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Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aß) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aß plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer's-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed. As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.
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BACKGROUND: About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care. OBJECTIVE: This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy. METHODS: The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. RESULTS: Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively). CONCLUSIONS: Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.
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Carcinoma de Células Renales , Procedimientos Quirúrgicos de Citorreducción , Inmunoterapia , Neoplasias Renales , Nefrectomía , Inhibidores de Proteínas Quinasas , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Estudios Retrospectivos , Masculino , Femenino , Nefrectomía/métodos , Persona de Mediana Edad , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Procedimientos Quirúrgicos de Citorreducción/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inmunoterapia/métodos , Anciano , Adulto , Metástasis de la Neoplasia , Anciano de 80 o más AñosRESUMEN
Background Cancer is a risk factor for developing severe COVID19. Additionally, SARS-CoV2 has a special tropism for renal cells and complications like thrombosis or cytokine storm could be enhanced by standard treatments in kidney cancer (i.e., antiangiogenics or immunotherapy). Thus, understanding the impact of COVID19 in patients with this tumor is key for their correct management. Methods We designed a retrospective casecontrol study comparing the outcome of three groups of advanced kidney cancer patients on systemic treatment: cohort A (developed COVID19 while on antiangiogenics), cohort B (developed COVID19 while on immunotherapy) and cohort C (non-infected). Matching factors were age, gender, and treatment. Results 95 patients were recruited in 16 centers in Spain from September 2020 to May 2021. Finally, 85 were deemed as eligible (23 cohort A, 21 cohort B, 41 cohort C). Patients with COVID required more dose interruptions (25 vs. six) and hospitalizations (10 vs. none) than those without COVID (both p = 0.001). No difference between cohorts A and B was observed regarding hospitalization or length of stay. No ICU admission was registered and one patient in cohort B died due to COVID19. Regarding cancer evolution, three patients in cohort A presented progressive disease after COVID19 compared to two in cohort B. One case in cohort B, initially deemed as stable disease, achieved a partial response after COVID19. Conclusions Kidney cancer patients who developed COVID19 while on systemic therapy required more treatment interruptions and hospitalizations than those non-infected. However, no significant impact on cancer outcome was observed. Also, no difference was seen between cases on antiangiogenics or immunotherapy (AU)
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Humanos , Neoplasias Renales/terapia , Inmunoterapia , Estudios de Casos y Controles , Estudios Retrospectivos , ARN ViralRESUMEN
Introduction Systemic therapy of patients with metastatic renal cell carcinoma (mRCC) has improved in the past years, with the advent of new immunotherapy-based combinations as a standard treatment option for first-line therapy. Nevertheless, particularly in good-risk patients by IMDC criteria, tyrosine-kinase inhibitors (TKI) may remain as an option for some patients. We reviewed our experience with TKI as first-line therapy for mRCC patients, trying to identify subgroups of patients that may still benefit from this strategy. Material and methods All patients with mRCC treated with first-line TKI, and adequate follow-up, in University Hospital La Paz (Madrid, Spain) between 2007 and 2020 were analyzed. Patients treated inside a clinical trial were excluded from this analysis. Results A total of 90 patients treated with first-line TKI were included. Regarding IMDC criteria, 33 patients (36.7%) were good-risk, 41 patients (45.5%) intermediate-risk, and 16 patients (17.8%) poor-risk. With a median follow-up of 49 months, the median overall survival (OS) for good, intermediate, and poor-risk patients was 54, 24, and 16 months (p = 0.004). When intermediate-risk was divided into patients with 1 or 2 risk factors, differences in OS were also statistically significant: patients with 1 risk factor had a median OS of 33 months, while patients with 2 risk factors had a median OS of 16 months, the same as poor-risk patients (p = 0.003). In the multivariate analysis, trying to find out which of the IMDC factors had a more remarkable weight in the prognosis of the patients, both ECOG and hemoglobin levels by themselves were significantly associated with OS. Conclusion In our group of patients, survival outcomes were different among patients with intermediate-risk with 1 or 2 risk factors by IMDC criteria(AU)
