Case Report: Imaging immune checkpoint inhibitor-induced yin-yang effects in the brain.

Background: Treatment with immune checkpoint inhibitors (ICI) can induce durable responses in cancer patients, but it is commonly associated with serious immune-related side effects. Both effects are suggested to be mediated by CD8+ T-cell infiltration. Whole body CD8+ T-cell distribution can be visualized by PET imaging of a 89Zr-labeled anti-humanCD8a minibody, currently investigated in a phase 2b trial. Main body: An adult patient diagnosed with metastatic melanoma developed ICI-related hypophysitis after two courses of combined immunotherapy (ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) at 3 weeks interval). On a [89Zr]Zr-crefmirlimab berdoxam PET/CT scan, made 8 days before clinical symptoms occurred, increased CD8+ T-cell infiltration in the pituitary gland was detected. Simultaneously, tracer uptake in a cerebral metastasis was increased, indicating ICI-induced tumor infiltration by CD8+ T-cells. Conclusions: The observations in this case report underscore the role of CD8+ T-cell in non-tumor tissues in ICI-related toxicity. In addition, it illustrates a potential role for molecular imaging by PET/CT for investigation and monitoring of ICI-induced effects.

Health-related quality of life analysis in stage III melanoma patients treated with adjuvant dendritic cell therapy.

BACKGROUND: Health-related quality of life (HRQoL) is an important issue in the rapidly evolving field of adjuvant treatment for stage III melanoma. Dendritic cell vaccination is one of the adjuvant forms of therapy currently investigated. METHODS: We enrolled adults with stage III melanoma to receive adjuvant dendritic cell vaccination after a complete radical lymph node dissection. HRQoL assessment was one of the secondary endpoints of this trial and investigated with the EORTC-QLQ-C30 questionnaire at baseline and week 26. RESULTS: Fifteen patients with a median age of 50 years were included in the study, with twelve evaluable patients on study at time of the second questionnaire. Global health status and role functioning improved clinically relevant with a mean difference of 15 (p = 0.010) and 26 points (p = 0.005), respectively. DISCUSSION: Despite the small number of patients, we found a clinically relevant improved global health status. Besides, compared to the other investigated therapies, toxicity of dendritic cell vaccination is low, which supports our finding. CONCLUSION: This is the first description of HRQoL in melanoma patients receiving dendritic cell vaccination. We show the expected improvement in global health status after surgical treatment of stage III melanoma. Thus, adjuvant dendritic cell vaccination does not seem to hamper this improvement, as shown in our small explorative study.

Imaging heterogeneity of peptide delivery and binding in solid tumors using SPECT imaging and MRI.

BACKGROUND: As model system, a solid-tumor patient-derived xenograft (PDX) model characterized by high peptide receptor expression and histological tissue homogeneity was used to study radiopeptide targeting. In this solid-tumor model, high tumor uptake of targeting peptides was expected. However, in vivo SPECT images showed substantial heterogeneous radioactivity accumulation despite homogenous receptor distribution in the tumor xenografts as assessed by in vitro autoradiography. We hypothesized that delivery of peptide to the tumor cells is dictated by adequate local tumor perfusion. To study this relationship, sequential SPECT/CT and MRI were performed to assess the role of vascular functionality in radiopeptide accumulation. METHODS: High-resolution SPECT and dynamic contrast-enhanced (DCE)-MRI were acquired in six mice bearing PC295 PDX tumors expressing the gastrin-releasing peptide (GRP) receptor. Two hours prior to SPECT imaging, animals received 25 MBq (111)In(DOTA-(ßAla)2-JMV594) (25 pmol). Images were acquired using multipinhole SPECT/CT. Directly after SPECT imaging, MR images were acquired on a 7.0-T dedicated animal scanner. DCE-MR images were quantified using semi-quantitative and quantitative models. The DCE-MR and SPECT images were spatially aligned to compute the correlations between radioactivity and DCE-MRI-derived parameters over the tumor. RESULTS: Whereas histology, in vitro autoradiography, and multiple-weighted MRI scans all showed homogenous tissue characteristics, both SPECT and DCE-MRI showed heterogeneous distribution patterns throughout the tumor. The average Spearman's correlation coefficient between SPECT and DCE-MRI ranged from 0.57 to 0.63 for the "exchange-related" DCE-MRI perfusion parameters. CONCLUSIONS: A positive correlation was shown between exchange-related DCE-MRI perfusion parameters and the amount of radioactivity accumulated as measured by SPECT, demonstrating that vascular function was an important aspect of radiopeptide distribution in solid tumors. The combined use of SPECT and MRI added crucial information on the perfusion efficiency versus radiopeptide uptake in solid tumors and showed that functional tumor characteristics varied locally even when the tissue appeared homogenous on current standard assessment techniques.

Optimization of combined temozolomide and peptide receptor radionuclide therapy (PRRT) in mice after multimodality molecular imaging studies.

