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177 Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although 177 Lu-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. α 1 -microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M's renal protective effect in a mouse 177 Lu-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post- 177 Lu-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with 177 Lu-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with 177 Lu-DOTATATE.

α 1 -Microglobulin (A1M) is an antioxidant found in all vertebrates, including humans. It has enzymatic reductase activity and can scavenge radicals and bind free heme groups. Infused recombinant A1M accumulates in the kidneys and has therefore been successful in protecting kidney injuries in different animal models. In this review, we focus on A1M as a radioprotector of the kidneys during peptide receptor radionuclide/radioligand therapy (PRRT/RLT). Patients with, e.g., neuroendocrine tumors or castration resistant prostate cancer can be treated by administration of radiolabeled small molecules which target and therefore enable the irradiation and killing of cancer cells through specific receptor interaction. The treatment is not curative, and kidney toxicity has been reported as a side effect since the small, radiolabeled substances are retained and excreted through the kidneys. In recent studies, A1M was shown to have radioprotective effects on cell cultures as well as having a similar biodistribution as the somatostatin analogue peptide 177 Lu-DOTATATE after intravenous infusion in mice. Therefore, several animal studies were conducted to investigate the in vivo radioprotective potential of A1M towards kidneys. The results of these studies demonstrated that A1M co-infusion yielded protection against kidney toxicity and improved overall survival in mouse models. Moreover, two different mouse studies reported that A1M did not interfere with tumor treatment itself. Here, we give an overview of radionuclide therapy, the A1M physiology and the results from the radioprotector studies of the protein.

Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α 1 -microglobulin (A1M) together with 177-Lutetium ( 177 Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [ 177 Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3-4 days and 3-4 weeks after injections). In a parallel set of experiments, mice were given [ 177 Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([ 99m Tc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [ 177 Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [ 99m Tc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [ 177 Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [ 99m Tc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [ 177 Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy.

Objectives: The aim of the study was to investigate therapeutic efficacy of single- or two-fraction radiotherapy in conjunction with IDO1-inhibition in a syngeneic rat glioblastoma model. IDO is known to cause immunosuppression through breakdown of tryptophan in the tumor microenvironment., Methods: Gene expression analyses of IDO in glioblastoma were performed with data from publicly available datasets. Fractionation studies were done on animals to evaluate tumor size, immune cell infiltration of tumors and serum profile on day 18 after tumor inoculation. Survival analyses were done with animals carrying intracranial glioblastomas comparing two-fraction radiotherapy+IDO1-inhibition to controls. IDO inhibition was achieved by administration of 1-methyl tryptophan (1-MT), and radiotherapy (RT) was delivered in doses of 8Gy., Results: The expression of IDO1 was increased on gene level in glioblastoma stem cells. Tumor size was significantly reduced in animals treated with 1-MT+RTx 2 (both long and short intervals, i.e. 7 and 4 days between the treatments) as compared to control animals, animals treated with only 1-MT or animals treated with 1-MT+RTx1. Serum levels of IL-1A were significantly altered in all treated animals as compared to control animals. Survival was significantly increased in the animals treated with 1-MT+RTx2 (7-day interval) compared to control animals., Conclusions: Addition of two-fraction RT to IDO1 inhibition with 1-MT significantly reduced tumor size in animals with glioblastoma. Survival was significantly increased in animals treated with two-fractioned RT+1-MT as compared to untreated controls increased significantly., Advances in Knowledge: The currently used combination of only two fractions of radiotherapy and immune therapy is a promising area of research, increasing efficacy compared to single fraction irradiation, while potentially lowering radiation side effects compared to radiation in current clinical practice., Competing Interests: The authors have declared that no competing interests exist.

Pathology residency training is currently a time-intensive process, frequently extending up to 6 years in duration as residents complete 1 or 2 fellowships following graduation. Innovative training curricula may help address the impending changes in the health-care landscape, particularly future shortfalls in pathology staffing and changing health-care models that incorporate more work within interdisciplinary teams. Montefiore has created a novel residency training program aimed at accelerating the acquisition of competency in pathology, preparing residents for independent practice at the completion of residency training, and providing residents with the requisite adaptability and consultative skills to excel wherever they choose to practice. We describe the implementation of this novel pathology residency training curriculum at Montefiore Medical Center/Albert Einstein College of Medicine and the perception of residents in both the old curriculum and the new curriculum., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Glioblastoma multiforme (GBM) or astrocytoma grade IV is the most common type of primary brain tumor in adults. In the present study, we investigate the role of the complement system in the glioblastoma situation in an experimental model, since we have previously been able to show a blockade of this system in the glioblastoma setting., Technique and Results: A GFP-positive glioblastoma cell line was used to induce glioblastomas subcutaneously in rats (n=42). Antibodies against C1-Inactivator (C1-IA) were used to try to re-activate the complement system. We were able to demonstrate an increased survival in rats treated with anti-C1-IA with an intratumoral route, and we could establish the same the results in a second series. Serum analyses revealed decreased levels of IL-1b and GM-CSF in animals 24 days after tumor cell inoculation in the anti-C1-IA group when compared to controls. Immunohistochemistry revealed decreased expression of C1-IA following treatment., Interpretation: These results are in line with our previous work showing an upregulation of C1-IA, which is able to block the classical complement pathway, in glioblastomas. Treatment with antibodies against C1-IA seems to be beneficial in the glioblastoma situation, and no side effects could be seen in our experiments., Competing Interests: CONFLICTS OF INTEREST The authors do not have any conflicts of interest.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, and available experimental and routine therapies result in limited survival benefits. A vulnerability of GBM cells to catastrophic vacuolization and cell death, a process termed methuosis, induced by Vacquinol-1 (VQ-1) has been described earlier. In the present study, we investigate the efficacy of VQ-1 treatment in two syngeneic rat GBM models, RG2 and NS1. VQ-1 treatment affected growth of both RG2 and NS1 cells in vitro . Intracranially, significant reduction in RG2 tumor size was observed, although no effect was seen on overall survival. No survival advantage or effect on tumor size was seen in animals carrying the NS1 models compared to untreated controls. Furthermore, immunological staining of FOXP3, CD4 and CD8 showed no marked difference in immune cell infiltrate in tumor environment following treatment. Taken together, a survival advantage of VQ-1 treatment alone could not be demonstrated here, even though some effect upon tumor size was seen. Staining for immune cell markers did not indicate that VQ-1 either reduced or increased host anti-tumor immune response., Competing Interests: CONFLICTS OF INTEREST The authors declare that there are no conflicts of interest.

Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.

Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected (125)I- and non-labelled recombinant human A1M and the (111)In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT.