy, blood for the two-blood samples method should be collected at 2 and 4 h and at 2 h for the single-blood sample method. The relationship between renal clearance and the 2-h volume of distribution (V120) is linear with a line of best fit: GFR (ml/min) = 3.108 × V120 - 2.557. CONCLUSION: Both the two- and the single-sample techniques can be used to measure GFR in children with the same accuracy as the three-blood sample. With the collection of only a single-blood sample, there are benefits to all involved: patients, families, and nuclear medicine personnel. In addition, institutions have a choice as to which technique to use and for which patients.

Radioiodine (131I) therapy in a child with autism spectrum disorder: A complex and demanding task.

In January 2017, an 11.5-year-old male child with autism was referred for radioiodine (RAI) therapy post total thyroidectomy for papillary thyroid carcinoma. The treatment required swallowing a RAI capsule and remaining isolated (48-72 h). Initially, obstacles to a successful treatment seemed insurmountable as he had complex needs and behavioral issues due to his autism, mild intellectual disability, and family environment. His mother was adamant that he would not be able to swallow the capsule and comply with the required isolation period. A multidisciplinary team was formed to explore options for successful treatment. Each option considered had its own risks and challenges. Behavioral therapy was considered to be the only possible option. It was pursued with regular, frequent contact between the child, his parents, and members of the team for counseling and behavioral modification, familiarization of the child with the staff, procedures, trial visits, and admission. The patient was successfully treated in October 2017.

Radioiodine (131I) therapies performed in a paediatric hospital: facilities and procedures.

Radioiodine (131I) therapies on younger children with thyroid cancer and neuroblastoma can be challenging as they are required to be isolated for a period of time due to radiation safety concerns. At our hospital these therapies are performed in a purpose-built child-friendly therapy room. Nursing staff are able to provide personal care during the isolation period with minimum radiation exposure. Patients are provided with various age-appropriate entertainment items such as iPad, X-Box, DVD, craft and books to keep them entertained while in isolation. Parents can communicate freely with their child via the audio-visual system located in the Ward Parent Lounge and can also stay in the shielded part of the ante room of the therapy room. Nursing staff can communicate with the patient via a similar audio-visual system located in the nurses station so that they only need to enter the therapy room when they are required to provide personal patient care. All persons entering the therapy room are monitored with personal digital dosimeters. Patients accept the isolation period with minimal aggravation and the personal radiation exposures to staff, parents and visitors are well below the general public annual limit of 1000 µSv. The design and facilities of the therapy room with its child-friendly surroundings and support network makes the experience of the isolation period easier and positive for both patients and parents. For Graves' disease, the patients are treated as outpatients in the Department of Nuclear Medicine and are discharged within a short time after the radioiodine administration.

A review of paediatric administered radiopharmaceutical activities to determine compliance with prescription guidelines.

OBJECTIVE: Attempts are underway to standardize paediatric administered activities, but equally important is knowing the actual activities administered to patients. In this work, paediatric administered activities are reviewed to determine compliance with the institution-prescribed guidelines. PATIENTS AND METHODS: Paediatric administered activities for common studies at our institution, August 2011 to January 2017, have been analysed to determine their deviations from the set guideline tolerance of 10% from prescribed activities. RESULTS: The results for technetium-99m hydroxy diphosphonate (Tc-HDP), technetium-99m mercaptoacetyl triglycine (Tc-MAG3) and technetium-99m dimercaptosuccinic acid (Tc-DMSA), are presented here. Tc-MAG3 mean activities were close to the tolerance guideline at 10.3% SD. For Tc-HDP and Tc-DMSA, the prescribed guidelines were reviewed and reduced in May 2014 and September 2015, respectively. SDs for these studies over the two acquisition periods were different (8.9 and 6.6%, respectively, for Tc-HDP and 11.8 and 14.2%, respectively, for Tc-DMSA).The administered activities (dispensed minus residual activities) to patients depend on prescribed activities and dispensing and injecting techniques. Deviations from the prescribed activities are primarily because of issues related to residual activities, particularly with small activities prescribed in young patients. Small activities in small volumes make residual activities significant. The skill and experience of the nuclear medicine staff are essential in minimizing deviations from prescribed activities. CONCLUSION: It is important to measure residual to accurately determine the administered activities. If precautions are taken with dispensing and injecting techniques, it is possible to administer activities close to 10% of the prescribed activities. The regular review of the administered activities is essential to ensure that patients are not unnecessarily irradiated.

