Therapy with 177Lu-octreotate - pharmacokinetics, dosimetry and kidney toxicity

177Lu-octreotate is used for treatment of patients with somatostatin receptor expressing neuroendocrine tumors in some clinics using a standard schedule. Renal and bone marrow toxicity are the main limiting factors. Results are in general positive, but no optimization of treatment schedule has been performed and animal studies suggest that higher cure rate might be possible. To optimize the treatment and minimize toxicity, individual biodistribution and dosimetric data are needed. The biological effects on kidney tissue of 177Lu must be studied, together with better ways to block the radionuclide retention in kidneys. The aims of the project were to determine the pharmacokinetics in patients and to perform dosimetric estimations for kidneys, bone marrow, liver, spleen and tumors after 177Lu-octreotate administration, to examine the radiobiological effects of 177Lu in the kidneys in an animal model, and to study how kidney blocking agents lysine and dimercaptosuccinic acid (DMSA) affect the uptake of111In-octreotide in the kidneys. The pharmacokinetics in patients who received 3.5-8 GBq 177Lu-octreotate up to six times combined with amino acids for kidney blocking, were determined using planar scintigraphy and conjugate view method. Large individual variations were observed in absorbed dose per administered activity to all tissues, e.g. 0.33-2.4 Gy/GBq to kidneys, 0.047-0.54 Gy/GBq to liver, 0.28-4.4 Gy/GBq to spleen, and 0.010-0.093 Gy/GBq to bone marrow. Tumors received up to 20 Gy/GBq. Long-term effects on the kidneys after injection of 0-150 MBq 177Lu–octreotate were evaluated in normal mice. Effects on renal functions, e.g. glomerular filtration, reabsorption, and excretion were observed after high administered activity using 99mTc-DTPA–scintigraphy and urea level in blood. Results may be important for defining potential biomarkers for early prediction of late renal toxicity and impairment. Blocking of the uptake of 111In-octreotide in the kidneys was studied in normal mice using lysine and DMSA. The results indicated that the uptake of 111In depends on the amount of lysine and DMSA administered, and the time for injection of respective agent. Lysine combined with DMSA did not give better blocking, probably due to less optimal time schedule. In conclusion, this work demonstrates the importance and some possibilities to optimize treatment of patients with neuroendocrine tumors using 177Lu-octreotate

Nationellt vårdprogram för adrenala incidentalom : Programmet har harmoniserats med europeiska riktlinjer – ger förenklad handläggning av patienter

Adrenal incidentalomas are seen in about five percent of abdominal CT examinations, and in most cases represent non-hormone-producing adrenocortical adenomas, but hormone-producing or malignant lesions occur. Revised Swedish guidelines for the evaluation and management of adrenal incidentalomas based on recently published European guidelines are presented. The importance of a thorough radiological, clinical and biochemical initial evaluation is emphasized. Longterm biochemical follow-up is not recommended and use of CT contrast medium »washout« calculation is omitted. No radiological evaluation or follow-up indicated for adrenal incidentalomas <1 cm size. For patients with diagnosed lipid rich adenomas (≤ 10 HU) 1-4 cm in size no radiological follow-up is suggested after initial evaluation

Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets.

We wanted to define the transcriptome of small intestinal neuroendocrine tumors in order to identify clinically relevant subgroups of tumors, prognostic markers and novel targets for treatment. Genome-wide expression profiling was conducted on tumor biopsies from 33 patients with well-differentiated neuroendocrine tumors of the distal ileum and metastatic disease at the time of diagnosis. Unsupervised hierarchical clustering analysis identified three groups of tumors. The largest group, comprising half of the tumors, was characterized by longer patient survival and higher expression of neuroendocrine markers, including SSTR2. Tumors with higher grade (G2/3) or gain of chromosome 14 were associated with shorter patient survival and increased expression of cell cycle-promoting genes. Pathway analysis predicted the prostaglandin E receptor 2 (PTGER2) as the most significantly activated regulator in tumors of higher grade, whereas Forkhead box M1 (FOXM1) was the most significantly activated regulator in tumors with gain of chromosome 14. Druggable genes identified from expression profiles included clinically proven SSTR2 and also novel targets, for example, receptor tyrosine kinases (RET, FGFR1/3, PDGFRB and FLT1), epigenetic regulators, molecular chaperones and signal transduction molecules. Evaluation of candidate drug targets on neuroendocrine tumors cells (GOT1) showed significant inhibition of tumor cell growth after treatment with tyrosine kinase inhibitors or inhibitors of HDAC, HSP90 and AKT. In conclusion, we have defined the transcriptome of small intestinal neuroendocrine tumors and identified novel subgroups with clinical relevance. We found specific gene expression patterns associated with tumor grade and chromosomal alterations. Our data also suggest novel prognostic biomarkers and therapies for these patients

Gordon River upstream from Knob, Tasmania, ca. 1968 [picture] /

Title devised by captioner from accompanying documentation.; Part of the Russ Ashton photographic collection.; Also available in an electronic version via the internet at: http://nla.gov.au/nla.pic-vn3991445-s103

Gene fusion involving the insulin-like growth factor 1 receptor in an ALK-negative inflammatory myofibroblastic tumour

