¿Ensayos clínicos de superioridad, equivalencia o no inferioridad? / ¿Clinical trials of superiority, non-inferiority or equivalence?

La eficacia de una nueva intervención se establece generalmente a través de ensayos clínicos (EC) con asignación aleatoria (AA). Sin embargo, entre otros tantos desafíos metodológicos, el especificar la hipótesis de un EC con AA, sigue siendo un problema complejo de resolver para los investigadores clínicos. En este manuscrito discutimos las características de tres variantes de los EC con AA: EC de superioridad (ECS), EC de no-inferioridad (ECNI), y EC de equivalencia (ECE). Estos tres tipos de EC tienen supuestos diferentes sobre los efectos de una intervención, por lo que plantear hipótesis y definir objetivos requiere conocer algunos supuestos subyacentes a estos EC, incluso hasta elementos relacionados con la estimación del tamaño de muestra para cada cual. El objetivo de este manuscrito fue describir las diferencias metodológicas entre ECS, ECNI y ECE.

Efficacy and effectivity of new interventions are generally established through randomized clinical trials (RCTs). However, among many other methodological challenges, specifying the hypothesis of a RCT remains complex problem for clinical researchers. In this manuscript we discuss the characteristics of three variants of RCTs: superiority RCT (SRCT), non-inferiority RCT (NIRCT), and equivalence RCT (ERCT). These three types of RCT have different assumptions about the effects of an intervention, so setting hypotheses and defining objectives requires knowing some assumptions underlying these RCTs, including elements related to the estimation of the sample size for each one. The aim of this manuscript was to describe methodological differences between SRCT, NIRCT and ERCT.

Causes and prognosis of adults experiencing a first seizure in adulthood: A pilot cohort study conducted in five countries in Latin America.

There are limited data on first seizure (FS) among adults in low and middle-income countries. We describe findings from a prospective cohort study involving 180 adults presenting with seizures in emergency departments in five Latin American countries. Overall, 102 participants (56.7%) had acute symptomatic seizures (ASyS) while 78 (43.3%) had unprovoked seizures (UPS). Among patients with ASyS, 55 (53.9%) had structural causes, with stroke (n = 24, 23.5%), tumor (n = 10, 9.8%), and trauma (n = 3, 3%) being the most frequent. Nineteen patients (18.6%) had infectious causes, including four (4%) with meningoencephalitis, three (3%) neurocysticercosis, and two (2%) bacterial meningoencephalitis. Twenty patients (19.6%) had metabolic/toxic evidence, including four (4%) with uremic encephalopathy, two (2%) hyponatremia, and three (3%) acute alcohol intoxication. Immune dysfunction was present in seven (7%) patients and neurodegenerative in two (2%). Among participants with UPS, 45 (57.7%) had unknown etiology, 24 (30.7%) had evidence of structural disorders (remote symptomatic), four (5%) were related to infectious etiology (>7 days before the seizure), and five (6.4%) had genetic causes. During the 3- and 6-month follow-up, 29.8% and 14% of patients with UPS, respectively, experienced seizure recurrence, while 23.9% and 24.5% of patients with ASyS had seizure recurrence. Longer follow-up is necessary to assess seizure recurrence for patients with ASyS after the acute cause is resolved and to determine the 10-year risk of recurrence, which is part of the definition of epilepsy. PLAIN LANGUAGE SUMMARY: We monitored 180 adults who presented with their first seizure in emergency departments across five Latin American countries. Among these patients, 57% had acute symptomatic seizures, with structural causes such as stroke (23%), infection (17%), or tumor (10%) being more prevalent. Among the 43% with unprovoked seizures, 58% showed no identifiable acute cause, while 6.4% were due to genetics. Within 3 months after their initial seizure, 26.6% of individuals experienced a second seizure, with 11.9% continuing to have seizures in Months 3-6. Between Months 3 and 6, an additional 20% of patients encountered a second seizure. Research is needed to better understand the cause and prognosis of these patients to improve outcomes.

