Selective Internal Radiotherapy in Liver Tumors: Early Promise Yet to be Fulfilled.

Selective intra-arterial radiotherapy (SIRT) is a technique which has evolved over the past 30 years. In present this is primarily used to treat primary and secondary tumors in the liver. The technique normally depends on the delivery of a therapeutic radiopharmaceutical or radiolabeled particulate via a radiologically placed intra-arterial catheter in the hepatic artery. This is because most of these tumors have a single arterial blood supply but normal hepatocytes are supplied by both the hepatic artery and portal vein. Initially, this was done with I-131 labelled poppy seed oil but this technique was only used in a few centers. The technique became more popular when Y-90 particulates become widely available. Early results were promising but in phase 3 randomized controlled trials resulted in disappointing results compared to systemic chemotherapy. More recent work however, have shown that increasing the radiation dose to the tumor to at least 60Gy and combining with more effective systemic therapies are starting to produce better clinical results. There have also been advances in the angiographic methods used to make this into a day-case technique and the use of new radionuclides such as Ho-166 and Re-188 provides a wider range of possible SIRT techniques.

Dosing lutetium Lu 177-dotatate for a hemodialysis patient.

Lu177-dotatate (Lutathera™) is a radioactive drug approved for the treatment of adults with gastro-entero-pancreatic neuroendocrine tumors and is predominantly renally excreted. Currently all patients receive 7400 MBq (200 mCi), and there are no guidelines for treating hemodialysis patients. We measured radioactivity prior to and post administration of two cycles of Lu177-dotatate in a hemodialysis patient, and radiation exposure to staff. We reduced the standard 7400 MBq by 33% for the first cycle and patient radioactivity fell by 40% following postdilution hemodiafiltration started 6 h post dosing, and by 45% for the second cycle and radioactivity fell by 47% with postdilution hemodiafiltration started 5 h post administration. By reducing the initial administered radioactivity, coupled with early dialysis, and choosing postdilution hemodiafiltration we were able to achieve radioactivity retention curves similar to those from patients with normal renal function receiving the standard administration of 7400 MBq.

Safety and Efficacy of 177 Lu-DOTATATE in Neuroendocrine Tumor Patients With Extensive Bone Disease.

AIM: The aim of this study was to assess the efficacy and safety of 177 Lu-DOTATATE in patients with neuroendocrine tumors (NETs) and extensive bone metastases, that is, more than 50% of the skeleton involved. METHOD: A single-center retrospective analysis was performed in 30 patients (13 women and 17 men, mean age, 60 years; range, 35-77 years) undergoing 177 Lu-DOTATATE therapy. Patients had progressive metastatic NETs with extensive skeletal metastases (>50% skeletal involvement seen on baseline 68 Ga-DOTATATE PET/CT). The average administered activity was 7.308 (SD, 0.02) GBq per cycle with average treatment interval of 15 weeks. Survival analyses (progression-free survival [PFS], overall survival), radiological response assessment, toxicity assessment, and health-related quality of life (QoL) was performed. RESULTS: Overall, 26 patients completed 4 cycles, and 4 patients had less than 4 cycles of 177 Lu-DOTATATE. One patient (3%) did not complete treatment because of hematological toxicity. The estimated median PFS and median overall survival were calculated at 27 and 35 months, respectively. End-of-treatment radiological assessment showed partial response in 5 patients (17%), stable disease in 20 patients (66%), and radiological progressive disease in 3 patients (10%). Clinical progression was seen in a further 2 patients (7%).The incidence of grade 3/4 bone marrow toxicity was 10%. No patient had grade 3/4 peptide receptor radionuclide therapy-related nephrotoxicity. There was overall improvement in global QoL score (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Gastrointestinal NET-21) ( P = 0.019). CONCLUSION: 177 Lu-DOTATATE seems to have satisfactory therapeutic outcome in patients with advanced metastatic NET with extensive bone disease, with reasonable PFS and significant improvement in the global health-related QoL. The bone marrow toxicity was within the accepted range. Increasing the interval between cycles does not seem to reduce efficacy and may reduce toxicity, ensuring the bone marrow has sufficient time to recover between cycles.