Inflammatory myofibroblastic tumour (IMT) is a soft tissue tumour primarily affecting children and young adults. Approximately 50% of IMTs have gene fusions involving the receptor tyrosine kinase (RTK)-encoding ALK gene, providing a molecular rationale for treating IMT patients with unresectable tumours with tyrosine kinase inhibitors (TKI). However, a subset of IMT instead displays fusions affecting other RTKencoding genes, so far including NTRK3, PDGFRB and ROS1. Also, IMTs with variant RTK fusions may respond well to TKI treatment, but can be dif?cult to identify as they are negative for ALK staining at immunohistochemistry, the standard method for detection of ALK rearrangements. Materials and methods: We used RNA-sequencing to search for alternate fusion events in an ALK-negative IMT. Results and conclusions: We found a novel fusion gene - FN1-IGF1R. The FN1 gene, encoding ?bronectin, is thought to provide a strong promoter activity for the kinase domain of the RTK insulin-like growth factor 1 receptor, a mechanism similar to previously described RTK fusions in IMT

Evaluation of SSTR2 Expression in SI-NETs and Relation to Overall Survival after PRRT

(1) Purpose: Small intestinal neuroendocrine tumors (SI-NETs) often present with distant metastases at diagnosis. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a systemic treatment that increases overall survival (OS) in SI-NET patients with stage IV disease. However, the treatment response after PRRT, which targets somatostatin receptor 2 (SSTR2), is variable and predictive factors have not been established. This exploratory study aims to evaluate if SSTR2 expression in SI-NETs could be used to predict OS after PRRT treatment. (2) Methods: Using a previously constructed Tissue Micro Array (TMA) we identified tissue samples from 42 patients that had received PRRT treatment during 2006–2017 at Sahlgrenska University hospital. Immunohistochemical expression of SSTR2, Ki-67 and neuroendocrine markers synaptophysin and Chromogranin A (CgA) were assessed. A retrospective estimation of 177Lu-DOTATATE uptake in 33 patients was performed. Data regarding OS and non-surgical treatment after PRRT were collected. Another subgroup of 34 patients with paired samples from 3 tumor sites (primary tumor, lymph node and liver metastases) was identified in the TMA. The SSTR2 expression was assessed in corresponding tissue samples (n = 102). (3) Results: The patients were grouped into Low SSTR2 or High SSTR2 groups based upon on levels of SSTR2 expression. There was no significant difference in 177Lu-DOTATATE uptake between the groups. The patients in the Low SSTR2 group had significantly longer OS after PRRT than the patients in the High SSTR2 group (p = 0.049). PRRT treated patients with low SSTR2 expression received less additional treatment compared with patients with high SSTR2 expression. SSTR2 expression did not vary between tumor sites but correlated within patients. (4) Conclusion: The results from the present study suggest that retrospective evaluation of SSTR2 expression in resected tumors cannot be used to predict OS after PRRT

Cytoplasmic HIF-2α as tissue biomarker to identify metastatic sympathetic paraganglioma

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features, presenting as a useful resource. Mutations in the pseudohypoxic marker HIF-2α correlate to an aggressive tumor phenotype. We show that HIF-2α localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2α was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that higher cytoplasmic HIF-2α expression could serve as a useful clinical marker to differentiate paragangliomas from pheochromocytomas, and may help predict outcome in sPGL patients

Transcriptional effects of 177Lu-octreotate therapy using a priming treatment schedule on GOT1 tumor in nude mice

Abstract Background 177Lu-octreotate is used for therapy of somatostatin receptor expressing neuroendocrine tumors with promising results, although complete tumor remission is rarely seen. Previous studies on nude mice bearing the human small intestine neuroendocrine tumor, GOT1, have shown that a priming injection of 177Lu-octreotate 24 h before the main injection of 177Lu-octreotate resulted in higher 177Lu concentration in tumor, resulting in increased absorbed dose, volume reduction, and time to regrowth. To our knowledge, the cellular effects of a priming treatment schedule have not yet been studied. The aim of this study was to identify transcriptional changes contributing to the enhanced therapeutic response of GOT1 tumors in nude mice to 177Lu-octreotate therapy with priming, compared with non-curative monotherapy. Results RNA microarray analysis was performed on tumor samples from GOT1-bearing BALB/c nude mice treated with a 5 MBq priming injection of 177Lu-octreotate followed by a second injection of 10 MBq of 177Lu-octreotate after 24 h and killed after 1, 3, 7, and 41 days after the last injection. Administered activity amounts were chosen to be non-curative, in order to facilitate the study of tumor regression and regrowth. Differentially regulated transcripts (RNA samples from treated vs. untreated animals) were identified (change ≥ 1.5-fold; adjusted p value < 0.01) using Nexus Expression 3.0. Analysis of the biological effects of transcriptional regulation was performed using the Gene Ontology database and Ingenuity Pathway Analysis. Transcriptional analysis of the tumors revealed two stages of pathway regulation for the priming schedule (up to 1 week and around 1 month) which differed distinctly from cellular responses observed after monotherapy. Induction of cell cycle arrest and apoptotic pathways (intrinsic and extrinsic) was found at early time points after treatment start, while downregulation of pro-proliferative genes were found at a late time point. Conclusions The present study indicates increased cellular stress responses in the tumors treated with a priming treatment schedule compared with those seen after conventional 177Lu-octreotate monotherapy, resulting in a more profound initiation of cell cycle arrest followed by apoptosis, as well as effects on PI3K/AKT-signaling and unfolded protein response