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Infertility is recognized globally as a social disease and a growing medical condition, posing a significant challenge to modern reproductive health. Endometriosis, the third-most frequent gynecologic disorder, is one of the most common and intricate conditions that can lead to female infertility. Despite extensive research, the etiology, malignant transformation, and biological therapy of endometriosis remain unknown. Blood and follicular fluid are two matrices that have been carefully studied and can provide insights into women's health. These matrices are clinically significant because they contain metabolites closely associated with women's illness stage and reproductive outcomes. Nowadays, the application of metabolomic analysis in biological matrices may be able to predict the outcome of assisted reproductive technologies with greater precision. From a molecular viewpoint on reproductive health, we evaluate and compare the utilization of human follicular fluid and blood as matrices in analysis for diagnostic and assisted reproductive technology (ART) predictors of success for endometriosis patients. In the follicular fluid (FF), plasma, and serum of endometriosis-affected women, researchers identified dysregulations of oxidative stress, upregulation of several immune factors, and aberrations in energy metabolic pathways. The altered signatures negatively correlate with the overall oocyte and embryo quality and fertilization rate.
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Biomarcadores , Endometriose , Líquido Folicular , Infertilidade Feminina , Humanos , Endometriose/sangue , Endometriose/metabolismo , Líquido Folicular/metabolismo , Feminino , Biomarcadores/sangue , Infertilidade Feminina/sangue , Infertilidade Feminina/metabolismo , Infertilidade Feminina/etiologia , Técnicas de Reprodução Assistida , Metabolômica/métodos , Estresse OxidativoRESUMO
Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1-5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development.
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Dor Crônica , Metilação de DNA , Transtornos Relacionados ao Uso de Opioides , Receptores Opioides mu , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Analgésicos Opioides/uso terapêutico , Estudos de Casos e Controles , Dor Crônica/tratamento farmacológico , Dor Crônica/epidemiologia , Dor Crônica/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética , Transtornos Relacionados ao Uso de Opioides/genética , Qualidade de Vida , Receptores Opioides mu/genética , Fatores SexuaisRESUMO
BACKGROUND: Megaprostheses contain many more modular components than conventional total hip and knee arthroplasty, which may lead to higher serum levels of metal ions. The aim of this study was to determine serum concentrations of titanium, chromium, and cobalt ions in cancer patients after limb salvage surgery with a megaprosthesis. METHODS: A retrospective, descriptive cohort analysis consisting of patients who underwent cancer-related limb salvage surgery with a megaprosthesis at our hospital between 2010 and 2020 was conducted. Baseline and follow-up data were extracted from clinical and surgical records. Blood samples were prospectively obtained. Descriptive statistics were used for the analysis. RESULTS: A total of 71 patients underwent limb salvage surgery during the study period. Of these, 22 (10 women, 12 men) were included in the study. The mean age was 52 years (range, 21 to 80). Most cases (n = 16; 72.7%) involved the femur. Most patients (n = 14, 63.6%) underwent total knee megaprosthesis surgery. Implant revision surgery was required in 45% of cases (n = 10), with a mean interval of 4.32 years between the initial and revision surgeries. The mean follow-up time after revision surgery was 4.05 years. High levels of chromium were observed in 22.7% of patients (n = 5). High cobalt levels were found in 68.2% (n = 15) of patients, with toxic levels in 9.1% (n = 2). Titanium levels were high in 77.3% (n = 17) of cases and toxic in 22.7% (n = 5). Postoperative chemotherapy was significantly associated with titanium levels (P = .017). No correlation was observed between metal ion levels and time from primary or revision surgery or time from the first to revision surgery. CONCLUSIONS: This study shows that cancer-related limb salvage surgery with megaprosthesis is associated with metal ion levels that exceed established safe thresholds. Compared to conventional hip arthroplasty, a higher proportion of the patients in this cohort presented elevated levels of metal ions. LEVEL OF EVIDENCE: III.
