The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours.

Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists (90)Y-DOTATOC ([(90)Y-DOTA(0),Tyr(3)]-octreotide) or (177)Lu-DOTATATE ([(177)Lu-DOTA(0),Tyr(3),Thr(8)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving (177)Lu-DOTATATE or (90)Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts' opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency.

Ectopic hematopoietic bone marrow in the appendicular skeleton after trauma.

METHODS: Combined bone scanning and immunoscintigraphy (IS) with 99mTc-monoclonal antigranulocyte antibodies were performed in two patients with suspected reactivation of chronic osteomyelitis of the lower extremity. Because bone scanning and IS were strongly positive, both patients underwent surgical intervention. RESULTS: Macroscopic findings did not show purulent infection and microbiologic results remained negative, but histology revealed unexpected ectopic bone marrow, explaining the strong uptake on IS. One patient exhibited active hematopoietic bone marrow at the former fracture site of the tibial bone. The second patient presented with interspersed bone marrow in the cortical bone of the femoral diaphysis after several intramedullary surgical procedures. CONCLUSION: Unexpected ectopic hematopoietic marrow may occur in the appendicular skeleton after trauma and repeated surgical interventions. The bone marrow shows a physiologic uptake with IS and may be misinterpreted as granulocyte accumulation due to infection. This may lead to false-positive diagnosis in cases of suspected osteomyelitis.

Acute deep vein thrombosis: early mobilization does not increase the frequency of pulmonary embolism.

Outpatient treatment for acute symptomatic deep vein thrombosis (DVT) was shown to be safe for most patients. However, little is known whether patients treated on an outpatient basis were ambulating or predominantly resting, a factor which may be decisive for the outcome. In the present study 129 DVT patients were randomized to either strict immobilization for 4 days or to ambulate for > or = 4 hours per day under supervision in order to show, whether the old concept of temporary immobilization is superior to early mobilization or not. The DVT diagnosis was based on duplex sonography; all patients were screened for PE at baseline and at day 4 by pulmonary ventilation-perfusion scanning, and were followed up for a total of 3 months. Clinically, changes in leg circumferences and leg pain were evaluated. The frequency of PE at baseline was 53.0% and 44.9% in the immobile and the mobile groups, respectively. During the 4 days observation period new PEs were found in 10.0% and in 14.4% of the immobilized and the ambulating patients (delta 4.4%; 95% CI -0.5 to 13.8; chi2 = 0.596, p = 0.44). The occurrence of new PE was related to the presence of PE at baseline but not to other potential predictors. The magnitude of a decrease in leg circumferences and leg pain was comparable in both groups. No patient died during the 4 day observation period. The total 3 month mortality rate was 3.9% (5 patients; 2 from the immobile, 3 from the ambulating group). All 5 patient suffered from malignancies. The results of this study show in accordance with the trial hypothesis that, regarding the frequency of PE, immobilization is not superior to early mobilization, suggesting that early mobilization is safe.

A new cause of renal thrombotic microangiopathy: yttrium 90-DOTATOC internal radiotherapy.

The chelator somatostatin analogue dota-D-phe(1)-tyr(3)-octreotide (DOTATOC), which is stably labeled with the beta-emitting radioisotope yttrium 90 ((90)Y), is used as internal radiotherapy for the treatment of patients with advanced neuroendocrine tumors. We report 5 patients who developed chronic renal failure, caused in 3 patients by biopsy-proven thrombotic microangiopathy (TMA). Twenty-nine patients (14 men, 15 women) with normal renal function before therapy were treated with divided intravenous doses of (90)Y-DOTATOC approximately 6 weeks apart (mean normalized cumulative dose, 165.4 +/- 36.4 mCi/m(2)). Twenty-two of 29 patients were administered a normalized cumulative dose of 200 mCi/m(2) without side effects. Among the 7 patients (6 women, 1 man) administered a normalized cumulative dose greater than 200 mCi/m(2), 5 patients (4 women, 1 man) developed renal failure. Increasing serum creatinine levels were observed within 3 months after the last (90)Y-DOTATOC injection. The evolution was rapidly progressive in 3 patients, resulting in end-stage renal failure within 6 months. The remaining 2 patients developed chronic renal insufficiency (mean serum creatinine level, 300 micromol/L an average 16 months after the end of treatment). Renal biopsies performed in 3 patients showed typical signs of TMA involving glomeruli, arterioles, and small arteries. Patients treated with high-dose (90)Y-DOTATOC internal radiotherapy (cumulative dose > 200 mCi/m(2)) are at high risk to develop severe renal failure caused by TMA lesions. The histopathologic lesions are identical to those found after external radiotherapy, which suggests a causal relationship between (90)Y-DOTATOC and renal TMA.