Single centre retrospective review of outcome of 177 Lu-DOTATATE peptide receptor radionuclide therapy in the treatment of progressive metastatic neuroendocrine tumours: Survival, toxicity, and prognostic factors.

The aim of this study was to evaluate the efficacy and safety of 177 Lu-DOTATATE therapy in advanced metastatic disease. A retrospective analysis of 395 patients (180 female, 215 males, mean age 62) with progressive metastatic neuroendocrine tumours (NETs) who were treated with 177 Lu-DOTATATE was performed. Overall, 115 patients had less than four cycles and 280 completed four cycles of treatment. Progression-free survival (PFS) and overall survival (OS) was performed using Kaplan-Meier analysis. Analysis of survival predictors was performed using Cox regression model. Toxicity was defined using the Common Terminology Criteria for Adverse Events version 5 (CTCAE 5.0). The percentage of patients with liver and skeletal metastases were 91 and 57%, respectively. Median PFS and OS were calculated at 33 months (95% CI: 29-37 months) and 46 months (95% CI: 48-56 months), respectively. End of treatment response assessment was performed using cross sectional imaging demonstrated partial response in 22%, stable disease in 64% and progressive disease in 14% of patients. Overall, grade 3 and 4 bone marrow toxicity was seen in 8%. One patient (0.3%) developed irreversible grade 4 nephrotoxicity. Myelodysplastic disease was recorded in one patient (0.3%). Univariate analysis of PFS predictors showed that body mass index (BMI), baseline chromogranin A (CgA) >400 ng/l, baseline alkaline phosphatase (ALP) >130 mg/dl, liver tumour volume and overall tumour burden were significant. On multivariate analysis only Ki67, high CgA and low BMI retained significance. 177 Lu-DOTATATE is an effective treatment in advanced NETs with generally high-volume metastases. It is well-tolerated. Ki-67, CgA and BMI appear to be predictors for PFS.

The Combined Interpretation of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT in Metastatic Gastroenteropancreatic Neuroendocrine Tumors: A Classification System With Prognostic Impact.

PURPOSE: Gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) are widely heterogeneous in their biological behavior, and predicting prognosis and optimal treatment strategies can be challenging. 68Ga-DOTATATE PET/CT is a sensitive imaging modality for well-differentiated NEN and indicates a favorable prognosis, whereas 18F-FDG PET/CT avidity indicates disease that is potentially more aggressive. There has been emerging interest in the combined interpretation of 68Ga-DOTATATE and 18F-FDG PET and its prognostic significance. We aimed to assess the prognostic utility of a classification system that incorporates the complex findings of 68Ga-DOTATATE and 18F-FDG PET interpreted side-by-side in patients with metastatic GEP NEN. METHODS: We defined 3 68Ga-DOTATATE/18F-FDG "dual-tracer PET" groups: D1 (68Ga-DOTATATE positive/18F-FDG negative), D2 (68Ga-DOTATATE positive/18F-FDG positive), and D3 (68Ga-DOTATATE negative/18F-FDG positive). We retrospectively assessed the association between the dual-tracer PET classification and progression-free and overall survival (OS) using Kaplan-Meier analysis. Univariate and multivariate analyses were performed using the Cox proportional hazards model. RESULTS: Eighty-seven patients with metastatic GEP NEN and contemporaneous 68Ga-DOTATATE and 18F-FDG PET were included. The dual-tracer PET classification was an independent predictor of OS (multivariate P = 0.016) and also predicted progression-free survival (univariate P = 0.030). Other independent predictors of OS included chromogranin A and World Health Organization (WHO) grade. WHO grade was not associated with OS from the time of dual-tracer PET but was an independent predictor of OS from the date of histological diagnosis (multivariate P = 0.003). CONCLUSION: Our study demonstrates that a classification system combining the complex findings of 68Ga-DOTATATE and 18F-FDG PET is correlated with prognosis. Further research is needed to prospectively validate these findings and to explore whether dual-tracer PET scores may also be able to predict response to treatment.

177Lu-DOTATATE in older patients with metastatic neuroendocrine tumours: safety, efficacy and health-related quality of life.

