SARS-CoV-2-related encephalitis with prominent parkinsonism: clinical and FDG-PET correlates in two patients

Considering the similarities with other pandemics due to respiratory virus infections and subsequent development of neurological disorders (e.g. encephalitis lethargica after the 1918 influenza), there is growing concern about a possible new wave of neurological complications following the worldwide spread of SARS-CoV-2. However, data on COVID-19-related encephalitis and movement disorders are still limited. Herein, we describe the clinical and neuroimaging (FDG-PET/CT, MRI and DaT-SPECT) findings of two patients with COVID-19-related encephalopathy who developed prominent parkinsonism. None of the patients had previous history of parkinsonian signs/symptoms, and none had prodromal features of Parkinson's disease (hyposmia or RBD). Both developed a rapidly progressive form of atypical parkinsonism along with distinctive features suggestive of encephalitis. A possible immune-mediated etiology was suggested in Patient 2 by the presence of CSF-restricted oligoclonal bands, but none of the patients responded favorably to immunotherapy. Interestingly, FDG-PET/CT findings were similar in both cases and reminiscent of those observed in post-encephalitic parkinsonism, with cortical hypo-metabolism associated with hyper-metabolism in the brainstem, mesial temporal lobes, and basal ganglia. Patient's FDG-PET/CT findings were validated by performing a Statistical Parametric Mapping analysis and comparing the results with a cohort of healthy controls (n = 48). Cerebrum cortical thickness map was obtained in Patient 1 from MRI examinations to evaluate the structural correlates of the metabolic alterations detected with FDG-PET/CT. Hypermetabolic areas correlated with brain regions showing increased cortical thickness, suggesting their involvement during the inflammatory process. Overall, these observations suggest that SARS-CoV-2 infection may trigger an encephalitis with prominent parkinsonism and distinctive brain metabolic alterations

Process development and validation of expanded regulatory T cells for prospective applications: an example of manufacturing a personalized advanced therapy medicinal product

Background: A growing number of clinical trials have shown that regulatory T (Treg) cell transfer may have a favorable effect on the maintenance of self-tolerance and immune homeostasis in different conditions such as graft-versus-host disease (GvHD), solid organ transplantation, type 1 diabetes, and others. In this context, the availability of a robust manufacturing protocol that is able to produce a sufficient number of functional Treg cells represents a fundamental prerequisite for the success of a cell therapy clinical protocol. However, extended workflow guidelines for nonprofit manufacturers are currently lacking. Despite the fact that different successful manufacturing procedures and cell products with excellent safety profiles have been reported from early clinical trials, the selection and expansion protocols for Treg cells vary a lot. The objective of this study was to validate a Good Manufacturing Practice (GMP)-compliant protocol for the production of Treg cells that approaches the whole process with a risk-management methodology, from process design to completion of final product development. High emphasis was given to the description of the quality control (QC) methodologies used for the in-process and release tests (sterility, endotoxin test, mycoplasma, and immunophenotype). Results: The GMP-compliant protocol defined in this work allows at least 4.11 7 109 Treg cells to be obtained with an average purity of 95.75 \ub1 4.38% and can be used in different clinical settings to exploit Treg cell immunomodulatory function. Conclusions: These results could be of great use for facilities implementing GMP-compliant cell therapy protocols of these cells for different conditions aimed at restoring the Treg cell number and function, which may slow the progression of certain diseases

Yttrium-90 DOTATOC therapy in GEP-NET and other SST2 expressing tumors: a selected review

Treatment of somatostatin receptor-positive tumors with radiolabeled somatostatin analog is a promising option. Several phase I and phase II studies done at a few centers around the world reported encouraging results with [⁹⁰Y-DOTA-Tyr³]-octreotide (DOTATOC) and/or [(177)Lu-DOTA-Tyr³-Thr⁸]-octreotate (DOTATATE). The current article is a selective review of patients who were treated mainly with ⁹⁰Y-DOTATOC after failure with conventional therapy. The aim is to provide an updated comprehensive evaluation of the overall effectiveness of ⁹⁰Y-DOTATOC therapy in patients with somatostatin-positive tumors. Review of several studies revealed an objective response rate ranging from 20 to 28% for all neuroendocrine tumors (NET)s. For gastroenteropancreatic-NET (GEP-NET), the response rate was found to be consistently better in the range 28-38%. Overall, the cumulative response rate was found to be 24%. An important issue in peptide receptor radionuclide therapy (PRRT) is the dose-response relationship and finding the correct dose of ⁹⁰Y-DOTATOC that will achieve an optimum tumor kill. Nephrotoxicity was common but could be minimized by taking adequate renal protective measures. In conclusion, PRRT remains a good option in patients with inoperable and/or metastatic NETs particularly of GEP origin. Over a decade of experience with ⁹⁰Y-DOTATOC proves that it is still an effective tool for the treatment of large infiltrative NETs with achievement of objective radiological responses in nearly a quarter and disease stabilization in more than half the patients studied so far