Cerebral blood flow and common carotid flow in neurologically asymptomatic carotid endarterectomy patients.

To define subgroups in 50 neurologically asymptomatic patients with carotid stenosis (mean diam. of stenosis 81.1 +/- 12.5%) regional cerebral blood flow (rCBF) and common carotid artery flow were measured by means of the intravenous Xenon-133 technique and a Doppler flowmeter, respectively. The rCBF studies were performed both at rest and after administration of acetazolamide (Diamox). In this asymptomatic cohort of 50 patients we found subgroups with significant hemispheric baseline asymmetry (BA) (five patients; BA = 7.2 +/- 1.8%) and/or pathological Diamox asymmetry enhancement (DAE) (five patients; DAE = 8.8 +/- 1.3%). Carotid endarterectomy in these cases resulted in a significant reduction of hemispheric differences of rCBF (postoperative BA = 0.4 +/- 3.4, postoperative DAE = 1.7 +/- 3.8). Measurements of common carotid flow revealed significantly higher flow rates in the postoperative period and compensation of intercarotid flow asymmetry. In pathophysiologically defined preclinical subgroups of cerebrovascular disease with hemispheric rCBF differences and/or impairment of the cerebral vascular reserve capacity surgical procedures might be useful.

Long-term outcome of angioplasty for multivessel coronary disease: importance and price of complete revascularization.

BACKGROUND: Complete revascularization of multivessel coronary artery disease (MVD) by coronary artery bypass surgery has been shown to improve outcome, but there is a lack of similar data for patients treated by angioplasty. METHODS: Therefore, a consecutive series of 250 patients with MVD was separated into two groups, those with complete revascularization (n=101) and those with incomplete revascularization (n=149). Six-month 'clinical restenosis' rate assessed by stress myocardial perfusion scintigraphy or symptom-driven angiography and long-term 32 months outcome were compared with an equally sized group of single vessel disease (SVD) patients. RESULTS: MVD patients with complete revascularization had a higher 'clinical restenosis' rate than patients with SVD (35 vs. 22%, P<0.02), although restenosis rate per treated vessel was similar (23%, 18%, P NS). If this higher early restenosis rate were accepted as 'price' for complete MVD angioplasty, long-term event-free survival was no longer different from that of SVD patients (86 vs. 93%, P NS). In contrast, patients with incomplete multivessel angioplasty had a significantly worse long-term outcome (22% events), especially if initially untreated, non-occluded vessels remained untreated (25% events). CONCLUSION: MVD angioplasty with complete revascularization has a long-term event-free survival similar to that of SVD angioplasty but at the price of a higher rate of 6-month restenosis and repeat interventions.

Exceptional results in neuroendocrine-metastases-caused paraplegia treated with [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC), a radiolabelled somatostatin analogue.

The case history is presented of a patient with paraplegia caused by progressive spinal cord compression due to bone metastases of a neuroendocrine pulmonary tumour. After failed external radiotherapy, the patient received targeted internal radiotherapy administered as a fractionated treatment with intravenous injections of a total of 7400 MBq/m2 of [90YDOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC), a radiolabelled somatostatin analogue. This case history highlights the value of 90Y-DOTATOC in the treatment of neuroendocrine tumours and the importance and possibility of good palliation of neuroendocrine bone metastases.

Radiopeptide transmitted internal irradiation of non-iodophil thyroid cancer and conventionally untreatable medullary thyroid cancer using.