PURPOSE: The safety and efficacy of 177Lu-DOTATATE in older patients with advanced neuroendocrine tumours (NET) are not well understood. METHODS: Patients ≥70 years of age and treated with 177Lu-DOTATATE were included. Toxicity, health-related quality of life (HRQoL), objective response, progression-free survival (PFS) and overall survival (OS) were assessed. The relationship between baseline characteristics and PFS and OS was analysed using the Kaplan-Meier method. Univariate analyses were performed using the Cox proportional hazards model. RESULTS: In total, 71 patients were included (76.1% midgut primary). The median age at diagnosis and age at 177Lu-DOTATATE treatment were 70 and 74 years, respectively. The majority (78.9%) of patients completed 4 cycles of 177Lu-DOTATATE. Clinically significant myelosuppression was rare (2.8%). There was no deterioration in HRQoL and 'disease-specific worries' significantly improved (P = 0.029). Radiological response assessment was available in 66 patients. Partial response, stable disease and progression of disease were found in 10 (15.2%), 52 (78.8%) and 4 patients (6.1%), respectively. Median PFS and OS were 36.0 and 47.0 months, respectively. Increased baseline alkaline phosphatase was associated with poorer PFS (P = 0.002) and OS (P = 0.006). CONCLUSION: Patients ≥70 years of age with advanced NET treated with 177Lu-DOTATATE have efficacy and toxicity profiles similar to the wider NET population, without deterioration of HRQoL.

Granulomatous CNS inflammation associated with seminoma.

Two cases in which a neurological disorder was identified pathologically to be due to a granulomatous infiltration were found after diagnosis to have an associated testicular seminoma with pathologically proven lymphatic metastasis. We present the clinical and imaging features, and pathological appearances of the lymphatic tissue and the brain. We summarise the literature to date and discuss the pathogenesis of the disorder and its treatment.

Early efficacy of and toxicity from lutetium-177-DOTATATE treatment in patients with progressive metastatic NET.

OBJECTIVE: Lutetium-177 DOTA-D-Phe1-Tyr3-octreotide (Lu-DOTATATE) is a treatment option for patients with well-differentiated metastatic neuroendocrine tumours. Our centre started administering this therapy in 2012. The aim of this study was therefore to analyse the first cohort of patients treated with Lu-DOTATATE to determine its early efficacy and toxicity. PATIENTS AND METHODS: We retrospectively analysed patient, tumour and treatment characteristics, end-of-treatment outcome, time to progression and toxicity in 79 consecutive patients treated with Lu-DOTATATE who had progressive NET according to Response Evaluation Criteria in Solid Tumours criteria. Follow-up time was 12-40 months. Study of Kaplan-Meier plots, analysis of time to progression and multiple regression analysis of factors predictive of time to progression were performed. RESULTS: At end-of-treatment radiological restaging, 13% of patients were found to have partial response and 64% to have stable disease; 23% of patients progressed through treatment. Overall, 47% of patients demonstrated a reduction in chromogranin A levels. The overall estimated median time to progression from the start of treatment was 28 months for the entire cohort and 31, 30 and 5 months for those with partial response, stable disease and progressive disease, respectively. On multivariate regression analysis, higher grade of tumour was found to be significantly associated with shorter progression-free survival. Three patients experienced grade 1 haematotoxicity, five grade 1 nephrotoxicity and one grade 2 nephrotoxicity. CONCLUSION: Early outcomes of patients treated with Lu-DOTATATE are similar to those in previously published series in terms of end-of-treatment efficacy and toxicity. This provides further evidence that this is a safe and efficacious form of treatment for patients with progressive metastatic neuroendocrine tumours.

Prognostic utility of the Perugini grading of 99mTc-DPD scintigraphy in transthyretin (ATTR) amyloidosis and its relationship with skeletal muscle and soft tissue amyloid.