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Cromo , Cobalto , Salvamento de Membro , Reoperação , Titânio , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Cobalto/sangue , Adulto , Titânio/sangue , Cromo/sangue , Reoperação/estatística & dados numéricos , Salvamento de Membro/métodos , Idoso de 80 Anos ou mais , Neoplasias/cirurgia , Neoplasias/sangue , Adulto Jovem , Prótese do Joelho/efeitos adversosRESUMO
BACKGROUND: Opioids are widely used in chronic non-cancer pain (CNCP) management. However, they remain controversial due to serious risk of causing opioid use disorder (OUD). Our main aim was to develop a predictive model for future clinical translation that include pharmacogenetic markers. METHODS: An observational study was conducted in 806 pre-screened Spanish CNCP patients, under long-term use of opioids, to compare cases (with OUD, N.=137) with controls (without OUD, N.=669). Mu-opioid receptor 1 (OPRM1, A118G, rs1799971) and catechol-O-methyltransferase (COMT, G472A, rs4680) genetic variants plus cytochrome P450 2D6 (CYP2D6) liver enzyme phenotypes were analyzed. Socio-demographic, clinical and pharmacological outcomes were also registered. A logistic regression model was performed. The model performance and diagnostic accuracy were calculated. RESULTS: OPRM1-AA genotype and CYP2D6 poor and ultrarapid metabolizers together with three other potential predictors: 1) age; 2) work disability; 3) oral morphine equivalent daily dose (MEDD), were selected with a satisfactory diagnostic accuracy (sensitivity: 0.82 and specificity: 0.85), goodness of fit (P=0.87) and discrimination (0.89). Cases were ten-year younger with lower incomes, more sleep disturbances, benzodiazepines use, and history of substance use disorder in front of controls. CONCLUSIONS: Functional polymorphisms related to OPRM1 variant and CYP2D6 phenotypes may predict a higher OUD risk. Established risk factors such as young age, elevated MEDD and lower incomes were identified. A predictive model is expected to be implemented in clinical setting among CNCP patients under long-term opioids use.
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Dor Crônica , Transtornos Relacionados ao Uso de Opioides , Humanos , Masculino , Feminino , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/genética , Adulto , Estudos Retrospectivos , Estudos de Coortes , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/efeitos adversos , Farmacogenética , Receptores Opioides mu/genética , Citocromo P-450 CYP2D6/genética , Catecol O-Metiltransferase/genética , Idoso , GenótipoRESUMO
Undifferentiated sarcomas characterized by a primitive monomorphic round to spindle cell phenotype and often non-specific immunoprofile remain difficult to subclassify outside molecular analysis. The increased application of RNA sequencing in clinical practice led to significant advances and discoveries of novel gene fusions that furthered our understanding and refined classification of otherwise undifferentiated neoplasms. In this study, we report an undifferentiated round to spindle cell sarcoma arising in the femur of a 34-year-old female. The round to spindle tumor cells were arranged in short fascicles, with focal rosette formation, within a hyalinized stroma. The tumor immunoprofile included diffuse reactivity for CD99, SATB2, and TLE1 and patchy positivity for Cyclin D1, Keratin AE1/AE3, synaptophysin, and chromogranin. Other markers, such as EMA, SMA, desmin, S100, ERG, and WT1, were negative. Fluorescence in situ hybridization analysis for EWSR1 gene alterations showed a break-apart signal and targeted RNA sequencing revealed an EWSR1::SSX3 gene fusion. The patient received neoadjuvant chemotherapy followed by surgery and subsequently relapsed in less than a year with lung metastasis. Larger series are needed to determine if this fusion defines a novel subset of undifferentiated tumors or represents a genomic variant of already existing primitive round cell sarcoma categories, such as Ewing sarcoma or synovial sarcoma.
