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.

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.

Prediction of the usefulness of combined mammography and scintimammography in suspected primary breast cancer using ROC curves.

UNLABELLED: The aim of this study was to compare the accuracy of 99mTc-methoxyisobutylisonitrile scintimammography (SMM) and conventional mammography in patients presenting with suspected primary breast cancer. Receiver-operating-characteristic (ROC) curve analysis was applied to determine if a combination of x-ray mammography (XMM) and SMM was more accurate than a single test alone. METHODS: The results of SMM, XMM, and a combination of both studies performed over a 3-y period on 374 suspicious lesions in 353 patients with no previous history of breast cancer were reviewed. Each scan report was reviewed and graded as follows: grade 1, definitely normal or benign; grade 2, probably normal or benign; grade 3, equivocal; grade 4, probably cancer; and grade 5, definitely cancer. The results were verified by pathologic examination of biopsy material obtained from each suspicious mass. ROC curves were generated from these results. RESULTS: There were 204 malignant breast tumors and 170 nonmalignant breast lesions. SMM diagnosed correctly 181 breast cancers and was true-negative in 122 benign breast lesions: sensitivity, 89%; specificity, 71%; positive predictive value (PPV), 79%; and negative predictive value (NPV), 84%. XMM diagnosed correctly 143 malignant tumors and was true-negative in 117 nonmalignant lesions. The sensitivity, specificity, PPV, and NPV for XMM were 70%, 69%, 73%, and 66%, respectively. Using a combination of the two tests, the combined sensitivity was 93%, specificity was 72%, PPV was 80%, and NPV was 90%. Using the index of the area under the ROC curve obtained by the rating method showed that the combination of XMM and SMM was significantly more accurate than either of the individual tests if performed alone (P < 0.05). CONCLUSION: This study shows that the combination of XMM and SMM produces more accurate results than either modality alone. Therefore, if there is doubt about the accuracy of XMM, SMM should be used as the second-line test in breast imaging.

Indium-111-labeled polyclonal human immunoglobulin: identifying focal infection in patients positive for human immunodeficiency virus.

Pooled human immunoglobulin labeled with indium-111 (111In-HIgG) was used to identify the presence and extent of infection in patients positive for human immunodeficiency virus (HIV), presenting with either symptoms and/or signs of acute chest infection or with pyrexia without localizing signs or symptoms. Fifty-five studies were performed in 51 patients with suspected chest infection or pyrexia without localizing signs. Of these, 111In-HIgG identified intrapulmonary accumulation in 17 patients with Pneumocystis carinii pneumonia, eight with bacterial pneumonia, five with cytomegalovirus pneumonia, three with pulmonary Mycobacterium avium intracellulare infection and one with a fungal pneumonia. There was no intrapulmonary accumulation of 111In-HIgG in five patients with bronchopulmonary Kaposi's sarcoma and in three patients with intrathoracic lymphoma. Quantification of lung/heart activity was significantly increased (p < 0.05) in patients with active chest infection compared with those with intrapulmonary tumor or no active lung pathology. Indium-111-HIgG scintigraphy also localized at 14 sites of extrapulmonary infection, including six patients with colitis. There were no false-negative studies but false-positive uptake was seen in four studies. These results confirm that 111In-HIgG correctly identifies the presence and extent of infection in patients positive for HIV antibody.

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.

Uptake of Tc-99m MIBI related to tumour size and type.

The accuracy of Tc-99m MIBI scintimammography depends on the uptake in cancer cells being greater than surrounding normal tissue. The aim of this study was to determine which were the dominant factors affecting uptake of Tc-99m MIBI in breast cancer cells in vivo. The tumour to background ratio (TBR) was measured in 74 focal breast lumps occurring in 70 women, of whom 53 had breast cancer. In patients with breast cancer the TBR was compared in those under and over 45, those with tumours over and under 20 mm, those who had auxiliary disease, the histological type of the tumour and whether ductal on the Bloom Richardson scale. The only factor which appeared to have an influence on uptake of Tc-99m MIBI was the histological type of the tumour. Ductal carcinomas had a mean TBR of 2.07, significantly greater than either other types of breast cancer (TBR = 1.31) and benign tumours (TBR = 1.46). The histological type of tumour appears to be the dominant factor affecting uptake of Tc99m MIBI in vivo.

Correlation between uptake of Tc-99m sestaMIBI and prognostic factors of breast cancer.