AIMS: High-grade (Perugini grade 2 or 3) cardiac uptake on bone scintigraphy with 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has lately been confirmed to have high diagnostic sensitivity and specificity for cardiac transthyretin (ATTR) amyloidosis. We sought to determine whether patient stratification by Perugini grade on 99mTc-DPD scintigraphy has prognostic significance in ATTR amyloidosis. METHODS AND RESULTS: Patient survival from time of 99mTc-DPD scintigraphy was determined in 602 patients with ATTR amyloidosis, including 377 with wild-type ATTR (ATTRwt) and 225 with mutant ATTR (ATTRm) amyloidosis. Patients were stratified according to Perugini grade (0-3) on 99mTc-DPD scan. The prognostic significance of additional patient and disease-related factors at baseline were determined. In the whole cohort, the finding of a Perugini grade 0 99mTc-DPD scan (n = 28) was invariably associated with absence of cardiac amyloid according to consensus criteria as well as significantly better patient survival compared to a Perugini grade 1 (n = 28), 2 (n = 436) or 3 (n = 110) 99mTc-DPD scan (P < 0.005). There were no differences in survival between patients with a grade 1, grade 2 or grade 3 99mTc-DPD scan in ATTRwt (n = 369), V122I-associated ATTRm (n = 92) or T60A-associated ATTRm (n = 59) amyloidosis. Cardiac amyloid burden, determined by equilibrium contrast cardiac magnetic resonance imaging, was similar between patients with Perugini grade 2 and Perugini grade 3 99mTc-DPD scans but skeletal muscle/soft tissue to femur ratio was substantially higher in the latter group (P < 0.001). CONCLUSION: 99mTc-DPD scintigraphy is exquisitely sensitive for identification of cardiac ATTR amyloid, but stratification by Perugini grade of positivity at diagnosis has no prognostic significance.

The Impact of Radiological Response to Peptide Receptor Radionuclide Therapy on Overall Survival in Patients With Metastatic Midgut Neuroendocrine Tumors.

PURPOSE OF THE REPORT: Peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced neuroendocrine tumors (NET); however, long-term survival data are scarce. The aim of this study is to determine long-term survival in patients with metastatic midgut NET, according to response to PRRT. PATIENTS AND METHODS: One hundred thirty-three consecutive patients with progressive metastatic midgut NET underwent PRRT. Response at 1 year post PRRT was classified as partial response, stable disease, disease progression, or death. Survival was assessed according to response to PRRT, and predictors of overall survival (OS) and progression-free survival (PFS) were identified. RESULTS: At 1 year post PRRT, 9% had partial response, 50.4% stable disease, 10.5% disease progression, and 30.1% were dead. The OS was 33.5, and PFS was 28.5 months. Predictors of disease progression/death were chromogranin A greater than 10 ULN (OR, 4.6; P = 0.007) and hepatic tumor load greater than 50% (OR, 5; P = 0.004). There was no difference in OS between patients with partial response and those with stable disease post PRRT. In multivariate Cox regression, predictors of OS were number of PRRT cycles (HR, 0.33; P < 0.0005), hepatic tumor load greater than 50% (HR, 3.46; P = 0.01), and outcome at 1 year post PRRT (HR, 21.37; P < 0.0005). Predictors of PFS were number of PRRT cycles (HR, 0.39; P < 0.0005), previous resection of liver metastases (HR, 3.56; P = 0,023), and hepatic tumor load greater than 50% (HR, 3.06; P < 0.0005). CONCLUSIONS: Patients with progressive metastatic midgut NET who achieved stable disease at 1 year post PRRT had similar OS with those with partial response. Hepatic tumor burden was a strong predictor of response to PRRT, PFS, and OS.

Is there a Role for Gallium-67 Citrate SPECT/CT, in Patients with Renal Impairment or Who are Renal Transplant Recipients, in Identifying and Localizing Suspected Infection?

To assess the added value of single-photon emission computed tomography/computed tomography (SPECT/CT) in patients with end-stage renal failure (ESRF) or renal transplant recipients in whom focal infection was suspected. Gallium-67 (Ga-67) citrate scintigrams of 18 patients (10 in ESRF and eight with renal transplants) were reviewed. Sites of abnormal uptake seen on the whole body and SPECT were noted. A SPECT/CT was also reviewed to see if additional information could be obtained. Imaging results were compared with the final diagnosis. Overall, 14 out of 18 (78%) patients had a proven cause to explain symptoms while four patients did not have a final cause identified. Infection was proven in the final diagnosis in 12 out of 14 (86%) patients. Of the 10 patients with ESRF, six had confirmed infection with the Ga-67 citrate study correctly identifying five out of six (83%) patients, and SPECT/CT providing additional information in four out of five (80%) patients. In the eight renal transplant recipients, six had a confirmed source of infection (all identified by the Ga-67 citrate study). SPECT/CT provided additional information in two out of six (33%) patients. Ga-67 citrate imaging had an overall sensitivity of 13/14 (93%), with one false negative. SPECT/CT provided an additional contribution in eight out of 18 (44%) patients by better defining the location/extent of infection and differentiating the physiological from the pathological uptake.

