Prospective analysis of the utility of 18-FDG PET in Merkel cell carcinoma of the skin: A Trans Tasman Radiation Oncology Group Study, TROG 09:03.

INTRODUCTION: TROG 09.03 prospectively studied the utility of Fluorine-18 Fluorodeoxyglucose (18-FDG) PET in the management of Merkel cell carcinoma of skin. METHODS: Following consent and registration, a pre-treatment FDG-PET/CT was performed. Sites of avid disease were confirmed by cytology where practicable. Following surgery, patients with AJCCv7 Stages IIA-IIIB disease were treated with chemo-radiotherapy and reassessed with a post-treatment PET. RESULTS: Fifty-eight subjects (45 males and 13 females, median age 68 years) were enrolled between 2011 and 2015, 43 patients of whom went on to receive chemo-radiotherapy. An occult primary was present in 22 (37.9%), T1 in 22 (37.9%) and T2 disease in 14 (24.1%). Nodal disease was present in 69% of cases. Fifty per cent of subjects had gross residual disease at the primary site and/or nodal site at the time of registration. 18-FDG PET/CT had a sensitivity of 94.74% (95% CI 82-99.3%) and a specificity of 88.24% (95% CI 63.56-98.54). The positive predictive value was 94.74% (83.01-98.51) and the negative predictive value was 88.24% (95% CI 65.81-96.69). The pre-treatment PET influenced a treatment decision in 27.6% of cases. Upstaging occurred in 15 (25.9%), with no down staging. Other diseases were identified in 4 (6.9%) patients. Univariate analysis failed to demonstrate that pre-treatment SUV levels or a negative post-treatment PET had any impact on overall survival. PET staged patients had 89% 3-year in-field loco-regional control and 76% 3-year overall survival. CONCLUSION: Staging 18-FDG-PET significantly influenced treatment decisions in approximately one-third of cases of MCC and should be considered in the routine pre-treatment work-up. Post-treatment PET was not found to be prognostic. Funding through the Medicare Benefits Schedule needs to be considered for high risk MCC.

A prospective study of the impact of fluorodeoxyglucose positron emission tomography with concurrent non-contrast CT scanning on the management of operable pancreatic and peri-ampullary cancers.

BACKGROUND: The role of fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) scanning in operable pancreas cancer is unclear. We, therefore, wanted to investigate the impact of PET/CT on management, by incorporating it into routine work-up. METHODS: This was a single-institution prospective study. Patients with suspected and potentially operable pancreas, distal bile duct or ampullary carcinomas underwent PET/CT in addition to routine work-up. The frequency that PET/CT changed the treatment plan or prompted other investigations was determined. The distribution of standard uptake values (SUV) among primary tumours, and adjacent to biliary stents was characterised. RESULTS: Fifty-six patients were recruited. The surgical plan was abandoned in 9 (16%; 95% CI: 6-26) patients as a result of PET/CT identified metastases. In four patients, metastases were missed and seven were inoperable at surgery, not predicted by PET/CT. Unexpected FDG uptake resulted in seven additional investigations, of which two were useful. Among primary pancreatic cancers, a median SUV was 4.9 (range 2-12.1). SUV was highest around the biliary stent in 17 out of 28 cases. PET/CT detected metastases in five patients whose primary pancreatic tumours demonstrated mild to moderate avidity (SUV < 5). CONCLUSIONS: PET/CT in potentially operable pancreas cancer has limitations. However, as a result of its ability to detect metastases, PET/CT scanning is a useful tool in the selection of such patients for surgery.

5α-reductase type 1 modulates insulin sensitivity in men.

