RESUMEN
BACKGROUND: Patients with melanoma brain metastases are now frequently treated with immunotherapy (IMT) or targeted therapy (TT). The aim of this systematic review was to determine relative survival outcomes after combining radiotherapy (RT) with IMT or TT. METHODS: 126 studies were identified by searching Medline, Embase and Cochrane CENTRAL (to 7Aug 2023). RESULTS: Multivariable analyses showed that the risk of death was reduced by 30â¯% for combined stereotactic radiosurgery (SRS)+IMT compared to IMT alone, by 65â¯% for patients treated with SRS+anti-PD1 and by 59â¯% for patients treated with SRS+anti-CTLA4 and/or anti-PD1 (HR 0.41, 95â¯%CI 0.31-0.54) compared to SRS alone. Four studies compared SRS+anti-CTLA4 with SRS+anti-PD1, showing a 42â¯% reduction in risk of death with SRS+anti-PD1 treatment. Combined treatment with SRS+TT showed a 59â¯% reduction in risk compared to SRS alone. CONCLUSION: The systematic review suggests a substantial survival benefit for combining SRS with IMT or TT for patients with melanoma brain metastases.
RESUMEN
Increased vulnerability to seizures in aging has been well documented both clinically and in various models of aging in epilepsy. Seizures can exacerbate cognitive decline that is already prominent in aging. Senescent cells are thought to contribute to cognitive impairment in aging and clearing senescent cells with senolytic drugs improves cognitive function in animal models. It remains unclear whether senescent cells render the aged brain vulnerable to seizures. Here, we demonstrate that prophylactic senolytic treatment with Dasatinib and Quercetin (D&Q) reduced both seizure severity and mortality in aged C57BL/6J mice. We subjected the D&Q and VEH-treated aged mice to spatial memory testing before and after an acute seizure insult, Status Epilepticus [SE], which leads to epilepsy development. We found that senolytic therapy improved spatial memory before injury, however, spatial memory was not rescued after SE. Senescence-related proteins p16 and senescence-associated ß-galactosidase were reduced in D&Q-treated aged mice. Our findings indicate that senescent cells increase seizure susceptibility in aging. Thus, prophylactically targeting senescent cells may prevent age-related seizure vulnerability.
RESUMEN
GABA modulators such as phenobarbital (PB) and sodium channel blockers such as phenytoin (PHT) have long been the mainstay of pharmacotherapy for the epilepsies. In the context of neonatal seizures, both PB and PHT display incomplete clinical efficacy. Moreover, in animal models, neonatal exposure to these medications result in neurodegeneration raising concerns about safety. Cenobamate, a more recently approved medication, displays unique pharmacology as it is both a positive allosteric modulator of GABA-A receptors, and a voltage-gated sodium channel blocker. While cenobamate is approved for adult use, its efficacy and safety profile against neonatal seizures is poorly understood. To address this gap, we assessed the efficacy and safety of cenobamate in immature rodents. Postnatal day (P)7 rat pups were pretreated with cenobamate and challenged with the chemoconvulsant pentylenetetrazole (PTZ) to screen for anti-seizure effects. In a separate experiment, P7 rats were treated with cenobamate, and brains were processed to assess induction of cell death. Cenobamate displays dose-dependent anti-seizure efficacy in neonatal rats. Unlike PHB and PHT, it does not induce neurotoxicity in P7 rats. Thus, cenobamate may be effective at treating neonatal seizures while avoiding unwanted neurotoxic side effects such as cell death.
Asunto(s)
Animales Recién Nacidos , Anticonvulsivantes , Carbamatos , Muerte Celular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ratas Sprague-Dawley , Convulsiones , Animales , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Anticonvulsivantes/farmacología , Ratas , Muerte Celular/efectos de los fármacos , Carbamatos/farmacología , Carbamatos/uso terapéutico , Clorofenoles/farmacología , Pentilenotetrazol/toxicidad , Masculino , Femenino , Convulsivantes/toxicidad , Encéfalo/efectos de los fármacos , TetrazolesRESUMEN
Selecting which patients with clinically-localized melanoma require treatment other than wide excision of the primary tumor is based on the risk or presence of metastatic disease. This in turn is linked to survival. Knowing if and when a melanoma is likely to metastasize is therefore of great importance. Several studies employing a range of different methodologies have suggested that many melanomas metastasize long before the primary lesion is diagnosed. Therefore, waiting for dissemination of metastatic disease to become evident before making systemic therapy available to these patients may be less effective than giving them post-operative adjuvant therapy initially if the metastatic risk is high. The identification of these high-risk patients will assist in selecting those to whom adjuvant systemic therapy can most appropriately be offered. Further studies are required to better identify high-risk patients whose primary melanoma is likely to have already metastasized.
