A practical guide to the handling and administration of talimogene laherparepvec in Europe.

Talimogene laherparepvec is a herpes simplex virus-1-based intralesional oncolytic immunotherapy and is the first oncolytic virus to be approved in Europe. It is indicated for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease. Talimogene laherparepvec is a genetically modified viral therapy, and its handling needs special attention due to its deep freeze, cold-chain requirements, its potential for viral shedding, and its administration by direct intralesional injection. This review provides a practical overview of handling, storage, and administration procedures for this agent in Europe. Talimogene laherparepvec vials should be transported/stored frozen at a temperature of -90°C to -70°C, and once thawed, vials must not be refrozen. Universal precautions for preparation, administration, and handling should be followed to avoid accidental exposure. Health care providers should wear personal protective equipment, and materials that come into contact with talimogene laherparepvec should be disposed of in accordance with local institutional procedures. Individuals who are immunocompromised or pregnant should not prepare or administer this agent. Talimogene laherparepvec is administered by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound. Treatment should be continued for ≥6 months. As with other immunotherapies, patients may experience an increase in the size of existing lesion(s) or the appearance of new lesions (ie, progression) prior to achieving a response ("pseudo-progression"). As several health care professionals (eg, physicians [dermatologists, surgeons, oncologists, radiologists], pharmacists, nurses) are involved in different stages of the process, there is a need for good interdisciplinary collaboration when using talimogene laherparepvec. Although there are specific requirements for this agent's storage, handling, administration, and disposal, these can be effectively managed in a real-world clinical setting through the implementation of training programs and straightforward standard operating procedures

Biological effects of EF24, a curcumin derivative, alone or combined with mitotane in adrenocortical tumor cell lines

Background: Curcumin has numerous properties and is used in many preclinical conditions, including cancer. It has low bioavailability, while its derivative EF24 shows enhanced solubility. However, its effects have never been explored in adrenocortical tumor cell models. The efficacy of EF24 alone or combined with mitotane (reference drug for adrenocortical cancer) was evaluated in two adrenocortical tumor cell lines, SW13 and H295R. Method and Results: EF24 reduced cell viability with an IC50 (half maximal inhibitory concentration) of 6.5 \ub1 2.4 \ub5M and 4.9 \ub1 2.8 \ub5M for SW13 and H295R cells, respectively. Combination index (EF24 associated with mitotane) suggested an additivity effect in both cell lines. Cell cycle analysis revealed an increase in subG0/G1 phase, while motility assay showed a decrease in migratory cell capacity, and similarly, clonogenic assay indicated that EF24 could reduce colony numbers. Furthermore, Wnt/\u3b2-catenin, NF-\u3baB, MAPK, and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with EF24 alone or combined with mitotane. In addition, intracellular reactive oxygen species levels increased in both cell lines. Conclusion: This work analyzed EF24 in adrenocortical tumor cell lines for the first time. These results suggest that EF24 could potentially impact on adrenocortical tumors, laying the foundation for further research in animal models

Analysis of circulating extracellular vesicle-associated microRNAs in cortisol-producing adrenocortical tumors

PURPOSE: Circulating microRNAs (miRNA) have been described in patients with adrenocortical tumors, but the expression of miRNAs in non-functioning and cortisol-producing tumors has not been yet compared. Therefore, the objective of this study was to evaluate the expression of plasma extracellular vesicle (EV)-associated microRNAs in patients with non-functioning adrenocortical adenoma (NFA), cortisol-producing adrenocortical adenoma (CPA) and cortisol-producing adrenocortical carcinoma (CP-ACC). METHODS: Preoperative plasma EV samples of 13 NFAs, 13 CPAs and 9 CP-ACCs were subjected to extracellular vesicle isolation. miRNAs were investigated by targeted quantitative real-time PCR normalized to cel-miR-39 as reference. Five miRNAs have been selected for this analysis based on the previous studies including hsa-miR-22-3p, hsa-miR-27a-3p, hsa-miR-210-3p, hsa-miR-320b and hsa-miR-375. RESULTS: We have observed significant overrepresentation of three miRNAs in both CPA and CP-ACC relative to NFA: hsa-miR-22-3p (p < 0.01 and p < 0.0001, respectively), hsa-miR-27a-3p (p < 0.05 in both comparisons) and hsa-miR-320b (p < 0.05 and p < 0.0001, respectively). Hsa-miR-320b has been significantly overrepresented in CP-ACC relative to CPA (p < 0.01). Hsa-miR-210-3p turned out to be significantly overrepresented only in CP-ACC compared to NFA (p < 0.05). Significant correlation was revealed between circulating miRNA concentrations and urinary free cortisol values for hsa-miR-22-3p, hsa-miR-27a-3p and hsa-miR-320b (p < 0.0001 for all) and cortisol after low-dose dexamethasone test for hsa-miR-22-3p and hsa-miR-320b (p < 0.05). Hsa-miR-27a-3p has been significantly stimulated by low-dose dexamethasone test (p < 0.05). CONCLUSIONS: EV-associated miRNAs are differentially expressed in different non-functioning and cortisol-producing adrenocortical tumors

