Certain cancers exert unexplained remote effects on the nervous system. Small cell carcinoma (SCC) of the lung, a tumour capable of spike electrogenesis and which is of possible neural crest origin, is present in approximately 70% of patients with the Lambert-Eaton myasthenic syndrome (LEMS), a disorder characterized by fatigable muscle weakness. Patients with this syndrome have a defect in the (Ca2+-dependent) quantal release of acetylcholine from motor nerve terminals evoked by a nerve impulse or by high K+ (ref.5), and a decreased number of presynaptic active zone particles. The physiological and morphological features of the syndrome can be transferred to mice by the patients' IgG, consistent with an autoantibody interfering with the function of voltage-dependent Ca2+ channels. Here we demonstrate that K+-induced 45Ca2+ flux in a cultured human SCC line is significantly reduced by LEMS IgG, suggesting that in SCC-LEMS an autoantibody to tumour Ca2+-channel determinants is triggered; its cross-reaction with similar determinants at the motor nerve terminal could lead to the remote neurological syndrome.

We compared functional imaging modalities including PET with 6-18 F-fluorodopamine ( 18 F-DA) with 123 I-metaiodobenzylguanidine ( 123 I-MIBG) and somatostatin receptor scintigraphy (SRS) with 111 In-pentetreotide in nonmetastatic and metastatic pheochromocytoma (PHEO). Methods: We studied 25 men and 28 women (mean age 6 SD, 44.2 6 14.2 y) with biochemically proven nonmetastatic (n 5 17) or metastatic (n 5 36) PHEO. Evaluation included anatomic imaging with CT or MRI and functional imaging that included at least 2 nuclear medicine modalities: 18 F-DA PET, 123 I-MIBG scintigraphy, or SRS. Sensitivity of functional imaging versus anatomic imaging was assessed on a per-patient and a per-region basis. Results: For this available cohort, on a per-patient basis overall sensitivity (combined for nonmetastatic and metastatic PHEO) was 90.2% for 18 F-DA PET, 76.0% for 123 I-MIBG scintigraphy, and 22.0% for SRS. On a per-region basis, overall sensitivity was 75.4% for 18 F-DA PET, 63.4% for 123 I-MIBG scintigraphy, and 64.0% for SRS. Conclusion: If available, 18 F-DA PET should be used in the evaluation of PHEO, because it is more sensitive than 123 I-MIBG scintigraphy or SRS. If 18 F-DA PET is not available, 123 I-MIBG scintigraphy (for nonmetastatic or adrenal PHEO) and SRS (for metastatic PHEO) should be the first alternative imaging methods to be used.

Pheochromocytomas are chromaffin cell-derived neuroendocrine tumors. There is presently no cure for metastatic pheochromocytoma and no reliable way to distinguish malignant from benign tumors before the development of metastases. In order to successfully manage pheochromocytoma, it is necessary to better understand the biological determinants of tumor behavior. For this purpose, we have recently established a mouse model of metastatic pheochromocytoma using tail vein injection of mouse pheochromocytoma (MPC) cells. We optimized this model modifying the number of cells injected, length of trypsin pre-treatment, and incubation temperature and duration for the MPC cells before injection, and by serial passage and re-selection of tumors exhibiting the metastatic phenotype. We evaluated the effect of these modifications on tumor growth using serial in vivo Magnetic Resonance Imaging studies. These results show that number of cells injected, the pre-injection incubation temperature, and duration of trypsin treatment are important factors to produce faster growing, more aggressive tumors that yielded secondary metastatic lesions. Serial harvest, culture and re-selection of metastatic liver lesions produced even more aggressive pheochromocytoma cells that retained their biochemical phenotype. Microarray gene expression comparison and quantitative real-time PCR of these more aggressive cells to the MPC-parental cell line identified genes that may be important for the metastatic process.

Purpose [131I]-meta-iodobenzylguanidine ([131I]-MIBG) is the most commonly employed treatment for metastatic pheochromocytoma and paraganglioma; however, its success is limited. Its efficacy depends on the [131I]-MIBG concentration reached within the tumor through its uptake via the norepinephrine transporter and retention in neurosecretory granules. Purpose is to enhance [123I]-MIBG uptake in cells and liver pheochromocytoma tumors. Experimental Design We report the in vitro effects of two histone deacetylase (HDAC) inhibitors, romidepsin and trichostatin A, on increased uptake of [3H]-norepinephrine and [123I]-MIBG in mouse pheochromocytoma (MPC) cells, and the effect of romidepsin on [18F]-fluorodopamine and [123I]-MIBG uptake in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in MPC cells by [123I]-MIBG uptake studies with and without the transporter blocking agent desipramine and the vesicular blocking agent reserpine. Results Both HDAC inhibitors increased [3H]-norepinephrine, [123I]-MIBG, and [18F]-fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in increased uptake of [18F]-fluorodopamine and in pheochromocytoma liver metastases as measured by maximal standardized uptake values on PET imaging (p < 0.001). Analysis of biodistribution after inhibitor treatment confirmed the PET results in that uptake of [123I]-MIBG was significantly increased in liver metastases (p < 0.05). Therefore, HDAC inhibitor treatment increased radioisotope uptake in MPC cells in vitro and in liver metastases in vivo, through increased norepinephrine transporter activity. Conclusion These results suggest that HDAC inhibitors could enhance the therapeutic efficacy of [131I]-MIBG treatment in patients with malignant pheochromocytoma.

