A combination of surgery, theranostics, and liquid biopsy - a personalised oncologic approach to treatment of patients with advanced metastatic neuroendocrine neoplasms.

Rationale: Neuroendocrine neoplasia (NEN) of small bowel (SBNEN) frequently present with metastatic disease. Theranostics (molecular imaging followed by targeting therapy) allow for personalised medicine. Liquid biopsies enable precise identification of residual disease and real-time monitoring of therapeutic response. Our aim was to determine the clinical utility of a combination of surgery, theranostics, and a multigene blood measurement in metastasised SBNEN. Methods: Inclusion criteria were SBNEN, G1/G2 NEN, initial tumour diagnosis, stage IV NEN, positivity on 68Ga somatostatin analogue PET/CT, eligible for surgery, and 177Lu peptide receptor radionuclide therapy (PRRT). Blood samples for NETest were collected longitudinally. Progression-free survival (PFS) and overall survival (OS) were calculated. NETest results were assessed prior to surgery and during clinical follow-up. Results: A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of 177Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively. Conclusions: Surgery combined with 177Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study.

PURPOSE: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. METHODS: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. RESULTS: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. CONCLUSIONS: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

Radioembolisation with 90Y microspheres for neuroendocrine liver metastases: an institutional case series, systematic review and meta-analysis.

BACKGROUND: Neuroendocrine liver metastases are clinically challenging due to their frequent disseminated distribution. This study aims to present a British experience with an emerging modality, radioembolisation with yttrium-90 labelled microspheres, and embed this within a meta-analysis of response and survival outcomes. METHODS: A retrospective case series of patients treated with SIR-Spheres (radiolabelled resin microspheres) was performed. Results were included in a systematic review and meta-analysis of published results with glass or resin microspheres. Objective response rate (ORR) was defined as complete or partial response. Disease control rate (DCR) was defined as complete/partial response or stable disease. RESULTS: Twenty-four patients were identified. ORR and DCR in the institutional series was 14/24 and 21/24 at 3 months. Overall survival and progression-free survival at 3-years was 77.6% and 50.4%, respectively. There were no grade 3/4 toxicities post-procedure. A fixed-effects pooled estimate of ORR of 51% (95% CI: 47%-54%) was identified from meta-analysis of 27 studies. The fixed-effects weighted average DCR was 88% (95% CI: 85%-90%, 27 studies). CONCLUSION: Current data demonstrate evidence of the clinical effectiveness and safety of radioembolisation for neuroendocrine liver metastases. Prospective randomised studies to compare radioembolisation with other liver directed treatment modalities are needed.

Hypoxia and tissue destruction in pulmonary TB.

BACKGROUND: It is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1). METHODS: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition. RESULTS: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion. CONCLUSIONS: Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.

Incidence of Second Primary Malignancies in Patients with Neuroendocrine Tumours.

BACKGROUND: An association between neuroendocrine tumours (NET) and increased risk of developing second primary malignancies (SPM) has been recognised. METHODS: This was a retrospective review of our institutional prospectively maintained database of NET patients. We identified patients who had been diagnosed with both neuroendocrine and any additional malignancies via examination of patient notes. RESULTS: Clinical data for 169 patients were analysed. After exclusion of patients known to have hereditary tumour predisposition syndromes, 29 SPM were identified in 26 patients (15.38%), the commonest being colorectal (n = 6), breast and renal carcinomas (both n = 5). SPM were classified as previous, synchronous or subsequent relative to NET diagnosis. Rates of SPM in pancreatic and small-bowel NET patients were comparable (15.7 vs. 19.6%, p = 0.78). A person-year methodology was used to compare observed numbers of SPM against expected values generated from age- and sex-specific incidence tables, with standardised incidence ratios (SIR) and 95% confidence intervals (CI) calculated. SPM incidence was significantly elevated in the synchronous subset (SIR 2.732, CI 1.177-5.382) whilst significantly fewer NET patients had a cancer history compared to the general population (SIR 0.4, CI 0.241-0.624). No overall differences were evident between observed and expected incidences of subsequent SPM (SIR 0.36, CI 0.044-1.051). The incidence of synchronous colorectal cancers was markedly elevated (SIR 13.079, CI 4.238-30.474). CONCLUSIONS: Our data support the use of colonoscopy in the diagnostic work-up of NET patients in anticipation of a colorectal SPM. The mechanistic underpinnings of this clinical phenomenon require further genetic investigation, and consideration of this knowledge in patient management pathways is warranted.