Metástasis Pancreática Metacrónica de un Carcinoma de Células Renales. Reporte de un Caso / Metachronic Pancreatic Metastasis of a Renal Cell Carcinoma. Case Report

El carcinoma de células renales (CCR) a nivel mundial presenta una incidencia de 431.288 casos anuales, causando 179.368 muertes en 2020. Sin embargo, a pesar de su incidencia, el desarrollo de metástasis pancreática (MP) de un RCC es un hecho inusual. El objetivo de este manuscrito fue reportar el caso de una paciente con una MP metacrónica de un CCR. Se trata de una paciente de 56 años, sexo femenino, nefrectomizada derecha hace 132 meses por un CCR, en adyuvancia con inmunoterapia. En un control imagenológico de rutina, se le pesquisó una lesión de aspecto tumoral en el cuerpo y cola del páncreas. Se intervino quirúrgicamente, realizándose una pancreatectomía córporo-caudal con preservación esplénica. Evolucionó de forma satisfactoria, sin complicaciones, siendo dada de alta al 4º día de su cirugía. El informe del estudio de la pieza operatoria con estudio inmunohistoquímico concluyó que se trataba de una MP de CCR. La paciente se encuentra en buenas condiciones generales y reinició quimioterapia con anticuerpos monoclonales. El seguimiento frecuente y prolongado de pacientes con antecedentes de CCR, facilita un diagnóstico y tratamiento oportuno de MP facilitando el mejor pronóstico de los pacientes, con tasas más altas de supervivencia.

SUMMARY: Renal cell carcinoma (RCC) worldwide has an incidence of 431,288 cases per year, causing 179,368 deaths in 2020. However, despite its incidence, the development of pancreatic metastasis (MP) from RCC is unusual. The aim of this manuscript was to report the case of a patient with a PM of a RCC. This is a 56-year-old female patient, underwent right nephrectomy 132 months earlier for RCC. While she was in adjuvant immunotherapy, in a routine imaging control, it was found a tumor lesion in the body and the tail of the pancreas. So, she underwent surgery, performing a corpora-caudal pancreatectomy with splenic preservation. Postoperative evolution was correct, without complications, and she was discharged on the 4th day after surgery. The report of the study of the surgical piece with an immunohistochemical study included, conclusive of PM of RCC. Currently, the patient is in good general condition and restarted chemotherapy with monoclonal antibodies. Frequent and prolonged follow-up of patients with a history of RCC facilitates timely diag- nosis and treatment of PM, facilitating the best prognosis for patients, with higher survival rates.

Placental, Foetal, and Maternal Serum Metabolomic Profiles in Pregnancy-Associated Cancer: Walker-256 Tumour Model in a Time-Course Analysis.

Cancer during pregnancy presents a delicate coexistence, imposing ethical and professional challenges on both the patient and medical team. In this study, we aimed to explore in a pre-clinical model the impact of tumour evolution in serum, placental and foetal metabolomics profiles during pregnancy in a time-course manner. Pregnant Wistar rats were distributed into two experimental groups: Control (C) and Walker-256 tumour-bearing (W). The rats were euthanised on three different gestational periods: at 12 days post-conception (dpc), at 16 dpc, and at 19 dpc. Serum, placenta and foetal metabolomic profiles were performed by 1H-NMR spectra following the analyses using Chenomx NMR Analysis Software V8.3. The tumour evolution was exponential, affecting the placental metabolomic profile during all the pregnancy stages. The placental tissue in tumour-bearing dams developed at a lower speed, decreasing the foetus's weight. Associated with the serum metabolomic changes related to tumour growth, the placental metabolomic alterations impacted many metabolic pathways related to energy provision, protein synthesis and signalling, which directly harmed the foetus's development. The development of the foetus is clearly affected by the damage induced by the tumour evolution, which alters the metabolic profile of both the serum and the placenta, impairing early embryonic development.

Serum miR-181d-5p levels in response to controlled ovarian stimulation: predictive value and biological function.