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Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina/uso terapéutico , Estudios Retrospectivos , PronósticoRESUMEN
BACKGROUND: Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions. OBJECTIVE: The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC. DESIGN, SETTING, AND PARTICIPANTS: Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature. CONCLUSIONS: Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations. PATIENT SUMMARY: Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Neoplasias Renales/tratamiento farmacológico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
INTRODUCTION: Systemic therapy of patients with metastatic renal cell carcinoma (mRCC) has improved in the past years, with the advent of new immunotherapy-based combinations as a standard treatment option for first-line therapy. Nevertheless, particularly in good-risk patients by IMDC criteria, tyrosine-kinase inhibitors (TKI) may remain as an option for some patients. We reviewed our experience with TKI as first-line therapy for mRCC patients, trying to identify subgroups of patients that may still benefit from this strategy. MATERIAL AND METHODS: All patients with mRCC treated with first-line TKI, and adequate follow-up, in University Hospital La Paz (Madrid, Spain) between 2007 and 2020 were analyzed. Patients treated inside a clinical trial were excluded from this analysis. RESULTS: A total of 90 patients treated with first-line TKI were included. Regarding IMDC criteria, 33 patients (36.7%) were good-risk, 41 patients (45.5%) intermediate-risk, and 16 patients (17.8%) poor-risk. With a median follow-up of 49 months, the median overall survival (OS) for good, intermediate, and poor-risk patients was 54, 24, and 16 months (p = 0.004). When intermediate-risk was divided into patients with 1 or 2 risk factors, differences in OS were also statistically significant: patients with 1 risk factor had a median OS of 33 months, while patients with 2 risk factors had a median OS of 16 months, the same as poor-risk patients (p = 0.003). In the multivariate analysis, trying to find out which of the IMDC factors had a more remarkable weight in the prognosis of the patients, both ECOG and hemoglobin levels by themselves were significantly associated with OS. CONCLUSION: In our group of patients, survival outcomes were different among patients with intermediate-risk with 1 or 2 risk factors by IMDC criteria. These could help select patients that may benefit from first-line treatment with a TKI, particularly in settings with difficult access to novel therapies, such as immunotherapy-based combinations.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Tirosina/uso terapéuticoRESUMEN
BACKGROUND: Cancer is a risk factor for developing severe COVID19. Additionally, SARS-CoV2 has a special tropism for renal cells and complications like thrombosis or cytokine storm could be enhanced by standard treatments in kidney cancer (i.e., antiangiogenics or immunotherapy). Thus, understanding the impact of COVID19 in patients with this tumor is key for their correct management. METHODS: We designed a retrospective case-control study comparing the outcome of three groups of advanced kidney cancer patients on systemic treatment: cohort A (developed COVID19 while on antiangiogenics), cohort B (developed COVID19 while on immunotherapy) and cohort C (non-infected). Matching factors were age, gender, and treatment. RESULTS: 95 patients were recruited in 16 centers in Spain from September 2020 to May 2021. Finally, 85 were deemed as eligible (23 cohort A, 21 cohort B, 41 cohort C). Patients with COVID required more dose interruptions (25 vs. six) and hospitalizations (10 vs. none) than those without COVID (both p = 0.001). No difference between cohorts A and B was observed regarding hospitalization or length of stay. No ICU admission was registered and one patient in cohort B died due to COVID19. Regarding cancer evolution, three patients in cohort A presented progressive disease after COVID19 compared to two in cohort B. One case in cohort B, initially deemed as stable disease, achieved a partial response after COVID19. CONCLUSIONS: Kidney cancer patients who developed COVID19 while on systemic therapy required more treatment interruptions and hospitalizations than those non-infected. However, no significant impact on cancer outcome was observed. Also, no difference was seen between cases on antiangiogenics or immunotherapy.