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Sarcoma de Ewing , Sarcoma , Neoplasias de Tecidos Moles , Feminino , Humanos , Adulto , Hibridização in Situ Fluorescente , Sarcoma/genética , Sarcoma/patologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Fatores de Transcrição/genética , Neoplasias de Tecidos Moles/genética , Fusão Gênica , Biomarcadores Tumorais/genética , Proteínas de Fusão Oncogênica/genética , Proteína EWS de Ligação a RNA/genéticaRESUMO
BACKGROUND: Chondroblastomas are uncommon primary bone tumors localized in long bone epiphyses in children and young adults. The risk of metastasis is rare, but they have a high capacity for local recurrence. Surgical curettage with bone grafting or bone substitute is the preferred treatment. METHODS: We performed an observational retrospective study of chondroblastomas treated in 2 hospitals in Barcelona from 1988 to 2018. We reviewed the location of the tumor, clinical presentation, imaging, histopathology, initial treatment, and cases of recurrence with a review of their treatment. We assessed the correlation between recurrence and index surgery, anatomic location, and certain histopathologic findings (presence of mitotic figures, necrosis, and positivity for protein S-100). RESULTS: The series included 55 patients treated from 1988 to 2018, with ages ranging from 6 to 26, and a mean follow-up of 6.1 years (±3.7). The most common location was the distal femur metaphyseal/epiphyseal region. The most frequent clinical presentation was pain in the affected. Forty-five cases (81.8%) were treated with curettage of the tumor, and 4 cases (7.3%) with a wide resection. Forty-two cases (85.7%) received bone substitutes after curettage or resection. We found 5 cases of recurrence (9.1% recurrence rate); however, we could not find a statistically significant correlation between index surgery and recurrence ( P =0.24), anatomic location and recurrence ( P =0.49), or recurrence and histopathologic findings (mitotic figures, P =0.49; necrosis, P =0.60; positivity for protein S-100, P =0.52). In all the cases the treatment for the local recurrence was surgical, with a final healing rate of 100%. CONCLUSIONS: Chondroblastomas should be considered in children and adolescents when presenting with pain and an image suggestive of a tumoral lesion on plain x-ray, most frequently in epiphyses of long bones.Surgical treatment is preferred, obtaining good results after curettage and bone substitute. Chondroblastomas are tumors with a high capacity for recurrence, therefore an adequate surgical technique and surgeon experience are paramount to achieve good outcomes. LEVEL OF EVIDENCE: Level IV (case series). Therapeutic studies-investigating results or treatment.
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Neoplasias Ósseas , Substitutos Ósseos , Condroblastoma , Adolescente , Criança , Humanos , Adulto Jovem , Neoplasias Ósseas/patologia , Condroblastoma/cirurgia , Curetagem , Necrose/etiologia , Necrose/cirurgia , Recidiva Local de Neoplasia/cirurgia , Dor/etiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: Up to 73% of individuals with autism spectrum disorder (ASD) and intellectual disability (ID) currently have prescriptions for psychotropic drugs. This is explained by a higher prevalence of medical and psychiatric chronic comorbidities, which favors polypharmacy, increasing the probability of the appearance of adverse events (AEs). These could be a preventable cause of harm to patients with ASD and an unnecessary waste of healthcare resources. OBJECTIVE: To study the impact of pharmacogenetic markers on the prevention of AE appearance in a population with ASD and ID. METHODS: This is a cross-sectional, observational study (n = 118, 72 participants completed all information) in the ASD population. Sociodemographic and pharmacological data were gathered. The Udvalg for Kliniske Undersøgelser Scale (UKU Scale) was used to identify AEs related to the use of psychotropic medication. Polymorphisms of DOP2, ABCB1, and COMT were genotyped and correlated with the AE to find candidate genes. Furthermore, a review of all medications assessed in a clinical trial for adults with autism was performed to enrich the search for potential pharmacogenetic markers, keeping in mind the usual medications. RESULTS: The majority of the study population were men (75%) with multiple comorbidities and polypharmacy, the most frequently prescribed drugs were antipsychotics (69%); 21% of the participants had four or more AEs related to psychotropic drugs. The most common were "Neurological" and" Psychiatric" (both 41%). Statistical analysis results suggested a significant correlation between the neurological symptoms and the DOP2 genotype, given that they are not equally distributed among its allelic variants. The final review considered 19 manuscripts of medications for adults with ASD, and the confirmed genetic markers for those medications were consulted in databases. CONCLUSION: A possible correlation between neurologic AEs and polymorphisms of DOP2 was observed; therefore, studying this gene could contribute to the safety of this population's prescriptions. The following studies are underway to maximize statistical power and have a better representation of the population.