The response to controlled ovarian stimulation (COS) for in vitro fertilization (IVF) varies dramatically from one patient to another, affecting success rates. A previous large-scale study identified increased serum miR-181d-5p levels in patients with high response to COS prior to stimulation. We aim to evaluate whether the expression of miR-181d-5p differs according to the ovarian response to COS in women undergoing intracytoplasmic sperm injection (ICSI) cycles. Samples collected prior to COS for ICSI were split into three groups depending on the ovarian response to COS: poor response (PR), <4 oocytes retrieved (n=25); normal response (NR), ≥8 and ≤12 oocytes retrieved (n=21); and high response (HR), >25 oocytes retrieved (n=20). miR-181d-5p serum levels were compared among experimental groups. miR-181d-5p levels were increased in the HR group when compared to the PR (p=0.0001) and NR groups (p=0.0079). miR-181d-5p levels correlated with the number of aspirated follicles (p<0.0001), retrieved oocytes (p<0.0001), and mature oocytes (p=0.0002). Increased miR-181d-5p levels independently predict a high response (p=0.006), with Positive and Negative Predictive Values of 66.7% and 69.4%, respectively. miR-181d-5p was also detected in the ovarian tissue in a mouse model. Moreover, computational analysis of miR-181d-5p predicted targets and promoter region suggested that this miRNA might be involved in the regulation of key signaling pathways and biological processes for female reproductive biology. In conclusion, miR-181d-5p is a promising circulating predictor of high stimulation and potential mediator of the hypothalamus-pituitary-gonad axis, providing opportunities for the individualization of COS protocols.

Evaluation of maintenance of the common androgen deprivation therapy with the new antiandrogen therapy in patients with castration-resistant prostate cancer: a systematic review.

PURPOSE: Advanced prostate cancer does not respond to traditional androgen deprivation therapy (ADT) at some point in the treatment. The development of new hormonal agents demonstrated clear efficacy and changed the treatment scenario. OBJECTIVES: To evaluate the use of new antiandrogens alone versus their use in combination with maintenance ADT in patients with advanced castration-resistant prostate cancer. METHODS: A literature systematic review of randomized clinical trials, cohorts, and real-life studies including patients who received the new antiandrogens with or without ADT due to histologic confirmed advanced castration-resistant prostate adenocarcinoma was carried out. RESULTS: 2181 articles were identified and three studies were included with a total of 246 patients. Two studies were randomized clinical trials, and the third was a retrospective study, which showed similar results for both arms, in relation to PSA response, radiological progression-free survival, and testosterone levels, in addition to cost analysis with savings avoided in the ADT maintenance-free arm. Despite the positive data, it is still not possible to categorically state whether there is a statistical benefit in suspending the ADT during the use of new antiandrogens, due to the heterogeneity of the studies. CONCLUSION: The literature is limited on the issue. Available data are still immature with no clear benefit of the use of newer antiandrogens alone in the setting of advanced castration-resistant prostate cancer.

PSA nadir predicts biochemical recurrence after external beam radiation therapy combined to high dose rate brachytherapy in the treatment of prostate cancer.