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COVID-19 , Neoplasias Renales , Humanos , SARS-CoV-2 , Estudios de Casos y Controles , Estudios Retrospectivos , ARN Viral , Neoplasias Renales/terapia , InmunoterapiaRESUMEN
BACKGROUND: Preclinical and early clinical data suggest that the irreversible ErbB family blocker afatinib may be effective in urothelial cancers harbouring ERBB mutations. METHODS: This open-label, phase II, single-arm trial (LUX-Bladder 1, NCT02780687) assessed the efficacy and safety of second-line afatinib 40 mg/d in patients with metastatic urothelial carcinoma with ERBB1-3 alterations. The primary endpoint was 6-month progression-free survival rate (PFS6) (cohort A); other endpoints included ORR, PFS, OS, DCR and safety (cohorts A and B). Cohort A was planned to have two stages: stage 2 enrolment was based on observed antitumour activity. RESULTS: Thirty-four patients were enroled into cohort A and eight into cohort B. In cohorts A/B, PFS6 was 11.8%/12.5%, ORR was 5.9%/12.5%, DCR was 50.0%/25.0%, median PFS was 9.8/7.8 weeks and median OS was 30.1/29.6 weeks. Three patients (two ERBB2-amplified [cohort A]; one EGFR-amplified [cohort B]) achieved partial responses. Stage 2 for cohort A did not proceed. All patients experienced adverse events (AEs), most commonly (any/grade 3) diarrhoea (76.2%/9.5%). Two patients (4.8%) discontinued due to AEs and one fatal AE was observed (acute coronary syndrome; not considered treatment-related). CONCLUSIONS: An exploratory biomarker analysis suggested that basal-squamous tumours and ERBB2 amplification were associated with superior response to afatinib. CLINICAL TRIAL REGISTRATION: NCT02780687.
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Afatinib , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Afatinib/efectos adversos , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/genética , Mutación , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
BACKGROUND: The upfront treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by the introduction of immune-based combinations. The role of cytoreductive nephrectomy (CN) in these patients is still debated. The ARON-1 study (NCT05287464) was designed to globally analyze real-world data of mRCC patients receiving first-line immuno-oncology combinations. This sub-analysis is focused on the role of upfront or delayed partial or radical CN in three geographical areas (Western Europe, Eastern Europe, America/Asia). METHODS: We conducted a multicenter retrospective observational study in mRCC patients treated with first-line immune combinations from 55 centers in 19 countries. From 1152 patients in the ARON-1 dataset, we selected 651 patients with de novo mRCC. 255 patients (39%) had undergone CN, partial in 14% and radical in 86% of cases; 396 patients (61%) received first-line immune-combinations without previous nephrectomy. RESULTS: Median overall survival (OS) from the diagnosis of de novo mRCC was 41.6 months and not reached (NR) in the CN subgroup and 24.0 months in the no CN subgroup, respectively (P<0.001). Median OS from the start of first-line therapy was NR in patients who underwent CN and 22.4 months in the no CN subgroup (P<0.001). Patients who underwent CN reported longer OS compared to no CN in all the three geographical areas. CONCLUSIONS: No significant differences in terms of patients' outcome seem to clearly emerge, even if the rate CN and the choice of the type of first-line immune-based combination varies across the different Cancer Centers participating in the ARON-1 project.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Estudios Retrospectivos , Nefrectomía , Procedimientos Quirúrgicos de CitorreducciónRESUMEN
BACKGROUND: Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC). OBJECTIVE: The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients. PATIENTS AND METHODS: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB). RESULTS: A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p = 0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p < 0.001). CONCLUSIONS: Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations. CLINICAL TRIAL REGISTRATION: NCT05287464.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Estudios Retrospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Supervivencia sin ProgresiónRESUMEN
Introducción y objetivo: La enfermedad inducida por adyuvantes (EIA) secundaria a inyección de biopolímeros es reciente pero compleja, con un alto impacto en la mortalidad, la salud de los pacientes y en su calidad de vida. La percepción de enfermedad se considera un factor influyente para que los pacientes busquen ayuda y prevengan la evolución de la misma. El objetivo del presente estudio es evaluar cómo los pacientes con EIA por inyección ilícita de biopolímeros perciben su enfermedad y cómo el proceso de la enfermedad afecta a su calidad de vida. Material y método: Estudio descriptivo transversal utilizando el Cuestionario Brief IPQ que incluyó pacientes mayores de 18 años con inyecciones ilícitas de biopolímeros; fueron excluidos los pacientes con resección completa del biomaterial. Resultados: Un total de 441 mujeres con una edad media de 35 años respondieron a la encuesta. Observamos una asociación significativa entre mala percepción de la enfermedad y deterioro de la calidad de vida con la inyección ilícita de biopolímeros. Conclusiones: Nuestro estudio sugiere que la EIA por inyección ilícita de biopolímeros tiene un alto impacto en la calidad de vida de los pacientes. El uso ilegal de estos materiales es una práctica que no solo tiene repercusiones en la calidad de vida, sino que puede tener riesgos y consecuencias letales. (AU)