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The long-term use of psychopharmacology medications in autism spectrum disorder (ASD) hitherto remains controversial due to a lack of evidence about safety and tolerability. In this regard, genotyping the metabolizing enzyme cytochrome P450 (CYP) 2D6, especially its extreme phenotypes, could help to prevent drug-related adverse reactions or adverse events (AEs). There are several medications warranting CYP2D6 screening that are consumed by people with ASD, such as risperidone and aripiprazole to name a few. A naturalistic observational study was carried out in participants with ASD to analyze the influence of the CYP2D6 phenotype in drug tolerability using a local pharmacovigilance system created for this study. In this case, AEs were identified from participants' electronic health records (EHRs) and paper registries. Other variables were collected: socio-demographic information, comorbidities, and psychopharmacology prescriptions (polypharmacy defined as ≥4 simultaneous prescriptions) and doses. The genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number variations. All of these were used to determine theoretical phenotypes of the metabolic profiles: poor (PM); intermediate (IM); normal (NM); and ultra-rapid (UM). Sex differences were analyzed. A total of 71 participants (30 ± 10 years old, 82% male, 45% CYP2D6 NM phenotype (32 participants)) with a median of 3 (IQR 2-4) comorbidities per person, mainly urinary incontinence (32%) and constipation (22%), were included. CYP2D6 UM showed the highest rate of polypharmacy, whilst, IM participants had the highest rates of neurological and psychiatric AEs, even worse if a CYP2D6 inhibitor drug was prescribed simultaneously. CYP2D6 pharmacogenomics and the monitoring of new antipsychotic prescriptions may make a difference in medication safety in adults with ASD. Particularly in those with psychopharmacology polymedication, it can help with AE avoidance and understanding.
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Introduction: Opioid deprescription is the process of supervised tapering and safe withdrawal when a potentially inappropriate use is detected. This represents a challenge in chronic non-cancer pain (CNCP) patients who may respond differently to the procedure. Our aim was to analyze the potential impact of CYP2D6 phenotypes and sex on the clinical and safety outcomes during an opioid use disorder (OUD) tapering process. Methods: A prospective observational study was conducted on CNCP ambulatory OUD patients (cases, n = 138) who underwent a 6-month opioid dose reduction and discontinuation. Pain intensity, relief and quality of life (Visual analogue scale, VAS 0-100 mm), global activity (GAF, 0-100 scores), morphine equivalent daily dose (MEDD), analgesic drugs adverse events (AEs) and opioid withdrawal syndrome (OWS, 0-96 scores) were recorded at basal and final visits. Sex differences and CYP2D6 phenotypes (poor (PM), extensive (EM) and ultrarapid (UM) metabolizers based on CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, *41, 2D6*5, 2D6 × N, 2D6*4 × 2 gene variants) were analyzed. Results: Although CYP2D6-UM consumed three-times less basal MEDD [40 (20-123) mg/day, p = 0.04], they showed the highest number of AEs [7 (6-11), p = 0.02] and opioid withdrawal symptoms (46 ± 10 scores, p = 0.01) after deprescription. This was inversely correlated with their quality of life (r = -0.604, p < 0.001). Sex-differences were evidenced with a tendency to a lower analgesic tolerability in females and lower quality of life in men. Discussion: These data support the potential benefits of CYP2D6-guided opioid deprescription, in patients with CNCP when OUD is detected. Further studies are required to understand a sex/gender interaction.