UNLABELLED: The purpose of this retrospective study was assessment of correlation between Tc-99m sestaMIBI uptake and some prognostic factors of breast cancer. The following prognostic factors have been included in this study: size of the tumour, age of the patients, axilla node involvement, oestrogen and progesterone receptor (ER, PR) status, grading system of Bloom-Richardson and Ki-67 antigen expression. METHODS: 79 patients were enrolled in this study, with 85 lesions confirmed as primary breast cancers. Mean age of patients was 53 years. Scintimammography (SMM) was performed after intravenous injection of 740MBq. At 5-10 min after injection standard planar images were obtained in prone lateral and anterior supine views. Assessment of correlation between known prognostic factors of breast cancer and uptake of MIBI (evaluated as a tumour to background ratio-TBR) was performed used non-parametric (Kendall-tau correlation) statistical analysis. RESULTS: There were 85 breast cancers (73 invasive ductal carcinomas, 11 DCIS (ductal carcinoma in situ) and 1 lobular carcinoma. There was positive correlation between TBR Tc-99m MIBI uptake and size of the tumour (t = 0.19, p = 0.01), presence of axilla node involvement (t = 0.2, p = 0.006) and also grade of the IDC tumours evaluated using Bloom-Richardson's criteria (t = 0.18, 0.03). There were negative correlation between TBR and presence of PR (t = -0.16, p = 0.02) and borderline negative correlation between TBR and age of patients (t = -0.137, p = 0.06) and also TBR and ER status (t = -0.135, p = 0.065). Patients who are younger and/or have PR or ER negative cancers have higher Tc-99m MIBI uptake. Patients who presented with high grade of malignancy (B-R) also have higher uptake of radiotracer. Also those with higher uptake of radiotracer often had axillary node involvement. This would suggest that more aggressive tumours have higher uptake of Tc-99m MIBI. Finally this study suggest correlation between in vivo uptake of MIBI and some of the known prognostic factors of breast cancer.

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.

Tc-99m MIBI in suspected recurrent breast cancer.

A prospective trial was performed to assess the accuracy of Tc-99m MIBI scintimammography in 63 women (mean age 65, range 33-85 years) with suspected recurrent breast cancer in the breast and/or loco-regional tissues. All patients had been diagnosed with breast cancer 1-23 years before the scintimammography. A total of 27 breasts had been removed by mastectomy so scintimammography was compared with mammography in the remaining 99 breasts. Pathological follow-up of patients confirmed 33 sites of recurrent disease within the breast, 26 (78%) were identified by scintimammography and 14 (42%) by mammography; 30 (90%) were positive on one test or the other. In addition Tc-99m MIBI scintimammography identified 10/16 (63%) of axillary lymph nodes with recurrent tumour and 4/6 sites of recurrent tumour present elsewhere. Tc-99m MIBI scintimammography is more accurate in identifying recurrent disease in the breast than mammography and can identify loco-regional recurrence outside of the breast.

67Ga scintigraphy in HIV antibody positive patients; a review of its clinical usefulness.

We reviewed the results of 67Ga scintigraphy in HIV antibody positive patients in order to determine how the result affected management. Case records of 37 HIV antibody positive patients undergoing 41 67Ga scintigraphic studies over a 31 month period were examined. New and additional information was provided by 67Ga scintigraphy in 22 studies (53%). In 13 studies (32%) there was a positive effect on patient management. 67Ga scintigraphy was most useful in differentiating Pneumocystis carinii pneumonia from Kaposi's sarcoma in the chest and for the diagnosis of unsuspected lymphoma. Factors which reduced the effectiveness of 67Ga scintigraphy included empirical use of antibiotics in patients with suspected infection and the low specificity of the test.

Clinical high resolution skeletal single photon emission tomography using a triple-headed gamma camera.

Planar skeletal scintigraphy has become established as a standard diagnostic test performed within the nuclear medicine department. Since the 1970s good quality images have been produced using an Anger gamma camera and 99Tcm-labelled diphosphonates. Single photon emission tomography (SPET) has improved the sensitivity of detection and the ability to localize bony pathology, particularly benign bone disease in the spine. Recently multi-detector gamma cameras dedicated to SPET have become available. One such system, the Toshiba GCA-9300A, has been used to perform routine clinical skeletal SPET in 81 patients. Good quality images have been obtained using an 8 min acquisition in the axial skeleton and a 16 min acquisition protocol in the peripheral skeleton. Multiple sites can be tomographed in the same patient during the same examination using two or more 8 min acquisitions. Such a multi-detector gamma camera offers advantages over the standard single-headed rotating camera for skeletal SPET in terms of both imaging time and image quality. A cost analysis was performed which demonstrated that the additional cost of purchasing such a multidector gamma camera was less than 30.00 pounds per SPET study.