Gallium-68 Dotatate PET/CT is superior to other imaging modalities in the detection of medullary carcinoma of the thyroid in the presence of high serum calcitonin.

OBJECTIVE: Medullary carcinoma of the thyroid (MTC) is a rare neuroendocrine tumour (NET) that expresses somatostatin receptors on the cell membrane and secretes calcitonin. Surgery is the primary curative modality but is achieved only when the diagnosis is timely so there is a high rate of persistent and recurrent disease indicated by a rise in the serum calcitonin levels. Successful management of recurrent disease requires accurate localisation with cross sectional and functional imaging. The introduction of gallium-68-Dotatate ((68)Ga-Dotatate) peptides positron emission tomography/computerized tomography (PET/CT) has significantly improved the detection of NET and has been reported as a valuable adjunct in MTC localisation. We retrospectively reviewed our cases of MTC to correlate the detectability of (68)Ga-Dotatate in relation to calcitonin levels and assess suitability of inoperable patients for peptide receptor radionuclide therapy (PRRT). SUBJECTS AND METHODS: Seven patients (age range 31-66 years, M:F 3:4) with raised calcitonin (mean=7,143pg/mL) were referred for (68)Ga-Dotatate PET/CT scan for localisation of persisting recurrent MTC. Six patients were known to have MTC treated with thyroidectomy and one patient was presenting for the first time. All patients had multiple imaging including ultrasound (US), CT, magnetic resonance imaging (MRI), fluorine-18-fluorodeoxyglucose ((18)F-FDG) PET/CT and iodine-123-metaiodobenzylguanidine ((123)I-MIBG). Positive findings were defined as areas of increased uptake other than the organs of normal distribution and were correlated with results of biopsies, other imaging, long term monitoring of calcitonin and clinical follow up. RESULTS: In 6/7 patients with very high serum calcitonin (range= 672-37,180, mean=8,320pg/mL) (68)Ga-Dotatate PET/CT confirmed the presence of active disease seen on other modalities or detected hitherto unsuspected lesions. In at least 3 cases, (68)Ga-Dotatate PET/CT showed many more lesions compared to other imaging combined. In 1/7 patient (68)Ga-Dotatate PET/CT was negative in line with a relatively low calcitonin level (80pg/mL) and negative disease on fine needle aspiration. CONCLUSION: (68)Ga-Dotatate PET/CT is an effective tool for localising metastatic spread of MTC. It appears to be most effective in the presence of higher levels of serum calcitonin, probably in excess of 500pg/mL. The results of our small cohort had an impact on staging and management with the introduction of peptide receptor radionuclide therapy for inoperable disease.

68Ga-labelled peptides in the management of neuroectodermal tumours.

Neuroectodermal tumours arise from chromaffin cells and possess the ability to secrete catecholamines. They are generally rare and may occur in association with a variety of hereditary syndromes such as MEN-2A and 2B, neurofibromatosis type 1 and von Hippel-Lindau disease. The most common types are phaeochromocytoma arising from the adrenal medulla and paraganglioma of extra-adrenal origin. Phaeochromocytomas tend to be benign and are often associated with a gene mutation if the disease is bilateral, while paragangliomas are often malignant, have a more aggressive nature and tend to metastasize. There are no specific histological or immunohistochemical features that indicate the malignant potential and the diagnosis of malignancy can only be established by the presence of distant metastases. Therefore, imaging can play a vital role in the diagnosis, localization, staging and assessment of spread. Traditionally, this is achieved with a combination of cross-sectional (CT and MRI) and functional ((123)I-MIBG or (111)In-octreotide) imaging. However, these modalities are not adequate and achieve moderate sensitivity. The introduction of (68)Ga-DOTA peptide in PET/CT imaging has led to improved receptor targeting and superb PET resolution, as well as accurate localization of lesions. The use of this technique in neuroectodermal tumours has been shown to be superior to all available modalities, but the available data are limited and larger studies are awaited to establish its role in the management of these tumours.