Liposomal cytarabine as cancer therapy: From chemistry to medicine

Cancer is the second leading cause of death worldwide. The main modality to fight against cancer is surgery, radiotherapy, and chemotherapy, and more recently targeted therapy, gene therapy and immunotherapy, which play important roles in treating cancer patients. In the last decades, chemotherapy has been well developed. Nonetheless, administration of the drug is not always successful, as limited drug dosage can reach the tumor cells.. In this context, the possibility to use an encapsulated anti-cancer drug may potentially solve the problem. Liposomal cytarabine is a formulation with pronounced effectiveness in lymphomatous meningitis and reduced cardiotoxicity if compared to liposomal anthracyclines. Thus, the future liposomal cytarabine use could be extended to other diseases given its reduction in cytotoxic side effects compared to the free formulation. This review summarizes the chemistry and biology of liposomal cytarabine, with exploration of its clinical implications.N. Martins would like to thank the Portuguese Foundation for Science and Technology (FCT-Portugal) for the strategic project ref. UID/BIM/04293/2013 and "NORTE2020 - Programa Operacional Regional do Norte" (NORTE-01-0145-FEDER-000012). M. Martorell would like to thank the support offered by CONICYT PIA/APOYO CCTE AFB170007

Anticancer Effects of Wild Mountain Mentha longifolia Extract in Adrenocortical Tumor Cell Models

Mint [Mentha longifolia (L.) Hudson] is an aromatic plant that belongs to Lamiaceae family. It is traditionally used as herbal tea in Europe, Australia and North Africa and shows numerous pharmacological effects, such as spasmolytic, antioxidant, antimicrobial and anti-hemolytic. Recently, its antiproliferative role has been suggested in a small number of tumor cell models, but no data are available on adrenocortical carcinoma, a malignancy with a survival rate at 5 years of 20%\u201330% which frequently metastasize. This work aimed to study the effects of Mentha longifolia L. crude extract (ME) on two adrenocortical tumor cell models (H295R and SW13 cells). Chemical composition of ME was assessed by gas-chromatography/mass spectrometry and NMR spectroscopy analysis. Brine shrimp lethality assay showed ME effects at >0.5 \ub5g/\ub5l (p 0.5 \ub5g/\ub5l, p 0.5 \ub5g/\ub5l, p < 0.05), while Wright staining demonstrated the presence of both necrotic and apoptotic cells. Cell cycle analysis showed a strong increase in subG0/G1 phase, related to cell death. Furthermore, MAPK and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with ME alone or combined with mitotane. The crude methanolic extract of wild mountain mint can decrease cell viability, vitality and survival of adrenocortical tumor cell models, in particular of SW13 cells. These data show the potential anticancer effects of ME, still more work is needed to corroborate these findings

Analysis of circulating extracellular vesicle-associated microRNAs in cortisol-producing adrenocortical tumors

