Background: To improve therapy outcome of Yttrium-90 selective internal radiation therapy (90 Y SIRT), patientspecific post-therapeutic dosimetry is required. For this purpose, various dosimetric approaches based on different available imaging data have been reported. The aim of this work was to compare post-therapeutic 3D absorbed dose images using Technetium-99m (99m Tc) MAA SPECT/CT, Yttrium-90 (90 Y) bremsstrahlung (BRS) SPECT/CT, and 90 Y PET/CT. Methods: Ten SIRTs of nine patients with unresectable hepatocellular carcinoma (HCC) were investigated. The 99m Tc SPECT/CT data, obtained from 99m Tc-MAA-based treatment simulation prior to 90 Y SIRT, were scaled with the administered 90 Y therapy activity. 3D absorbed dose images were generated by dose kernel convolution with scaled 99m Tc/ 90 Y SPECT/CT, 90 Y BRS SPECT/CT, and 90 Y PET/CT data of each patient. Absorbed dose estimates in tumor and healthy liver tissue obtained using the two SPECT/CT methods were compared against 90 Y PET/CT. Results: The percentage deviation of tumor absorbed dose estimates from 90 Y PET/CT values was on average − 2 ± 18% for scaled 99m Tc/ 90 Y SPECT/CT, whereas estimates from 90 Y BRS SPECT/CT differed on average by − 50 ± 13%. For healthy liver absorbed dose estimates, all three imaging methods revealed comparable values. Conclusion: The quantification capabilities of the imaging data influence 90 Y SIRT tumor dosimetry, while healthy liver absorbed dose values were comparable for all investigated imaging data. When no 90 Y PET/CT image data are available, the proposed scaled 99m Tc/ 90 Y SPECT/CT dosimetry method was found to be more appropriate for HCC tumor dosimetry than 90 Y BRS SPECT/CT based dosimetry.

Purpose: Peptide receptor radionuclide therapy (PRRT) with [ 177 Lu]Lu-DOTA 0 ,TYR 3 -octreotate ([ 177 Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [ 177 Lu]Lu-DOTA-TATE in female Lewis rats. Methods: Animals received 200 MBq of [ 177 Lu]Lu-DOTA-TATE once and/or 5 mg/kg body weight everolimus or placebo weekly for 16 weeks and were divided into four groups (group 1, placebo; group 2, everolimus; group 3, placebo + [ 177 Lu]Lu-DOTA-TATE; group 4, everolimus + [ 177 Lu]Lu-DOTA-TATE). Blood levels of creatinine and blood urea nitrogen (BUN) were assessed weekly to monitor nephrotoxicity, and a full blood count was performed at the time of euthanasia to monitor myelotoxicity. Additionally, renal function was analysed by sequential [ 99m Tc]Tcmercaptoacetyltriglycine ([ 99m Tc]Tc-MAG3) scintigraphies. Histopathological examination was performed in all the kidneys using a standardized renal damage score (RDS). Results: Rats receiving everolimus showed a significantly lower increase in creatinine levels than those receiving placebo. Everolimus therapy reduced white blood count significantly, which was not observed for [ 177 Lu]Lu-DOTA-TATE. Functional renal scintigraphies using [ 99m Tc]Tc-MAG3 showed a compromised initial tracer uptake after PRRT and slower but still preserved excretion after everolimus. Histology showed no significant RDS differences between groups. Conclusion: Renal scintigraphy is a highly sensitive tool for the detection of renal function impairment after a combination of everolimus and PRRT. Additional treatment with everolimus does not increase renal and haematological toxicity of PRRT with [ 177 Lu]Lu-DOTA-TATE.

Therapy options for advanced pancreatic neuroendocrine tumors (pNETs) include the mTOR inhibitor everolimus and peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE, however further optimization in the therapeutic landscape is required as response rates are still low. In this study, we investigated the synergistic and potentially enhanced efficacy of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in a mouse model. Baseline [68Ga]Ga-DOTA-TATE PET scans were obtained five days after athymic CD1 mice were inoculated with AR42J tumor cells, before separating the animals into four groups. Group 1 received a placebo, group 2 everolimus, group 3 a placebo and PRRT, and group 4 everolimus and PRRT. The treatment response was monitored by manually measuring the tumor volumes (manual tumor volume, MTV) and conducting sequential [68Ga]Ga-DOTA-TATE PET scans at one, two, and four weeks after treatment induction. The biological tumor volume (BTV) was derived from PET scans using threshold-based volume of interest (VOI) measurements. Tracer uptake was measured semi-quantitatively as a tumor to background ratio (TBR). Mice were euthanized due to excessive tumor growth according to the ethics protocol; blood samples were drawn for the preparation of full blood counts and kidneys were obtained for histological analysis. For the histological assessment, a standardized score (renal damage score, RDS) was used. Full blood counts showed significantly increased numbers of neutrophils and lymphocytes in the groups receiving PRRT. All other parameters did not differ relevantly. In the histological analysis, groups receiving PRRT had a significantly higher RDS, whereas everolimus only tended to cause an increase in the RDS. Mice in groups 1 and 2 had to be euthanized due to excessive tumor growth two weeks after the start of the therapy, whereas follow-up in groups 3 and 4 comprised four weeks. PRRT significantly inhibited tumor growth; the administration of everolimus did not induce an additional effect. A good correlation existed between MTV and BTV. PRRT significantly reduced the TBR. [68Ga]Ga-DOTA-TATE PET is suitable for monitoring tumor growth in the applied model. The high efficacy of [177Lu]Lu-DOTA-TATE is not enhanced by the combination with everolimus.

The histopathology slide seminar “Classic Examples in Toxicologic Pathology XXVII” was held on February 21 and 22, 2020, at the Department of Pathology at the University of Veterinary Medicine in Hannover, Germany, with joint organization by the European Society of Toxicologic Pathology. The goal of this annual seminar is to present and discuss classical and actual cases of toxicologic pathology. This article summarizes the presentations given during the seminar, including images of representative lesions. Ten actual and classical cases of toxicologic pathology, mostly induced by a test article, were presented. These included small intestine pathology and transcriptomics induced by a γ-secretase modulator, liver findings in nonhuman primates induced by gene therapy, drug-induced neutropenia in dogs, device-induced growth plate lesions, polycystic lesions in CAR/PXR double knockout mice, inner ear lesions in transgenic mice, findings in Beagle dogs induced by an inhibitor of the myeloid leukemia cell differentiation protein MCL1, findings induced by a monovalent fibroblast growth factor receptor 1 antagonist, kidney lesions induced by a mammalian target of rapamycin inhibitor in combination therapy, and findings in mutation-specific drugs.

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