Comparison of effective I-131 half-life between thyroid hormone withdrawal and recombinant human thyroid-stimulating hormone for thyroid cancer: a retrospective study.

INTRODUCTION: Preparation for postoperative radioiodine ablation for differentiated thyroid carcinoma is performed by either thyroid hormone withdrawal or recombinant human thyroid-stimulating hormone (rhTSH) administration. There is little information on the impact of the method of preparation with respect to whole-body effective I-131 half-life and its potential clinical implications in the Australian setting. METHODS: A retrospective study was performed on patients admitted for adjuvant radioiodine ablation for non-metastatic differentiated thyroid carcinoma at the Royal Adelaide Hospital over a 4½-year period from 2009. Dose rate measurements were analysed for 19 rhTSH and 31 thyroid hormone withdrawal patients. RESULTS: The mean effective I-131 half-lives were 11.51 and 13.29 h for the rhTSH and thyroid hormone withdrawal groups, respectively, with no statistically significant difference between the two groups (P = 0.761). This result differs from previously published data where withdrawal periods were typically longer, resulting in slower renal clearance and longer half-lives for withdrawal patients. CONCLUSIONS: Our study did not demonstrate a significant difference in whole-body effective half-life of I-131 between the two methods of preparation for radioiodine ablation. This suggests that putative advantages of rhTSH over withdrawal in terms of whole-body radiation dose, duration of hospital admission and quality of life may be sensitive to duration of withdrawal.

Positron emission tomography changes management, improves prognostic stratification and is superior to gallium scintigraphy in patients with low-grade lymphoma: results of a multicentre prospective study.

PURPOSE: Positron emission tomography (PET) was evaluated in low-grade non-Hodgkin lymphoma (NHL) to determine its impact on staging and management and to compare PET and gallium scans. METHODS: PET resulted in management plan changes in 74 patients with untreated low-grade NHL stages I to III. Patient outcomes to 12 months were documented. RESULTS: PET identified additional lesions in 50% of patients, led to a change in stage in 32%, and had a significant impact on management in 34%. Inferior progression-free survival was noted in patients with additional lesions detected by PET (p=0.001) and in the 28% of patients upstaged by PET to stage III or IV (p=0.024). In a subset of 16 patients undergoing both PET and gallium scans, PET was found to be superior. CONCLUSION: PET has a major role in the management of low-grade NHL in addition to its proven role in aggressive lymphoma.

Use of [14C]-sodium bicarbonate/urea to measure total energy expenditure in overweight men and women before and after low calorie diet induced weight loss.

The aim of this study was to evaluate the use of the [14C]-sodium bicarbonate/urea technique to measure the change in total energy expenditure after weight loss and a period of weight maintenance. Eleven healthy subjects (6 men and 5 women aged 50 +/- 3 yrs, BMI 34.1 +/-2.1 kg/ m2, body fat 38.7 +/-3%) underwent 8 weeks of energy restriction using a combination of "Modifast" formula and one small meal per day (approximately 3.3 MJ/day). For an additional 2 weeks, subjects resumed a solid food diet that contained enough energy to stabilize body weight at the newly reduced level. Body composition, total energy expenditure (TEE), resting energy expenditure (REE) and the thermic effect of a 2.7 MJ test meal (TEF) were measured at both weeks 0 and 10. At week 10 as compared to week 0, body weight decreased by 12.2+/-1.6 kg (12.5%)(P<0.001). Total fat and lean mass decreased by 8.4+/-1.0 kg (20.4%) and 3.8+/-0.7 kg (6.7%), respectively (P< 0.001). REE decreased by 500+/-128 kJ/day (5.6+/-1.3%)(P<0.002). Decreases in the TEE (0.18 +/-;3.7%)and TEF(1.4+/-0.9%) were not significant. In conclusion, although [14C]-sodium bicarbonate/urea was well tolerated and did not interfere with normal daily activities, it did not have sufficient sensitivity to accurately measure weight loss induced changes in TEE in the range of 0.1-10%.