PURPOSE: Circulating microRNAs (miRNA) have been described in patients with adrenocortical tumors, but the expression of miRNAs in non-functioning and cortisol-producing tumors has not been yet compared. Therefore, the objective of this study was to evaluate the expression of plasma extracellular vesicle (EV)-associated microRNAs in patients with non-functioning adrenocortical adenoma (NFA), cortisol-producing adrenocortical adenoma (CPA) and cortisol-producing adrenocortical carcinoma (CP-ACC). METHODS: Preoperative plasma EV samples of 13 NFAs, 13 CPAs and 9 CP-ACCs were subjected to extracellular vesicle isolation. miRNAs were investigated by targeted quantitative real-time PCR normalized to cel-miR-39 as reference. Five miRNAs have been selected for this analysis based on the previous studies including hsa-miR-22-3p, hsa-miR-27a-3p, hsa-miR-210-3p, hsa-miR-320b and hsa-miR-375. RESULTS: We have observed significant overrepresentation of three miRNAs in both CPA and CP-ACC relative to NFA: hsa-miR-22-3p (p < 0.01 and p < 0.0001, respectively), hsa-miR-27a-3p (p < 0.05 in both comparisons) and hsa-miR-320b (p < 0.05 and p < 0.0001, respectively). Hsa-miR-320b has been significantly overrepresented in CP-ACC relative to CPA (p < 0.01). Hsa-miR-210-3p turned out to be significantly overrepresented only in CP-ACC compared to NFA (p < 0.05). Significant correlation was revealed between circulating miRNA concentrations and urinary free cortisol values for hsa-miR-22-3p, hsa-miR-27a-3p and hsa-miR-320b (p < 0.0001 for all) and cortisol after low-dose dexamethasone test for hsa-miR-22-3p and hsa-miR-320b (p < 0.05). Hsa-miR-27a-3p has been significantly stimulated by low-dose dexamethasone test (p < 0.05). CONCLUSIONS: EV-associated miRNAs are differentially expressed in different non-functioning and cortisol-producing adrenocortical tumors

Epidemiological aspects associated to toxocarosis in Gualeguaychú, Entre Ríos, Argentina

The aim of the present estudy was to determine the epidemiological factors of toxocarosis in Gualeguaychú, Argentina. It was evaluated the seroprevalence of this parasitoses in 272 healthy blood donors (ELISA test), and the relationship of this parameter with the socioeconomic conditions of persons, presence or absence of parasitized dogs in their dwellings and sorroundings; and the contamination of publics places of this city with Toxocara spp ova. The seroprevalence was 12,13% with most of the individuals being asymptomatic. Neither socioeconomic status nor dog ownership correlated significantly with positive serology. Toxocara canis eggs were found 25% of the dogs studied and in 100% of relevated public places. It can be therefore concluded that there is a high frequency of contamination in the soils of public places with T. canis eggs, as well as a high percentage of dog infected with this nematode. This situation establishes an important risk to acquire toxocarosis for the inhabitans of this city.Facultad de Ciencias Médica

A systematic review on the excess health risk of antibiotic-resistant bloodstream infections for six key pathogens in Europe

Background Antimicrobial resistance is a global threat, which requires novel intervention strategies, for which priority pathogens and settings need to be determined. Objectives We evaluated pathogen-specific excess health burden of drug-resistant bloodstream infections (BSIs) in Europe. Methods A systematic review and meta-analysis. Data sources MEDLINE, Embase, and grey literature for the period January 1990 to May 2022. Study eligibility criteria Studies that reported burden data for six key drug-resistant pathogens: carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, third-generation cephalosporin or CR Escherichia coli and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Excess health outcomes compared with drug-susceptible BSIs or uninfected patients. For MRSA and third-generation cephalosporin E. coli and K. pneumoniae BSIs, five or more European studies were identified. For all others, the search was extended to high-income countries. Participants Paediatric and adult patients diagnosed with drug-resistant BSI. Interventions Not applicable. Assessment of risk of bias An adapted version of the Joanna-Briggs Institute assessment tool. Methods of data synthesis Random-effect models were used to pool pathogen-specific burden estimates. Results We screened 7154 titles, 1078 full-texts and found 56 studies on BSIs. Most studies compared outcomes of drug-resistant to drug-susceptible BSIs (46/56, 82.1%), and reported mortality (55/56 studies, 98.6%). The pooled crude estimate for excess all-cause mortality of drug-resistant versus drug-susceptible BSIs ranged from OR 1.31 (95% CI 1.03–1.68) for CR P. aeruginosa to OR 3.44 (95% CI 1.62–7.32) for CR K. pneumoniae. Pooled crude estimates comparing mortality to uninfected patients were available for vancomycin-resistant Enterococcus and MRSA BSIs (OR of 11.19 [95% CI 6.92–18.09] and OR 6.18 [95% CI 2.10–18.17], respectively). Conclusions Drug-resistant BSIs are associated with increased mortality, with the magnitude of the effect influenced by pathogen type and comparator. Future research should address crucial knowledge gaps in pathogen- and infection-specific burdens to guide development of novel interventions