CONTEXT: 5α-Reductase (5αR) types 1 and 2 catalyze the A-ring reduction of steroids, including androgens and glucocorticoids. 5α-R inhibitors lower dihydrotestosterone in benign prostatic hyperplasia; finasteride inhibits 5αR2, and dutasteride inhibits both 5αR2 and 5αR1. In rodents, loss of 5αR1 promotes fatty liver. OBJECTIVE: Our objective was to test the hypothesis that inhibition of 5αR1 causes metabolic dysfunction in humans. DESIGN, SETTING, AND PARTICIPANTS: This double-blind randomized controlled parallel group study at a clinical research facility included 46 men (20-85 years) studied before and after intervention. INTERVENTION: Oral dutasteride (0.5 mg daily; n = 16), finasteride (5 mg daily; n = 16), or control (tamsulosin; 0.4 mg daily; n = 14) was administered for 3 months. MAIN OUTCOME MEASURE: Glucose disposal was measured during a stepwise hyperinsulinemic-euglycemic clamp. Data are mean (SEM). RESULTS: Dutasteride and finasteride had similar effects on steroid profiles, with reduced urinary androgen and glucocorticoid metabolites and reduced circulating DHT but no change in plasma or salivary cortisol. Dutasteride, but not finasteride, reduced stimulation of glucose disposal by high-dose insulin (dutasteride by -5.7 [3.2] µmol/kg fat-free mass/min, versus finasteride +7.2 [3.0], and tamsulosin +7.0 [2.0]). Dutasteride also reduced suppression of nonesterified fatty acids by insulin and increased body fat (by 1.6% [0.6%]). Glucose production and glycerol turnover were unchanged. Consistent with metabolic effects of dutasteride being mediated in peripheral tissues, mRNA for 5αR1 but not 5αR2 was detected in human adipose tissue. CONCLUSION: Dual inhibition of 5αRs, but not inhibition of 5αR2 alone, modulates insulin sensitivity in human peripheral tissues rather than liver. This may have important implications for patients prescribed dutasteride for prostatic disease.

The 'double pituitary hot spot' sign of skull base meningioma on gallium-68-labelled somatostatin analogue PET.

Gallium-68 ((68) Ga)-labelled somatostatin analogue imaging by positron emission tomography (PET) is increasingly replacing single photon (such as (111) In-labelled octreotide) imaging in the detection and staging of carcinoid and other neuroendocrine tumours. Among other tissues, pituitary uptake of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-octreotate (DOTA-TATE) and other somatostatin analogues is physiological. DOTA-TATE also accumulates in meningiomas, which have a high density of somatostatin receptor expression. The combination of pituitary and skull base meningioma uptake results in a characteristic 'double hot spot' appearance, which indicates the presence of a meningioma. This is a case of a middle-aged woman who underwent (68) Ga-DOTA-TATE PET for confirmation and staging of clinically suspected carcinoid tumour, in whom a skull base meningioma was incidentally discovered. With the increasing use of PET in the management of neuroendocrine tumours - and the not infrequent occurrence of meningiomas - the appearance of meningiomas on somatostatin analogue imaging should be one with which reporting clinicians are familiar.

Subclinical and asymptomatic parathyroid disease: implications of emerging data.

Primary hyperparathyroidism, a disorder in which there is a tendency for hypercalcaemia caused by autonomous overproduction of parathyroid hormone, is common, especially in postmenopausal women. Although parathyroidectomy is indicated for symptomatic patients, most individuals with the disorder are asymptomatic and without classic complications, such as renal stones and osteoporosis, at diagnosis. Consensus guidelines suggest which individuals might be suitable for medical follow-up rather than parathyroidectomy, but there are no long-term randomised controlled trials to support the safety of medical surveillance, and some patients progress with time. Data from observational studies suggest that cardiovascular morbidity and mortality are increased in patients with primary hyperparathyroidism, and might be predicted by parathyroid hormone concentrations, even in individuals with asymptomatic primary hyperparathyroidism. Whether parathyroidectomy improves cardiovascular outcomes in patients with asymptomatic primary hyperparathyroidism is unproven, but data suggest that surgery decreases fracture risk and might improve neuropsychological symptoms. Studies also show that patients with normocalcaemic (subclinical) hyperparathyroidism and hypoparathyroidism have a low risk of progression to overt disease, but their long-term risks are not defined. In this Review, we explore the increasing range of asymptomatic parathyroid disorders, focusing on current evidence about their natural history and potential complications, with a particular emphasis on primary hyperparathyroidism.

Should 'mild primary hyperparathyroidism' be reclassified as 'insidious': is it time to reconsider?

Primary hyperparathyroidism (PHPT) is a common incidental finding on routine biochemical testing, affecting around 1% of the population. The majority of individuals will be asymptomatic at diagnosis, with no evidence of end organ damage, and unless individuals aged <50 years at diagnosis, they are often considered to have 'mild' PHPT, as they do not meet published criteria for parathyroidectomy (PTX). However, there is increasing evidence that 'mild' PHPT is associated with adverse health outcomes. Long-term observational studies describing the natural history of 'mild' PHPT suggest that even though biochemistry may be relatively stable in the majority, bone mineral density (BMD) does decline after approximately 10 years of observation, whereas significant improvements in BMD are seen following PTX. Recent large European record linkage studies of 'mild PHPT' demonstrate significantly increased all-cause and cardiovascular mortality, similar to rates published for patients with PHPT who meet the NIH surgical criteria. 'Mild' PHPT was also associated with increased admissions for nonfatal cardiovascular disease, renal failure, renal stones, fractures, hypertension, psychiatric disease, cancer and diabetes, suggesting that 'insidious' PHPT may be a more appropriate description, or at least that the term 'mild' should be abandoned. Randomized controlled trials (RCTs) have begun to explore the benefits of PTX in this condition, demonstrating improvements in BMD and some psychiatric outcomes at approximately 2 years of follow-up. However, larger, adequately powered, long-term, RCTs will be required to determine whether PTX improves potential long-term morbidity and mortality in patients with PHPT who do not meet standard surgical criteria.