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More than half of patients with opioid use disorder for chronic non-cancer pain (CNCP) reduced their dose through a progressive opioid withdrawal supported by a rotation to buprenorphine and/or tramadol. The aim of this research is to analyse the long-term effectiveness of opioid deprescription taking into account the impact of sex and pharmacogenetics on the inter-individual variability. A cross-sectional study was carried out from October 2019 to June 2020 on CNCP patients who had previously undergone an opioid deprescription (n = 119 patients). Demographic, clinical (pain, relief and adverse events) and therapeutic (analgesic use) outcomes were collected. Effectiveness (< 50 mg per day of morphine equivalent daily dose without any aberrant opioid use behaviour) and safety (number of side-effects) were analysed in relation to sex differences and pharmacogenetic markers impact [OPRM1 genotype (rs1799971) and CYP2D6 phenotypes]. Long-term opioid deprescription was achieved in 49 % of the patients with an increase in pain relief and a reduction of adverse events. CYP2D6 poor metabolizers showed the lowest long-term opioid doses. Here, women showed a higher degree of opioid deprescription, but increased use of tramadol and neuromodulators, as well as an increased number of adverse events. Long-term deprescription was successful in half of the cases. Understanding sex and gender interaction plus a genetic impact could help to design more individualized strategies for opioid deprescription.
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Dor Crônica , Desprescrições , Transtornos Relacionados ao Uso de Opioides , Tramadol , Feminino , Masculino , Humanos , Caracteres Sexuais , Analgésicos Opioides , Estudos Transversais , Citocromo P-450 CYP2D6 , FarmacogenéticaRESUMO
BACKGROUND: Nicotine is a psychostimulant drug with purported use in sports environments, though the use of nicotine among athletes has not been studied extensively. OBJECTIVE: The aim of this study was to assess the nicotine positivity rate in 60,802 anti-doping urine samples from 2012 to 2020. METHODS: Urine samples obtained in-competition at different national and international sports events held in Italy during the period 2012-2020 were analysed. All samples were from anonymous athletes that were collected and analysed at the WADA-accredited antidoping laboratory in Rome, Italy. Samples were analysed by gas chromatography coupled with mass spectrometry, with a cut-off concentration for nicotine of > 50 ng/mL. Results were stratified by year, sport and sex. RESULTS: An overall mean of 22.7% of the samples (n = 13,804; males: n = 11,099; females: n = 2705) showed nicotine intake, with male samples also displaying higher positivity rates than female (24.1% vs 18.5%). Sample positivity was higher during 2012-2014 (25-33%) than 2015-2020 (15-20%). Samples from team sports displayed a higher positivity rate than those from individual sports (31.4 vs 14.1%). CONCLUSIONS: The current data demonstrates that one in five samples from a range of 90 sports test positive for nicotine in-competition. There is a lower positivity rate in endurance versus power/strength athletes and higher positivity rate in team versus individual sports, probably accounted for by differences in physiological and psychological demands and the desire for socialisation. WADA, international and national sports federations should consider these findings with concern, proactively investigate this phenomenon and act in order to protect the health and welfare of its athletes.
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Estimulantes do Sistema Nervoso Central , Dopagem Esportivo , Esportes , Humanos , Masculino , Feminino , Nicotina , Atletas/psicologia , ItáliaRESUMO
Despite the large body of research on sex differences in pain, there is a lack of translation to real-world pain management. Our aim was to analyse the sex differences in the analgesic response to oxycodone/naloxone (OXN) and tapentadol (TAP), in comparison with other opioids (OPO) commonly prescribed for chronic non-cancer pain (CNCP). An observational and cross-sectional study was conducted on ambulatory CNCP patients (n = 571). Sociodemographic, clinical (pain intensity, relief, and quality of life), safety (adverse events (AEs), adverse drug reactions), hospital frequentations and pharmacological (morphine equivalent daily dose (MEDD)) variables were collected. Multiple linear regressions were carried out to assess the association between sex and outcomes. Sex differences were observed, with lower female tolerability and higher hospital frequentation, especially in the OXN group (OR AEs report = 2.8 [1.8−4.4], p < 0.001). Here, females showed higher hospital use (23% hospital admission, 30% prescription change, p < 0.05), requiring a higher MEDD (127 ± 103 mg/day, p < 0.05), compared to OXN men. Regardless of the opioid group, CNCP women were significantly older than men (three years), with significantly higher benzodiazepine use (OR = 1.6 [1.1−2.3]), more constipation (OR = 1.34 [0.93−1.90]) and headache (OR = 1.45 [0.99−2.13]) AEs, than men who were more likely to refer sexual dysfunction (OR = 2.77 [1.53−5.01]), and loss of libido (OR = 1.93 [1.22−3.04]). Sex-differences were found related to poorer female drug tolerability and higher hospital resources, even worst in OXN female users. Other differences related to older female ages and benzodiazepine prescription, need to be further analysed from a gender perspective.
