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Purpose: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is usually efficient subsequent to treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy; NETest monitors disease. We prospectively evaluated: (1) NETest as a surrogate biomarker for RECIST; (2) the correlation of NETest levels with PPQ prediction., Methods: Three independent 177 Lu-PRRT-treated GEP-NET and lung cohorts (Meldola, Italy: n = 72; Bad-Berka, Germany: n = 44; Rotterdam, Netherlands: n = 41). Treatment response: RECIST1.1 (responder (stable, partial, and complete response) vs non-responder). Blood sampling: pre-PRRT, before each cycle and follow-up (2-12 months). PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable < 40; progressive > 40). CgA (ELISA) as comparator. Samples de-identified, measurement and analyses blinded. Kaplan-Meier survival and standard statistics., Results: One hundred twenty-two of the 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p < 0.0001) decreased in RECIST "responders" (- 47 ± 3%); in "non-responders," it remained increased (+ 79 ± 19%) (p < 0.0005). NETest monitoring accuracy was 98% (119/122). Follow-up levels > 40 (progressive) vs stable (< 40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04 (95%CI, 0.02-0.07). PPQ response prediction was accurate in 118 (97%) with a 99% accurate positive and 93% accurate negative prediction. NETest significantly (p < 0.0001) decreased in PPQ-predicted responders (- 46 ± 3%) and remained elevated or increased in PPQ-predicted non-responders (+ 75 ± 19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06 (95%CI, 0.03-0.12). CgA did not reflect PRRT treatment: in RECIST responders decrease in 38% and in non-responders 56% (p = NS)., Conclusions: PPQ predicts PRRT response in 97%. NETest accurately monitors PRRT response and is an effective surrogate marker of PRRT radiological response. NETest decrease identified responders and correlated (> 97%) with the pretreatment PPQ response predictor. CgA was non-informative.

Purpose: In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from (131)I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with (177)Lu-DOTA(0)-Tyr(3)-octreotate ((177)Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit., Methods: The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined., Results: Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0 × 10(9)/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67 ± 7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq (177)Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients., Conclusion: The incidence of subacute haematological toxicity after PRRT with (177)Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from (131)I, seems not to be valid for PRRT with (177)Lu-DOTATATE.

Background: During childhood and adolescence, bone mass and lean body mass (LBM) increase till a plateau is reached. In this longitudinal and cross-sectional study, the age of reaching the plateau was evaluated for lumbar spine and total body bone mass measurements and lean body mass. The association between fractures and bone mineral density (BMD) was studied., Patients and Methods: We included 501 healthy participants, 141 males and 360 females, aged 13-29 years. Of these 90 had participated in a previous longitudinal study of 444 participants, aged 4-20 years (for the first measurement) and 198 participants, aged 8-25 years (for a second measurement). BMD and body composition were measured with dual energy X-ray absorptiometry (DXA). Volumetric BMD (bone mineral apparent density, BMAD) was calculated. All the data were used to determine the age of reaching the plateau., Results: The plateau for lumbar spine BMD, BMAD, total body BMD, bone mineral content and LBM was reached between 18 and 20 years of age in females and between 18 and 23 years in males. The prevalence of fractures was 37% in males and 28% in females. Total body BMD Z-score was significantly lower in all participants who had had a fracture (p<0.05), whereas lumbar spine BMD and BMAD was only significantly lower in females who had had fractures (p=0.007 and p<0.001, respectively). Mean lumbar spine BMAD Z-score at the previous measurement was significantly lower in the participants who had a first fracture between the last two measurements (p=0.04)., Conclusion: Peak BMD and peak LBM were attained between 18 and 20 years in females and between 18 and 23 years in males in this study using longitudinal and cross sectional data in the age range of 4 to 30 years. A significantly lower total body BMD was seen in participants who had had a fracture and a lower lumbar spine BMD and BMAD in females who had had a fracture. Lumbar spine BMAD Z-score seems to be a good predictor for future fractures., ((c) 2009 Elsevier Inc. All rights reserved.)