Changes in 18F-fluorodeoxyglucose and 18F-fluorodeoxythymidine positron emission tomography imaging in patients with non-small cell lung cancer treated with erlotinib.

PURPOSE: Assessing clinical activity of molecularly targeted anticancer agents, especially in the absence of tumor shrinkage, is challenging. To evaluate on-treatment 18F-fluorodeoxyglucose (FDG) and/or 18F-fluorodeoxythymidine (FLT) positron emission tomography (PET) for this purpose, we conducted a prospective multicenter trial assessing PET response rates and associations with progression-free (PFS) and overall survival (OS) in 2nd/3rd-line non-small-cell lung cancer patients treated with erlotinib. EXPERIMENTAL DESIGN: PET/computed tomography (CT) scans were conducted at baseline, day (d)14 and d56 after the first daily erlotinib dose, with diagnostic CT at baseline and d56 (all scans centrally reviewed). PET partial metabolic response (PMR) was defined as a mean decrease (in ≤ 5 lesions/patient) of 15% or more maximum standardized uptake value. PFS was investigator-determined. RESULTS: Of 74 erlotinib-treated patients, 51 completed all imaging assessments through d56; 13 of 51 (26%) FDG-evaluable patients had PMR at d14, as did 9 of 50 (18%) FLT-evaluable patients. Four (7.8%) showed partial responses (PR) by d56 CT; all 4 had PMR by d14 FDG-PET with 3 PMRs by d14 FLT-PET. Three of the 4 patients with CT PR had evaluable archival tumor tissue; all 3 had epidermal growth factor receptor mutations. D14 and d56 PMRs by FDG or FLT were associated with improved PFS; HRs for PET responders versus nonresponders were 0.3 to 0.4. D14 FDG-PET PMR was associated with improved OS (P = 0.03) compared with FDG-PET nonresponders. CONCLUSION: Early (d14) FDG-PET PMR is associated with improved PFS and OS, even in the absence of subsequent Response Evaluation Criteria in Solid Tumors response. These data support inclusion of FDG-PET imaging in clinical trials testing novel targeted therapies, particularly those with anticipated cytostatic effects.

Compliance with PET acquisition protocols for therapeutic monitoring of erlotinib therapy in an international trial for patients with non-small cell lung cancer.

PURPOSE: The Response Evaluation Criteria in Solid Tumors (RECIST) are widely used but have recognized limitations. Molecular imaging assessments, including changes in (18)F-deoxyglucose (FDG) or (18)F-deoxythymidine (FLT) uptake by positron emission tomography (PET), may provide earlier, more robust evaluation of treatment efficacy. METHODS: A prospective trial evaluated on-treatment changes in FDG and FLT PET imaging among patients with relapsed or recurrent non-small cell lung cancer treated with erlotinib to assess the relationship between PET-evaluated response and clinical outcomes. We describe an audit of compliance with the study imaging charter, to establish the feasibility of achieving methodological consistency in a multicentre setting. RESULTS: Patients underwent PET scans at baseline and approximately day 14 and day 56 of treatment (n = 73, 66 and 51 studies, and n = 73, 63 and 50 studies for FDG PET and FLT PET, respectively). Blood glucose levels were within the target range for all FDG PET scans. Charter-specified uptake times were achieved in 86% (63/73) and 89% (65/73) of baseline FDG and FLT scans, respectively. On-treatment scans were less consistent: 72% (84/117) and 68% (77/113), respectively, achieved the target of ±5 min of baseline uptake time. However, 96% (112/117) and 94% (106/113) of FDG and FLT PET studies, respectively, were within ±15 min. Bland-Altman analysis of intra-individual hepatic average standardized uptake value (SUV(ave)), to assess reproducibility, showed only a small difference in physiological uptake (-0.006 ± 0.224 in 118 follow-up FDG scans and 0.09 ± 0.81 in 111 follow-up FLT scans). CONCLUSION: It is possible to achieve high reproducibility of scan acquisition methodology, provided that strict imaging compliance guidelines are mandated in the study protocol.

Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis.

The pathological mechanisms that distinguish simple steatosis from steatohepatitis (or NASH, with consequent risk of cirrhosis and hepatocellular cancer) remain incompletely defined. Whereas both a methionine- and choline-deficient diet (MCDD) and a choline-deficient diet (CDD) lead to hepatic triglyceride accumulation, MCDD alone is associated with hepatic insulin resistance and inflammation (steatohepatitis). We used metabolic tracer techniques, including stable isotope ([¹³C4]palmitate) dilution and mass isotopomer distribution analysis (MIDA) of [¹³C2]acetate, to define differences in intrahepatic fatty acid metabolism that could explain the contrasting effect of MCDD and CDD on NASH in C57Bl6 mice. Compared with control-supplemented (CS) diet, liver triglyceride pool sizes were similarly elevated in CDD and MCDD groups (24.37 ± 2.4, 45.94 ± 3.9, and 43.30 ± 3.5 µmol/liver for CS, CDD, and MCDD, respectively), but intrahepatic neutrophil infiltration and plasma alanine aminotransferase (31 ± 3, 48 ± 4, 231 ± 79 U/l, P < 0.05) were elevated only in MCDD mice. However, despite loss of peripheral fat in MCDD mice, neither the rate of appearance of palmitate (27.2 ± 3.5, 26.3 ± 2.3, and 28.3 ± 3.5 µmol·kg⁻¹·min⁻¹) nor the contribution of circulating fatty acids to the liver triglyceride pool differed between groups. Unlike CDD, MCDD had a defect in hepatic triglyceride export that was confirmed using intravenous tyloxapol (142 ± 21, 122 ± 15, and 80 ± 7 mg·kg⁻¹·h⁻¹, P < 0.05). Moreover, hepatic de novo lipogenesis was significantly elevated in the MCDD group only (1.4 ± 0.3, 2.3 ± 0.4, and 3.4 ± 0.4 µmol/day, P < 0.01). These findings suggest that important alterations in hepatic fatty acid metabolism may promote the development of steatohepatitis. Similar mechanisms may predispose to hepatocyte damage in human NASH.

Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice.

BACKGROUND & AIMS: Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5beta-reductase. METHODS: The effect of bile acids on glucocorticoid metabolism was studied in vitro in hepatic subcellular fractions and hepatoma cells, allowing quantitation of the kinetics and transcript abundance of 5beta-reductase. Metabolism was subsequently examined in vivo in rats following dietary manipulation or bile duct ligation. Finally, glucocorticoid metabolism was assessed in humans with obstructive jaundice. RESULTS: In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5beta-reductase (K(i) 9.19+/-0.40 microM) and reduced its transcript abundance (in H4iiE cells) and promoter activity (reporter system, HepG2 cells). In Wistar rats, dietary chenodeoxycholic acid (1% w/w chow) inhibited hepatic 5beta-reductase activity, reduced urinary excretion of 3alpha,5beta-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5beta-reductase activity, supplementation of the fat-free diet with CDCA reduced 5beta-reductase activity, and urinary 3alpha,5beta-reduced corticosterone. Cholestasis in rats suppressed hepatic 5beta-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3alpha,5beta-tetrahydrocortisol was significantly lower than in healthy controls. CONCLUSION: These data suggest a novel role for bile acids in inhibiting hepatic glucocorticoid clearance, of sufficient magnitude to suppress hypothalamic-pituitary-adrenal axis activity. Elevated hepatic bile acids may account for adrenal insufficiency in liver disease.

Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers.

PURPOSE: This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti-Lewis Y (Le(y)) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Le(y) antigen. EXPERIMENTAL DESIGN: The primary objectives were to determine biodistribution and pharmacokinetics of CMD-193. Secondary objectives included response rates and change in tumor metabolism. Patients with progressive, measurable, and Le(y) positive malignancies were eligible for enrollment in one of two dose cohorts, 1.0 and 2.6 mg/m(2). The first cycle was trace labeled with (111)In for biodistribution assessment using gamma camera imaging. Subsequent cycles were administered every 3 weeks up to a maximum of six cycles, depending on toxicity and response. Pharmacokinetic analysis was based on radioassay and ELISA. RESULTS: Nine patients were enrolled in the study. Biodistribution images showed initial blood pool activity, followed by markedly increased hepatic uptake by day 2, and fast blood clearance in all patients. There was low uptake in tumor in all patients. The overall T(1/2)beta of (111)In-CMD-193 was 102.88 +/- 35.67 hours, with no statistically significant difference between the two dose levels. One patient had a partial metabolic response on (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG PET) after four cycles, but no radiological responses were observed. Myelosuppression and effects on liver function were the most significant adverse effects. CONCLUSIONS: CMD-193 shows rapid blood clearance and increased hepatic uptake compared with prior studies of the parental antibody hu3S193. These results highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development.

