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Background Lutetium-177-DOTA-octreotate ( 177 Lu-DOTATATE) significantly increases survival and response rates in patients with grade I and grade II neuroendocrine tumors (NETs). However, survival and response rates are significantly lower in patients with bulky liver metastases. Increasing the tumor-absorbed dose in liver metastases may improve response to 177 Lu-DOTATATE. The LUTIA (Lutetium Intra-Arterial) study aims to increase the tumor-absorbed dose in liver metastases by intra-arterial (IA) administration of 177 Lu-DOTATATE, compared to conventional intravenous (IV) administration. Methods A multicenter, within-patient randomized controlled trial (RCT) in 26 patients with progressive, liver-dominant, unresectable grade I or grade II NET will be conducted. Patients with bilobar bulky disease will be randomly allocated to receive IA treatment into either the left or the right hepatic artery. Using this approach, one liver lobe will be treated intra-arterially (first-pass effect), while the contralateral lobe will receive an intravenous treatment as a second-pass effect. The primary endpoint of this study is the difference in tumor-to-non-tumor ratio of 177 Lu-DOTATATE uptake between the two liver lobes on post-treatment SPECT/CT (IA versus IV). Secondary endpoints include absorbed dose in both liver lobes, tumor response, dose-response relationship, toxicity, uptake in extrahepatic lesions, and renal uptake. Discussion This multicenter, within-patient RCT will investigate whether IA administration of 177 Lu-DOTATATE results in a higher activity concentration in liver metastases compared to IV administration. Trial registration ClinicalTrials.gov, NCT03590119 . Registered on 17 July 2018.

Objective(s):Bacterial endotoxin test (BET) for detection and quantification of endotoxin in radiopharmaceuticals (RPs), used for therapy or diagnosis, is prerequisite to administration in patients. Out of the two established methods used for this purpose (Kinetic Chromogenic Assay: KCM and Gel Clot Bacterial Endotoxin Test: GC-BET), GC-BET is recommended by pharmacopeias to evaluate the interferences exhibited during the assay due to presence of various ingredients in samples. In the present study, the influence of excess of cations in [177Lu]Lu-DOTATATE, used for Peptide Receptor Radionuclide Therapy (PRRT), were studied and a protocol to negate the enhancement observed was developed. Additionally, a protocol for carrying out GC-BET for extremely viscous [131I]I-Lipiodol was standardized.Methods:GC-BET was performed for [177Lu]Lu-DOTATATE and [131I]I-Lipiodol at maximum valid dilution (MVD), using LRW as a diluent. To negate the false positivity observed in case of [177Lu]Lu-DOTATATE, various concentrations of calcium chloride (CaCl2) were added and evaluated for the reversal of the interference observed initially. To prevail the difficulty in performing GC-BET for [131I]I-Lipiodol various modification in the protocols like orbital vortexing at different rpm and time intervals were performed. KCM assays were also performed for studied RPs at MVD.Results:It was observed that at MVD, [177Lu]Lu-DOTATATE exhibited false positivity in GC-BET. However, all the individual reagents used in labeling of [177Lu]Lu-DOTATATE did not show any false positivity. Finally, performing the assay with an addition of 2mM CaCl2 (final concentration) nullified the false positivity. Further, intricacy in performing GC-BET for [131I]I-Lipiodol due to its viscosity was resolved by orbital vortexing at 3000 rpm for 5 minutes.Conclusions:Our study proved that false positivity was observed in GC-BET for [177Lu]Lu-DOTATATE due to the presence excess M3+ ions. Further, our study is the first of its kind which demonstrated methods for negating these false positive results by using modified protocol and hypothesizing the reason behind the enhancement. Additionally, ours is the first study which proved that a simple step of vortexing the viscous RPs like [131I]I-Lipiodol can resolved the problems encountered during performing GC-BET due to viscosity of RPs.

PurposeIn patients with neuroendocrine tumor liver metastases, additional tumor reduction can be achieved by sequential treatment with [166Ho]-radioembolization after peptide receptor radionuclide therapy (PRRT). The aim of this study was to analyze hematotoxicity profiles, (i.e. lymphocyte and neutrophile toxicity) and the prognostic value of neutrophil-to-lymphocyte ratio (NLR) and thrombocyte-to-lymphocyte ratio (TLR).MethodsAll patients included in the prospective HEPAR PLuS study were included in this study. Blood testing was performed at baseline (before radioembolization) and at regular intervals during 1-year follow-up. Radiological response was assessed at 3, 6, 9, and 12 months according to RECIST 1.1. Logistic regression was used to analyze the prognostic value of NLR and TLR on response.ResultsThirty-one patients were included in the toxicity analysis; thirty were included in the response analysis. Three weeks after radioembolization, a significant decrease in lymphocyte count (mean change − 0.26 × 109/L) was observed. Ten patients (32.2%) experienced grade 3–4 lymphocyte toxicity. This normalized at 6 weeks and 3 months after treatment, while after 6 months a significant increase in lymphocyte count was observed. An increase in NLR and TLR at 3 weeks, compared to baseline, significantly predicted response at 3 months (AUC = 0.841 and AUC = 0.839, respectively) and at 6 months (AUC = 0.779 and AUC = 0.765). No significant relation with survival was found.ConclusionsToxicity after sequential treatment with PRRT and [166Ho]-radioembolization is limited and temporary, while significant additional benefit can be expected. Change in NLR and TLR at 3-weeks follow-up may be valuable early predictors of response.Trial registration ClinicalTrials.gov, NCT02067988. Registered 20 February 2014, https://clinicaltrials.gov/ct2/show/record/NCT02067988.

Purpose Lutetium-177-Dotatate (Lutathera ® ) is a combined radionuclide-peptide that is FDA-approved for the treatment of well-differentiated, somatostatin receptor-positive, gastroenteropancreatic neuroendocrine tumors. Carcinoid crisis is a rare, but potentially life-threatening risk of this radiopharmaceutical, of which prompt recognition and treatment is essential to reducing morbidity. This manuscript provides an overview of the topic to promote awareness of this adverse event, with emphasis on early recognition and management. In addition, we present our institution’s experience with Lutetium-177-Dotatate-associated complications across a five-year period. Methods A literature review of lutetium-177-dotatate therapy and its potential implication of carcinoid crisis was performed. Additionally, a review of our institution’s experience is presented. Results The incidence of carcinoid crisis induced by Lutetium-177-Dotatate therapy is estimated to range between 1 and 2% of treatment recipients. Those who have tumors located within the midgut, higher tumor burden, and the presence of metastasis have an increased risk of developing carcinoid crisis, among other risk factors. Carcinoid crisis is most often encountered within 12–48 h of receiving the first treatment dose, with the most common symptoms being nausea/vomiting, flushing, and diarrhea. Conclusion Carcinoid crisis is a rare but potentially life-threatening complication of Lutetium-177-Dotatate therapy. Knowledge of risk factors and prompt recognition of symptoms is essential to successful treatment, with early initiation of intravenous octreotide serving a critical step in reducing morbidity of this adverse event.