Exploring the nature of atheroma and cardiovascular inflammation in vivo using positron emission tomography (PET).

Positron emission tomography (PET) has become widely established in oncology. Subsequently, a whole new "toolbox" of tracers have become available to look at different aspects of cancer cell function and dysfunction, including cell protein production, DNA synthesis, hypoxia and angiogenesis. In the past 5 years, these tools have been used increasingly to look at the other great killer of the developed world: cardiovascular disease. For example, inflammation of the unstable plaque can be imaged with 18-fludeoxyglucose (18F-FDG), and this uptake can be quantified to show the effect that statins have in reducing inflammation and explains how these drugs can reduce the risk of stroke. 18F-FDG has also become established in diagnosing and monitoring large-vessel vasculitis and has now entered routine practice. Other agents such as gallium-68 (68Ga) octreotide have been shown to identify vascular inflammation possibly more specifically than 18FFDG.Hypoxia within the plaque can be imaged with 18F-fluoromisonidazole and resulting angiogenesis with 18F-RGD peptides. Active calcification such as that found in unstable atheromatous plaques can be imaged with 18F-NaF. PET imaging enables us to understand the mechanisms by which cardiovascular disease, including atheroma, leads tomorbidity and death and thus increases the chance of finding new and effective treatments.

Sentinel node studies in truncal melanoma: does an increased number of draining basins correlate with an increased risk of lymph metastasis?

OBJECTIVES: To assess whether an association exists between drainage to multiple basins and lymphatic metastasis in patients with truncal melanoma. METHODS: We retrospectively reviewed 227 patients with primary malignant melanoma between January 2006 and December 2009. All patients received an intradermal injection of (99m)Tc-nanocolloid and lymphoscintigraphy followed by sentinel node biopsy. Pre-staging histology with Breslow thickness from excision biopsy was also obtained. RESULTS: 82/227 (36%) patients with primary truncal melanoma were identified. Nodal histology was positive for metastatic disease in 27/82 (32.9%) patients. Of these 27, 15 had 1 basin of drainage, 7 had 2 basins of drainage and 5 had 3 basins of drainage. Of the 55 node-negative patients, 35 had 1 basin, 18 had 2 basins and 2 had 3 basins of drainage. We found no significant correlation with sentinel node positivity and those that had ≥2 drainage basins. Breslow thickness was available in 65/82(79.2%) patients. Sentinel node biopsy was positive in 6/28 patients who had <1.5 mm thickness, 8/14 who had a 1.5-3.9 mm thickness and 9/23 who had ≥4 mm thickness. There was a significant correlation between Breslow thickness of ≥4 mm and nodal positivity (P = 0.03). CONCLUSION: This study demonstrates no association between multiple drainage basins and sentinel node histology. Sentinel lymph node status did correlate with Breslow thickness.

Correlation between serum calcium levels and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy in primary hyperparathyroidism.

AIM: The goal of the study is to correlate serum calcium levels with the results of dual-phase (99m)Tc-sestamibi parathyroid scintigraphy to find the best cut-off level of the serum calcium that correlates with a positive presurgery. METHODS: In 111 patients, serum calcium and plasma parathormone (PTH) levels were compared with the results of the (99m)Tc-MIBI scintigraphy and with this data determined the level of calcium above which the (99m)Tc-MIBI scintigraphy was likely to be positive and below which the study was likely to be negative. RESULTS: In total, 11 men (18%) and 50 women (82%) had a positive (99m)Tc-MIBI study. Overall 67% of those patients with a positive (99m)Tc-MIBI study had a PTH >200 ng l(-1) compared to only 9% of those with a negative (99m)Tc-MIBI scintigraphy; however, for those with a positive study on an early (99m)Tc-MIBI scintigraphy, this rose to 85%. Overall a serum calcium of >2·70 mmol l(-1) was found in 82% of patients with a positive (99m)Tc-MIBI study but only 14% of those with a negative (99m)Tc-MIBI study, this is rose to 97% of patients with a parathyroid adenoma identified on early images. It is also shown that patients whose serum total calcium <2·51 mmol l(-1) rarely have positive (99m)Tc-MIBI scintigraphy. CONCLUSION: (99m)Tc-MIBI parathyroid scintigraphy is most likely to yield identification and localization of a parathyroid adenoma when both PTH and calcium are elevated; however, although there is no lower limit of PTH which can predict a negative study, we cannot recommend (99m)Tc-MIBI parathyroid scintigraphy if the serum calcium is <2·51 mmol l(-1).

Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study.