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(1) Background: It is essential to focus attention on sex-specific factors which are clinically relevant in pain management, especially with regards to opioid use disorder (OUD) risk. The aim of this study was to explore potential sex-differences in chronic non-cancer pain (CNCP) outpatients. (2) Methods: An observational cross-sectional study was conducted under CNCP outpatients with long-term prescribed opioids (n = 806), wherein 137 patients had an OUD diagnosis (cases, 64% females) and 669 did not (controls, 66% females). Socio-demographic, clinical, and pharmacological outcomes were analyzed. (3) Results: Female controls presented an older age and less intensive pain therapy but higher psychotropic prescriptions and emergency department visits compared to male controls. Meanwhile, cases demonstrated a younger age, higher work disability, double morphine equivalent daily dose, and benzodiazepine use compared with controls. Here, female cases showed an 8% greater substance use disorder (OR 2.04 [1.11-3.76]) and 24% lower tramadol use, while male cases presented a 22% higher fentanyl use (OR 2.97 [1.52-5.81]) and reported the highest number of adverse drug reactions (24%, OR 2.40 [1.12-5.16]) compared with controls. (4) Conclusions: An OUD individual risk profile was evidenced with sex-differences to take into consideration to design equal prevention programs.
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Tapentadol (TAP) and oxycodone/naloxone (OXN) potentially offer an improved opioid tolerability. However, real-world studies in chronic non-cancer pain (CNCP) remain scarce. Our aim was to compare effectiveness and security in daily pain practice, together with the influence of pharmacogenetic markers. An observational study was developed with ambulatory test cases under TAP (n = 194) or OXN (n = 175) prescription with controls (prescribed with other opioids (control), n = 216) CNCP patients. Pain intensity and relief, quality of life, morphine equivalent daily doses (MEDD), concomitant analgesic drugs, adverse events (AEs), hospital frequentation and genetic variants of OPRM1 (rs1799971, A118G) and COMT (rs4680, G472A) genes, were analysed. Test CNCP cases evidenced a significantly higher pain relief predictable due to pain intensity and quality of life (R2 = 0.3), in front of controls. Here, OXN achieved the greatest pain relief under a 28% higher MEDD, 8-13% higher use of pregabalin and duloxetine, and 23% more prescription change due to pain, compared to TAP. Whilst, TAP yielded a better tolerability due the lower number of 4 [0-6] AEs/patient, in front of OXN. Furthermore, OXN COMT-AA homozygotes evidenced higher rates of erythema and vomiting, especially in females. CNCP real-world patients achieved higher pain relief than other traditional opioids with a better tolerability for TAP. Further research is necessary to clarify the potential influence of COMT and sex on OXN side-effects.
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Dor do Câncer , Dor Crônica , Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Dor Crônica/induzido quimicamente , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Constipação Intestinal/tratamento farmacológico , Preparações de Ação Retardada , Combinação de Medicamentos , Feminino , Humanos , Morfina/efeitos adversos , Naloxona/efeitos adversos , Oxicodona/efeitos adversos , Testes Farmacogenômicos , Qualidade de Vida , TapentadolRESUMO
Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are substantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chemotherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to establish their clinical utility.
