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Objective. Adjuvant therapy with sodium-glucose cotransport 2 inhibitors (SGLT2i) in type 1 diabetes (T1D) is associated with an improvement in glycemic control, but increases the risk of diabetic ketoacidosis (DKA). However, real-life studies in individuals with T1D under continuous subcutaneous insulin infusion (CSII) are still scarce. We present the first real-life study performed in patients with T1D exclusively treated with CSII. The aim of the present study was to assess the metabolic impact and safety of SGLT2i in T1D individuals under CSII.

Objectives. Immune reconstitution therapies (IRT), which include antibody-based cell-depleting therapies targeting CD52+ (alemtuzumab) or CD20+ (rituximab, ocrelizumab) leukocytes, are approved for the treatment of multiple sclerosis. Thyroid autoimmunity is a common adverse effect of alemtuzumab treatment, Graves’ disease (GD) being the most prevalent manifestation. To date, thyroid autoimmunity events have not been reported with CD20-targeting monoclonal antibodies.

Elevated maternal triglycerides (TGs) have been associated with excessive fetal growth. However, the role of maternal lipid profile is less studied in gestational diabetes mellitus (GDM). We aimed to study the association between maternal lipid profile in the third trimester and the risk for large-for-gestational-age (LGA) newborns in women with GDM. We performed an observational and retrospective study of pregnant women with GDM who underwent a lipid profile measurement during the third trimester. We applied a logistic regression model to assess predictors of LGA. A total of 100 singleton pregnant women with GDM and third-trimester lipid profile evaluation were included. In the multivariate analysis, pre-pregnancy BMI (OR 1.19 (95% CI 1.03–1.38), p = 0.022) and hypertriglyceridemia (OR 7.60 (1.70–34.10), p = 0.008) were independently associated with LGA. Third-trimester hypertriglyceridemia was found to be a predictor of LGA among women with GDM, independently of glycemic control, BMI, and pregnancy weight gain. Further investigation is needed to confirm the role of TGs in excessive fetal growth in GDM pregnancies. [ABSTRACT FROM AUTHOR]

This essay reflects upon the challenges and the achievements of an exploration of the marginalized experiences of the armed conflict in Colombia. Our methods – interdisciplinary, rooted in an ethos of co-production and openness to a great plurality of ways of storytelling – have created a fuller and richer representation of the horrors of war and their consequences. The lessons we have learned through making it happen will have major policy and administrative implications for the delivery of bilateral research collaborations funded by state resources. [ABSTRACT FROM AUTHOR]

The content, management, and implementation of social skills have been developed since the end of the 20th century as a model of capabilities. Thus, as human beings develop and train their basic cognitive and perceptual–motor functions, they increase their ability to solve and cope with difficulties. This article aims to present a bibliometric and systematic review of social skills, using query sources in databases such as Web of Science (WoS) and Scopus between the years 2000 and 2022, with platforms such as Bibliometrix and Gephi. This search yielded a total of 233 records in WoS and 250 records in Scopus that were merged and, after eliminating 143 duplicate data, were consolidated into 340 records that enclose the academic production of 20 years. Through scientific mapping, the main authors, journals, and countries in this field were determined; similarly, the most relevant studies were classified into three categories, namely, classic, structural, and perspectives, which were represented by means of the metaphor of the tree of science. In addition, a program for further studies was planned, such as in-depth qualitative research measuring observationally and directly taking into account emotional expressiveness, emotional understanding, emotion regulation, and behavior, and the impact of social skills training on social problem-solving. Finally, another important aspect to mention is that this research work is useful for the scientific academic community in many areas of knowledge such as psychology, education, and managers of educational institutions. [ABSTRACT FROM AUTHOR]

