Simple bench‐top bioassays involving brine shrimp lethality, Lemna frond proliferation, and the inhibition of crown gall tumours on potato discs, as well as the human tumour cell lines A‐549 lung carcinoma, MCF‐7 breast carcinoma and HT‐29 colon adenocarcinoma, were compared for their accuracy to detect known in vivo (P‐388) active antitumour agents supplied by the National Cancer Institute. The potato disc assay was the best and showed excellent correlation to in vivo activity (p=0.008). The brine shrimp assay (p = 0.033) proved to be superior or equally as accurate as the in vitro human solid tumour cell lines (p = 0.033‐0.334). The Lemna assay (p = 0.708) showed the poorest correlation. The brine shrimp and potato disc assays are suggested as convenient in‐house prescreens to existing cytotoxicity or antitumour assays.

Magnetic resonance elastography (MRE) is an increasingly used method for non-invasive determination of tissue stiffness. MRE has shown its ability to measure in vivo elasticity or viscoelasticity depending on the chosen rheological model. However, few data exist on quantitative comparison of MRE with reference mechanical measurement techniques. MRE has only been validated on soft homogeneous gels under both Hookean elasticity and linear viscoelasticity assumptions, but comparison studies are lacking concerning viscoelastic properties of complex heterogeneous tissues. In this context, the present study aims at comparing an MRE-based method combined with a wave equation inversion algorithm to rotational rheometry. For this purpose, experiments are performed on in vitro porcine brain tissue. The dynamic behavior of shear storage (G') and loss (G ('')) moduli obtained by both rheometry and MRE at different frequency ranges is similar to that of linear viscoelastic properties of brain tissue found in other studies. This continuity between rheometry and MRE results consolidates the quantitative nature of values found by MRE in terms of viscoelastic parameters of soft heterogeneous tissues. Based on these results, the limits of MRE in terms of frequency range are also discussed.

Background Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with 177Lu-labeled PSMA ligands has achieved remarkable results in advanced disease stages of metastatic castration-resistant prostate cancer (mCRPC). However, not all patients benefit from this therapy. Different treatment responses could be explained by tumor heterogeneity triggered by progression and the number of prior treatments. PSMA-negative lesions can be missed on PSMA ligand PET/CT, which subsequently results in an underestimation of tumor burden. Conversely, high FDG uptake may also be an indicator of tumor aggressiveness and thus a poor prognostic marker for response to RLT and overall survival (OS). The aim of this analysis was to investigate the prognostic value of combined PSMA ligand PET/CT and [18F]fluorodeoxyglucose (FDG) PET/CT for outcome prediction in patients undergoing RLT. Materials and methods This bicentric analysis included 54 patients with mCRPC who underwent both FDG and PSMA ligand PET/CT imaging before RLT. In all patients, the pattern of PSMA ligand and FDG uptake was visually assessed. Patients with at least one FDG-positive, but PSMA-negative (FDG+/PSMA−) lesions were compared to patients without any FDG+/PSMA− lesions. A log-rank analysis was used to assess the difference in OS between subgroups. Results Median OS was 11 ± 1.8 months (95% CI 7.4–14.6). A significantly lower OS (p < 0.001) was found in patients with at least one FDG+/PSMA− lesion at baseline PET/CTs (n = 18) with a median OS of 6.0 ± 0.5 months (95% CI: 5.0–7.0 months). In comparison, patients without any FDG+/PSMA− lesions (n = 36) had a median OS of 16.0 ± 2.5 months (95% CI: 11.2–20.8 months). Conclusion FDG+/PSMA− lesions are a negative predictor of overall survival in patients with mCRPC undergoing RLT. However, it remains to be determined if patients with FDG+/PSMA− lesions should be excluded from PSMA RLT.

Many animal viruses exhibit proficient growth in transformed cells, a property that has been harnessed for the development of novel therapies against cancer. Despite overwhelming evidence for this phenomenon, understanding of the molecular mechanisms enabling tumor-cell killing is rudimentary for most viruses. We report here that growth and cytotoxicity of the prototype oncolytic poliovirus (PV), PVSRIPO, in glioblastoma multiforme (GBM) is promoted by mitogen-activated protein kinases (MAPKs) converging on the MAPK signal-integrating kinase 1 (Mnk1) and its primary substrate, the eukaryotic initiation factor (eIF) 4E. Inducing Mnk1-catalyzed eIF4E phosphorylation through expression of oncogenic Ras substantially enhanced PVSRIPO translation, replication, and cytotoxicity in resistant cells. This effect was mimicked by expression of constitutively active forms of Mnk1 and correlated with enhanced translation of subgenomic reporter RNAs. Our findings implicate Mnk1 activity in stimulation of PVSRIPO cap-independent translation, an effect that can be synergistically enhanced by inhibition of the phosphoinositide-3 kinase (PI3K).