INTRODUCTION: Prostate cancer (PCa) is the second most prevalent neoplasm among men in the world. Its treatment has a wide spectrum of alternatives and variables, ranging from active surveillance through radio and/or brachytherapy, to surgery. OBJECTIVE: The present work aimed to identify the predictive factors for biochemical recurrence and to evaluate the toxicity of the treatment using the association of external beam radiation therapy (EBRT) with high dose rate brachytherapy (HDR-BT) applied in the treatment of patients with prostate cancer. METHODS: Longitudinal retrospective study, using a prospectively collected database between 2005 and 2014 of 186 consecutive patients records with a diagnosis of low, intermediate, or high-risk prostate cancer treated with EBRT combined with HDR-BT, in a single medical institution located in the city of Campinas, SP, Brazil (Radium Institute). PSA increase over 2 ng/ml above the nadir PSA was considered as biochemical recurrence, following the definition of the Phoenix Consensus. Continuous and clinically relevant categorical variables (age, initial PSA, delivered dose in EBRT, number of implants, number of positive cores in transrectal biopsy, use of hormone blockade, Gleason score, TNM staging, post treatment PSA and PSA Nadir) were evaluated with absolute (n) and percentage (%) values using multiple logistic regression and validated our previously described optimal PSA nadir as predictor of biochemical recurrence. RESULTS: Post treatment PSA was the only independent predictor of biochemical recurrence, P<0.0001. The lower the PSA nadir the lower the biochemical recurrence risk (P=0.0009). PSA nadir >1 was the best cutoff (P=0.018) determinant of biochemical recurrence. The incidence of grade 3 late toxicity to the genitourinary tract was 0.6%, and there were no cases of severe complications to the gastrointestinal tract. CONCLUSION: External Beam Radiation Therapy conjugated to Brachytherapy in the treatment of Prostate Cancer has demonstrated low biochemical recurrence rates, mainly when PSA nadir <1, with low toxicity into both GU and GI tracts.

Walker-256 Tumour-Induced Cachexia Altered Liver Metabolomic Profile and Function in Weanling and Adult Rats.

Cancer cachexia occurs in up to 85% of advanced cancer patients, affecting different tissues and organs, mainly the liver, which plays a central role in body metabolism control. However, liver responses to cancer cachexia progression are still poorly understood. Considering the possible different challenges provided by the rodent's phase of life and the cachexia progression, we evaluated the liver metabolic alterations affected by Walker-256 tumour growth in weanling and young-adult rats. For this, we applied a metabolomics approach associated with protein and gene expression analyses. Higher amino acid levels and impaired glucose metabolism were important features in tumour-bearing animals' liver tissue. The weanling hosts had more pronounced cachexia, with higher carcass spoliation, liver lipid metabolism and impaired CII and CIV mitochondrial complexes. The liver alterations in young adult tumour-bearing rats were related to energy status and nucleotide metabolites, such as uridine, NAD+, xanthosine, hypoxanthine and inosine. In conclusion, the Walker-256 tumour-induced cachexia impaired liver metabolism, being more severe in the weanling hosts. Further studies are needed to correlate these changes in the preclinical model, which can be correlated to the clinical features of cancer cachexia, allowing for a translational potential involving the liver function and its responses to potential treatments.

Leucine-Rich Diet Improved Muscle Function in Cachectic Walker 256 Tumour-Bearing Wistar Rats.

Skeletal muscle atrophy occurs in several pathological conditions, such as cancer, especially during cancer-induced cachexia. This condition is associated with increased morbidity and poor treatment response, decreased quality of life, and increased mortality in cancer patients. A leucine-rich diet could be used as a coadjutant therapy to prevent muscle atrophy in patients suffering from cancer cachexia. Besides muscle atrophy, muscle function loss is even more important to patient quality of life. Therefore, this study aimed to investigate the potential beneficial effects of leucine supplementation on whole-body functional/movement properties, as well as some markers of muscle breakdown and inflammatory status. Adult Wistar rats were randomly distributed into four experimental groups. Two groups were fed with a control diet (18% protein): Control (C) and Walker 256 tumour-bearing (W), and two other groups were fed with a leucine-rich diet (18% protein + 3% leucine): Leucine Control (L) and Leucine Walker 256 tumour-bearing (LW). A functional analysis (walking, behaviour, and strength tests) was performed before and after tumour inoculation. Cachexia parameters such as body weight loss, muscle and fat mass, pro-inflammatory cytokine profile, and molecular and morphological aspects of skeletal muscle were also determined. As expected, Walker 256 tumour growth led to muscle function decline, cachexia manifestation symptoms, muscle fibre cross-section area reduction, and classical muscle protein degradation pathway activation, with upregulation of FoxO1, MuRF-1, and 20S proteins. On the other hand, despite having no effect on the walking test, inflammation status or muscle oxidative capacity, the leucine-rich diet improved muscle strength and behaviour performance, maintained body weight, fat and muscle mass and decreased some protein degradation markers in Walker 256 tumour-bearing rats. Indeed, a leucine-rich diet alone could not completely revert cachexia but could potentially diminish muscle protein degradation, leading to better muscle functional performance in cancer cachexia.