BACKGROUND: To evaluate the clinical and radiological effectiveness of [DOTA(0), D-Phe(1), Tyr(3)]-octreotate (DOTATATE) Y-90 in patients with extensive progressive gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs). MATERIALS AND METHODS: Sixty patients with histologically proven GEP-NETs were treated with DOTATATE Y-90. Clinical responses were assessed 6 weeks after completing therapy and then after each of the 3- to 6-month intervals. The radiological response was classified according to RECIST criteria. RESULTS: At 6 months after final treatment, radiological partial response (PR; at least a 30% decrease in the sum of the longest diameter of target lesions) was observed in 13 patients (23%), and the remaining patients had stable disease (SD; less than 30% decrease in the sum of the longest diameter of target lesions or less than 20% increase in the sum of the longest diameter of target lesions) (77%). Clinical PR at 6 months was in 43 patients (72%), nine patients had SD and progressive disease (PD) was noted in eight patients. Median progression-free survival (PFS) was 17 months, while the median overall survival (OS) was 22 months. In eight patients with early PD, the PFS was 4.5 and OS 9.5 months, while in those with SD or PR, PFS and OS were 19.5 and 23.5 months, respectively. After 12 months of follow-up, five patients had World Health Organization (WHO) grade 2 or 3 renal toxicity. Haematological toxicity (WHO grade 3 and 4) was noted during therapy in 10% of patients and persisted in 5%. CONCLUSIONS: DOTATATE Y-90 therapy is effective and relatively safe in patients with GEP-NET. Standard doses of DOTATATE Y-90 result in a relatively low risk of myelotoxicity. However, due to ongoing risk of renal toxicity, careful monitoring of the kidney is recommended.

Radionuclides in the management of thyroid cancer.

Nuclear medicine imaging was born over 60 years ago with imaging of thyroid conditions. Most of our present imaging devices were developed for imaging of the thyroid and thyroid cancer. Millions of patients in over 100 countries have been diagnosed and treated for thyroid cancer using nuclear medicine techniques. It remains, however, one of the most dynamic areas of development in nuclear medicine with new roles for positron emission tomography and receptor based imaging. In addition to this is research into combinations of genetic therapy and radioisotopes and receptor based therapy using beta emitting analogues of somatostatin. Despite the use of ultrasound computed tomography and magnetic resonance, nuclear medicine techniques remain central to both imaging and therapy in thyroid disease and the field has recently become one of the most dynamic within the specialty.

The future of infection imaging.

Over the past 10 years, there has been an unprecedented explosion in new agents suggested for imaging infection. These agents have been based on our understanding of the processes involved in invasive infection of the body by microorganisms and the body's response to them. Work with antibodies has traditionally yielded the most likely candidates, 3 of which have entered clinical use in Europe and the USA. However, the expense and limitations of producing antibodies have resulted in investigations into the use of cytokine and anti-microbial radiolabelled peptides. This work is very promising in that these types of tracers may be more specific for infection than labelled leukocytes. There remains a big question mark, however, as to whether or not these will progress from phase I/II trials to phase III trials and, ultimately, to clinical use. Finally, the investigation of radiolabelled anti-microbials continues and may prove to be most useful with anti-fungals especially in the immuno-suppressed host. We live in exciting times in the evolution of infection imaging; time and commercial constraints will determine which, if any of these tracers make it to the market and will they do so before PET rules all nuclear medicine?

Imaging cancer using single photon techniques.

Though positron emission tomography (PET) has attained a rightful place in the vanguard of nuclear oncology imaging there is still much that can be done using single photon tracers. Whether or not it is the use of general agents such as (201)Tl or receptor targeting using somatostatin analogues many cancers and the processes involved with them are still best seen with g-emitting radionuclides and gamma cameras. This article reviews the scope of using these tracers in oncology and emphasises that in nuclear oncology we are as much concerned with the questions as what the cancer is doing and how can be exploit differences between the cancer and normal tissue to aid diagnosis. The advent of new radionuclide therapy techniques will mean that preassessment with diagnostic agents will increase the need to have high quality single photon imaging. New receptor systems such as those using gastrin and bombesin are being developed. We can also use (99m)Tc based agents to identify hypoxia in cancer, angiogenesis and apoptosis. For those who are interested in the biology of cancer and interested in exploiting this for treatment will find that there is still much that can be done without a PET scanner and normally at a lower cost. About this issue, it is important to consider the recent development of dual-modality integrated imaging systems (SPET/CT) that allows to co-register the acquired images by means of the hardware in the same session. These new devices have a particular added value in tumour imaging since they provide the exact localisation of lesions and exclude some non correct interpretations of the physiologic uptakes for SPET findings. In addition there are many evidences that the fused images can give additional information in the diagnostic work up of patients by improving the accuracy of single photon scintigraphy. These new technologies lead to a continuous optimisation in the quality of imaging and contribute more and more to integrate the nuclear medicine modalities in the clinical management of cancer diseases.