Asunto(s)
Melanoma , Humanos , Melanoma/secundario , Melanoma/terapia , Metástasis de la Neoplasia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapiaRESUMEN
BACKGROUND: There is a strong correlation between cigarette smoking and the development of many cancer types. It is therefore paradoxical that multiple reports have suggested a reduced incidence of melanoma in smokers. This study aimed to analyze all existing studies of melanoma incidence in smokers relative to non-smokers. METHODS: Searches of MEDLINE and Embase were conducted for studies reporting data on melanoma in smokers and never-smokers. No study design limitations or language restrictions were applied. The outcome examined was the association between smoking status and melanoma. Analyses focussed on risk of melanoma in smokers and never-smokers generated from multivariable analyses and these were pooled using a fixed effects model. Risk of bias was assessed using the Newcastle-Ottawa tool. FINDINGS: Forty-nine studies that included 59,429 melanoma patients were identified. Pooled analyses showed that current-smokers had a significantly-reduced risk of melanoma both in males (risk ratio (RR) 0.60, 95%CI_0.56 to0.65, p < .001) and females (RR 0.79- 95%-CI-0.73-to-0.86, p < .001). Male former-smokers had a 16% reduction in melanoma risk compared to never-smokers (RR-0.84,-95%CI-0.77-to-0.93, p < .001), but no risk reduction was observed in female former-smokers (RR-1.0-95%CI-0.92-to-1.08). INTERPRETATION: Current-smokers have a significantly-reduced risk of developing melanoma compared to never-smokers, with a reduction in melanoma risk of 40% in men and 21% in women.
RESUMEN
Epitope mapping provides critical insight into antibody-antigen interactions. Epitope mapping of autoantibodies from patients with autoimmune diseases can help elucidate disease immunogenesis and guide the development of antigen-specific therapies. Similarly, epitope mapping of commercial antibodies targeting known autoantigens enables the use of those antibodies to test specific hypotheses. Anti-Neutrophil Cytoplasmic Autoantibody (ANCA) vasculitis results from the formation of autoantibodies to multiple autoantigens, including myeloperoxidase (MPO), proteinase-3 (PR3), plasminogen (PLG), and peroxidasin (PXDN). To perform high-resolution epitope mapping of commercial antibodies to these autoantigens, we developed a novel yeast surface display library based on a series of >5000 overlapping peptides derived from their protein sequences. Using both FACS and magnetic bead isolation of reactive yeast, we screened 19 commercially available antibodies to the ANCA autoantigens. This approach to epitope mapping resulted in highly specific, fine epitope mapping, down to single amino acid resolution in many cases. Our study also identified cross-reactivity between some commercial antibodies to MPO and PXDN, which suggests that patients with apparent autoantibodies to both proteins may be the result of cross-reactivity. Together, our data validate yeast surface display using maximally overlapping peptides as an excellent approach to linear epitope mapping.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos , Saccharomyces cerevisiae , Humanos , Mapeo Epitopo , Autoanticuerpos , Mieloblastina , Autoantígenos , Peroxidasa , PéptidosRESUMEN
BACKGROUND: Cranberries contain proanthocyanidins (PACs), which inhibit the adherence of p-fimbriated Escherichia coli to the urothelial cells lining the bladder. Cranberry products have been used widely for several decades to prevent urinary tract infections (UTIs). This is the fifth update of a review first published in 1998 and updated in 2003, 2004, 2008, and 2012. OBJECTIVES: To assess the effectiveness of cranberry products in preventing UTIs in susceptible populations. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 13 March 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-RCTs of cranberry products compared with placebo, no specific treatment or other intervention (antibiotics, probiotics) for the prevention of UTIs were included. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed and extracted data. Information was collected on methods, participants, interventions and outcomes (incidence of symptomatic UTIs, positive culture results, side effects, adherence to therapy). Risk ratios (RR) with 95% confidence intervals (CI) were calculated where appropriate. Study quality was assessed using the Cochrane risk of bias assessment tool. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: For this update, 26 new studies were added, bringing the total number of included studies to 50 (8857 randomised participants). The risk of bias for sequence generation and allocation concealment was low for 29 and 28 studies, respectively. Thirty-six studies were at low risk of performance bias, and 23 studies were at low risk of detection bias. Twenty-seven, 41, and 17 studies were at low risk of attrition bias, reporting bias and other bias, respectively. Forty-five studies compared cranberry products with placebo, water or no specific treatment in six different groups of participants. Twenty-six of these 45 studies could be meta-analysed for the outcome of symptomatic, culture-verified UTIs. In moderate certainty evidence, cranberry products reduced the risk of UTIs (6211 participants: RR 0.70, 95% CI 0.58 to 0.84; I² = 69%). When studies were divided into groups according to the treatment indication, cranberry products probably reduced the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs (8 studies, 1555 