AIM: Differentiated thyroid carcinomas (DTC) and medullary thyroid carcinomas (MTC) overexpress somatostatin receptor subtypes (sstr). The aim of this pilot study was to evaluate the tumour response of thyroid carcinomas to targeted irradiation with the radiolabelled somatostatin analogue [90Y]-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1-Tyr3-octreotide ([90Y]-DOTA-D-Phe1-Tyr3-octreotide, or 90Y-DOTATOC) which has a high affinity to subtype 2 and a low affinity to subtype 5. It shows no affinity to sstr1, sstr3 and sstr4. PATIENTS AND METHODS: Twenty patients (mean age 58 years; 50% female, 50% male) with thyroid cancer were included (medullary thyroid cancer (MTC), 12 patients; differentiated thyroid cancer (DTC), seven patients; papillar carcinoma (PC), four patients; follicular carcinoma (FC), three patients; anaplastic carcinoma (AC), one patient). All patients had been therapy resistant and had progressive disease before 90Y-DOTATOC therapy. The dose applied was between totals of 1700 MBq x m(-2) to 7400 MBq x m(-2) 90Y-DOTATOC, administered in one to four injections at intervals of 6 weeks. In the case of tumour progression under therapy, treatment was terminated. RESULTS: The overall antitumour effect (objective response and stable disease) was 35%; in MTC 42%, in DTC 29%, and in AC 0%. The objective overall response rate was 0%. A stable disease was achieved in 35% (7/20), and progressive disease was found in 65% (13/20). The median time to progression was 8 months, with a median follow-up of 15 months. The treatment was very well tolerated. There were no grade III/IV haematological or renal toxicities. CONCLUSION: Targeted radiotherapy using 90Y-DOTATOC is able to stop tumour progression in a small number of patients and therefore may be an alternative treatment option for resistant disease. More significant tumour responses in thyroid and medullary thyroid cancer may be obtained by using radiopeptides with pan-somatostatin characteristics.

Comparing monoclonal antibodies and small peptidic hormones for local targeting of malignant gliomas.

Monoclonal antibodies, F(ab')2 fragments and peptidic vectors have been clinically tested for systemic and locoregional treatment of malignant gliomas. Since these brain-intrinsic neoplasms are characterized by relentless tumor cell infiltration of normal brain parenchyma, targeting agents require diffusive properties in order to reach invading tumor cell clusters that migrate along vascular clefts and axonal pathways. Tumor uptake was significantly improved by using small peptidic hormone receptors, e.g. modified octreotide, following systemic injections as compared to macromolecules which only led to limited stabilization of the disease. More importantly, biodistribution was found to be superior following direct intratumoral injection by using these small drug-like radioconjugates. Rapid and extensive distribution within 30 minutes was observed in large tumors, even crossing the corpus callosum in bihemispheric lesions following injection of 2-3 ml of the radiopharmakon injected into the center of non-resected tumors. Distribution was far more extensive after direct intratumoral injection as compared to intracavitary injection after surgical debulking. Increased interstitial pressure gradients and the much larger and chaotic structure of the interstitial space of a tumor compared to the extremely tight architecture of normal brain tissue might explain this unexpected biodistribution pattern. Peptidic hormone vectors might become useful agents to deliver radiopharmaceuticals into human invasive gliomas.

Is there need for radioimmunotherapy? results of a phase I/II study in patients with indolent B-cell lymphomas using lutetium-177-DOTA-rituximab.

AIM: The aim of the study was to explore the clinical response to 177Lutetium-DOTA-rituximab (177Lu-D-R) and to determine the maximum tolerated dose (MTD) in the treatment of patients with relapsed follicular, mantle cell or other indolent lymphomas such as marginal zone lymphoma as well as to put these results into context with other therapy options for these patients. METHODS: Treatment consisted of cold rituximab (250 mg/m2) on day 1 and day 8 and 177Lu-DOTA-Rituximab on day 8. Reassessment was done at week 10. Thirty-one patients (males=17, females=14, median number of pretreatments: 3) were treated in seven cohorts. Escalation of injected activity was carried out in steps of 5 mCi/m². Dosimetry was performed in the first 20 patients. RESULTS: The MTD was found to be 45 mCi/m2. Thrombocytopenia and leukopenia were the dose-limiting toxicities. Significant anemia only occurred at dose level 7. We observed the nadir of platelets after a median of 36 days from treatment with 177Lu-D-R and a nadir of granulocytes after a median of 50 days from 177Lu-D-R treatment. Non-hematological toxicity was negligible. We observed clinical responses at all dose levels and for all lymphoma entities. Some of the responses were durable; the longest follow up in complete remission is currently over eight years. CONCLUSION: The MTD of 177Lu-DOTA-Rituximab was found to be 45 mCi/m². Non hematologic toxicity was negligible. Responses were seen in all lymphoma entities and at all dose levels tested. Further testing seems to be most promising mainly in follicular and marginal zone lymphoma in particular as the results compare well to other therapy options for these patients with regard to effectiveness, toxicity and discomfort for the patients.

Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma.