Highlights of the EANM Congress 2011: Birmingham, UK.

The EANM Congress 2011 took place in Birmingham between the 15th and 19th October 2011 under the presidency of Professor Werner Langsteger. The attendance was reassuringly high, in line with other EANM congresses, despite the current 'Eurozone Crisis'. Participants from 87 countries came along, met old friends and made new ones. They were presented with a massive programme of 1,480 abstracts, symposia, and CME, scientific, plenary and featured sessions. The industry made a substantial contribution to the success of the congress with 109 hardware, software and radiopharmaceutical companies demonstrating the latest technology and innovations in the field. A feature in this year's congress was the emphasis on the role of the young generation. The highlight lecture was presented and this article was compiled by three young EANM members chosen from the young investigator project of the EANM. They review the most highly rated presentations in clinical and preclinical imaging in oncology, neuroendocrine tumours, cardiology, paediatrics and neurology, and provide an update on radionuclide therapy, physics, instrumentation, innovative tracers and techniques.

EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma.

PURPOSE: Radionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice. METHODS: Guidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations. CONCLUSION: Although several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

Treatment of Neuroendocrine Neoplasms with Radiolabeled Peptides-Where Are We Now.

Peptide receptor radionuclide therapy (PRRT) has been one of the most successful and exciting examples of theranostics in nuclear medicine in recent decades and is now firmly embedded in many treatment algorithms for unresectable or metastatic neuroendocrine neoplasms (NENs) worldwide. It is widely considered to be an effective treatment for well- or moderately differentiated neoplasms, which express high levels of somatostatin receptors that can be selectively targeted. This review article outlines the scientific basis of PRRT in treatment of NENs and describes its discovery dating back to the early 1990s. Early treatments utilizing Indium-111, a γ-emitter, showed promise in reduction in tumor size and improvement in biochemistry, but were also met with high radiation doses and myelotoxic and nephrotoxic effects. Subsequently, stable conjugation of DOTA-peptides with ß-emitting radionuclides, such as Yttrium-90 and Lutetium-177, served as a breakthrough for PRRT and studies highlighted their potential in eliciting progression-free survival and quality of life benefits. This article will also elaborate on the key trials which paved the way for its approval and will discuss therapeutic considerations, such as patient selection and administration technique, to optimize its use.

Renal scintigraphy predicts global cardiovascular risk in hypertensive subjects with normal serum creatinine levels.

BACKGROUND. This cross-sectional study investigates the role of renal scintigraphy on cardiovascular (CV) risk stratification in normoalbuminuric, non-diabetic hypertensive subjects (HTs) free from CV disease and renal dysfunction. METHODS. In 200 HTs aged 55-75 years, glomerular filtration rate (GFR) was measured by technetium-99m-diethylene triamine pentacetic acid clearance during renal scintigraphy. Stage III chronic kidney disease (CKD) was defined as GFR < 60 ml/min/1.73 m(2). For comparing the impact of different methods for CKD diagnosis on CV risk stratification, CKD was also considered as GFR estimated by the Modification of Diet in Renal Disease (MDRD) equation and Cockcroft-Gault's formula. Target organ damage (TOD) was assessed by echocardiography and carotid ultrasonography. Gender-specific odds ratio (OR) with 95% confidence intervals for CKD were derived from a multiple stepwise logistic regression analysis. Global CV risk was stratified according to routine examinations, TOD and CKD. RESULTS. In 38% of cases, an unknown stage III CKD was found. Independent of age, CKD was predicted by history of hypertension (OR = 1.69, p = 0.0001), albuminuria (OR = 1.25, p = 0.0001), smoking (OR = 1.85, p = 0.028) and pulse pressure (OR = 1.21, p = 0.019) in men only. Men had an increased risk of CKD (OR = 2.62, p = 0.002) in comparison with women. Prevalence of TOD was significantly higher only in HTs having CKD diagnosed by renal scintigraphy; TOD and CKD assessment added to classic risk factors modified the CV risk stratification from low-moderate to high and very high. CONCLUSIONS. Renal scintigraphy is an important aid in risk stratification and should be performed in HTs aged >55 years. Pulse pressure was the main blood pressure component that predicted the risk of stage III CKD.