participants: RR 0.74, 95% CI 0.55 to 0.99; I² = 54%), in children (5 studies, 504 participants: RR 0.46, 95% CI 0.32 to 0.68; I² = 21%) and in people with a susceptibility to UTIs due to an intervention (6 studies, 1434 participants: RR 0.47, 95% CI 0.37 to 0.61; I² = 0%). However, there may be little or no benefit in elderly institutionalised men and women (3 studies, 1489 participants: RR 0.93, 95% CI 0.67 to 1.30; I² = 9%; moderate certainty evidence), pregnant women (3 studies, 765 participants: RR 1.06, 95% CI 0.75 to 1.50; I² = 3%; moderate certainty evidence), or adults with neuromuscular bladder dysfunction with incomplete bladder emptying (3 studies, 464 participants: RR 0.97, 95% CI 0.78 to 1.19; I² = 0%; low certainty evidence). Other comparisons were cranberry products with probiotics (three studies) or antibiotics (six studies), cranberry tablets with cranberry liquid (one study), and different doses of PACs (two studies). Compared to antibiotics, cranberry products may make little or no difference to the risk of symptomatic, culture-verified UTIs (2 studies, 385 participants: RR 1.03, 95% CI 0.80 to 1.33; I² = 0%) or the risk of clinical symptoms without culture (2 studies, 336 participants: RR 1.30, 95% CI 0.79 to 2.14; I² = 68%). Compared to probiotics, cranberry products may reduce the risk of symptomatic, culture-verified UTIs (3 studies, 215 participants: RR 0.39, 95% CI 0.27 to 0.56; I = 0%). It is unclear whether efficacy differs between cranberry juice and tablets or between different doses of PACs, as the certainty of the evidence was very low. The number of participants with gastrointestinal side effects probably does not differ between those taking cranberry products and those receiving a placebo or no specific treatment (10 studies, 2166 participants: RR 1.33, 95% CI 1.00 to 1.77; I² = 0%; moderate certainty evidence). There was no clear relationship between compliance with therapy and the risk for repeat UTIs. No difference in the risk for UTIs could be demonstrated between low, moderate and high doses of PACs. AUTHORS' CONCLUSIONS: This update adds a further 26 studies, taking the total number of studies to 50 with 8857 participants. These data support the use of cranberry products to reduce the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs, in children, and in people susceptible to UTIs following interventions. The evidence currently available does not support its use in the elderly, patients with bladder emptying problems, or pregnant women.
Asunto(s)
Infecciones Urinarias , Vaccinium macrocarpon , Masculino , Femenino , Niño , Adulto , Humanos , Anciano , Infecciones Urinarias/prevención & control , Riñón , Antibacterianos , Fitoterapia/métodos , Extractos Vegetales/uso terapéuticoRESUMEN
BACKGROUND: Cranberries contain proanthocyanidins (PACs), which inhibit the adherence of p-fimbriated Escherichia coli to the urothelial cells lining the bladder. Cranberry products have been used widely for several decades to prevent urinary tract infections (UTIs). This is the fifth update of a review first published in 1998 and updated in 2003, 2004, 2008, and 2012. OBJECTIVES: To assess the effectiveness of cranberry products in preventing UTIs in susceptible populations. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 13 March 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register Search Portal (ICTRP) and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-RCTs of cranberry products compared with placebo, no specific treatment or other intervention (antibiotics, probiotics) for the prevention of UTIs were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed and extracted data. Information was collected on methods, participants, interventions and outcomes (incidence of symptomatic UTIs, positive culture results, side effects, adherence to therapy). Risk ratios (RR) with 95% confidence intervals (CI) were calculated where appropriate. Study quality was assessed using the Cochrane risk of bias assessment tool. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: For this update 26 new studies were added, bringing the total number of included studies to 50 (8857 randomised participants). The risk of bias for sequence generation and allocation concealment was low for 29 and 28 studies, respectively. Thirty-six studies were at low risk of performance bias, and 23 studies were at low risk of detection bias. Twenty-seven, 41, and 17 studies were at low risk of attrition bias, reporting bias and other bias, respectively. Forty-five studies compared cranberry products with placebo or no specific treatment in six different groups of participants. Twenty-six of these 45 studies could be meta-analysed for the outcome of symptomatic, culture-verified UTIs. In moderate certainty evidence, cranberry products reduced the risk of UTIs (6211 participants: RR 0.70, 95% CI 0.58 to 0.84; I² = 69%). When studies were divided into groups according to the treatment indication, cranberry products probably reduced the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs (8 studies, 1555 participants: RR 0.74, 95% CI 0.55 to 0.99; I² = 54%), in children (5 studies, 504 participants: RR 0.46, 95% CI 0.32 to 0.68; I² = 21%) and in people with a susceptibility to UTIs due to an intervention (6 studies, 1434 participants: RR 0.47, 95% CI 0.37 to 0.61; I² = 0%). However, in low certainty evidence, there may be little or no benefit in elderly institutionalised men and women (3 studies, 1489 participants: RR 0.93, 95% CI 0.67 to 1.30; I² = 9%), pregnant women (3 studies, 765 participants: RR 1.06, 95% CI 0.75 to 1.50; I² = 3%), or adults with neuromuscular bladder dysfunction with incomplete bladder emptying (3 studies, 464 participants: RR 0.97, 95% CI 0.78 to 1.19; I² = 0%). Other comparisons were cranberry products with probiotics (three studies) or antibiotics (six studies), cranberry tablets with cranberry liquid (one study), and different doses of PACs (two studies). Compared to antibiotics, cranberry products may make little or no difference to the risk of symptomatic, culture-verified UTIs (2 studies, 385 participants: RR 1.03, 95% CI 0.80 to 1.33; I² = 0%) or the risk of clinical symptoms without culture (2 studies, 336 participants: RR 1.30, 95% CI 0.79 to 2.14; I² = 68%). Compared to probiotics, cranberry products may reduce the risk of symptomatic, culture-verified UTIs (3 studies, 215 participants: RR 0.39, 95% CI 0.27 to 0.56; I = 0%). It is unclear whether efficacy differs between cranberry juice and tablets or between different doses of PACs as the certainty of the evidence was very low. The number of participants with gastrointestinal side effects probably does not differ between those taking cranberry products and those receiving placebo or no specific treatment (10 studies, 2166 participants: RR 1.33, 95% CI 1.00 to 1.77; I² = 0%; moderate certainty evidence). There was no clear relationship between compliance with therapy and the risk for repeat UTIs. No difference in the risk for UTIs could be demonstrated between low, moderate and high doses of PACs. AUTHORS' CONCLUSIONS: This update adds a further 26 studies taking the total number of studies to 50 with 8857 participants. These data support the use of cranberry products to reduce the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs, in children, and in people susceptible to UTIs following interventions. The evidence currently available does not support its use in the elderly, patients with bladder emptying problems, or pregnant women.
Asunto(s)
Infecciones Urinarias , Vaccinium macrocarpon , Masculino , Femenino , Niño , Adulto , Humanos , Anciano , Infecciones Urinarias/prevención & control , Riñón , Antibacterianos , Fitoterapia/métodos , Extractos Vegetales/uso terapéuticoRESUMEN
Little guidance is currently available for managing patients with melanocytic tumours of uncertain or low malignant potential (MelTUMPs, including melanocytomas), in particular the optimal excision margins and whether to offer sentinel node biopsy (SNB). The objective of this review was to evaluate excision margins and the prognostic utility of SNB by systematic review of the literature and meta-analysis. PRISMA guidelines were followed. Medline, EMBASE and Cochrane databases were searched to October 2021 for studies of patients with MelTUMPs reporting excision margins and/or SNB-positivity. Meta-analysis was performed on the SNB-positivity rate using a random effects model, followed by sensitivity analyses on subgroups. 111 primary studies reported excision margins and/or SNB data for 1962 patients. Follow-up was available for 1649 patients: 1561 (94.7%) were alive without disease at last review, 53 (3.2%) had developed further disease, 29 (1.8%) had died of metastatic disease (melanoma) and six (0.4%) died of unrelated causes. SNB was performed in 837 patients. The pooled positivity rate on meta-analysis was 32% (95% CI: 23-44%). Clinical outcome could be correlated with excision margin in only 171 patients (60% of those with known follow up) and was therefore not analysed further. Evidence indicating the ideal excision margins for MelTUMPs was lacking. SNB had a high positivity rate despite very low rates of recurrence or melanoma-related death. Consequently, SNB should not be offered routinely for MelTUMPs (including melanocytomas), due to its lack of prognostic utility for this tumour type (high certainty of evidence).
Asunto(s)
Melanoma , Nevo de Células Epitelioides y Fusiformes , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Márgenes de Escisión , Melanoma/patología , Biopsia del Ganglio Linfático Centinela , PronósticoRESUMEN
BACKGROUND: Radiation therapy (RT) for melanoma brain metastases, delivered either as whole brain radiation therapy (WBRT) or as stereotactic radiosurgery (SRS), is an established component of treatment for this condition. However, evidence allowing comparison of the outcomes, advantages and disadvantages of the two RT modalities is scant, with very few randomised controlled trials having been conducted. This has led to considerable uncertainty and inconsistent guideline recommendations. The present systematic review identified 112 studies reporting outcomes for patients with melanoma brain metastases treated with RT. Three were randomised controlled trials but only one was of sufficient size to be considered informative. Most of the evidence was from non-randomised studies, either specific treatment series or disease cohorts. Criteria for determining treatment choice were reported in only 32 studies and the quality of these studies was variable. From the time of diagnosis of brain metastasis, the median survival after WBRT alone was 3.5 months (IQR 2.4-4.0 months) and for SRS alone it was 7.5 months (IQR 6.7-9.0 months). Overall patient survival increased over time (pre-1989 to 2015) but this was not apparent within specific treatment groups. CONCLUSIONS: These survival estimates provide a baseline for determining the incremental benefits of recently introduced systemic treatments using targeted therapy or immunotherapy for melanoma brain metastases.