Background and objective: Adjuvant human disease (AHD) by injection of modeling substances is a relatively recent yet complex disease with a high impact on mortality, health of patients and their quality of life. Disease perception is considered an influential factor for patients to seek help and prevent disease evolution to detrimental outcomes. The objective of this study is to assess how patients with AHD by injection of illicit cosmetic biopolymers perceive their illness and how the disease process impacts their quality of life. Methods: Descriptive cross-sectional study using the Brief IPQ Questionnaire which included female patients with biopolymer injection. Inclusion criteria were patients older than 18 years with illicit cosmetic biopolymer injections; patients with complete surgical resection of the biomaterial were excluded. Results: A total of 441 females with a mean age of 35 years responded to the survey. A significant association between poor illness perception, quality of life deterioration, and illicit cosmetic biopolymer injection was observed. Conclusions: Our study suggests that AHD by injection of illicit cosmetic biopolymers has a high impact on the patient's quality of life. The illegal use of these materials is a practice that carries not only repercussions on quality of life but is considered to have life-threatening risks and lethal consequences. (AU)
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Humanos , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Calidad de Vida , Quimioterapia Adyuvante/efectos adversos , Biopolímeros , Epidemiología Descriptiva , Estudios Transversales , Encuestas y CuestionariosRESUMEN
BACKGROUND: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival. RESULTS: A total of 675 patients were included; BMI was >25 kg/m2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m2 versus those with BMI ≤25 kg/m2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI ≤25 kg/m2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002). CONCLUSION: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Índice de Masa Corporal , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios RetrospectivosRESUMEN
INTRODUCTION: The long-term clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) and a complete response (CR) to the tyrosine kinase inhibitor (TKI) sunitinib are poorly known. The characteristics of these patients could reveal previously undetected associations with clinical variables. PATIENTS AND METHODS: This observational, retrospective study (ATILA) used data from a registry of patients with mRCC who had received first-line sunitinib and had achieved CR from 2007 to 2018 in Spain. RESULTS: Sixty-two patients with CR were included; 48 patients (77.4%) received sunitinib in monotherapy and 14 (22.6%) combined with or followed by local treatment. Median age was 58.5 years (range, 32-81). Most patients (79.0%) had clear cell histology and had undergone previous nephrectomy (90.3%). The majority (70.2%) had an intermediate IMDC prognosis, 23% favorable and 7.0% poor. The median time on treatment with sunitinib was 28.2 months (IQR, 16.7-41.0) and the median time to CR was 10.9 months (IQR, 7.2-19.3). After a median follow-up of 8 years (range, 3-13 years), the median PFS was not reached. The overall median duration of complete response was 64.1 months (IQR, 32.2-99.4). The tolerance and safety profile of sunitinib was consistent with previous reports. CONCLUSION: Durable CR to sunitinib was observed in patients regardless the prognosis group, metastasis site or histology type, with 75% of patients remaining in CR after 10 years. CLINICALTRIALS: gov: NCT03916458.
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Antineoplásicos , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Persona de Mediana Edad , Sunitinib/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Antineoplásicos/uso terapéutico , Estudios Retrospectivos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Indoles/uso terapéutico , Pirroles/uso terapéuticoRESUMEN
INTRODUCTION: Docetaxel 75 mg/m2 every 3 weeks is the standard schedule for metastatic prostate cancer (mPC). Alternative dosing of 50 mg/m2 every 2 weeks may be an option for frail patients. Our aim is to define which factors influence the choice of schedule and to compare the outcomes of both schedules in daily clinical practice. PATIENTS AND METHODS: We retrospectively included patients with mPC treated with docetaxel in our institution. We compared data from patients treated with 3-weekly, 75 mg/m2 docetaxel or 2-weekly, 50 mg/m2 docetaxel, including basal characteristics, predefined prognostic factors, treatment received, toxicity and survival data. RESULTS: We included 200 patients, 86% of whom presented castration resistant mPC. A total of 158 patients (79%) were treated with 3-weekly scheme. Compared with these patients, patients treated with 2-weekly scheme were significantly older, had higher Eastern Cooperative Oncology Group performance status (ECOG PS) and Charlson Comorbidity Index, presented more visceral metastases and needed opioid treatment more frequently. Patients treated with 2-weekly scheme presented shorter median overall survival; however, these differences were not shown after multivariate analysis with significant prognostic factors. Patients treated with 2-weekly scheme had more treatment delays and suspensions, but less clinically impairing toxicities such as febrile neutropenia, neuropathy and diarrhea; toxic deaths were 5 in the 3-weekly group while none in the 2-weekly group. CONCLUSION: Compared to docetaxel 75 mg/m2 every 3 weeks, dosing of 50 mg/m2 every 2 weeks may be an alternative for older, frailer and more comorbid patients. Two-weekly dosing may be used more frequently in selected patients.