Cancer is regard as one of the key factors of mortality and morbidity in the world. Treatment is mainly based on chemotherapeutic drugs that, when used in targeted therapies, have serious side effects. 5-fluorouracil (5-FU) is a drug commonly used against colorectal cancer (CRC), despite its side effects. Combination of this compound with natural products is a promising source in cancer treatment research. In recent years, propolis has become the subject of intense pharmacological and chemical studies linked to its diverse biological properties. With a complex composition rich in phenolic compounds, propolis is described as showing positive or synergistic interactions with several chemotherapeutic drugs. The present work evaluated the in vitro cytotoxic activity of the most representative propolis types, such as green, red and brown propolis, in combination with chemotherapeutic or CNS drugs on HT-29 colon cancer cell lines. The phenolic composition of the propolis samples was evaluated by LC-DAD-ESI/MSn analysis. According to the type of propolis, the composition varied; green propolis was rich in terpenic phenolic acids and red propolis in polyprenylated benzophenones and isoflavonoids, while brown propolis was composed mainly of flavonoids and phenylpropanoids. Generally, for all propolis types, the results demonstrated that combing propolis with 5-FU and fluphenazine successfully enhances the in vitro cytotoxic activity. For green propolis, the combination demonstrated an enhancement of the in vitro cytotoxic effect compared to green propolis alone, at all concentrations, while for brown propolis, the combination in the concentration of 100 μg/mL gave a lower number of viable cells, even when compared with 5-FU or fluphenazine alone. The same was observed for the red propolis combination, but with a higher reduction in cell viability. The combination index, calculated based on the Chou–Talalay method, suggested that the combination of 5-FU and propolis extracts had a synergic growth inhibitory effect in HT-29 cells, while with fluphenazine, only green and red propolis, at a concentration of 100 μg/mL, presented synergism. [ABSTRACT FROM AUTHOR]

The combination of Carboplatin with Paclitaxel is the mainstay treatment for high-grade serous carcinoma; however, many patients with advanced disease undergo relapse due to chemoresistance. Drug repurposing coupled with a combination of two or more compounds with independent mechanisms of action has the potential to increase the success rate of the antineoplastic treatment. The purpose of this study was to explore whether the combination of Carboplatin with repurposed drugs led to a therapeutic benefit. Hence, we assessed the cytotoxic effects of Carboplatin alone and in combination with several repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) in two tumoral models, i.e., Carboplatin (OVCAR8) and Carboplatin-Paclitaxel (OVCAR8 PTX R P) chemoresistant cell lines and in a non-tumoral (HOSE6.3) cell line. Cellular viability was measured using the Presto Blue assay, and the synergistic interactions were evaluated using the Chou–Talalay, Bliss Independence and Highest Single Agent reference models. Combining Carboplatin with Pitavastatin or Metformin displayed the highest cytotoxic effect and the strongest synergism among all combinations for OVCAR8 PTX R P cells, resulting in a chemotherapeutic effect superior to Carboplatin as a single agent. Concerning HOSE6.3 cells, combining Carboplatin with almost all the repurposed drugs demonstrated a safe pharmacological profile. Overall, we propose that Pitavastatin or Metformin could act synergistically in combination with Carboplatin for the management of high-grade serous carcinoma patients with a Carboplatin plus Paclitaxel resistance profile. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a dramatic illness that ranks among the most pressing health concerns facing humanity and necessitates a proactive approach to treatment. Phytochemicals are regarded as interesting molecules for the development of anticancer drugs due to their pleiotropic effects on broad targets. The actions of phytochemicals are focused on tumor cells alone, with no negative effects on normal cells. The intricate process of carcinogenesis involves numerous signaling cascades. This study examined the effects of four organ extracts from a Mediterranean endemic plant, Cladanthus mixtus, on human tumor cells. To the best of our knowledge, this is the first study on this plant from northern Morocco showing relevant antiproliferative activity against two cancer cell lines and one non-tumoral cell line. Many of the chemotherapeutic drugs for the treatment of cancer are molecules identified and isolated from plants or their synthetic derivatives. This work aimed to identify the bioactive compounds using LC-MS and GC-MS and to evaluate the anticancer activity of the methanolic extracts of roots, stems, leaves, and flowers from Cladanthus mixtus. The anticancer activity was evaluated in vitro against two cancer cell lines: human breast carcinoma (MCF-7) and human prostate carcinoma (PC-3), using the MTT assay and microscopic observation. A human normal lung fibroblast (MRC-5) was included to determine the extract's safety for non-tumoral cells. The chemical composition results by LC-MS analysis revealed the presence of 24 phenolic compounds. Furthermore, GC-MS analysis allowed the identification of many biomolecules belonging to terpenoids, esters, alcohols, alkanes, fatty acids, organic acids, benzenes, phenols, ketones, carbonyls, amines, sterols, and other groups. The findings suggest that the majority of C. mixtus extracts have antiproliferative activity against two cancer cell lines, MCF-7 and PC-3, and one non-tumoral cell line, MRC-5. The activity was dose-dependent, and the highest effect was obtained with leaf extract in the two cancer cell lines. Moreover, these extracts demonstrated an acceptable toxicological profile against normal cells. Overall, C. mixtus extracts revealed promising antitumor properties provided by their phytochemical composition. [ABSTRACT FROM AUTHOR]