Asunto(s)
Neoplasias Encefálicas , Melanoma , Radiocirugia , Neoplasias Encefálicas/cirugía , Irradiación Craneana , Humanos , Inmunoterapia , Melanoma/secundario , Radiocirugia/efectos adversosRESUMEN
BACKGROUND: Dialysis treatments weigh heavily on patients' physical and psychosocial health. Multiple studies have assessed the potential for exercise training to improve outcomes in adults undergoing dialysis. However, uncertainties exist in its relevance and sustainable benefits for patient-important outcomes. This is an update of a review first published in 2011. OBJECTIVES: To assess the benefits and safety of regular structured exercise training in adults undergoing dialysis on patient-important outcomes including death, cardiovascular events, fatigue, functional capacity, pain, and depression. We also aimed to define the optimal prescription of exercise in adults undergoing dialysis. SEARCH METHODS: In this update, we conducted a systematic search of the Cochrane Kidney and Transplant Register of Studies up to 23 December 2020. The Register includes studies identified from CENTRAL, MEDLINE, EMBASE, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov as well as kidney-related journals and the proceedings of major kidney conferences. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of any structured exercise programs of eight weeks or more in adults undergoing maintenance dialysis compared to no exercise or sham exercise. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the search results for eligibility, extracted the data and assessed the risk of bias using the Cochrane risk of bias tool. Whenever appropriate, we performed random-effects meta-analyses of the mean difference in outcomes. The primary outcomes were death (any cause), cardiovascular events and fatigue. Secondary outcomes were health-related quality of life (HRQoL), depression, pain, functional capacity, blood pressure, adherence to the exercise program, and intervention-related adverse events. MAIN RESULTS: We identified 89 studies involving 4291 randomised participants, of which 77 studies (3846 participants) contributed to the meta-analyses. Seven studies included adults undergoing peritoneal dialysis. Fifty-six studies reported aerobic exercise interventions, 21 resistance exercise interventions and 19 combined aerobic and resistance training within the same study arm. The interventions lasted from eight weeks to two years and most often took place thrice weekly during dialysis treatments. A single study reported death and no study reported long-term cardiovascular events. Five studies directly assessed fatigue, 46 reported HRQoL and 16 reported fatigue or pain through their assessment of HRQoL. Thirty-five studies assessed functional capacity, and 21 reported resting peripheral blood pressure. Twelve studies reported adherence to exercise sessions, and nine reported exercise-related adverse events. Overall, the quality of the included studies was low and blinding of the participants was generally not feasible due to the nature of the intervention. Exercise had uncertain effects on death, cardiovascular events, and the mental component of HRQoL due to the very low certainty of evidence. Compared with sham or no exercise, exercise training for two to 12 months may improve fatigue in adults undergoing dialysis, however, a meta-analysis could not be conducted. Any exercise training for two to 12 months may improve the physical component of HRQoL (17 studies, 656 participants: MD 4.12, 95% CI 1.88 to 6.37 points on 100 points-scale; I² = 49%; low certainty evidence). Any exercise training for two to 12 months probably improves depressive symptoms (10 studies, 441 participants: SMD -0.65, 95% CI -1.07 to -0.22; I² = 77%; moderate certainty evidence) and the magnitude of the effect may be greater when maintaining the exercise beyond four months (6 studies, 311 participants: SMD -0.30, 95% CI 0.14 to -0.74; I² = 71%). Any exercise training for three to 12 months may improve pain (15 studies, 872 participants: MD 5.28 95% CI -0.12 to 10.69 points on 100 points-scale; I² = 63%: low certainty evidence) however, the 95% CI indicates that exercise training may make little or no difference in the level of pain. Any exercise training for two to six months probably improves functional capacity as it increased the distance reached during six minutes of walking (19 studies, 827 participants: MD 49.91 metres, 95% CI 37.22 to 62.59; I² = 34%; moderate certainty evidence) and the number of sit-to-stand cycles performed in 30 seconds (MD 2.33 cycles, 95% CI 1.71 to 2.96; moderate certainty evidence). There was insufficient evidence to assess the safety of exercise training for adults undergoing maintenance dialysis. The results were similar for aerobic exercise, resistance exercise, and a combination of both aerobic and resistance exercise. AUTHORS' CONCLUSIONS: It is uncertain whether exercise training improves death, cardiovascular events, or the mental component of HRQoL in adults undergoing maintenance dialysis. Exercise training probably improves depressive symptoms, particularly when the intervention is maintained beyond four months. Exercise training is also likely to improve functional capacity. Low certainty evidence suggested that exercise training may improve fatigue, the physical component of quality of life, and pain. The safety of exercise training for adults undergoing dialysis remains uncertain.