PVS-RIPO is a genetically recombinant, non-pathogenic poliovirus chimera with a tumor-specific conditional replication phenotype. Consisting of the genome of the live attenuated poliovirus type 1 (Sabin) vaccine with its cognate IRES element replaced with that of human rhinovirus type 2, PVS-RIPO displays an inability to translate its genome in untransformed neuronal cells, but effectively does so in cells originating from primary tumors in the central nervous system or other cancers. Hence, PVS-RIPO unleashes potent cytotoxic effects on infected cancer cells and produces sustained anti-tumoral responses in animal tumor models. PVS-RIPO presents a novel approach to the treatment of patients with glioblastoma multiforme, based on conditions favoring an unconventional viral translation initiation mechanism in cancerous cells. In this review, we summarize advances in the understanding of major molecular determinants of PVS-RIPO oncolytic efficacy and safety and discuss their implications for upcoming clinical investigations.

In preoperative assessment of primary hyperparathyroidism and to guide surgery, we propose to perform first subtraction SPECT/CT and to complete it with neck pinhole, only if tomoscintigraphy is negative.

A dependence of poliovirus on an unorthodox translation initiation mode can be targeted selectively to drive viral protein synthesis and cytotoxicity in malignant cells. Transformed cells are naturally susceptible to poliovirus, due to widespread ectopic upregulation of the poliovirus receptor, Necl-5, in ectodermal/neuroectodermal cancers. Viral tumor cell killing and the host immunologic response it engenders produce potent, lasting antineoplastic effects in animal tumor models. Clinical application of this principle depends on unequivocal demonstration of safety in primate models for paralytic poliomyelitis. We conducted extensive dose-range-finding, toxicity, biodistribution, shedding, and neutralizing antibody studies of the prototype oncolytic poliovirus recombinant, PVS-RIPO, after intrathalamic inoculation in Macaca fascicularis. These studies suggest that intracerebral PVS-RIPO inoculation does not lead to viral propagation in the central nervous system (CNS), does not cause histopathological CNS lesions or neurological symptoms that can be attributed to the virus, is not associated with extraneural virus dissemination or replication and does not induce shedding of virus with stool. Intrathalamic PVS-RIPO inoculation induced neutralizing antibody responses against poliovirus serotype 1 in all animals studied. Several years ago, we proposed consideration of recombinant, nonpathogenic poliovirus (PV) for the treatment of glioblastoma (GBM) (17). This proposal is based on widespread ectopic expression of the PV receptor, nectin-like molecule-5 (Necl-5), in such cancers (26). Necl-5, an onco-fetal cell adhesion molecule of the nectin family, is broadly associated with ectodermal/neuroectodermal cancers (reviewed in reference 42). Necl-5 expression is abundant in GBM cells, "stem cell-like" GBM cells, and tumorassociated vasculature (6) and is implicated in GBM cell dispersion and invasion (39,40). Due to Necl-5 expression, GBM cells are naturally susceptible to infection with and rapid destruction by PV (17). Direct cytocidal effects of PV elicit host immunogenic responses directed against tumors in vivo (43).Any clinical application of engineered PVs must include a rigorous demonstration of safety in established nonhuman primate models for paralytic poliomyelitis. Such safety studies are modeled after standard neurovirulence assays for the live-attenuated (Sabin) PV vaccines (41). The three Sabin vaccine serotypes (PV1-S, PV2-S, and PV3-S), some stemming from serial passage in diverse simian tissue culture systems, exhibit substantially reduced primate neurovirulence (36). While the genetic base for attenuation is different for each Sabin strain (29), they have key sequence variables in common.PV plus-strand RNA genomes are not equipped with a 7-methyl-guanidine cap (31) and thus are unable to recruit ribosomal subunits via the cap-binding eukaryotic initiation factor (eIF) 4E. Instead, PV RNAs rely on an internal ribosomal entry site (IRES) within their 5= untranslated region (UTR) to recruit 40S ribosoma...

This article reviews and explains the basic physical principles of metal-induced MRI artifacts, describes simple ways to reduce them, and presents specific reduction solutions. Artifacts include signal loss, pile-up artifacts, geometric distortion, and failure of fat suppression. Their nature and origins are reviewed and explained though schematic representations that ease the understanding. Then, optimization of simple acquisition parameters is detailed. Lastly, dedicated sequences and options specifically developed to reduce metal artifacts (VAT, SEMAC, and MAVRIC) are explained.