Chemotherapy is the main treatment for most early-stage cancers; nevertheless, its efficacy is usually limited by drug resistance, toxicity, and tumor heterogeneity. Cell-penetrating peptides (CPPs) are small peptide sequences that can be used to increase the delivery rate of chemotherapeutic drugs to the tumor site, therefore contributing to overcoming these problems and enhancing the efficacy of chemotherapy. The drug combination is another promising strategy to overcome the aforementioned problems since the combined drugs can synergize through interconnected biological processes and target different pathways simultaneously. Here, we hypothesized that different peptides (P1–P4) could be used to enhance the delivery of chemotherapeutic agents into three different cancer cells (HT-29, MCF-7, and PC-3). In silico studies were performed to simulate the pharmacokinetic (PK) parameters of each peptide and antineoplastic agent to help predict synergistic interactions in vitro. These simulations predicted peptides P2–P4 to have higher bioavailability and lower Tmax, as well as the chemotherapeutic agent 5-fluorouracil (5-FU) to have enhanced permeability properties over other antineoplastic agents, with P3 having prominent accumulation in the colon. In vitro studies were then performed to evaluate the combination of each peptide with the chemotherapeutic agents as well as to assess the nature of drug interactions through the quantification of the Combination Index (CI). Our findings in MCF-7 and PC-3 cancer cells demonstrated that the combination of these peptides with paclitaxel (PTX) and doxorubicin (DOXO), respectively, is not advantageous over a single treatment with the chemotherapeutic agent. In the case of HT-29 colorectal cancer cells, the combination of P2–P4 with 5-FU resulted in synergistic cytotoxic effects, as predicted by the in silico simulations. Taken together, these findings demonstrate that these CPP6-conjugates can be used as adjuvant agents to increase the delivery of 5-FU into HT-29 colorectal cancer cells. Moreover, these results support the use of in silico approaches for the prediction of the interaction between drugs in combination therapy for cancer. [ABSTRACT FROM AUTHOR]

Cancer is a very challenging disease to treat, both in terms of therapeutic efficiency and harmful side effects, which continues to motivate the pursuit for novel molecules with potential anticancer activity. Herein, we have designed, synthesized, and evaluated the cytotoxicity of different brominated coelenteramines, which are metabolic products and synthesis precursors of the chemi-/bioluminescent system of marine coelenterazine. The evaluation of the anticancer potential of these molecules was carried out for both prostate and breast cancer, while also exploring their potential for use in combination therapy. Our results provided further insight into the structure–activity relationship of this type of molecule, such as their high structural specificity, as well highlighting the 4-bromophenyl moiety as essential for the anticancer activity. The obtained data also indicated that, despite their similarity, the anticancer activity displayed by both brominated coelenteramines and coelenterazines should arise from independent mechanisms of action. Finally, one of the studied coelenteramines was able to improve the profile of a known chemotherapeutic agent, even at concentrations in which its anticancer activity was not relevant. Thus, our work showed the potential of different components of marine chemi-/bioluminescent systems as novel anticancer molecules, while providing useful information for future optimizations. [ABSTRACT FROM AUTHOR]

The use of FDA-approved drugs for new indications represents a faster and more economical way to find novel therapeutic agents for cancer therapy, compared to the development of new drugs. Repurposing drugs is advantageous in a pharmacological context since these drugs already have extensive data related to their pharmacokinetics, facilitating their approval process for different diseases. Several studies have reported the promising anticancer effects of sertraline, both alone and combined, in different types of cancer cell lines. Here, we performed a literature review on the anticancer potential of sertraline against different human cancer cells, more specifically in lung, colorectal, breast, hepatocellular, leukemia, brain, skin, oral, ovarian, and prostate cancer. Taken together, these findings suggest that sertraline decreases cell viability, proliferation, migration, and invasion, induces apoptosis, and causes cell cycle arrest in different types of cancer cells, besides being an established P-glycoprotein modulator. It was also found that this drug is able to modulate autophagy, cause DNA fragmentation, and induce radical oxygen species (ROS) formation. Moreover, it was found this drug targets important cellular pathways involved in tumorigeneses such as the TNF-MAP4K4-JNK pathway, the antiapoptotic pathway PI3K/Akt/mTOR, and the AMPK/mTOR axis. This drug also interferes with the TCTP/P53 feedback loop and with the cytosolic free Ca2+ levels. Together, these results suggest that sertraline may be a promising compound for further evaluation in novel cancer therapies. [ABSTRACT FROM AUTHOR]