Insights into schizophrenia using positron emission tomography: building the evidence and refining the focus.

Schizophrenia involves dysregulation in dopaminergic transmission. Studies show heightened presynaptic striatal dopaminergic function and elevated striatal D(2)/D(3) receptor density in the brain. Cognitive impairments result from hypostimulation of D(1) receptors and are associated with dysfunction in the prefrontal cortex. Here we discuss relevant positron emissions tomography (PET) studies and provide future directions.

Radioguided surgery and systemic radionuclide therapy of neuroendocrine tumours.

Neuroendocrine tumours (NETs) may be fatal, though at a significantly slower pace than their exocrine counterparts. Nuclear medicine procedures for diagnosis and treatment of NETs are based on expression of somatostatin receptors. Radioguided surgery is a new method for diagnosing and treating many tumours and uses introperative gamma probes. The use and development of intraoperative gamma probes in the last 10 years has enabled the development of minimally invasive procedures in oncological surgery, with an improvement in both the survival rate and the quality of life. Systemic therapy with radiolabeled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastatic NETs. In terms of tumour regression, the results obtained are encouraging.

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [18F]fluoromethyl-(1,2-2H4)-choline.

Purpose: The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [18F]fluoromethyl-(1,2-2H4) choline ([18F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design: [18F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [18F]fluorodeoxyglucose ([18F]FDG) scans. Results: Oxidation of [18F]D4-FCH to [18F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [18F]D4-FCH-derived uptake (SUV60max) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [18F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [18F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions: [18F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

Factors affecting the measurement of left ventricular ejection fraction in myocardial perfusion imaging.

BACKGROUND: Estimation of the left ventricular ejection fraction (LVEF) using myocardial perfusion imaging is increasingly used in the evaluation of coronary artery disease. This study aims to compare the effect of (i) two commercially available software packages: quantitative gated single-photon emission computed tomography (SPECT) (QGS) and 4DM-SPECT, and (ii) prereconstruction filtering, on LVEF quantification. METHODS: Images from 101 patients were reconstructed using AutoCardiac and processed using QGS and 4DM-SPECT. Filtering was performed before reconstruction using Hermes FBP SPET on a group of 32 consecutive patients using Butterworth filters (orders 5 and 10; cut-off frequency 0.5-1.2 cycles/cm). RESULTS: Good correlation was observed between QGS and 4DM-SPECT (r=0.88), with an average difference of 2.1%. The difference in LVEF between the two packages ranged from 21 to -28%. The LVEF was overestimated at cut-off frequencies < or = 0.8 cycles/cm compared with higher cut-off frequencies in 26 of 30 (87%) patients. CONCLUSION: There was a clinically significant difference between the LVEF calculated by QGS and 4DM-SPECT and consequently the two packages should not be used interchangeably. The effect of cut-off frequency on LVEF estimation was found to be very patient specific. Changing the cut-off frequency by as little as 0.1 cycles/cm can cause clinically significant differences in LVEF estimation.

68Ga-DOTA-NOC: a new PET tracer for evaluating patients with bronchial carcinoid.