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.

Hepatobiliary scintigraphy in the diagnosis of AIDS-related sclerosing cholangitis.

Twenty human immunodeficiency virus (HIV)-positive patients were studied who presented with right upper quadrant abdominal pain, with or without abnormal biochemical liver function tests, in whom AIDS-related sclerosing cholangitis (ASC) was suspected. The results obtained from hepatobiliary scintigraphy using 99Tcm-IODIDA were compared with data from endoscopic retrograde cholangiopancreatography (ERCP), ultrasound and histological data from liver biopsy or post mortem. 99Tcm-IODIDA was abnormal in 14 patients. Liver biopsy, ERCP or post mortem confirmed ASC in 11 patients of whom 10 had an abnormal 99Tcm-IODIDA study. Ultrasound was performed in eight of the patients with confirmed ASC but was abnormal in only five of these. One patient with mild ASC on ERCP and Kaposi's sarcoma had a normal 99Tcm-IODIDA. In HIV-positive patients with right upper quadrant pain, imaging with 99Tcm-IODIDA provides a non-invasive screening test which may help to determine those patients who should be referred for ERCP.

Combined 67Ga citrate and 99Tcm-human immunoglobulin imaging in human immunodeficiency virus-positive patients with fever of undetermined origin.

Patients infected with the human immunodeficiency virus (HIV) suffer from serious and life-threatening infections. These patients often present with pyrexia but without localizing signs. Despite its high sensitivity in identifying focal infection 67Ga citrate scintigraphy lacks specificity; lymphoma and solid tumours may also be imaged. This presents particular problems in HIV-positive patients with pyrexia where the differential diagnosis is often between infection and lymphoma. In an attempt to improve the specificity of radionuclide imaging in these patients a combination of 67Ga citrate and the new agent 99Tcm-labelled human immunoglobulin (99Tcm-HIG) was used in 25 patients who were sequentially imaged with the two agents. Fourteen patients had 29 sites of microbiologically confirmed infection; 67Ga citrate identified 27 sites and 99Tcm-HIG identified 16 sites. Seven of the nine sites visualized with 99Tcm-HIG, but positive with 67Ga citrate, were intrathoracic. Abnormal concentration of 67Ga citrate, not due to infection, occurred at eight sites; five lymphoma, one gout, one recent fracture and one patient with prominent bone marrow islands. 99Tcm-HIG showed increased concentration of tracer in only one of the patients with lymphoma. A combination of 67Ga citrate and 99Tcm-HIG imaging in HIV-positive patients with pyrexia of unknown origin enables a differentiation between infection and lymphoma to be made more readily. The poor sensitivity of 99Tcm-HIG in the chest will limit its sole use in this patient group.

Computer-generated attenuation correction does not improve the accuracy of myocardial perfusion scintigraphy.

A short study was performed to determine if it is possible to increase the accuracy of thallium-201 (201T1) single photon emission tomographic myocardial perfusion imaging using computer-generated ('Chang') attenuation correction. The stress and rest myocardial perfusion studies from 22 patients with suspected or known ischaemic heart disease were reconstructed with and without "Chang' attenuation correction. For all patients, the scintigraphy results were compared with those of coronary angiography. Attenuation correction improved the accuracy of 201T1 myocardial perfusion imaging for defining myocardial ischaemia or infarction in 8% of coronary artery territories (23% of patients), but it was worse in 5% of coronary artery territories (14% of patients). These changes were not significant (McNemar's test). Therefore, computer-generated 'Chang' attenuation correction does not appear to improve the accuracy of myocardial perfusion scintigraphy. It is important that all techniques suggested to improve the accuracy of clinical images should be tested on patients before being widely used.

Scintigraphic imaging of breast cancer: a review.

Scintimammography is a recently verified technique that will expand the use of nuclear medicine to a new group of patients in whom scintigraphic imaging has not been widely used. If performed correctly, and in certain groups of patients, it delivers a sensitivity as high as X-ray mammography or magnetic resonance imaging (MRI) in palpable tumours but with greater specificity. It is best used in patients in whom X-ray mammography, ultrasound and MRI prove non-diagnostic or unhelpful, particularly those women with dense breasts or who have had previous breast surgery. The mechanism of uptake of 99Tcm-MIBI in breast tissue is only partly understood and in itself may help in determining important aspects of tumour function, such as the response to cytotoxic chemotherapy. Other scintigraphic methods for imaging breast cancer may be able to look at other aspects of cancer function, for example blood supply, metabolic rate or the in vivo assessment of oestrogen or somatostatin receptor status. This in turn may be useful in planning treatment. Metastatic disease may best be monitored with 18F-FDG PET, which has a sensitivity greater than MRI but a similar specificity. Much furtner work will need to be done on the use of nuclear medicine in breast cancer, but the addition of unique functional information to the anatomical data from X-ray and MRI should benefit future patients' management.