Dural Metastases of Advanced Prostate Cancer Detected by 18F-Fluorocholine

Prostate cancer with extensive dural metastases is very rare, with only few cases described in the literature. We report one such case of a 74-year-old man with advanced prostate cancer, and in relatively good clinical condition. The patient returned with complaints of headache and diplopia. Fluorocholine (18F) chloride (18F-FCH) is an analog of choline in which a hydrogen atom has been replaced by fluorine (18F). After crossing the cell membrane by a carrier-mediated mechanism, choline is phosphorylated by choline kinase to produce phosphorylcholine. 18F-FCH positron emission tomography–computed tomography (PET/CT) is widely used to stage and restage patients affected by prostate cancer with good sensitivity. 18F-FCH PET/CT showed disease progression with the onset of multiple skull lesions. Numerous suspicious dural hypermetabolic lesions indicating neoplastic involvement were detected along the fronto-parietal convexities, in the left fronto-orbital region and right lateral wall of the orbit, concerning for metastases in these regions. A contrast-enhanced computed tomography (CECT) scan was performed which showed corresponding enhancing tissue which correlated with the PET findings. The final imaging diagnosis was osteo-dural metastases from prostate cancer associated with poor outcome. Awareness of this pattern of metastases may be of clinical relevance in order to avoid unnecessary invasive diagnostic procedures in groups of patients with a dismal prognosis

Big data, observational research and p-value: a recipe for false positive findings? A study of simulated and real prospective cohorts

Background: An increasing number of observational studies combine large sample sizes with low participation rates, which could lead to standard inference failing to control the false discovery rate. We investigated if the \u201cempirical calibration of p-value\u201d method (EPCV), reliant on negative controls, can preserve type-I error in the context of survival analysis. Methods. Simulated cohort studies with 50% participation rate and two different selection bias mechanisms, and a real-life application on predictors of cancer mortality using data from four population-based cohorts in Northern Italy (n=6976 men and women aged 25-74 years at baseline and 17 years of median follow-up). Results: Type-I error for the standard Cox model was above the 5% nominal level in 15 out of 16 simulated settings; for n=10,000, the chances of a null association with hazard ratio=1.05 having a p-value<0.05 were 42.5%. Conversely, EPCV with 10 negative controls preserved the 5% nominal level in all the simulation settings, reducing bias in the point estimate by 80-90% when its main assumption was verified. In the real case, 15 out of 21 (71%) blood markers with no association with cancer mortality according to literature had a p-value<0.05 in age- and gender-adjusted Cox models. After calibration, only 1 (4.8%) remained statistically significant. Conclusions. In the analyses of large observational studies prone to selection bias, the use of empirical distribution to calibrate p-values can substantially reduce the number of trivial results needing further screening for relevance and external validit

Positron Emission Tomography for the Response Evaluation following Treatment with Chemotherapy in Patients Affected by Colorectal Liver Metastases: A Selected Review

The aim of the present paper is to review the scientific literature concerning the usefulness of 18F-FDG PET/CT in the evaluation of response to chemotherapy in patients affected by liver metastases from colorectal cancer. Material and Methods. Studies were identified by searching PubMed electronic databases. Both prospective and retrospective studies were included. Information regarding the figure of merit of PET for the evaluation of therapy response was extracted and analyzed. Results. Existing data suggests that 18F-FDG PET/CT may have an outstanding role in evaluating the response. The sensitivity of PET in detecting therapy response seems to be greater than conventional imaging (CT and MRI). PET/CT response is strictly related to better overall survival and progression-free survival. Conclusions. PET/CT is more than a promising technique to assess the response to chemotherapy in colorectal and liver metastases. However, to be fully validated, this examination needs further studies by recruiting more patients