BACKGROUND: Conventional imaging techniques [computed tomography (CT), ultrasound, magnetic resonance] and somatostatin receptor scintigraphy are often insufficient to make a conclusive diagnosis of bronchial carcinoid (BC). PET is commonly used for the assessment of lung cancer but 18F-fluorodeoxyglucose, the most frequently used PET tracer, presents a low sensitivity for the detection of neuroendocrine tumours (NETs). New PET radiopharmaceuticals such as 68Ga-DOTA peptides, which directly bind to somatostatin receptors and are usually expressed on NET cell surfaces, have been reported to be superior to both morphological and somatostatin receptor scintigraphy imaging for gastroenteropancreatic NETs. However, their role in BC has never been evaluated. Our aim is to evaluate the role of 68Ga-DOTA-NOC (68Ga-labelled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-Nal3-octreotide) PET for the assessment of BC patients. METHODS: Ten patients with pathologically proven well-differentiated BC and one patient with highly suggestive CT images for BC were studied by 68Ga-DOTA-NOC PET/CT. PET findings were compared with clinical follow-up, pathology and contrast-enhanced CT findings. RESULTS: 68Ga-DOTA-NOC PET/CT detected at least one lesion in nine of 11 patients and was negative in two. PET/CT and contrast-enhanced CT were discordant in eight of 11 patients, whereas in only three patients both provided similar results. PET/CT detected a higher number of lesions in five patients and excluded malignancy at sites considered positive on CT in three of 11; follow-up confirmed PET/CT findings in all patients. In PET/CT-positive patients, the mean maximal standardized uptake value was 25.9 [4.4-60.5]. On a clinical basis, PET/CT provided additional information in nine of 11 patients leading to the changes in the clinical management of three of nine patients. CONCLUSION: PET/CT with Ga-DOTA-NOC was useful in BC patients because it led to a better evaluation of the extent of the disease.

Can we avoid inadvertent parathyroidectomy during thyroid surgery?

OBJECTIVES: To identify risk factors of inadvertent parathyroidectomy (IP) during thyroid surgery with the aim of decreasing the incidence of this unpleasant complication and to evaluate the impact on temporary and permanent hypocalcaemia following bilateral thyroidectomy. PATIENTS AND METHODS: All consecutive thyroid surgical procedures performed at the Special Surgical Pathology Department of Padova General Hospital and Padova University during one year (January-December 2005) were retrospectively reviewed. Demographic data as well as data on diagnosis, operative reports, pathology findings, and postoperative serum calcium values were collected. A total of 882 patients (F=685 M=197) were included in the study. The patients were divided into 2 groups: those with IP and those without IP, and their data were compared to find factors affecting the occurrence of IP. The impact of IP on residual early and late postoperative parathyroid function was assessed. Hypercalcaemic (calcium level below 2.10 mMol/L) patients were followed from 1 week to 3 years. RESULTS: Seventy of 882 patients (7.9%) were found to have IP. In 11 cases (16% of IP cases and 1.2 % of entire series) the parathyroid glands were completely intrathyroidal. The results of bivariate analysis showed young age (p=0.037), malignant disease (p<0.0001), total thyroidectomy with lymph node dissection (p<0.0001), low weight of thyroid specimen (p<0.0001), and non-visualisation of any parathyroid gland at operation (p<0.0001) as predictive factors for IP. Multivariate analysis revealed significant correlation between IP and malignant disease (p=0.004), and between lymph node dissection and permanent postoperative hypocalcaemia (p=0.018). The incidence rate of transient and permanent hypocalcaemia was higher in IP than in those without. The mean diameter of excised parathyroid glands was 3.2 mm, suggesting more extended or difficult surgical procedures. CONCLUSION: IP is not uncommon during thyroidectomy and is associated with a higher, though not statistically significant, incidence of transient and permanent postoperative hypocalcaemia. Malignant disease, lymph node dissection, non-visualization of any parathyroid gland at operation and younger age seem to be risk factors and should be considered by the surgeon. Further efforts must be taken to reduce the incidence beginning by avoiding parathyroid fragmentation.

Positron-emission tomography in gynaecologic malignancies.