Use of [14C]-sodium bicarbonate/urea to measure physical activity induced increases in total energy expenditure in free-living healthy males.

The aim of this study was to evaluate the utility of the [(14)C]-sodium bicarbonate/urea technique to detect physical activity-induced increases in total energy expenditure in free-living healthy men. Thirteen healthy males aged 34.1 +/- 11.7 yrs with body mass index 24.1 +/- 3.1 kg/m(2) were studied on three separate occasions, during which [(14)C]-bicarbonate was infused over 48-hours and urine was collected during the second 24-hours. On three separate occasions and in random order, subjects either remained sedentary, or performed a bout of physical activity on an electro-magnetically braked cycle ergometer sufficient to increase energy expenditure by 7% or 11% above predicted sedentary total energy expenditure. Urine samples were analyzed to evaluate the amount of [(14)C]-bicarbonate incorporated into urinary urea, thereby reflecting the amount of CO(2) produced per day, and upon conversion, the number of kilojoules of energy expended in 24-hours. All 13 subjects successfully completed the two physical activity treatments and there were no adverse events. As measured by the [(14)C]-urea assay, mean total energy expenditure values were not significantly different between sedentary activity (17902 +/- 905 kJ/day), the physical activity treatment designed to increase TEE by 7% (17701 +/- 594 kJ/day) and the physical activity treatment designed to increase TEE by 11% (18538 +/- 485 kJ/day) (P=0.668). In conclusion, although the [(14)C]-sodium bicarbonate/urea technique was well tolerated and did not interfere with normal daily activities, it was not able to accurately measure physical activity-induced increases in EE in the range of 7-11% above predicted sedentary total energy expenditure.

Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction.

OBJECTIVES: This study was designed to explore the relationships of early diabetic microangiopathy to alterations of cardiac sympathetic tone and myocardial blood flow (MBF) regulation in subjects with stable type 1 diabetes. BACKGROUND: In diabetes, augmented cardiac sympathetic tone and abnormal MBF regulation may predispose to myocardial injury and enhanced cardiac risk. METHODS: Subject groups comprised healthy controls (C) (n = 10), healthy diabetic subjects (DC) (n = 12), and diabetic subjects with very early diabetic microangiopathy (DMA+) (n = 16). [(11)C]meta-hydroxyephedrine ([(11)C]HED) and positron emission tomography (PET) were used to explore left ventricular (LV) sympathetic integrity and [(13)N]ammonia-PET to assess MBF regulation in response to cold pressor testing (CPT) and adenosine infusion. RESULTS: Deficits of LV [(11)C]HED retention were extensive and global in the DMA+ subjects (36 +/- 31% vs. 1 +/- 1% in DC subjects; p < 0.01) despite preserved autonomic reflex tests. On CPT, plasma norepinephrine excursions were two-fold greater than in C and DC subjects (p < 0.05), and basal LV blood flow decreased (-12%, p < 0.05) in DMA+ but not in C or DC subjects (+45% and +51%, respectively). On adenosine infusion, compared with C subjects, MBF reserve decreased by approximately 45% (p < 0.05) in DMA+ subjects. Diastolic dysfunction was detected by two-dimensional echocardiography in 5 of 8 and 0 of 8 consecutively tested DMA+ and DC subjects, respectively. CONCLUSIONS: Augmented cardiac sympathetic tone and responsiveness and impaired myocardial perfusion may contribute to myocardial injury in diabetes.