A Time-Course Comparison of Skeletal Muscle Metabolomic Alterations in Walker-256 Tumour-Bearing Rats at Different Stages of Life.

Cancer cachexia is a severe wasting condition that needs further study to find ways to minimise the effects of damage and poor prognosis. Skeletal muscle is the most impacted tissue in cancer cachexia; thus, elucidation of its metabolic alterations could provide a direct clue for biomarker research and be applied to detect this syndrome earlier. In addition, concerning the significant changes in the host metabolism across life, this study aimed to compare the metabolic muscle changes in cachectic tumour-bearing hosts at different ages. We performed 1H-NMR metabolomics in the gastrocnemius muscle in weanling and young adult Walker-256 tumour-bearing rats at different stages of tumour evolution (initial, intermediate, and advanced). Among the 49 metabolites identified, 24 were significantly affected throughout tumour evolution and 21 were significantly affected regarding animal age. The altered metabolites were mainly related to increased amino acid levels and changed energetic metabolism in the skeletal muscle, suggesting an expressive catabolic process and diverted energy production, especially in advanced tumour stages in both groups. Moreover, these changes were more severe in weanling hosts throughout tumour evolution, suggesting the distinct impact of cancer cachexia regarding the host's age, highlighting the need to adopting the right animal age when studying cancer cachexia.

Pregnancy and Cancer: Cellular Biology and Mechanisms Affecting the Placenta.

Cancer during pregnancy is rarely studied due to its low incidence (1:1000). However, as a result of different sociocultural and economic changes, women are postponing pregnancy, so the number of pregnant women with cancer has been increasing in recent years. The importance of studying cancer during pregnancy is not only based on maternal and foetal prognosis, but also on the evolutionary mechanisms of the cell biology of trophoblasts and neoplastic cells, which point out similarities between and suggest new fields for the study of cancer. Moreover, the magnitude of how cancer factors can affect trophoblastic cells, and vice versa, in altering the foetus's nutrition and health is still a subject to be understood. In this context, the objective of this narrative review was to show that some researchers point out the importance of supplementing branched-chain amino acids, especially leucine, in experimental models of pregnancy associated with women with cancer. A leucine-rich diet may be an interesting strategy to preserve physiological placenta metabolism for protecting the mother and foetus from the harmful effects of cancer during pregnancy.

Clinical aspects of abdominal actinomycosis: a systematic review.

BACKGROUND: Abdominal actinomycosis (AA) is a rare infection. The aim of this study was to summarize the evidence available on AA. METHODS: A systematic review was conducted. Data sources included Trip Database, BIREME, SciELO, Cochrane Library, WoS, MEDLINE, EMBASE, SCOPUS, IBECS and LILACS. Eligibility criteria included: studies related to surgically treated AA, in adult population, without language and sex restriction, published between 1966 and 2019. The following variables were analysed: publication year, age, sex, geographical origin, location of lesions, clinical manifestations, risk factors, species isolated and treatments used. RESULTS: A total of 1505 studies were initially identified. After scrutinizing titles and abstracts, and checking duplications, 221 articles including 406 subjects with AA were included. All were case reports or series. Mean age of subjects was 49.2 years and 56.2% were female. The highest proportion of articles was published between 2015 and 2019 (18.7%). Publications were predominantly from the USA (12.2%). Structures usually involved were abdominal wall, colon and appendix. The most common presentation was abdominal mass (39.2%). In 42.1% of patients, an associated factor was found, highlighting intrauterine devices (14.3%). The microbiology studies highlighted Actinomyces israelli. Morbidity, recurrence and verified mortality were 18.2%, 1.0% and 2.2%, respectively. Penicillin was the most used antibiotic. CONCLUSION: Evidence about AA is scarce and dispersed within a reduced range of articles and cases.