Asunto(s)
Diálisis Renal , Entrenamiento de Fuerza , Adulto , Ejercicio Físico , Fatiga/etiología , Humanos , Calidad de VidaRESUMEN
BACKGROUND: Primary membranous nephropathy (PMN) is a common cause of nephrotic syndrome in adults. Without treatment, approximately 30% of patients will experience spontaneous remission and one third will have persistent proteinuria. Approximately one-third of patients progress toward end-stage kidney disease (ESKD) within 10 years. Immunosuppressive treatment aims to protect kidney function and is recommended for patients who do not show improvement of proteinuria by supportive therapy, and for patients with severe nephrotic syndrome at presentation due to the high risk of developing ESKD. The efficacy and safety of different immunosuppressive regimens are unclear. This is an update of a Cochrane review, first published in 2004 and updated in 2013. OBJECTIVES: The aim was to evaluate the safety and efficacy of different immunosuppressive treatments for adult patients with PMN and nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 1 April 2021 with support from the Cochrane Kidney and Transplant Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating effects of immunosuppression in adults with PMN and nephrotic syndrome were included. DATA COLLECTION AND ANALYSIS: Study selection, data extraction, quality assessment, and data synthesis were performed using Cochrane-recommended methods. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Sixty-five studies (3807 patients) were included. Most studies exhibited a high risk of bias for the domains, blinding of study personnel, participants and outcome assessors, and most studies were judged unclear for randomisation sequence generation and allocation concealment. Immunosuppressive treatment versus placebo/no treatment/non-immunosuppressive treatment In moderate certainty evidence, immunosuppressive treatment probably makes little or no difference to death, probably reduces the overall risk of ESKD (16 studies, 944 participants: RR 0.59, 95% CI 0.35 to 0.99; I² = 22%), probably increases total remission (complete and partial) (6 studies, 879 participants: RR 1.44, 95% CI 1.05 to 1.97; I² = 73%) and complete remission (16 studies, 879 participants: RR 1.70, 95% CI 1.05 to 2.75; I² = 43%), and probably decreases the number with doubling of serum creatinine (SCr) (9 studies, 447 participants: RR 0.46, 95% CI 0.26 to 0.80; I² = 21%). However, immunosuppressive treatment may increase the number of patients relapsing after complete or partial remission (3 studies, 148 participants): RR 1.73, 95% CI 1.05 to 2.86; I² = 0%) and may lead to a greater number experiencing temporary or permanent discontinuation/hospitalisation due to adverse events (18 studies, 927 participants: RR 5.33, 95% CI 2.19 to 12.98; I² = 0%). Immunosuppressive treatment has uncertain effects on infection and malignancy. Oral alkylating agents with or without steroids versus placebo/no treatment/steroids Oral alkylating agents with or without steroids had uncertain effects on death but may reduce the overall risk of ESKD (9 studies, 537 participants: RR 0.42, 95% CI 0.24 to 0.74; I² = 0%; low certainty evidence). Total (9 studies, 468 participants: RR 1.37, 95% CI 1.04 to 1.82; I² = 70%) and complete remission (8 studies, 432 participants: RR 2.12, 95% CI 1.33 to 3.38; I² = 37%) may increase, but had uncertain effects on the number of patients relapsing, and decreasing the number with doubling of SCr. Alkylating agents may be associated with a higher rate of adverse events leading to discontinuation or hospitalisation (8 studies 439 participants: RR 6.82, 95% CI 2.24 to 20.71; I² = 0%). Oral alkylating agents with or without steroids had uncertain effects on infection and malignancy. Calcineurin inhibitors (CNI) with or without steroids versus placebo/no treatment/supportive therapy/steroids We are uncertain whether CNI with or without steroids increased or decreased the risk of death or ESKD, increased or decreased total or complete remission, or reduced relapse after complete or partial remission (low to very low certainty evidence). CNI also had uncertain effects on decreasing the number with a doubling of SCr, temporary or permanent discontinuation or hospitalisation due to adverse events, infection, or malignancy. Calcineurin inhibitors (CNI) with or without steroids versus alkylating agents with or without steroids We are uncertain whether CNI with or without steroids increases or decreases the risk of death or ESKD. CNI with or without steroids may make little or no difference to total remission (10 studies, 538 participants: RR 1.01, 95% CI 0.89 to 1.15; I² = 53%; moderate certainty evidence) or complete remission (10 studies, 538 participants: RR 1.15, 95% CI 0.84 to 1.56; I² = 56%; low certainty evidence). CNI with or without steroids may increase relapse after complete or partial remission. CNI with or without steroids had uncertain effects on SCr increase, adverse events, infection, and malignancy. Other immunosuppressive treatments Other interventions included azathioprine, mizoribine, adrenocorticotropic hormone, traditional Chinese medicines, and monoclonal antibodies such as rituximab. There were insufficient data to draw conclusions on these treatments. AUTHORS' CONCLUSIONS: This updated review strengthened the evidence that immunosuppressive therapy is probably superior to non-immunosuppressive therapy in inducing remission and reducing the number of patients that progress to ESKD. However, these benefits need to be balanced against the side effects of immunosuppressive drugs. The number of included studies with high-quality design was relatively small and most studies did not have adequate follow-up. Clinicians should inform their patients of the lack of high-quality evidence. An alkylating agent (cyclophosphamide or chlorambucil) combined with a corticosteroid regimen had short- and long-term benefits, but this was associated with a higher rate of adverse events. CNI (tacrolimus and cyclosporin) showed equivalency with alkylating agents however, the certainty of this evidence remains low. Novel immunosuppressive treatments with the biologic rituximab or use of adrenocorticotropic hormone require further investigation and validation in large and high-quality RCTs.