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A good therapeutic alliance is relevant for healthcare providers exposed to patients' suffering, especially since patients and physicians may understand the painful experience differently. Our aim was to explore the impact of therapeutic alliance on analgesic outcomes in a real-world interdisciplinary pain unit (PU). A cross-sectional observational study was conducted on outpatients (n = 69) using opioids on a long-term basis for the treatment of chronic non-cancer pain, where clinical pharmacologists and pharmacists advised patients about their opioid treatment. Responses to the patient-doctor relationship questionnaire (PDRQ), sociodemographic and clinical information (pain level, quality of life and hospital use) were collected, whereas pharmacology data (analgesic prescription, adverse events, and compliance) were obtained from electronic health records. Patients were predominantly middle-aged (75 % women, 72 % retired), experiencing moderate pain (VAS 40-70 mm) on average, and under a high morphine equianalgesic dosage (95 ± 88 mg per day, mainly tapentadol or fentanyl). Patients with better PDRQ outcomes, and therefore better therapeutic alliance, showed lower pain intensity than patients with worse PDRQ outcomes (pain intensity: high scores 60 ± 47 mm and medium scores 60 ± 45 mm vs. low scores 80 ± 75 mm, p < 0.01). Along with this, pain intensity was lower when patients affirmed that, thanks to the health-care providers, they "gained new insight", "felt better", or "felt content with their doctor's treatment". What´s more, patients who affirmed "I benefit from the treatment" experienced increased pain relief (benefit 40 ± 30 vs. non-benefit 19 ± 26 mm, p = 0.010) and improved quality of life (benefit 33 ± 25 vs. non-benefit 18 ± 16 mm, p = 0.031). However, there was a percentage of patients who did not fully understand the provided information, which is something to be taken into account to improve in clinical routine. Therapeutic alliance supported by pharmacist experts on pain management can be an effective strategy to improve analgesic outcomes. Further efforts are needed to improve communication strategies for pain management. Future directions of research should include the analysis of the role of the pharmacist in poly-professional consultations as related to the advice of patients about their medication, and the mutual trust with the patients.
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Dor Crônica , Aliança Terapêutica , Pessoa de Meia-Idade , Humanos , Feminino , Masculino , Analgésicos Opioides/efeitos adversos , Dor Crônica/tratamento farmacológico , Dor Crônica/induzido quimicamente , Qualidade de Vida , Estudos TransversaisRESUMO
Adults with autism spectrum disorder (ASD) and associated intellectual disability (ID) take a high number of different psychotropic drugs simultaneously. Nowadays, little is known about this multidrug pattern efficacy and safety. The present study has endeavored to fill this gap creating a local pharmacovigilance system. A 36-month, retrospective and prospective, observational, and multicenter pharmacovigilance study was carried out in adults with ASD and ID (n = 83). Information regarding ongoing medications (polypharmacy: taking simultaneously >4 drugs; safety profile: adverse events' number, adverse drug reactions' number, and affected system; and observed-to-expected [O/E] ratio using the summary of product characteristics), and current diagnoses were recorded. A median of four ongoing medications per participant was registered, half of the sample was under polypharmacy regimen. Regarding all ongoing medications, 50% were antipsychotic drugs, and 47% of participants had >1 antipsychotic prescribed. In contrast, only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related either to nervous or metabolic systems, and almost a third were not previously described in the corresponding drug summary of products characteristics. Extrapyramidalism, gynecomastia, hypercholesterolemia, and urinary retention were some AEs that occurred more frequently than expected (O/E ratio > 6 times) according to our data. The highest O/E ratio scores (>120 times) were for hypercholesterolemia and rhabdomyolysis caused by valproic acid. According to the number of adverse events and adverse drug reactions reported in electronic health records locally and nationally by clinicians, we need to increase awareness about medications safety. LAY SUMMARY: A 36-month study in adults with autism, ID, and polypharmacy (>4 drugs) was done to investigate drug safety on everyone. A median of four medications per person was registered, half were antipsychotic drugs, and 47% of participants had >1 antipsychotic medication simultaneously. Only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related to nervous or metabolic systems and a third were not previously described in the drug information sheet.