Automated quantification with BRASS reduces equivocal reporting of DaTSCAN (123I-FP-CIT) SPECT studies.

BACKGROUND: ¹²³I-FP-CIT (DaTSCAN) SPECT studies of the nigrostriatal pathway are a valuable tool in the diagnosis of movement disorders. However some scans are reported as equivocal with potential adverse consequences. We investigated whether the use of quantification of tracer uptake within the striatum can be used to reduce the number of equivocal reports. MATERIAL AND METHODS: BRASS software (Hermes, Sweden) was used to quantify striatal tracer uptake in DaTSCAN studies of patients referred to our institution. Scans were quantified and numerical limits were determined to distinguish between normal and abnormal scans. Scans were then re-reported both with, and without, the use of quantification. Number of equivocal reports and accuracy of reporting between the two types of reporting were compared. RESULTS: Scan reporting using quantification led to a significant reduction in the number of equivocal reports with no significant change in reporting accuracy. CONCLUSION: Automated quantification of DaTSCAN studies with BRASS and the use of numerical limits can decrease the number of equivocal reports without affecting report accuracy.

(18)F-fluorodeoxyglucose positron emission tomography/computed tomography in diagnosis of post-transplant lymphoproliferative disorder.

The aim of the present study was to investigate the role of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the diagnosis of post-transplant lymphoproliferative disorder (PTLD), a serious complication of solid organ and bone marrow transplant. Between January 2004 and January 2012, 40 patients (22 males; median age 52 ± 17.4 years, range 11-77 years) underwent (18)F-FDG PET/CT scans in our department for diagnostic evaluation of PTLD. Twenty-three (57.5%) patients had negative (18)F-FDG PET/CT and 17 (42.5%) had a positive examination. In five patients PET/CT revealed extranodal disease (adrenal, pleural, spleen, liver, lung, esophagus and bone involvement). On the basis of our results, (18)F-FDG PET/CT had a sensitivity of 88.2% (95% confidence interval [CI] 0.62-0.98), a specificity of 91.3% (CI 0.70-0.98), a positive predictive value of 88.2% (CI 0.62-0.98) and a negative predictive value of 91.3% (CI 0.70-0.98). The diagnostic performance of CT in patient-based analysis was: a sensitivity of 87.5% (CI 0.60-0.97), a specificity of 88.8% (CI 0.64-0.98), a positive predictive value of 87.5% (CI 0.60-0.97) and a negative predictive value of 88.8% (CI 0.64-0.98). PET/CT in five cases revealed more findings than CT, upstaging the disease, and revealed three extranodal findings, not visualized in conventional imaging. (18)F-FDG PET/CT plays a significant role in the setting of PTLD diagnosis, demonstrating its high accuracy in detecting PTLD.

Is hybrid imaging (SPECT/CT) a useful adjunct in the management of suspected facet joints arthropathy?

PURPOSE: The purpose of this study was to assess the value of SPECT/CT imaging in patients with chronic spinal pain. METHODS: This was a retrospective consecutive study. Patients with chronic neck or back pain from outpatient spinal clinics with clinical features raising the possibility of a facetogenic pain generator and non-conclusive MRI/CT findings were included. Imaging was performed on a dual-headed, hybrid SPECT/CT γ-camera with a low-dose CT transmission scan acquired after the SPECT study. SPECT/CT studies were viewed in the coronal, axial, and sagittal planes and in 3-dimensional mode. Descriptive statistical analysis was performed. RESULTS: Seventy-two patients were included (37 females, 35 males, mean age of 53.9 years). There were 25 cervical spine scans and 49 lumbar spine scans. In the cervical spine group, 13 (52 %) patients had scintigraphically active cervical facet joint arthropathy and ten (36 %) had other pathology identified. Two thirds of patients diagnosed with facet joint arthropathy received steroid guided injections following their scans. In the lumbar spine group 34 (69.4 %) patients had scintigraphically active lumbar facet joint arthropathy and eight had other pathology identified. Twenty patients (58.8 %) diagnosed with facet joint arthropathy subsequently received steroid guided injections. CONCLUSIONS: Hybrid SPECT/CT imaging identified potential pain generators in 92 % of cervical spine scans and 86 % of lumbar spine scans. The scan precisely localised SPECT positive facet joint targets in 65 % of the referral population and a clinical decision to inject was made in 60 % of these cases.