Asunto(s)
Glomerulonefritis Membranosa , Síndrome Nefrótico , Azatioprina , Ciclosporina , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/tratamiento farmacológico , Humanos , Inmunosupresores/efectos adversos , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/tratamiento farmacológicoRESUMEN
Most international clinical guidelines recommend 5-10 mm clinical margins for excision of melanoma in situ (MIS). While the evidence supporting this is weak, these guidelines are generally consistent. However, as a result of the high incidence of subclinical extension of MIS, especially of the lentigo maligna (LM) subtype, wider margins will often be needed to achieve complete histologic clearance. In this review, we assessed all available contemporary evidence on clearance margins for MIS. No randomized trials were identified and the 31 non-randomized studies were largely retrospective reviews of single-surgeon or single-institution experiences using Mohs micrographic surgery (MMS) for LM or staged excision (SE) for treatment of MIS on the head/neck and/or LM specifically. The available data challenge the adequacy of current international guidelines as they consistently demonstrate the need for clinical margins > 5 mm and often > 10 mm. For LM, any MIS on the head/neck, and/or ≥ 3 cm in diameter, all may require wider clinical margins because of the higher likelihood of subclinical spread. Histologic clearance should be confirmed prior to undertaking complex reconstruction. However, it is not clear whether wider margins are necessary for all MIS subtypes. Indeed, it seems that this is unlikely to be the case. Until optimal surgical margins can be better defined in a randomized trial setting, ideally controlling for MIS subtype and including correlation with histologic excision margins, techniques such as preliminary border mapping of large, ill-defined lesions and, most importantly, sound clinical judgement will be needed when planning surgical clearance margins for the treatment of MIS.
Asunto(s)
Peca Melanótica de Hutchinson , Melanoma , Neoplasias Cutáneas , Humanos , Peca Melanótica de Hutchinson/cirugía , Márgenes de Escisión , Melanoma/cirugía , Estudios Retrospectivos , Neoplasias Cutáneas/cirugíaRESUMEN
Melanoma in-transit metastases (ITMs) can sometimes be difficult to manage by surgical excision due to their number, size or location. Treatment by intralesional injection of PV-10, a 10% solution of rose bengal, has been reported to be a simple, safe and effective alternative, but more outcome data are required to confirm its value in the management of ITMs. Two hundred and twenty-six melanoma ITMs in 48 patients were treated with intralesional PV-10 supplied under a special-access scheme. By 8 weeks a complete response in all injected ITMs was achieved in 22 patients (46%) and a partial response in 19 patients (40%). Of 19 patients who had uninjected metastases, 3 (16%) had a response in these. The most common adverse event was transient localised pain in injected tumours. New ITMs developed in 25 patients within 8 weeks, and later in another 8 patients. Repeat injection cycles were given to 21 patients: 13 of these received repeat injection into partially responding or nonresponding tumours, 5 had new ITMs, as well as partially-responding lesions injected, and 3 received injection into new ITMs only. Twenty-two patients received subsequent systemic therapy. At 1 year 37 of the 48 patients were alive, 28 with melanoma, and at 2 years 27 were alive, and 19 with melanoma. Injection of PV-10 was simple and safe and resulted in tumour involution in most patients and sometimes in noninjected tumours. However, many patients developed new lesions; these were treated by further PV-10 injections or with alternative therapies.
Asunto(s)
Inyecciones Intralesiones/métodos , Melanoma/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: The incidence of melanoma is steadily rising around the world. There is uncertainty about the safety of solid organ transplantation in patients with a prior history of melanoma. AIM: To review studies reporting patients with a history of melanoma before solid organ transplantation. METHODS: Electronic searches of Medline, Embase, and the Cochrane library up to March 2020. All study designs, in any language and without sample size restriction, were eligible for inclusion. Risk of bias was assessed using established tools, and meta-analysis was performed using a random-effects model. RESULTS: We identified 41 studies reporting 703 100 transplant recipients and 1692 had pre-transplantation melanomas. Risk of death, expressed as a hazard ratio, in patients with pre-transplantation melanoma relative to those without prior melanoma, was 1.32 (95% CI: 1.09-1.59). After transplantation, 13.1% of patients with pre-transplantation melanoma developed new or recurrent melanoma (IQR: 4.8%-18.2%). CONCLUSIONS: Around 1-in-400 transplant recipients had a prior history of melanoma. This was associated with a greater than 1-in-10 risk of new or recurrent melanoma after transplantation and an increased risk of death. A 5-year waiting time between a melanoma diagnosis and transplantation has been recommended based on historic registry data, but very little additional information is available to justify or revise this.