BACKGROUND: Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine tumours (NET) comprise somatostatin-analogue lutetium-177-labelled octreotate ((177)Lu-TATE) treatment, also referred to as peptide receptor radionuclide therapy (PRRT), and temozolomide (TMZ) treatment. Their combination might result in additive effects. Using MRI and SPECT/CT, we studied tumour characteristics and therapeutic responses after different (combined) administration schemes in a murine tumour model in order to identify the optimal treatment schedule for PRRT plus TMZ. METHODS: We performed molecular imaging studies in mice bearing SSTR-expressing H69 (humane small cell lung cancer) tumours after single intravenous (i.v.) administration of 30 MBq (177)Lu-TATE or TMZ (oral 50 mg/kg daily for 14 days). Tumour perfusion was evaluated weekly by dynamic contrast-enhanced MRI (DCE-MRI), whereas tumour uptake of (111)In-octreotide was quantified using SPECT/CT until day 39 after treatment. Based on these results, seven different (177)Lu-octreotate and TMZ combination schemes were evaluated for therapy response, varying the order and time interval of the two therapies and compared with single treatments. RESULTS: PRRT and TMZ both resulted in tumour size reduction, accompanied by significant changes in MRI characteristics such as an enhanced tumour perfusion. Moreover, TMZ treatment also resulted in increased uptake of the SST analogue (111)In-octreotide until day 13. In the subsequent therapy study, 90 % of animals receiving (177)Lu-TATE at day 14 after TMZ treatment showed complete response, being the best anti-tumour results among groups. CONCLUSIONS: Molecular imaging studies indicated that PRRT after TMZ treatment could induce optimal therapeutic effects because of enhanced tumour uptake of radioactivity after TMZ, which was confirmed by therapy responses. Therefore, clinical translation of TMZ treatment prior to PRRT might increase tumour responses in NET patients as well.

Modeling cancelation of periodic inputs with burst-STDP and feedback.

Prediction and cancelation of redundant information is an important feature that many neural systems must display in order to efficiently code external signals. We develop an analytic framework for such cancelation in sensory neurons produced by a cerebellar-like structure in wave-type electric fish. Our biologically plausible mechanism is motivated by experimental evidence of cancelation of periodic input arising from the proximity of conspecifics as well as tail motion. This mechanism involves elements present in a wide range of systems: (1) stimulus-driven feedback to the neurons acting as detectors, (2) a large variety of temporal delays in the pathways transmitting such feedback, responsible for producing frequency channels, and (3) burst-induced long-term plasticity. The bursting arises from back-propagating action potentials. Bursting events drive the input frequency-dependent learning rule, which in turn affects the feedback input and thus the burst rate. We show how the mean firing rate and the rate of production of 2- and 4-spike bursts (the main learning events) can be estimated analytically for a leaky integrate-and-fire model driven by (slow) sinusoidal, back-propagating and feedback inputs as well as rectified filtered noise. The effect of bursts on the average synaptic strength is also derived. Our results shed light on why bursts rather than single spikes can drive learning in such networks "online", i.e. in the absence of a correlative discharge. Phase locked spiking in frequency specific channels together with a frequency-dependent STDP window size regulate burst probability and duration self-consistently to implement cancelation.

Model-based measurements of the diameter of the internal carotid artery in CT angiography images.

PURPOSE: Computed tomography angiography (CTA) is often used to determine the degree of stenosis in patients that suffer from carotid artery occlusive disease. Accurate and precise measurements of the diameter of the stenosed internal carotid artery are required to make decisions on treatment of the patient. However, the inherent blurring of images hampers a straightforward measurement, especially for smaller vessels. The authors propose a model-based approach to perform diameter measurements in which explicit allowance is made for the blurring of structures in the images. Three features of the authors' approach are the use of prior knowledge in the fitting of the model at the site of the stenosis, the applicability to vessels both with circular and noncircular cross-section, and the ability to deal with additional structures close to the arteries such as calcifications. METHODS: Noncircular cross-sections of vessels were modeled with elliptic Fourier descriptors. When calcifications or other high-intensity structures are adjacent to the lumen, both the lumen and the high-intensity structures were modeled in order to improve the diameter estimates of the vessel. Measurements were performed in CT scans of a phantom mimicking stenosed carotids and in CTA scans of two patients with an internal carotid stenosis. In an attempt to validate the measurements in CTA images, measurements were also performed in three-dimensional rotational angiography (3DRA) images of the same patients. RESULTS: The validity of the approach for diameter measurements of cylindrical arteries in CTA images is evident from phantom measurements. When prior knowledge about the enhancement and the blurring parameter was used, accurate and precise diameter estimates were obtained down to a diameter of 0.4 mm. The potential of the presented approach, both with respect to the extension to noncircular cross-sections and the modeling of adjacent calcifications, appears from the patient data. The accuracy of the size estimates in the patient images could not be unambiguously established because no gold standard was available and the quality of the 3DRA images was often suboptimal. CONCLUSIONS: The authors have shown that the inclusion of a priori information results in accurate and precise diameter measurements of arteries with a small diameter. Furthermore, in patient data, the assumption of a circular cross-section often appears to be too simple. The extension to noncircular cross-sections and adjacent calcifications paves the way to realistic modeling of the carotid artery.

Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial.

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity. (Blood. 2001;97:3361-3369)

Increased stability of peptidesulfonamide peptidomimetics towards protease catalyzed degradation.

Replacement of amide bonds in peptides by sulfonamide moieties resulted in peptidosulfonamides with an increased stability towards protease catalyzed degradation. In addition to protection of the protease cleavage site, it was found that introduction of a sulfonamide also influenced the stability of adjacent amide bonds.