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Transtorno do Espectro Autista , Deficiência Intelectual , Adulto , Transtorno do Espectro Autista/tratamento farmacológico , Humanos , Masculino , Estudos Prospectivos , Psicotrópicos/uso terapêutico , Estudos RetrospectivosRESUMO
INTRODUCTION: Conjunctival melanoma is extremely rare in children and has low rates of resolution. Definitive histopathological diagnosis based exclusively on microscopic findings is sometimes difficult. Thus, early diagnosis and adequate treatment are essential to improve clinical outcomes. CLINICAL CASE: We present the first case in which the fluorescent in situ hybridization (FISH) diagnostic technique was applied to a 10-year-old boy initially suspected of having amelanotic nevi in his right eye. Based on the 65% of tumor cells with 11q13 (CCND1) copy number gain and 33% with 6p25 (RREB1) gain as measured by the FISH analysis, and on supporting histopathological findings, the diagnosis of conjunctival melanoma could be made. Following a larger re-excision, adjuvant therapy with Mitomycin C (MMC), cryotherapy and an amniotic membrane graft, the patient has remained disease-free during 9 years of long-term follow-up. CASE DISCUSSION: Every ophthalmologist should remember to consider and not forget the possibility of using FISH analyses during the differential diagnosis of any suspicious conjunctival lesions. Genetic techniques, such as FISH, have led to great advances in the classification of ambiguous lesions. Evidence-based guidelines for diagnosing conjunctival melanoma in the pediatric population are needed to determine the most appropriate strategy for this age group.
Assuntos
Neoplasias da Túnica Conjuntiva , Melanoma , Neoplasias Cutâneas , Criança , Neoplasias da Túnica Conjuntiva/diagnóstico , Neoplasias da Túnica Conjuntiva/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Mitomicina , Doenças RarasRESUMO
The prevalence of personality disorders (PDs) and sexual dysfunction in chronic pain patients is higher than in general population. Our main objective was to analyse the influence of PD in patients with erectile dysfunction and chronic non-cancer pain and their response to andrological treatment. One-hundred one patients were included along 30 months. Pain intensity, quality of life, sexual life quality, anxiety and depression were analysed together with opioid dose. Erectile functioning was measured with the International Index of Erectile Function (IIEF) and PDs with Millon Clinical Multiaxial Inventory (MCMI-III). The mean age was 57 ± 12 years old, with moderate to severe pain, 70% were sexually active and presented moderate to severe ED. PDs were very frequent (31%, cut-off 85 and 84% cut-off 75 scores) mostly anxiety, compulsive, though disorder, somatoform and narcissistic. Self-defeating feature presence was significantly correlated (r = -0.4, 95% CI = -0.605 to -0.145, p = 0.002) with a more severe baseline ED and narcissistic, and a better response to andrological treatment (p = 0.010, d = 1.082). Patients with dysthymia features required significantly higher opioid doses vs. control (238 vs. 102 mg/day, respectively). These findings underline the importance of diagnosing PDs to rigorously treat patients with chronic pain and ED.
Assuntos
Dor Crônica , Disfunção Erétil , Idoso , Analgésicos Opioides/uso terapêutico , Dor Crônica/complicações , Disfunção Erétil/complicações , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Personalidade , Transtornos da Personalidade/complicações , Transtornos da Personalidade/epidemiologia , Estudos Prospectivos , Qualidade de VidaRESUMO
Nowadays, adults with autism spectrum disorder (ASD) experience several comorbidities whose treatment implies a wide range of psychotropic prescriptions. This study aimed to evaluate medication-related safety, drug-drug interactions, and psychotropics prescription trends. We conducted an observational and multicentric pharmacovigilance study in subjects with ASD and Intellectual disability (ID, n = 83). Clinical information (diagnoses, ongoing medications, comorbidities [multimorbidity ≥ 4 chronic health conditions]) and psychotropic prescriptions (polypharmacy ≥ 4 chronic drugs, daily drug doses, co-prescription) were registered. Ethical approval for this study was obtained. Participants (30±10 years old, 86% men, BMI 27±6 kg/m2) displayed 37% multimorbidity (mean of 3, IQR 2-4), and 57% polypharmacy (13% out of dose recommended range). Most drugs prescribed were psychotropic risperidone which is related to nervous system comorbidities (18% epilepsy, 16% insomnia, and 14% psychotic agitations). Risperidone and quetiapine were co-prescribed in 60% of the cases without any monitoring adverse event routine. The rates of multimorbidity and polypharmacy, among our young adults with ASD and ID, are concerning. Data suggest the need to develop a pharmacovigilance monitoring system to evaluate prescription accuracy, long-term safety of ongoing medications, and the fixed doses in this autistic population with associated ID.