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Neoplasias de la Próstata , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/etiología , Estudios Retrospectivos , Taxoides/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. METHODS: Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). RESULTS: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. CONCLUSIONS: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.
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BACKGROUND: Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified. PATIENTS AND METHODS: Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs. disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed. RESULTS: In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data. CONCLUSIONS: This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Axitinib/uso terapéutico , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Estudios Retrospectivos , SunitinibRESUMEN
Objective To evaluate the better potential and functional results in pain control in the treatment of pathological fractures and prophylactic fixation with an intramedullary nail associated with polymethylmethacrylate, compared with the utilization of an intramedullary nail in long bone tumor lesions. Methods From January 2012 to September 2017, 38 patients with 42 pathological lesions (fractures or impending fractures according to the Mirels criteria) were treated surgically. Sixteen patients allocated to the control group underwent a locked intramedullary nail fixation, and 22 patients with pathological lesions were allocated to treatment with an intramedullary nail associated with polymethylmethacrylate. Postoperatively, the patients were submitted to the Musculoskeletal Tumor Society (MSTS) rating scale, radiographic assessment, and to the assessment of events and complications related to the treatment. Results The evaluation using the MSTS questionnaire showed better functional results in the group associated with polymethylmethacrylate, in comparison with the control group, which obtained an average score of 16.375 out of a maximum of 30 points (54.6%). The group studied with association with polymethylmethacrylate obtained a mean of 22.36 points (74.5%). The procedure proved to be safe, with similar complication and severity rates, and with no statistical difference in comparison with the standard treatment. Conclusion Stabilization of tumor lesions with an internal fixation associated with the polymethylmethacrylate demonstrated early rehabilitation and improved the quality of life, allowing rapid functional recovery. The use of polymethylmethacrylate has advantages such as reduced bleeding, tumor necrosis and higher mechanical stability.
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Introduction The COVID-19 pandemic generated many controversies in the management of critically ill pediatric patients. The main ones were about ventilatory support, phenotypic differences between adults and children, and acute and subacute clinical forms. For this reason, the Respiratory Committee (RC) of the Latin American Society of Pediatric Intensive Care (SLACIP) generated a document to summarize the recommendations with the best evidence. The objective of these recommendations is to provide an update on issues related to pediatric COVID-19. Methods and Materials The Respiratory Committee created a group composed of 19 pediatric kinesiologists/physiotherapists and intensivists from 8 Latin American countries and defined on 3/27/20 the 15 most relevant topics, assigning 3 referents and 2 reviewers for each. The manuscripts went through 4 stages until their final version. The complete document was freely distributed on 22/05/20 and updated twice (07/08/20 and 02/09/21). For the current version there were 3 special collaborators. Result The material consists of a complete 94-page document and an executive summary. The topics included are case definition, epidemiology, clinical classification, subacute inflammatory syndrome, personal protective equipment, aerosolization situations (intubation, extubation, suctioning, sampling, filter replacement, cardiopulmonary resuscitation, early mobilization), high flow cannula support, invasive, non-invasive and high frequency mechanical ventilation, pharmacological treatment, laboratory and imaging. Conclusion The purpose of this document is to serve as a guide for nurses, kinesiologists/physiotherapists and physicians in the management of critically ill pediatric patients with COVID-19.