AIM: Paragangliomas and pheochromocytomas are rare tumors arising from chromaffin cells. Approximately 10% are malignant. Treatment options are limited in metastatic, surgically incurable situations. These tumors often express somatostatin receptors in high density. Therefore, treatment with the radiolabeled somatostatin analogue [DOTA-Tyr(3)]-octreotide (DOTATOC) is an option. We evaluated the effectiveness and toxicity of radiolabeled DOTATOC in patients with metastatic paraganglioma and pheochromocytoma. METHODS: Twenty-eight patients (16 female and 12 male) with surgically incurable paragangliomas and pheochromocytomas were included. Twenty-five patients were scheduled for treatment with a total of 200 mCi/m(2) body surface [(90)Y]DOTATOC and 3 for one cycle with 100 mCi/m(2) [(90)Y]DOTATOC followed by 2 cycles of 200 mCi [(177)Lu]DOTATOC. Restaging was performed 8-12 weeks after the last treatment cycle, followed by regular controls every 3 to 6 months. RESULTS: The treatment was well tolerated. At restaging we found 2 partial remissions, 5 minor responses; 13 stable disease, 2 mixed responses and 6 patients remained progressive. We found 1 thrombocytopenia grade I and 1 anemia grade I. No non-hematological toxicity, especially no kidney toxicity occurred. The follow-up ranged from 6 to 50 months (mean: 19+/-14.6 months). Time to progression ranged from 3 to >42 months. Ten responses, 9 stable diseases and one partial remission, are still ongoing. CONCLUSIONS: In these 28 patients, it was shown that radiolabeled DOTATOC can be effective in patients with somatostatin receptor positive paraganglioma. However, the therapy seems to be less effective than in gastroentero-pancreatic neuroendocrine tumors. Nevertheless, DOTATOC appears to be a treatment option for surgically incurable paragangliomas, because toxicity is very low and especially the fact that long lasting remissions could be achieved justifies the treatment. The final time to progression is not yet reached after a mean follow-up time of 19 months.

Use of pro-atrial natriuretic peptide in the detection of myocardial ischaemia.

BACKGROUND: Because of its unique storage and release mechanisms allowing a very rapid response to haemodynamic changes, pro-atrial natriuretic peptide (proANP) may be a helpful cardiac marker in the detection of myocardial ischaemia. MATERIALS AND METHODS: A total of 260 consecutive patients with suspected myocardial ischaemia referred for rest/ergometry myocardial perfusion single-photon emission computed tomography (SPECT) were enrolled. Levels of plasma proANP were determined before and 1 min after maximal exercise. RESULTS: Baseline proANP and peak exercise proANP were significantly higher in patients with myocardial ischaemia as compared to those without ischaemia (median, 82 [IQR, 57-112] vs. 67 [IQR, 50-106] pmol L(-1), P = 0.007; and 89 [IQR, 65-121] vs. 78 [IQR, 57-116] pmol L(-1), P = 0.033). The area under the ROC curve for baseline proANP was 0.597 (95% CI, 0.527-0.667), as compared to 0.577 (95% CI, 0.507-0.648) for peak exercise proANP. Exercise-induced changes in proANP were similar in patients with and without myocardial ischaemia, and showed no correlation with the extent of myocardial ischaemia. CONCLUSIONS: Baseline proANP and peak exercise proANP are significantly higher in patients with myocardial ischaemia. However, because of considerable overlap in proANP levels between patients with and without myocardial ischaemia, neither measurement seems helpful in the detection of myocardial ischaemia in clinical practice.

Parieto-occipital hypoperfusion in late whiplash syndrome: first quantitative SPET study using technetium-99m bicisate (ECD).

Brain single-photon emission tomography (SPET) with N,N''-1,2-ethylene-diylbis-L-cysteine diethyl ester dihydrochloride (ECD) was performed on ten patients with a clinically high grade late whiplash syndrome and on 11 controls. Two independent readers blinded to the clinical diagnosis were able to separate the ten patients from normal controls. All these patients had qualitative bilateral parieto-occipital hypoperfusion. To confirm this, the perfusion rate of parieto-occipital over global (perfusion index) was calculated after drawing elliptical regions of interest in transversal-oblique slices. The perfusion indices in patients were significantly lower than in controls as tested by the Mann-Whitney U test. This quantitative study proves our recent qualitatively analysed observation (Lancet 1995; 345: 1513- 1514).

Chronic complicated osteomyelitis of the appendicular skeleton: diagnosis with technetium-99m labelled monoclonal antigranulocyte antibody-immunoscintigraphy.