Radioisotope bone scans in the preoperative staging of hepatopancreatobiliary cancer.

BACKGROUND: The aim of the study was to determine the value of radioisotope bone scans in the preoperative staging of patients with hepatopancreatobiliary (HPB) cancer. METHODS: Bone scanning was performed as part of a routine staging protocol in 402 consecutive patients with HPB cancer over a period of 5 years. Patients with positive bone scans underwent coned radiography, computed tomography with review on bone windows, or a bone biopsy. Bone scans were reviewed along with staging investigations, surgical and histological findings. Patients were followed for a minimum of 6 months. RESULTS: There were 171 patients with colorectal liver metastases, 106 with suspected pancreatic cancer, 47 with hepatocellular cancer, 52 with gallbladder cancer or cholangiocarcinoma, and 26 with other types of HPB cancer. Bone scans were negative in 377 patients (93.8 per cent) and positive in 25 patients (6.2 per cent). Of the 25 positive scans, 16 were falsely positive as a result of degenerative bone disease. Of nine patients with a true-positive bone scan, four had locally irresectable disease and four distant metastases. In only one patient did the bone scan result alone influence the decision to resect the HPB cancer. Overall sensitivity was 100 per cent, specificity 95.9 per cent, positive predictive value 36.0 per cent and negative predictive value 100 per cent. CONCLUSION: Bone scanning should not be included in the routine staging protocol for HPB cancer.

Position of nuclear medicine modalities in the diagnostic work-up of breast cancer.

Breast tumors can be imaged by different modalities: mammography is the most widely used technique because of its diagnostic value, patient compliance and low costs. Some techniques such as ultrasound (US) are often indicated, while others, such as digital mammography and magnetic resonance imaging (MRI) are still under evaluation and seem to be very promising. Among the nuclear medicine techniques breast scintigraphy with (99m)Tc-labelled lipophilic cations (SestaMIBI or tetrofosmin), positron emission tomography (PET) with 18F-2-deoxy-2-fluoro-D-glucose (FDG) have been evaluated in many clinical trials. At present breast scintigraphy has limited applications due to its poor spatial resolution, which has a minimum of 8 mm. It is questionable whether single photon emission tomography (SPECT) can offer any substantially better information on the breast; however, SPECT is more accurate in detecting axillary lymph nodes. Recent approaches using breast dedicated collimators and cameras have greatly improved the SPECT resolution and sensitivity. The most interesting technique offered by nuclear medicine today are PET and lymphoscintigraphy with the intraoperative detection of handled gamma probe. The sentinel node detection has achieved a large consensus of reliability and at present it has an important place in the clinical management. In the same time many authors have acknowledged the value of PET in the differential diagnosis of breast lesions and in locoregional staging, since breast cancer is strongly avid for glucose. PET demonstrated also its efficacy in detecting axillary lymph node metastases. Even in some clinical trials its accuracy proved nearly comparable to that of lymphoscintigraphy with sentinel node biopsy, other studies showed that PET scanning does not currently have adequate spatial resolution to detect both micro- and small macrometastatic disease in axillary lymph nodes. The added value of PET in breast cancer staging is that with a single examination PET allows the characterisation of breast lesions, in addition to complete viewing of the entire body. Whole-body PET may substitute other diagnostic assessments by examining the various regions of potential tumour spread. The current diagnostic work-up for pre- and postoperative staging includes various examinations: chest X-rays, US of the abdomen, mammography of the contralateral breast. Bone scintigraphy with (99m)Tc-diphosphonates and laboratory tests can also be considered in women with large tumors or in symptomatic patients. Computed tomography (CT) and MRI may be used in order to resolve particular diagnostic problems. The current application of some of these modalities depends on the risk of the single patient of developing metastatic spread, which is revealed by a number of prognostic parameters of tumor aggressiveness and of course, clinical stage. Bone scintigraphy and PET may be useful in monitoring therapy response and in detecting tumour relapses during follow-up. In particular PET guided by tumor markers measurements shows to detect more lesions than other non nuclear medicine modalities.

SPECT scans for monitoring response to pleconaril therapy in chronic enteroviral meningoencephalitis.

Chronic enteroviral meningoencephalitis (CEMA) is a rare complication of immunodeficient individuals and may present as insidious intellectual deterioration. Diagnosis requires isolation or PCR identification of enterovirus from the CSF. Pleconaril, a novel anti-picornaviral compound is available on a compassionate release basis to treat patients with potentially life threatening enteroviral infection. Non-invasive neuroimaging is an important new technique for both the diagnosis of encephalitis and as an objective assessment of response to treatment. We report two immunodeficient patients, one with common variable immunodeficiency and one with HIV, with an insidious presentation of CEMA. In both patients, perfusion single photon emission tomography scans were effective in monitoring treatment, correlating with clinical and virological response to pleconaril.