Role of FDG-PET in surgical management of patients with colorectal liver metastases.

BACKGROUND: [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is reported to change the management in 20-56% of patients with recurrent or metastatic colorectal cancer. It is not clear if FDG-PET has a role in all such patients or only a subgroup. The aim of the present study was to assess the influence of FDG-PET on the surgical management of patients with known or suspected colorectal liver metastases. METHODS: Patients undergoing FDG-PET for investigation of known or suspected colorectal liver metastases were identified from a South Australian database. Case notes were reviewed retrospectively to determine the influence of FDG-PET findings on patient management. Findings from FDG-PET scanning were compared with findings from conventional diagnostic investigations and operative findings. RESULTS: Overall, in four of 16 patients (25%) management was influenced by FDG-PET findings. FDG-PET altered management in four of eight (50%) patients with non-diagnostic liver lesions on computed tomography (CT) or with elevated carcinoembryonic antigen levels but no liver lesion on CT. In all eight patients with CT diagnosed resectable liver metastases, the addition of FDG-PET did not influence the management. CONCLUSIONS: The findings support the use of FDG-PET in the assessment of selected patients with suspected colorectal liver metastases and equivocal findings on conventional diagnostic investigation.

Erythema nodosum associated with diffuse, large B-cell non-Hodgkin lymphoma detected by FDG PET.

A patient is described with non-Hodgkin lymphoma and erythematous skin nodules suspected to be erythema nodosum. The patient underwent serial fluorodeoxyglucose (FDG) positron emission tomography (PET), which demonstrated normalization of FDG uptake by the lymphoma after 2 cycles of chemotherapy, but there was new abnormal uptake involving the subcutaneous tissues of the lower extremities. A typical skin lesion was sampled and showed the appearance of erythema nodosum with no evidence of lymphoma. The FDG uptake gradually diminished on serial PET imaging after treatment with nonsteroidal antiinflammatory drugs. In view of the recognized association of erythema nodosum with malignancy and the differential rate of response to chemotherapy, the lesions of erythema nodosum may be a source of a false-positive PET interpretation, and histologic assessment should be considered.

Liquid gastric emptying in the pig: effect of concentration of inhaled isoflurane.

UNLABELLED: An animal model of gastric emptying may have use in the study of gastric physiology and pharmacoscintigraphy. The pig has anatomy and physiology similar to that of humans. Our aim was to develop a model of gastric emptying in the pig. It was not possible to perform this study in conscious pigs; therefore, an anesthetic model was developed. METHODS: Fifteen studies were performed on 4 pigs (age, 2-6 mo; weight, 20-100 kg). After acclimatization and training, pigs were fasted overnight before the study. Pigs were anesthetized using inhaled isoflurane without the use of injected premedication agents. An orogastric tube was inserted for the administration of a liquid meal, which consisted of (99m)Tc-diethylenetriaminepentaacetic acid either in water (nonnutrient) or with dextrose (nutrient meal). The pig was laterally positioned to enable right lateral dynamic acquisition to be performed. Anesthesia was maintained at 2% +/- 0.5% isoflurane in 4 studies and 0.8% +/- 0.5% in 11 studies (4 nutrient, 7 nonnutrient). RESULTS: With 2% +/- 0.5% isoflurane, there was delayed gastric emptying with a mean 50% emptying time (+/-SEM) of 141 +/- 14 min. With 0.8% +/- 0.5% isoflurane, the liquid meal emptied in an exponential manner similar to that of humans, with mean 50% emptying times (+/-SEM) of 30 +/- 7 min (nutrient) and 31 +/- 4 min (nonnutrient). CONCLUSION: The results indicate that high-dose anesthesia inhibits gastric emptying, but with low-dose anesthesia a useful pig model of liquid gastric emptying can be developed.