INTRODUCTION: The role of (18)F-FDG PET in the management of gynaecologic malignancies remains unclear mainly due to the failure of clinicians to appreciate the significance of this imaging tool. However, this under utilisation is being actively re-addressed with a large number of reviews and studies, particularly in the last few years. METHODS AND RESULTS: PET has been shown to have high sensitivity and specificity in the evaluation of relapse and nodal disease in cervical cancer, while other uses such as staging and monitoring response to therapies being under further investigation. Similarly, promising results have been published in the use of PET in patients affected by endometrial cancer and uterine sarcomas for detecting lymph nodes metastasis and recurrent disease. In ovarian cancer, PET appears to have a great potential in staging and assessment of disease relapse. An important utility of PET in gynaecologic tumours, which is shared with a large number of other malignancies, is its value in positively changing the patients' management. CONCLUSION: The surge in studies using PET in gynaecological malignancies is in its early stages, and further studies are required to optimise the role of PET in these conditions.

Can gallium-68 compounds partly replace (18)F-FDG in PET molecular imaging?

The development of gallium-68 -1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid ((68)Ga-DOTA) compounds was made possible due to the chemistry of (68)Ga, which matches the pharmacokinetics of many peptides, specially the chelators DOTA and DOTAderivatives with the formation of stable (68)Ga (3+) complexes. The availability of this tracer from a germanium-68-gallium-68 generator with a relatively long half-life makes it attractive to use in busy nuclear medicine departments, particularly those with limited access to cyclotrons. The recent clinical experience with (68)Ga-peptides includes imaging neuroendocrine tumours particularly carcinoid, as well as neuroectodermal tumours such as phaeochromocytoma and paraganglioma. In vitro and animal testing are still progressing alongside clinical studies, with promising results in the use of (68)Ga-DOTA-rhenium-cyclized alpha-melanocyte stimulating hormone (MSH) and (68)Ga-DOTA-napamide (NAP) in melanoma, (68)Ga-DOTA-PEG(4)-BN(7-14) (PESIN) for the imaging of bombesin receptor- positive tumours and (68)Ga-ethylene dicysteine-metronidazole (EC-MN) for imaging tumour hypoxia. In addition to tumours, (68)Ga- DOTA peptide inhibitor of vascular peptide protein 1(VAP-P1) is being assessed for imaging inflammatory reaction. An additional value following a positive scan is the use of beta emitters labelled to the same peptides for radionuclide treatment. In conclusion, the recent introduction of (68)Ga-peptides, made available by a convenient (68)Ga/(68)Ge generator, could greatly contribute to the management of a wide range of clinical conditions including tumours and inflammation.

Peptide Receptor Radionuclide Therapy for Pancreatic Neuroendocrine Tumours.

BACKGROUND: The incidence of pancreatic Neuroendocrine Tumours (pNETs) has increased considerably in the last few decades. The characteristic features of this tumour and the development of new investigative and therapeutic methods had a great impact on its management. OBJECTIVE: The aim of this review is to investigate the outcome of Peptide Receptor Radionuclide Therapy (PRRT) in the treatment of pancreatic neuroendocrine tumours. METHODS: A comprehensive literature search strategy was used based on two databases (SCOPUS, and PubMed). We considered all studies published in English, evaluating the use of PRRT (177Luteciuim- DOTA-conjugated peptides and 90Yetrium- DOTA- conjugated peptides) in the treatment of pancreatic neuroendocrine tumours as a standalone entity or as a subgroup within the wider category of Gastroenteropancreatic Neuroendocrine Tumours (GEP NETs). RESULTS: PRRT was found to be an effective treatment modality as a monotherapy or in combination with other therapies in the treatment of non-operable and metastatic pNETs where other options are limited. Complete response was reported to be between 2-6% while partial response was achieved in up to 60% of cases. Survival analysis was also impressive. Progression Free Survival (PFS) reached a mean of 34 months and Overall Survival (OS) of 53 months. PRRT also proved to improve patients' Quality of Life (QoL). Acute and sub-acute side effects like nephrotoxicity and haematotoxicity are usually mild and reversible. CONCLUSION: PRRT is well tolerated and effective treatment option for non-operable and/or metastatic pNETs. Side effects are usually mild and reversible. Larger randomized controlled trails need to be done to compare PRRT with other treatment modalities and to provide more detailed guidelines regarding patient selections, the choice of PRRT, follow up and response assessment to maximum potential benefit.