Unlabelled: Nuclear imaging using (18)F-FDG is an established method for the noninvasive assessment of myocardial viability. Data on the value of (18)F-FDG imaging in patients with diabetes mellitus are scarce. The aim of this study was to assess whether, in patients with diabetes mellitus and ischemic left ventricular (LV) dysfunction, (18)F-FDG imaging can predict improvement of LV function and heart failure symptoms after coronary revascularization., Methods: A total of 130 consecutive patients with ischemic LV dysfunction who were already scheduled for surgical revascularization were studied; 34 of the patients had diabetes mellitus. All patients underwent radionuclide ventriculography to assess left ventricular ejection fraction (LVEF), resting 2-dimensional echocardiography to identify dysfunctional myocardial tissue, and dual-isotope (18)F-FDG/(99m)Tc-tetrofosmin SPECT after oral administration of acipimox. Nine to 12 mo after coronary revascularization, radionuclide ventriculography and echocardiography were repeated. An improvement in LVEF by at least 5% was considered significant., Results: (18)F-FDG SPECT demonstrated that 610 (50%) of 1,212 dysfunctional segments were viable. Patients with and without diabetes mellitus had a comparable number of dysfunctional but viable segments per patient. Also, the number of patients with a substantial amount of dysfunctional but viable myocardium (>or=4 viable segments) was comparable between the groups with and without diabetes mellitus. The presence of substantial viability on (18)F-FDG SPECT was predictive of improvement in LVEF and heart failure symptoms postoperatively (sensitivity and specificity of 82% and 89%, respectively, in patients with diabetes and 83% and 93%, respectively, in patients without diabetes; not statistically significant)., Conclusion: (18)F-FDG SPECT is practical for routine assessment of myocardial viability in patients with ischemic LV dysfunction with or without diabetes mellitus. Patients with substantial myocardial viability on (18)F-FDG SPECT have a high probability of improvement of LV function and symptoms after coronary revascularization, irrespective of the absence or presence of diabetes mellitus.

Background: Dexamethasone is known to have both more potent leukemic activity and is associated with a higher incidence of side effects than prednisolone. In this study, we compared the long-term effects of dexamethasone and prednisolone on bone mineral density (BMD), body composition and growth in long-term survivors of ALL in first complete remission., Procedure: Ninety patients (51 male, 49 female; 8.6-38.5 year), treated with either a prednisolone containing protocol (n = 47; n = 19 also with CNS-irradiation) or a dexamethasone containing protocol (n = 43; no cranial irradiation) participated in this cross-sectional single center study. Mean follow-up was 12.7 years (2.0-29.7 years). BMD of lumbar spine and total body, and body composition were expressed as standard deviation scores (SDS) using dual energy X-ray absorptiometry. Bone mineral apparent density of the lumbar spine (BMAD) was calculated to correct for bone size., Results: There was no difference in height, height corrected for target height, BMD, or lean body mass between prednisolone and dexamethasone treated patients. Prednisolone treated patients had an increased percentage body fat (SDS +0.46; P < 0.05) and increased body mass index (SDS 0.88; P < 0.01) compared to normal. Dexamethasone treated patients had only an increased body mass index (SDS 0.52; P < 0.05). Height, total body BMD, and lean body mass were lower in patients treated with cranial irradiation as compared to non-irradiated patients, but differences in the latter two disappeared when corrected for height. BMAD was normal after CNS-irradiation., Conclusions: Long term survivors of ALL treated with prednisolone or dexamethasone containing regimens do not differ in height, BMD, or body composition.

Objective: To evaluate fracture rate and bone mineral density (BMD) and body composition in children with acute lymphoblastic leukemia (ALL) treated with dexamethasone-based chemotherapy., Study Design: Children with ALL (n = 61) participated. At diagnosis, during therapy, and one year after cessation of therapy, BMD and body composition were measured using dual energy X-ray absorptiometry of lumbar spine (LS) and total body (TB). Serum markers of bone turnover were assessed., Results: BMD(LS) was significantly reduced at diagnosis, and remained low during therapy. BMD(TB) was normal at diagnosis, with a fast decrease in the first 32 weeks, in which chemotherapy was relatively intensive. Apparent ("volumetric") BMD(LS) was also reduced, but this did not reach significance at diagnosis and follow-up. Bone formation markers were reduced at diagnosis; formation as well as resorption markers increased during treatment. Fracture rate was 6 times higher in ALL patients compared with healthy controls. Lean body mass was decreased at baseline. Percentage of body fat increased significantly during therapy. After ALL treatment was completed, BMD and body composition tended to improve., Conclusions: Children with ALL are at risk for osteopenia because of the disease itself and the intensive chemotherapy. Fracture rate increases substantially, not only during but also shortly after treatment.