Chronic post-traumatic osteomyelitis (OM) represents a particular challenge for nuclear medicine and radiology since clinical and biochemical parameters are frequently unreliable. The aim of this study was to investigate the value of combined bone scan (BS) and immunoscintigraphy (IS) with technetium-99m labelled monoclonal antigranulocyte antibody (MAB) in patients with suspected chronic OM of the appendicular skeleton. Twenty-four patients (17 females and 7 males) with suspected chronic post-traumatic OM were evaluated with three-phase BS/99mTc-MAB-IS. The final diagnosis was established by means of bone culture and histology in 19 cases and clinical follow-up in five cases. The studies were reviewed by two independent and experienced observers; the interobserver agreement was calculated by kappa statistics. The sensitivity, specificity and accuracy of BS alone were 92%, 18% and 58%, respectively. Combined BS/99mTc-MAB-IS had a sensitivity, specificity and accuracy of 84%, 72% and 79%, respectively. Of 24 studies, 11 were true-positive, two false-negative, eight true-negative and three false-positive. Two patients presented with unexpected ectopic haematopoietic bone marrow in the appendicular skeleton that caused false-positive results. A high degree of interobserver agreement was found (kappa=0. 85). It is concluded that combined BS/99mTc-MAB-IS represents a very sensitive and reproducible method with an acceptable specificity for the investigation of chronic OM. Problems may occur in the differentiation of low-grade OM from aseptic inflammation. Another problem is ectopic marrow that may occur in the appendicular skeleton due to a chronic inflammatory stimulus. A former intramedullary intervention in the femur with displacement of haematopoietic marrow may also lead to an ectopic location.

Successful targeted radiotherapy with 90Y-DOTATOC in a patient with Merkel cell carcinoma. A Case Report.

Merkel cell carcinomas (MCC) belong to the family of neuroendocrine tumors. In addition to other markers, they express somatostatin receptors. They are uncommon, highly malignant skin tumors with an aggressive clinical course. They develop in sun-exposed areas of the skin, mostly in elderly patients. In addition to frequent locoregional recurrences, there is a high incidence of distant metastases. Treatment is stage dependent and consists of operation and chemo- and/or radiotherapy, respectively. The advanced age of patients often impedes adequate therapy. (90)Y-DOTATOC is a novel radiolabeled somatostatin analogue containing the active octapeptide of somatostatin. It is very well tolerated and offers the option of treating somatostatin receptor-positive tumors by targeted radiotherapy. We report the case of an 83-year-old woman with recurrent MCC of the left cheek. The primary tumor and several relapses were treated with surgery and locoregional radiotherapy. After the 3rd relapse, she was treated 4 times with (90)Y-DOTATOC and two complete remissions were achieved. The fourth administration after the 2nd relapse was ineffective and conventional chemotherapy was started. There were no side effects of the (90)Y-DOTATOC. We conclude that due to its good tolerability, (90)Y-DOTATOC therapy should be evaluated further as a new therapy for somatostatin receptor-positive MCC.

The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study.

PURPOSE: The aim of this phase II study was to evaluate the tumour response of neuroendocrine tumours to targeted irradiation with the radiolabelled somatostatin analogue 90Y-DOTATOC. In addition, the palliative effect of 90Y-DOTATOC treatment on the malignant carcinoid syndrome and tumour-associated pain was investigated. PATIENTS AND METHODS: Forty-one patients (mean age 53 years) with neuroendocrine gastroenteropancreatic and bronchial tumours were included. Eighty-two percent of the patients had therapy resistant and progressive disease. The treatment consisted of four intravenous injections of a total of 6000 MBq/m2 90Y-DOTATOC, administered at intervals of six weeks. RESULTS: The overall response rate was 24%. For endocrine pancreatic tumours it was 36%. Complete remissions (CR) were found in 2% (1 of 41), partial remissions (PR) in 22% (9 of 41), minor response in 12% (5 of 41), stable disease (SD) in 49% (20 of 41) and progressive disease (PD) in 15% (6 of 41). The median follow up was 15 months (range 1 month to 36 months). The median duration of response has not been reached at 26 months. The two-year survival time was 76 +/- 16%. Eighty-three percent of the patients suffering from the malignant carcinoid syndrome achieved a significant reduction of symptoms. The treatment was well tolerated. A reduction of pain score was observed in all patients (5 of 41) with morphine dependent tumour-associated pain. Side effects included grade III (NCIGC) pancytopenia in 5%, and vomiting shortly after injection in 23%. No grade III-IV renal toxicity was observed. CONCLUSION: Targeted radiotherapy with 90Y-DOTATOC is a novel, well-tolerated treatment for neuroendocrine tumours with a remarkable objective response rate, survival time, and symptomatic response.