Introducción La pandemia por COVID-19 generó muchas controversias en el manejo de los pacientes pediátricos críticos. Las principales fueron sobre el soporte ventilatorio, las diferencias fenotípicas entre adultos y niños y las formas clínicas aguda y subaguda.Por esa razón el Comité Respiratorio (CR) de la Sociedad Latinoamericana de Cuidados Intensivos Pediátricos (SLACIP) generó un documento para resumir las recomendaciones con mayor evidencia. El objetivo de estas recomendaciones es brindar una actualización de temas relacionados a COVID-19 pediátrico.Métodos y Materiales El Comité Respiratorio creó un grupo compuesto por 19 kinesiólogos/fisioterapeutas y médicos intensivistas pediátricos de 8 países de Latinoamérica y definió el 27/03/20 los 15 temas más relevantes, asignando 3 referentes y 2 revisores por cada uno. Los manuscritos pasaron por 4 etapas hasta su versión final. El documento completo se distribuyó libremente el 22/05/20, actualizándose en dos oportunidades (07/08/20 y el 02/09/21). Para la versión actual se contó con 3 colaboradores especiales.Resultado El material se compone de un documento completo de 94 páginas y un resumen ejecutivo. Los temas incluidos son definición de caso, epidemiología, clasificación clínica, síndrome inflamatorio subagudo, equipos de protección personal, situaciones de aerosolización (intubación, extubación, aspiración, toma de muestras, recambio de filtros, reanimación cardiopulmonar, movilización temprana), soporte con cánula de alto flujo, ventilación mecánica invasiva, no invasiva y de alta frecuencia, tratamiento farmacológico, laboratorio e imágenes.Conclusión La elaboración de este documento ha tenido como fin servir de guía para enfermeros, kinesiólogos/fisioterapeutas y médicos en el manejo de pacientes pediátricos en estado crítico por COVID-19.
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Abstract Objective To evaluate the better potential and functional results in pain control in the treatment of pathological fractures and prophylactic fixation with an intramedullary nail associated with polymethylmethacrylate, compared with the utilization of an intramedullary nail in long bone tumor lesions. Methods From January 2012 to September 2017, 38 patients with 42 pathological lesions (fractures or impending fractures according to the Mirels criteria) were treated surgically. Sixteen patients allocated to the control group underwent a locked intramedullary nail fixation, and 22 patients with pathological lesions were allocated to treatment with an intramedullary nail associated with polymethylmethacrylate. Postoperatively, the patients were submitted to the Musculoskeletal Tumor Society (MSTS) rating scale, radiographic assessment, and to the assessment of events and complications related to the treatment. Results The evaluation using the MSTS questionnaire showed better functional results in the group associated with polymethylmethacrylate, in comparison with the control group, which obtained an average score of 16.375 out of a maximum of 30 points (54.6%). The group studied with association with polymethylmethacrylate obtained a mean of 22.36 points (74.5%). The procedure proved to be safe, with similar complication and severity rates, and with no statistical difference in comparison with the standard treatment. Conclusion Stabilization of tumor lesions with an internal fixation associated with the polymethylmethacrylate demonstrated early rehabilitation and improved the quality of life, allowing rapid functional recovery. The use of polymethylmethacrylate has advantages such as reduced bleeding, tumor necrosis and higher mechanical stability.
Resumo Objetivo Avaliar o potencial melhor resultado funcional e controle álgico no tratamento de fraturas patológicas e fixações profiláticas tratadas com haste intramedular associada ao polimetilmetacrilato (PMMA) em comparação com o uso de haste intramedular em lesões tumorais em ossos longos. Métodos De janeiro de 2012 a setembro de 2017, 38 pacientes com 42 lesões patológicas (fraturas ou iminência segundo os critérios de Mirels) foram tratados cirurgicamente. Dezesseis pacientes submetidos a fixação com haste intramedular bloqueada foram alocados ao grupo controle e 22 pacientes com lesões patológicas foram alocados para tratamento com haste intramedular associada ao PMMA. No pósoperatório, foi realizada a submissão dos pacientes ao escore da Musculoskeletal Tumor Society (MSTS, na sigla em inglês) e à avaliação radiográfica do tratamento realizado, assim como à avaliação de intercorrências e complicações relacionadas ao tratamento. Resultados A avaliação através do questionário MSTS demonstrou melhor resultado funcional do grupo associado com PMMA quando comparado com o grupo controle, o qual obteve uma pontuação média de 16,375 em um máximo de 30 pontos (54,6%), enquanto o grupo em estudo com associação do PMMA obteve uma média de 22,36 pontos (74,5%). O procedimento mostrou-se seguro, taxas de complicações e gravidade semelhantes e sem diferença estatística quando comparado com o tratamento padrão. Conclusão A estabilização de lesões tumorais com fixação associada ao PMMA demonstrou reabilitação precoce e melhora na qualidade de vida, permitindo rápida recuperação funcional. A utilização do PMMA apresenta vantagens como diminuição do sangramento e da necrose tumoral e maior estabilidade mecânica.