Nesidioblastosis as a cause of focal pancreatic 111In-pentetreotide uptake in a patient with putative VIPoma: another differential diagnosis.

In adults, nesidioblastosis is a very infrequent condition and a rare cause of symptomatic presentations. The diagnosis of nesidioblastosis may be difficult with functional and anatomical imaging modalities. "Slight focal" pancreatic abnormalities using (111)In-pentetreotide imaging has been reported in patients with hyperinsulinaemic hypoglycaemia, confirmed histologically as nesidioblastosis. We describe a 60-year-old man who presented with a 1-year history of intermittent faecal urgency and refractory diarrhoea, non-specific laboratory results, negative imaging results (CT, MRI and EUS), a FNA biopsy that was inconclusive, but suggested an endocrine cell neoplasm, and a (111)In-pentetreotide scan that showed a moderately intense focal uptake clearly localised to the pancreatic head on a low-dose fusion CT. The histopathology of the specimen confirmed the diagnosis of nesidioblastosis.

Therapeutic activation of Valpha24+Vbeta11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity.

Human Valpha24+Vbeta11+ natural killer T (NKT) cells are a distinct CD1d-restricted lymphoid subset specifically and potently activated by alpha-galactosylceramide (alpha-GalCer) (KRN7000) presented by CD1d on antigen-presenting cells. Preclinical models show that activation of Valpha24+Vbeta11+ NKT cells induces effective antitumor immune responses and potentially important secondary immune effects, including activation of conventional T cells and NK cells. We describe the first clinical trial of cancer immune therapy with alpha-GalCer-pulsed CD1d-expressing dendritic cells. The results show that this therapy has substantial, rapid, and highly reproducible specific effects on Valpha24+Vbeta11+ NKT cells and provide the first human in vivo evidence that Valpha24+Vbeta11+ NKT cell stimulation leads to activation of both innate and acquired immunity, resulting in modulation of NK, T-, and B-cell numbers and increased serum interferon-gamma. We present the first clinical evidence that Valpha24+Vbeta11+ NKT cell memory produces faster, more vigorous secondary immune responses by innate and acquired immunity upon restimulation.

Dosimetry and toxicity of Quadramet for bone marrow ablation in multiple myeloma and other haematological malignancies.

Standard treatment regimens for haematological malignancies include myeloablative chemoradiotherapy and subsequent rescue by stem cell transplantation. However, these treatment regimens have significant associated mortality and morbidity, and disease recurrence remains a problem. One alternative approach is the targeted delivery of radiotherapy to the marrow using a bone-seeking agent labelled with an appropriate radioisotope, with the aim of delivering a potentially ablative radiation dose to marrow while minimising non-haematological toxicity. Pharmacokinetics and radiation dosimetry for a commercial preparation of samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP; Quadramet) were evaluated in 43 tracer (average dose 740 MBq) studies of 42 patients with haematological malignancies. Measurements of 24-h retention were also available following infusion of 18-48 GBq in 15 patients. Quadramet cleared rapidly from the tissue, with a median biological half-life of 1.4 h. Activity taken up by the skeleton was firmly bound, with activity decreasing according to physical half-life at 24 h in 29 of the 43 cases. The percentage activity retained in the skeleton at 24 h with tracer doses was high (62%+/-13%), although this decreased to approximately 30% with therapy infusions. Because of this decrease in retention, the maximum feasible therapy activity for this formulation of Quadramet is 35 GBq. Median absorbed marrow radiation dose was 0.78 Gy/GBq in tracer studies: the decreased retention at high activities means that this corresponds to a median dose of 12 Gy for 35 GBq administered activity. It is possible to use 24-h retention as a rough guide to marrow dose in individual patients. In tracer studies, median bladder radiation dose was 0.22 Gy/GBq and radiation dose to the liver was very conservatively estimated at 0.2 Gy/GBq. After therapy infusions of up to 50 GBq in 37 patients, non-haematopoietic toxicity was not seen in any patient. In addition, myelosuppression was achieved without evidence of myelofibrosis. The residual dose rate to marrow fell to a level acceptable for stem cell re-infusion by 2 weeks after administration.