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Background: Radioembolization (RE) with intra-arterial administration of Y microspheres is a promising technique for the treatment of liver metastases from small intestinal neuroendocrine tumors (SI-NET) not amenable to surgery or local ablation. However, studies comparing RE to other loco-regional therapies are lacking. The aim of this randomized study was to compare the therapeutic response and safety after RE and bland hepatic arterial embolization (HAE), and to investigate early therapy-induced changes with diffusion-weighted MRI (DWI-MRI). Methods: Eleven patients were included in a prospective randomized controlled pilot study, six assigned to RE and five to HAE. Response according to RECIST 1.1 using MRI or CT at 3 and 6 months post-treatment was recorded as well as changes in DWI-MRI parameters after 1 month. Data on biochemical tumor response, toxicity, and side effects were also collected. Results: Three months after treatment, all patients in the HAE group showed partial response according to RECIST while none in the RE group did ( p = 0.0022). After 6 months, the response rates were 4/5 (80%) and 2/6 (33%) in the HAE and RE groups, respectively (NS). DWI-MRI metrics could not predict RECIST response, but lower pretreatment ADC and larger ADC increase at 1 month were related to larger decrease in tumor diameter when all tumors were counted. Conclusion: HAE resulted in significantly higher RECIST response after 3 months, but no difference compared to RE remained after 6 months. These preliminary findings indicate that HAE remains a safe option for the treatment of liver metastases from SI-NET, and further studies are needed to establish the role of RE and the predictive value of MR-DWI. [ABSTRACT FROM AUTHOR]

Background: Lu-DOTATATE is a valuable treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. Though well tolerated in general, bone marrow toxicity can, besides renal exposure, become dose limiting and affect the ability to sustain future therapies. The aim of this study was to develop a novel planar image-based method for bone marrow dosimetry and evaluate its correlation with haematological toxicity during Lu-DOTATATE treatment. In this study, 46 patients with advanced neuroendocrine tumours were treated with 7.2 GBq (3.5-8.3 GBq) of Lu-DOTATATE on two to five occasions. Planar gamma camera images were acquired at 2, 24, 48 and 168 h post-injection. Whole-body regions of interest were created in the images, and a threshold-based segmentation algorithm was applied to separate the uptake of Lu-DOTATATE into high and low uptake compartments. The conjugate view method was used to quantify the activity, the accumulated activity was calculated and the absorbed dose to the bone marrow was estimated according to the MIRD scheme. Patients were monitored for haematological toxicity based on haemoglobin (Hb), white blood cell (WBC) and platelet (PLT) counts every other week during the treatment period. Results: The mean absorbed dose to the bone marrow was estimated to 0.20 Gy (0.11-0.37 Gy) per 7.4 GBq of Lu-DOTATATE, and the mean dose per fraction correlated with a decrease in Hb ( p = 0.01), WBC ( p < 0.01) and PLT ( p < 0.01) counts. The total mean absorbed dose to the bone marrow was 0.64 Gy (0.30-1.5 Gy) per 24 GBq (8.2-37 GBq) of Lu-DOTATATE and also correlated with a decrease in Hb ( p < 0.01), WBC ( p = 0.01) and PLT ( p < 0.01) counts. Conclusions: The planar image-based method developed in this study resulted in similar absorbed doses to the bone marrow as reported in earlier studies with blood-based bone marrow dosimetry. The results correlated with haematological toxicity, making it a promising method for estimating bone marrow doses in Lu-DOTATATE treatment without the need for blood and urine sampling. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogue-based radionuclide therapy with Lu-DOTATATE is an important treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. In addition to the kidneys, the bone marrow is a major dose-limiting organ. The correlation between developed haematological toxicity and absorbed dose to the bone marrow is poor, which indicates that other factors affect haematological response. The spleen has an important role in the haematopoetic system, including being a reservoir for blood cells. It is also the organ that receives the highest mean absorbed dose during Lu-DOTATATE treatment. The aim of this study was to analyse mean absorbed dose to the spleen and its correlation with haematological toxicity, and to explore changes in splenic volume. The study included 41 patients treated with 7.2 GBq (3.5-8.3 GBq) of Lu-DOTATATE on two to five occasions. Following each fraction, planar whole-body scans were acquired at 2, 24, 48, and 168 h, and a SPECT/CT at 24 h post-injection. Mean absorbed spleen dose was calculated utilising planar images for time-activity data and SPECT to adjust activity amounts. Splenic volume information was collected from diagnostic CT scans at baseline and follow-up. Results: Median and total absorbed spleen doses were estimated to 4.5 and 15 Gy, respectively. Total absorbed spleen dose correlated with decrease in Hb ( p = 0.02), but not WBC ( p = 0.31) or PLT ( p = 0.65) counts. For patients without bone metastases, mean absorbed spleen dose correlated with decrease in PLT ( p = 0.04) but not Hb ( p = 0.16) or WBC ( p = 0.42) counts. The spleen volume was reduced to 75 % ( p < 0.001) of original values (200 vs. 260 ml) at a mean follow-up of 36 months. Conclusions: Haematological toxicity according to Hb counts was moderately but significantly correlated with total absorbed spleen dose. This supports the possibility that radiation exposure of the spleen affects overall haematological response during Lu-DOTATATE treatment. [ABSTRACT FROM AUTHOR]

Background/Aims: Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class I and class IIa HDACs, on neuroendocrine tumour (NET) cell growth. Methods: Three NET cell lines, GOT1 (small intestinal), KRJ-I (small intestinal), and BON (pancreatic), were treated with VPA and examined with respect to cell viability, cell cycle arrest, apoptosis, and global transcriptional response. Results: We found that VPA induced a dose-dependent growth inhibition of NET cells in vitro , which was mainly due to activation of extrinsic and intrinsic apoptotic pathways. VPA induced a major transcriptional response by altering the expression of 16–19% of the protein-coding genes in NET cell lines. Pathway analysis allowed the prediction of alterations in key regulatory pathways, e.g. activation of TGF-β1, FOXO3, p53 signalling, and inhibition of MYC signalling. Analysis of GOT1 xenografts showed reduced growth and reduced Ki-67 index, as well as an increase in apoptosis and necrosis after VPA treatment. Conclusions: We found that VPA treatment has a cytotoxic effect on NET cells of intestinal and pancreatic origin. There are several mechanisms by which VPA kills NET cells, which suggests the possibility of combination therapy. We propose that epigenetic therapy with HDAC inhibitors should be evaluated further in patients with NET disease. [ABSTRACT FROM AUTHOR]