Efficacy of using a standard activity of (131)I-MIBG therapy in patients with disseminated neuroendocrine tumours.

PURPOSE: The aim of this analysis was to evaluate the response to standard activity of (131)I-meta-iodobenzylguanidine (MIBG) in patients with disseminated neuroendocrine tumours (NETs), comparing overall survival of patients with symptomatic response, tumour size (as assessed by CT) and relevant plasma tumour markers. METHODS: A retrospective review of patients who had undergone (131)I-MIBG treatment between March 2001 and December 2006 was carried out. The administered activity of (131)I-MIBG was 5.5 GBq (NETs) and 7 GBq (phaeochromocytoma). Three cycles of treatment were planned with an interval of 10-12 weeks. A pre-therapy scan with (123)I-MIBG was performed to ascertain appropriate biodistribution. RESULTS: Thirty-eight patients were identified. Only two patients developed significant bone marrow suppression. Symptomatic response: data were available in 37 of 38 patients: 15 patients had improved symptoms, 19 had no improvement in symptoms and 3 were asymptomatic. In those with a symptomatic response, the median overall survival was 58 months vs no response of 20.0 months (p = 0.001). CT response: in those with stable disease, the median overall survival was 58 months compared with progressive disease of 16.0 months. The difference between these groups was significant (p = 0.006). Hormonal response: this was available in only 20 of 38 patients. The median overall survival was the same for patients that had increased hormone levels and patients that had stable/decreased hormone levels (48 months). CONCLUSION: Standard activity (131)I-MIBG is well tolerated. Symptomatic response to treatment is a significant predictor of overall survival. Whilst CT response also appears to predict survival, hormonal levels do not appear to correlate with survival.

The role of 99mTc-depreotide in the management of neuroendocrine tumours.

BACKGROUND: In-pentetreotide scan (OctreoScan) is a widely available agent with high sensitivity for imaging neuroendocrine tumours. Negative In-pentetreotide poses diagnostic as well as therapeutic problems in terms of staging and consideration of targeted radionuclide therapy. AIM: To assess the role of Tc-depreotide in patients with negative or weakly positive OctreoScan (Krenning score< or =1; measured on a scale range 0-4). To determine the usefulness of Tc-depreotide scintigraphy for highlighting lesions that may be missed by OctreoScan and/or CT/MRI imaging. STUDY DESIGN: Prospective analysis of 25 patients with neuroendocrine tumours, with negative or weakly positive In-pentetreotide scans, who were consecutively enrolled to undergo In-pentetreotide and Tc-depreotide imaging. The results were compared with either CT or MRI scans. RESULTS: Histology was available for 20 of 25 patients: of these 40% had high-grade tumours (cellular proliferation marker Ki-67 score >20%), a further 35% had intermediate-grade tumours (Ki-67 2-20%), and the remaining 25% had low-grade tumours (Ki-67 <2%). Fifty-two percent of patients had completely negative and 48% had weakly positive OctreoScan results. Thirty-two percent of these same patients had significantly positive Tc-depreotide scans (Krenning score> or =2), with the histology demonstrating intermediate-grade or high-grade tumours. CONCLUSION: Tc-depreotide imaging has low sensitivity but is useful in a one-third of OctreoScan-negative patients, displaying significantly better uptake than In-pentetreotide in this patient group. It aids diagnosis by highlighting lesions not seen by OctreoScan and/or CT/MRI imaging, and can possibly identify a group of patients amenable to therapy with radionuclide agents, such as SOM230, targeting somatostatin receptor subtypes 2, 3 and 5.