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC50). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action. [ABSTRACT FROM AUTHOR]

Drug repurposing is a strategy that can speed up and find novel clinical uses for already-approved drugs for several diseases, such as cancer. This process is accelerated compared to the development of new drugs because these compounds have already been tested in clinical trials and data related to their pharmacokinetics is already described, reducing the costs and time associated with the development of new anticancer therapeutics. Several studies suggest that the repurposing of fluphenazine for cancer therapy may be a promising approach, as this drug proved to reduce the viability of diverse cancer cell lines. In this review, intensive research of the literature was performed related to the anticancer potential of fluphenazine in different human cancer cells. We have found several research articles on the cytotoxic effect of fluphenazine in lung, breast, colon, liver, brain, leukemia, oral, ovarian, and skin cancer and have summarized the main findings in this review. Taken together, these findings suggest that fluphenazine may regulate the cell cycle, reduce cell proliferation, and cause apoptosis in several types of cancer cells, besides being an established calmodulin inhibitor. It was also found that this drug is able to target cancer-related proteins, such as ABCB1 and P-glycoprotein as well as to regulate the Akt and Wnt signaling pathways. Some studies also refer this drug causes DNA alterations and interferes with cell invasion and migration ability as well as with ROS generation. Collectively, these results imply that fluphenazine may be a favorable compound for further research in oncologic therapy. [ABSTRACT FROM AUTHOR]

Introduction: MODY probability calculator (MPC) represents an easy‐to‐use tool developed by Exeter University to help clinicians prioritize which individuals should be oriented to genetic testing. We aimed to assess the utility of MPC in a Portuguese cohort with early‐onset monogenic diabetes. Methods: This single‐centre retrospective study enrolled 132 participants submitted to genetic testing between 2015 and 2020. Automatic sequencing and, in case of initial negative results, generation sequencing were performed. MODY probability was calculated using the probability calculator available online. Positive and negative predictive values (PPV and NPV, respectively), accuracy, sensitivity and specificity of the calculator were determined for this cohort. Results: Seventy‐three individuals were included according to inclusion criteria: 20 glucokinase (GCK‐MODY); 16 hepatocyte nuclear factor 1A (HNF1A‐MODY); 2 hepatocyte nuclear factor 4A (HNF4A‐MODY) and 35 DM individuals with no monogenic mutations found. The median probability score of MODY was significantly higher in monogenic diabetes‐positive subgroup (75.5% vs. 24.2%, p <.001). The discriminative accuracy of the calculator, as expressed by area under the curve, was 75% (95% CI: 64%–85%). In our cohort, the best cut‐off value for the MODY calculator was found to be 36%, with a PPV of 74.4%, NPV of 73.5% and corresponding sensitivity and specificity of 76.2% and 71.4%, respectively. Conclusions: In a highly pre‐selected group of probands qualified for genetic testing, the Exeter MODY probability calculator provided a useful tool in individuals' selection for genetic testing, with good discrimination ability under an optimal probability cut‐off of 36%. Further geographical and population adjustments are warranted for general use. [ABSTRACT FROM AUTHOR]