Background Micronutrient supplementation is recommended in Ebola virus disease (EVD); however, there are limited data on therapeutic impacts of specific micronutrients. Objective To evaluate the association between vitamin A supplementation and mortality in EVD. Methods This retrospective cohort included patients with EVD admitted to 5 International Medical Corps Ebola Treatment Units (ETUs) in 2 countries during 2014–2015. Protocolized treatments with micronutrients were used at all ETUs: however, because of resource constraints, only a subset of patients received vitamin A. Standardized data on demographics, clinical characteristics, malaria status, and Ebola viral loads (cycle threshold values) were collected. The outcome of interest was mortality between cases treated with 200,000 IU of vitamin A on care days 1 and/or 2, and those not. Propensity scores based on the first 48 h of care were derived using covariates of age, ETU duration, malaria status, cycle threshold values, and clinical symptoms. Patients were matched 1:1 using nearest neighbors with replacement. Mortality between cases treated and not treated with vitamin A was compared using generalized estimating equations to calculate RR with associated 95% CI. Results There were 424 cases analyzed, of which 330 (77.8%) were treated with vitamin A. The mean age was 30.5 y and 40.3% were men. The most common symptoms were diarrhea (85.6%), anorexia (80.7%), and abdominal pain (76.9%). Mortality proportions among cases treated and not treated with vitamin A were 55.0% and 71.9%, respectively. In the propensity-matched analysis, mortality was significantly lower among cases receiving vitamin A (RR = 0.77, 95% CI: 0.59, 0.99; P = 0.041). In a subgroup analysis of patients treated with multivitamins already containing vitamin A, additional vitamin A supplementation did not impact mortality. Conclusion Early vitamin A supplementation was associated with reduced mortality in patients with EVD, and should be further studied and considered for use in future epidemics.

Vaccine hesitancy among displaced populations is associated with inequitable access to services and mistrust of authorities, among other factors. This study evaluated variations in attitudes toward COVID-19 vaccines and factors associated with vaccine acceptance among refugees and Lebanese nationals accessing 60 International Medical Corps-supported health facilities through two cross-sectional surveys pre- (n = 3927; Survey 1) and post- (n = 4174; Survey 2) vaccine rollout. Logistic regression was used to assess predictors of vaccine acceptance using the health beliefs model. Refugees comprised 52.9% (Survey 1) and 54.2% (Survey 2) of respondents. Vaccine acceptance was low among both groups in Survey 1 (25.9% refugees vs. 23.1% Lebanese nationals), but higher in Survey 2 in Lebanese (57.6%) versus refugees (32.9%). Participants reported greater perceived benefits of vaccination, higher perceived COVID-19 susceptibility, and lower perceived vaccination barriers in Survey 2 versus Survey 1. Post-vaccine rollout, refugees had lower odds of vaccine acceptance compared to Lebanese (OR 0.50, 95%CI 0.41–0.60), while older age (OR 1.37, 95%CI 1.06–1.78, ≥51 years vs. 18–30 years) was associated with greater vaccine acceptance. Health beliefs model variables were associated with vaccine acceptance in both surveys. Tailored strategies to respond dynamically to changes in vaccine attitudes among vulnerable groups in Lebanon are essential for equitable vaccine uptake.

Signs and symptoms associated with pheochromocytomas are predominantly caused by catecholamine excess, but tend to be highly variable and non-specific. In this study, we evaluated 23 male and 35 female pheochromocytoma patients for symptoms and signs of pheochromocytoma with special regard to gender-related differences in presentation. Total symptom score comparison between genders showed significant differences (12.0 vs. 7.8, P-value 0.0001). Female patients reported significantly more headache (80% vs. 52%), dizziness (83% vs. 39%), anxiety (85% vs. 50%), tremor (64% vs. 33%), weight change (88% vs. 43%), numbness (57% vs. 24%), and changes in energy level (89% vs. 64%). Females and males displayed comparable biochemical phenotypes (60% and 65% noradrenergic phenotype, respectively). Use of alpha- and/or beta-blockade between males and females did not differ significantly. Subgroup analyses and multiple regression analysis revealed gender differences to be irrespective of benign or malignant disease, use of adrenoceptor-blockade, age and biochemical phenotype. We conclude female patients have significantly more self-reported pheochromocytoma signs and symptoms than male patients irrespective of biochemical phenotype and tumor presentation which may be related to distinct catecholamine receptor sensitivity. Clinicians should be aware of these complaints in female pheochromocytoma patients and offer adequate treatment if indicated.

Background Experiments in vitro have shown that the drug amodiaquine may inhibit Ebola virus activity. During the Ebola virus disease (EVD) epidemic in West Africa in 2014–2016, 2 mass drug administrations (MDAs) of artesunate-amodiaquine (ASAQ) were implemented to decrease the burden of malaria. The objective of this study was to assess the effect of the ASAQ MDAs on the mortality of patients with EVD. Methods A retrospective cohort design was used to analyze mortality data for patients with EVD admitted to 5 Ebola treatment units in Liberia and Sierra Leone. Patients admitted to the ETUs during the time period of ASAQ’s therapeutic effect from areas where the MDA was implemented were matched to controls not exposed to ASAQ, using a range of covariates, including malaria co-infection status, and a logistic regression analysis was performed. The primary outcome was Ebola treatment unit mortality. Results A total of 424 patients with EVD had sufficient data for analysis. Overall, the mortality of EVD patients was 57.5%. A total of 22 EVD patients were exposed to ASAQ during the MDAs and were found to have decreased risk of death compared with those not exposed in a matched analysis, but this did not reach statistical significance (relative risk, 0.63; 95% confidence interval, 0.37–1.07; P = .086). Conclusions There was a non–statistically significantly decreased risk of mortality in EVD patients exposed to ASAQ during the 2 MDAs as compared with EVD patients not exposed to ASAQ. Further prospective trials are needed to determine the direct effect of ASAQ on EVD mortality.