A comparison of 111In-HIG scintigraphy and chest radiology in the identification of pulmonary infection in patients with HIV infection.

Prospectively, we compared the results of chest radiology and functional imaging, using 111In-labelled polyclonal human IgG (111In-HIG), in the identification of pulmonary infection in patients infected by the human immunodeficiency virus (HIV). Sixty-three studies were performed on 57 HIV-infected patients presenting with suspected chest infection or fever of unknown cause, in each of whom a planar chest radiograph was obtained within 24 h of the 111In-HIG study. The results of the two imaging modalities were compared with the final microbiological or cytological diagnosis. Forty patients were found to have pulmonary infection, 25 of whom were correctly identified with chest radiology (sensitivity 62%) and 39 with 111In-HIG (sensitivity 97%). In those patients without infection, chest radiology was abnormal in 13 cases (specificity 43%), while there was only one false-positive 111In-HIG study (specificity 95%). 111In-HIG correctly identified the presence or absence of active lung infection in 61 of 63 cases (accuracy 93%). This was significantly better (chi 2 = 8.25, upsilon = 1, P < 0.01) than chest radiology, which correctly identified the presence or absence of infection in 35 of 63 cases (accuracy 55%). In HIV antibody-positive patients, functional imaging with 111In-HIG is more accurate than chest X-ray in the identification of pulmonary infection.

Prone SPET scintimammography.

Prone single photon emission tomography (SPET) was performed in 24 patients with suspected primary or recurrent breast cancer to determine if this technique offers more accurate imaging than that obtained from planar scintimammography. All patients were imaged on a specially designed couch with two cushion inserts. The first insert was lined with lead and was used to perform prone lateral planar scintimammography 5 min after the injection of 740 MBq 99Tcm-MIBI. The second insert did not contain lead and was used to perform a prone SPET acquisition for 30 min immediately after planar imaging. The results of both studies were read independently and there was agreement between the two techniques in 23 cases (96%). All cases of cancer proven on histology were found on planar imaging, but a 4-mm ductal cancer was missed on prone SPET. This was thought to be due to activity from this medial cancer being obscured by the star artefact produced by back-projection reconstruction from activity in the heart. There were two false-positive studies with both techniques. However, prone SPET enabled better localization and characterization of breast cancers than planar imaging. Prone SPET imaging of the breast produces results similar to prone lateral imaging and may be used instead of planar imaging if a reduced total acquisition time is desirable. Care must be taken when reading scans in the presence of small tumours near the heart when back-projection reconstruction techniques are used.

Use of 99Tcm-MIBI in the assessment of patients with suspected recurrent breast cancer.

A prospective trial was performed to assess the accuracy of 99Tcm-methoxyisobutyl isonitrile (99Tcm-MIBI) scintimammography and X-ray mammography in 18 patients (mean age 58 years, range 46-79 years) with suspected recurrent breast cancer in the breast and/or loco-regional tissues. All patients had been diagnosed to have breast cancer 1-23 years before scintimammography. Two patients had undergone mastectomy, so that a total of 34 breasts were studied with X-ray mammography and with prone-lateral and anterior scintimammography. Any abnormalities on X-ray mammograms and scintimammograms were noted, as was any additional local or nodal uptake of 99Tcm-MIBI. The nature of any lesion seen with either modality, or in which there was a clinical suspicion of recurrence, was confirmed by cytological or histological examination of tissue samples. There were nine breasts with recurrent cancer in eight patients. X-ray mammography identified six of these cancers. 99Tcm-MIBI scintimammography identified eight of nine recurrent breast cancers (the one cancer not seen was positive on X-ray mammography). In the 26 breasts without cancer, two were reported as having changes consistent with cancer and one was reported equivocal. There were three false-positive and one equivocal scintimammograms. The accuracy of 99Tcm-MIBI scintimammography within the breast (85%) was similar to X-ray mammography (82%). Axillary lymph node recurrence occurred in five patients, four of whom were positive with 99Tcm-MIBI. An additional patient had focal uptake of 99Tcm-MIBI at the site of recurrent cancer on the anterior chest wall. In conclusion, 99Tcm-MIBI scintimammography may provide useful complementary information in patients with suspected recurrence of cancer in the breast or loco-regional tissues.