Nanoparticulate systems have been widely investigated as delivery vectors for efficient drug delivery in different diseases. Nanostructured lipid carriers (NLC) are composed of both solid and liquid lipids (glyceryl dibehenate and diethylene glycol monoethyl ether) and have demonstrated enhanced biological compatibility and increased drug loading capability. Furthermore, the use of peptides, in particular cell-penetrating peptides, to functionalize nanoparticles and enhance cell membrane permeation was explored in this paper. In this paper, we described the synthesis of a new conjugated of tranylcypromine with MAP. In addition, taking into consideration our previous results, this study developed different NLCs loaded with three central nervous system (CNS) drugs (tacrine (TAC), rasagiline (RAS), and tranylcypromine (TCP)) functionalized with model amphipathic peptide (MAP) and evaluated their activity against cancer cells. Particle size analysis demonstrated NLC presented less than 200 nm and a polydispersity index less than 0.3. Moreover, in vitro results showed that conjugation of MAP with drugs led to a higher decrease in cell viability of a neuroblastoma cell line and Caco-2 cell line, more than MAP alone. Furthermore, NLC encapsulation contributed to higher cellular delivery and enhanced toxic activity at lower concentrations when compared with free or co-administration drug-MAP conjugate. [ABSTRACT FROM AUTHOR]

Cancer is among the leading causes of death worldwide and it is estimated that in 2040 more than 29 million people will be diagnosed with some type of cancer. The most prevalent type of cancer in women, worldwide, is breast cancer, a type of cancer associated with a huge death rate. This high mortality is mainly a consequence of the development of drug resistance, which is one of the major challenges to overcome in breast cancer treatment. As a result, research has been focused on finding novel therapeutical weapons, specifically ones that allow for a personalized treatment, based on patients' characteristics. Although the scientific community has been concerned about guaranteeing the quality of life of cancer patients, researchers are also aware of the increasing costs related to cancer treatment, and efforts have been made to find alternatives to the development of new drugs. The development of new drugs presents some disadvantages as it is a multistep process that is time- and money-consuming, involving clinical trials that commonly fail in the initial phases. A strategy to overcome these disadvantages is drug repurposing. In this review, we focused on describing potential repurposed drugs in the therapy of breast cancer, considering their pharmacogenomic profile, to assess the relationship between patients' genetic variations and their response to a certain therapy. This review supports the need for the development of further fundamental studies in this area, in order to investigate and expand the knowledge of the currently used and novel potential drugs to treat breast cancer. Future clinical trials should focus on developing strategies to group cancer patients according to their clinical and biological similarities and to discover new potential targets, to enable cancer therapy to be more effective and personalized. [ABSTRACT FROM AUTHOR]

5-fluorouracil (5-FU) and doxorubicin (DOX) are potent anti-tumour agents commonly used for colon and breast cancer therapy, respectively. However, their clinical application is limited by their side effects and the development of drug resistance. Honeybee venom is a complex mixture of substances that has been reported to be effective against different cancer cells. Its active compound is melittin, a positively charged amphipathic peptide that interacts with the phospholipids of the cell membrane, forming pores that enable the internalization of small molecules with cytotoxic activities,. and consequently, causing cell death. Some central nervous system (CNS) drugs have recently demonstrated great anti-cancer potential, both in vitro, in vivo and in clinical trials, being promising candidates for drug repurposing in oncology. The present work evaluated the anti-cancer efficacy of honeybee venom in combination with chemotherapeutic or CNS drugs in HT-29 colon and MCF-7 breast cancer cell lines. The chemical characterization of a Portuguese sample of honeybee venom was done by LC-DAD-ESI/MSn analysis. For single treatments, cells were incubated with increasing concentrations of bee venom. For combination treatments, increasing concentrations of bee venom were first combined with the half-maximal inhibitory concentration (IC50) of 5-FU and DOX, in HT-29 and MCF-7 cells, respectively. Cells were also treated with increasing concentrations of bee venom in combination with the IC50 value of four CNS drugs (fluphenazine, fluoxetine, sertraline and thioridazine). Cytotoxicity was evaluated by MTT and SRB assays. The combination index (CI) value was calculated using CompuSyn software, based on the Chou–Talalay method. Synergy scores of different reference models (HSA, Loewe, ZIP and Bliss) were also calculated using SynergyFinder. The results demonstrate that honeybee venom is active against HT-29 colon and MCF-7 breast cancer cells, having better anti-tumour activity in MCF-7 cells. It was found that bee venom combined with 5-FU and fluphenazine in HT-29 cells resulted in less cytotoxic effects compared to the co-treatment of fluoxetine, sertraline and thioridazine plus bee venom, which resulted in less than 15% of viable cells for the whole range of concentrations. The combination of MCF-7 cells with repurposed drugs plus honeybee venom resulted in better anti-cancer efficacies than with DOX, notably for lower concentrations. A combination of fluoxetine and thioridazine plus honeybee venom resulted in less than 40% of viable cells for all ranges of concentrations. These results support that the combination of honeybee venom with repurposed drugs and chemotherapeutic agents can help improve their anti-cancer activity, especially for lower concentrations, in both cell lines. Overall, the present study corroborates the enormous bioactive potential of honeybee venom for colon and breast cancer treatments, both alone and in combination with chemotherapy or repurposed drugs. [ABSTRACT FROM AUTHOR]