Asunto(s)
Melanoma , Trasplante de Órganos , Neoplasias Cutáneas , Humanos , Melanoma/etiología , Modelos de Riesgos Proporcionales , Neoplasias Cutáneas/etiología , Receptores de TrasplantesRESUMEN
MicroRNAs are known to be critical regulators of neuronal plasticity. The highly conserved, hypoxia-regulated microRNA-210 (miR-210) has been shown to be associated with long-term memory in invertebrates and dysregulated in neurodevelopmental and neurodegenerative disease models. However, the role of miR-210 in mammalian neuronal function and cognitive behaviour remains unexplored. Here we generated Nestin-cre-driven miR-210 neuronal knockout mice to characterise miR-210 regulation and function using in vitro and in vivo methods. We identified miR-210 localisation throughout neuronal somas and dendritic processes and increased levels of mature miR-210 in response to neural activity in vitro. Loss of miR-210 in neurons resulted in higher oxidative phosphorylation and ROS production following hypoxia and increased dendritic arbour density in hippocampal cultures. Additionally, miR-210 knockout mice displayed altered behavioural flexibility in rodent touchscreen tests, particularly during early reversal learning suggesting processes underlying updating of information and feedback were impacted. Our findings support a conserved, activity-dependent role for miR-210 in neuroplasticity and cognitive function.
Asunto(s)
Conducta Animal , Dendritas/metabolismo , MicroARNs/metabolismo , Animales , Hipocampo/citología , Aprendizaje , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Modelos Biológicos , Regulación hacia Arriba/genéticaRESUMEN
INTRODUCTION: People with chronic kidney disease (CKD) experience reduced quality of life (QoL) because of the high symptom and treatment burden. Limited data exist on the factors associated with overall and domain-specific QoL across all CKD stages. METHODS: Using data from a prospective, multinational study (Australia, New Zealand, Canada, and Spain) in 1696 participants with CKD, we measured overall and domain-specific QoL (pain, self-care, activity, mobility, anxiety/depression) using the EuroQoL, 5 dimension, 3 level. Multivariable linear regression and logistic modeling were used to determine factors associated with overall and domain-specific QoL. RESULTS: QoL for patients with CKD stages 3 to 5 (n = 787; mean, 0.81; SD, 0.20) was higher than in patients on dialysis (n = 415; mean, 0.76; SD, 0.24) but lower than in kidney transplant recipients (n = 494; mean, 0.84; SD, 0.21). Factors associated with reduced overall QoL (ß [95% confidence intervals]) included being on dialysis (compared with CKD stages 3-5: -0.06 [-0.08 to -0.03]), female sex (-0.03 [-0.05 to -0.006]), lower educational attainment (- 0.04 [-0.06 to -0.02), lacking a partner (-0.04 [-0.06 to -0.02]), having diabetes (-0.05 [-0.07 to -0.02]), history of stroke (-0.09 [-0.13 to -0.05]), cardiovascular disease (-0.06 [-0.08 to -0.03]), and cancer (-0.03 [-0.06 to -0.009]). Pain (43%) and anxiety/depression (30%) were the most commonly affected domains, with dialysis patients reporting decrements in all 5 domains. Predictors for domain-specific QoL included being on dialysis, presence of comorbidities, lower education, female sex, and lack of a partner. CONCLUSIONS: Being on dialysis, women with CKD, those with multiple comorbidities, lack of a partner, and lower educational attainment were associated with lower QoL across all stages of CKD.
Asunto(s)
Neoplasias Colorrectales , Fallo Renal Crónico , Trasplante de Riñón , Humanos , Tamizaje MasivoRESUMEN
BACKGROUND: In patients with CKD, the risk of developing colorectal cancer is high and outcomes are poor. Screening using fecal immunochemical testing (FIT) is effective in reducing mortality from colorectal cancer, but performance characteristics of FIT in CKD are unknown. METHODS: To determine the detection rates and performance characteristics of FIT for advanced colorectal neoplasia (ACN) in patients with CKD, we used FIT to prospectively screen patients aged 35-74 years with CKD (stages 3-5 CKD, dialysis, and renal transplant) from 11 sites in Australia, New Zealand, Canada, and Spain. All participants received clinical follow-up at 2 years. We used a two-step reference standard approach to estimate disease status. RESULTS: Overall, 369 out of 1706 patients who completed FIT (21.6%) tested positive; 323 (87.5%) underwent colonoscopies. A total of 1553 (91.0%) completed follow-up; 82 (4.8%) had died and 71 (4.2%) were lost. The detection rate of ACN using FIT was 6.0% (5.6%, 7.4%, and 5.6% for stages 3-5 CKD, dialysis, and transplant). Sensitivity, specificity, and positive and negative predictive values of FIT for ACN were 0.90, 0.83, 0.30, and 0.99, respectively. Of participants who underwent colonoscopy, five (1.5%) experienced major colonoscopy-related complications, including bowel perforation and major bleeding. CONCLUSIONS: FIT appears to be an accurate screening test for patients with CKD, such that a negative test may rule out the diagnosis of colorectal cancer within 2 years. However, the risk of major complications from work-up colonoscopy are at least ten-fold higher than in the general population.