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

Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location, and poor prognosis.

In gastrointestinal stromal tumors (GISTs), KIT exon 11 deletions are associated with poor prognosis. The aim of this study was to determine the gene expression profiles of GISTs carrying KIT exon 11 deletions and to identify genes associated with poor prognosis. Expression profiling was performed on 9 tumors with KIT exon 11 deletions and 7 without KIT exon 11 mutations using oligonucleotide microarrays. In addition, gene expression profiles for 35 GISTs were analyzed by meta-analysis. Expression of CD133 (prominin-1) protein was examined by tissue microarray (TMA) analysis of 204 GISTs from a population-based study in western Sweden. Survival analysis was performed on patients subjected to R0 resection (n=180) using the Cox proportional hazards model. Gene expression profiling, meta-analysis, and qPCR showed up regulation of CD133 in GISTs carrying KIT exon 11 deletions. Immunohistochemical analysis on TMA confirmed CD133 expression in 28% of all tumors. CD133 positivity was more frequent in gastric GISTs (48%) than in small intestinal GISTs (4%). CD133 positivity was also more frequent in GISTs with KIT exon 11 mutations (41%) than in tumors with mutations in KIT exon 9, PDGFRA, or wild-type tumors (0-17%). Univariate survival analysis showed a significant correlation between the presence of CD133 protein and shorter overall survival (hazard ratio=2.23, P=0.027). Multivariate analysis showed that CD133 provided additional information on patient survival compared to age, sex, NIH risk group and mutational status. CD133 is expressed in a subset of predominantly gastric GISTs with KIT exon 11 mutations and poor prognosis

Multiplex protein analysis and ensemble machine learning methods of fine needle aspirates from prostate cancer patients reveal potential diagnostic signatures associated with tumour grade

Background Improved molecular diagnosis is needed in prostate cancer (PC). Fine needle aspiration (FNA) is a minimally invasive biopsy technique, less traumatic compared to core needle biopsy, and could be useful for diagnosis of PC. Molecular biomarkers (BMs) in FNA-samples can be assessed for prediction, eg of immunotherapy efficacy before treatment as well as at treatment decision time points during disease progression. Methods In the present pilot study, the expression levels of 151 BM proteins were analysed by proximity extension assay in FNA-samples from 16 patients, including benign prostate lesions (n = 3) and cancers (n = 13). An ensemble data analysis strategy was applied using several machine learning models. Results Twelve potentially predictive BM proteins correlating with International Society of Urological Pathology grade groups were identified, among them vimentin, tissue factor pathway inhibitor 2, and integrin beta-5. The validity of the results was supported by network analysis that showed functional associations between most of the identified putative BMs. We also showed that multiple immune checkpoint targets can be assessed (eg PD-L1, CD137, and Galectin-9), which may support the selection of immunotherapy in advanced PC. Results are promising but need further validation in a larger cohort. Conclusions Our pilot study represents a "proof of concept" and shows that multiplex profiling of potential diagnostic and predictive BM proteins is feasible on tumour material obtained by FNA sampling of prostate cancer. Moreover, our results demonstrate that an ensemble data analysis strategy may facilitate the identification of BM signatures in pilot studies when the patient cohort is limited