• Combination of repurposed drugs in colorectal cancer: has become increasingly costly and ineffective, resulting in few highly effective drugs reaching the market yearly. • Drug repurposing and drug combination therapies can be alternatives to the de novo drug development, being low cost, rapid and easy-to-apply. • These strategies can improve cancer therapy efficacy, reduce chemotherapy's toxicity, and overcome drug resistance. • Combination of antineoplastic drugs is already being applied in cancer therapy, but the combination of repurposed drugs is still under-explored in pre- and clinical studies. The drug development process, especially of antineoplastic agents, has become increasingly costly and ineffective. Drug repurposing and drug combination are alternatives to de novo drug development, being low cost, rapid, and easy to apply. These strategies allow higher efficacy, decreased toxicity, and overcoming of drug resistance. The combination of antineoplastic agents is already being applied in cancer therapy, but the combination of repurposed drugs is still under-explored in pre- and clinical development. In this review, we provide a set of pharmacological concepts focusing on drug repurposing for treating colorectal cancer (CRC) and that are relevant for the application of new drug combinations against this disease. [ABSTRACT FROM AUTHOR]

Pituitary apoplexy is a rare complication of Cushing's disease (CD), especially in the paediatric age and even more rarely it can occur following anterior pituitary stimulation tests. We report a case of a 14-year-old girl who was admitted to our Hospital for evaluation of a possible Cushing's syndrome (CS). Her symptoms and initial laboratory tests were suggestive of CD. Magnetic resonance imaging (MRI) revealed a microadenoma of the pituitary gland. As part of her evaluation she was submitted to a corticotropin-releasing hormone (CRH) stimulation test. Two and a half months later the patient was re-evaluated and presented with both clinical improvement of CS, biochemical resolution of hypercortisolism and tumour size reduction in the MRI, also evidencing a haemorrhagic component favouring the diagnosis of pituitary apoplexy after CRH stimulation test. The patient denied any episodes of severe headache, nausea, vomiting or visual changes. To our knowledge, the authors report the first case of a pituitary apoplexy after a CRH stimulation test in the paediatric age. [ABSTRACT FROM AUTHOR]

Introduction: Pheochromocytomas are rare catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal sympathetic paraganglia. Recent studies have indicated that up to 40% of pheochromocytomas could be attributable to an inherited germline variant in an increasing list of susceptibility genes. Germline variants of the MYC-associated factor (MAX) gene have been associated with familial pheochromocytomas and paragangliomas with an autosomal dominant pattern of inheritance, a median age at onset of 33 years and an overall frequency estimated at 1.9%. We describe a deleterious MAX variant associated with hereditary pheochromocytoma in a family with four affected individuals. Case presentation: The first patient presented with bilateral pheochromocytoma in 1995; genetic testing was proposed to his oldest son, when he was diagnosed with a bilateral pheochromocytoma with a synchronous neuroblastoma. Upon the identification of the MAX variant c.97C>T, p.(Arg33Ter), in the latter individual, his two siblings and their father were tested and the same variant was identified in all of them. Both siblings were subsequently diagnosed with pheochromocytoma (one of them bilateral) and choose to remain on active surveillance before they were submitted to adrenalectomy. All the tumours secreted predominantly norepinephrine, accordingly to the typical biochemical phenotype ascribed to variants in the MAX gene. Conclusion: This case series is, to our knowledge, the one with the largest number of individuals with hereditary pheochromocytoma with a deleterious MAX variant in the same family. It is also the first case with a synchronous pheochromocytoma and neuroblastoma in carriers of a MAX deleterious variant. This report draws attention to some ill-defined features of pheochromocytoma and other malignancies associated with a MAX variant and highlights the importance of understanding the genotype-phenotype correlation in hereditary pheochromocytoma and the impact of oriented genetic testing to detect, survey and treat patients and kindreds at risk. [ABSTRACT FROM AUTHOR]