Sandostatin LAR (long-acting octreotide acetate) for malignant carcinoid syndrome: a 3-year experience.

BACKGROUND: Somatostatin analogues are the best therapy for controlling the symptoms of malignant carcinoid syndrome. Octreotide acetate given as subcutaneous injection up to three times daily, intramuscular Lanreotide injection given once per 1-2 weeks and monthly intramuscular Sandostatin LAR have demonstrated similar efficacy in short-term studies. AIM: To assess the long-term effect of Sandostatin LAR on the management of patients with malignant carcinoid syndrome. METHODS: This was a 3-year retrospective study. Twenty-seven patients were assessed with a median follow-up of 23 months. Thirteen patients were switched from subcutaneous octreotide and 14 patients were octreotide naive. All patients showed avid uptake on indium-111 octreotide imaging. RESULTS: Ten of the 13 patients previously on subcutaneous octreotide and 13 of the 14 patients who were octreotide naive had good symptom control on Sandostatin LAR. Over the period of follow-up, many patients showed progression of their tumour and required additional therapies. Patients expressed a preference for monthly intramuscular Sandostatin LAR as opposed to daily subcutaneous injections of octreotide. Although Sandostatin LAR was difficult to administer in certain instances, overall it was well tolerated. CONCLUSIONS: Sandostatin LAR provides good long-term symptomatic control in patients with malignant carcinoid syndrome; it is well tolerated and patients expressed improved satisfaction in their management.

Interventional nuclear medicine in hepatocellular carcinoma and other tumours.

The range of cancers which can be successfully treated by radioisotopes can be expanded by the use of combined pharmacological and physical targeting of the relevant radioisotope. This has been used extensively in the management of hepatocellular cancer (HCC) which has been treated with (131)I iodized poppy seed oil (Lipiodol) or (90)Y labelled glass microspheres infused into the liver under radiological control via a catheter placed into the right or left hepatic artery. In the treatment of extensive disease survival may not be changed but there is an improved quality of life after treatment. If given in the adjuvant setting, improved survival has been noted. These techniques have now been applied to other tracers for example in the use of (131)I-mIBG in treatment of rare tumours where concise localization and destruction of tumours in vital structures needs to occur without the risk of damage to surrounding tissues.

Monitoring therapy in breast cancer.

Breast cancer remains one of the most common cancers in the developed world. New treatments are proving effective against both limited disease and metastases. Nuclear medicine is in a unique position as it is one of the only methods used to image the breast which is linked to cell cycle changes, the receptors on the cell surface and the cells' response to chemotherapy. Nuclear medicine is unaffected by the anatomical changes seen post-chemotherapy and radiotherapy and is uniquely placed to become a major methodology in the continued assessment of the breast cancer patient. However, before this can happen the utility of nuclear medicine techniques must be proved in multi-centre trials.

Can scintimammography with (99m)Tc-MIBI identify multifocal and multicentric primary breast cancer?

Scintimammography with (99m)Tc-MIBI has been shown to be an effective adjunct to imaging of the breast with mammography. Uptake of (99m)Tc-MIBI is particularly high in sites of non-calcified cancer and ductal carcinoma in situ (DCIS), and as a consequence it may be possible to use this method of imaging in identifying multifocal or multicentric disease. The aim of this study was to evaluate the efficacy of preoperative scintimammography in the detection of multifocal and multicentric breast cancer and compare these results with mammography. A retrospective review was performed of 353 women imaged with (99m)Tc-MIBI as part of the clinical assessment of their suspected primary breast cancer. The results of the scintimammography and mammography were then compared with the final pathological diagnosis obtained after mastectomy in all patients. Histopathological assessments of breast tissue from mastectomy confirmed 40 women (12%) had multifocal (34) or multicentric (six) breast cancer. Scintimammography correctly identified 39 of these cancers and the multifocal or multicentric character of the cancer was identified in 22 (52%) of these patients. Anatomical imaging performed in all 40 patients including 25 with mammography alone, mammography and ultrasound in 11 cases and ultrasound alone in four patients. Anatomical imaging identified cancer to be present in 28 patients (70%) and the combination of mammography and ultrasound identified correctly that the cancer was multifocal or multicentric in eight patients (22%). In this study scintimammography was able to identify more cases of multifocal and multicentric cancer than mammography and/or ultrasound. In patients where pre-operative identification of multicentric or multifocal disease can alter treatment scintimammography may be a useful investigative tool.