Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: a GEICO phase II trial (ROLANDO study)

Inhibidor de PARP; Olaparib; Càncer d'ovari recurrent resistent al platíInhibidor de PARP; Olaparib; Cáncer de ovario recurrente resistente al platinoPARP inhibitor; Olaparib; Platinum-resistant recurrent ovarian cancerBackground There is limited evidence for the benefit of olaparib in platinum-resistant ovarian cancer (PROC) patients with BRCA wild-type tumors. This study investigated whether this combination of a DNA-damaging chemotherapy plus olaparib is effective in PROC regardless BRCA status. Patients and methods Patients with high-grade serous or endometrioid ovarian carcinoma and one previous PROC recurrence were enrolled regardless of BRCA status. Patients with ≤4 previous lines (up to 5 in BRCA-mut) with at least one previous platinum-sensitive relapse were included; primary PROC was allowed only in case of BRCA-mut. Patients initially received six cycles of olaparib 300 mg b.i.d. (biduum) + intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m2 (PLD40) every 28 days, followed by maintenance with olaparib 300 mg b.i.d. until progression or toxicity. The PLD dose was reduced to 30 mg/m2 (PLD30) due to toxicity. The primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS) by RECIST version 1.1. A proportion of 40% 6m-PFS or more was considered of clinical interest. Results From 2017 to 2020, 31 PROC patients were included. BRCA mutations were present in 16%. The median of previous lines was 2 (range 1-5). The overall disease control rate was 77% (partial response rate of 29% and stable disease rate of 48%). After a median follow-up of 10 months, the 6m-PFS and median PFS were 47% and 5.8 months, respectively. Grade ≥3 treatment-related adverse events occurred in 74% of patients, with neutropenia/anemia being the most frequent. With PLD30 serious AEs were less frequent than with PLD40 (21% versus 47%, respectively); moreover, PLD30 was associated with less PLD delays (32% versus 38%) and reductions (16% versus 22%). Conclusions The PLD–olaparib combination has shown significant activity in PROC regardless of BRCA status. PLD at 30 mg/m2 is better tolerated in the combination.This work was supported by Grupo Español de Investigación en Cáncer de Ovario (GEICO) (no grant number). AstraZeneca provided olaparib and awarded a grant to GEICO (no grant number) to pay the costs of the study but did not take part in the conduct of the current clinical trial or in the analysis and interpretation of the results. Pegylated ribosomal doxorubicin was provided by the sites according to local standard procedures

Fetal sex modulates developmental response to maternal malnutrition

The incidence of obesity and metabolic diseases is dramatically high in rapidly developing countries. Causes have been related to intrinsic ethnic features with development of a thrifty genotype for adapting to food scarcity, prenatal programming by undernutrition, and postnatal exposure to obesogenic lifestyle. Observational studies in humans and experimental studies in animal models evidence that the adaptive responses of the offspring may be modulated by their sex. In the contemporary context of world globalization, the new question arising is the existence and extent of sex-related differences in developmental and metabolic traits in case of mixed-race. Hence, in the current study, using a swine model, we compared male and female fetuses that were crossbred from mothers with thrifty genotype and fathers without thrifty genotype. Female conceptuses evidence stronger protective strategies for their adequate growth and postnatal survival. In brief, both male and female fetuses developed a brain-sparing effect but female fetuses were still able to maintain the development of other viscerae than the brain (mainly liver, intestine and kidneys) at the expense of carcass development. Furthermore, these morphometric differences were reinforced by differences in nutrient availability (glucose and cholesterol) favoring female fetuses with severe developmental predicament. These findings set the basis for further studies aiming to increase the knowledge on the interaction between genetic and environmental factors in the determination of adult phenotype

SEOM clinical guideline in ovarian cancer (2020)

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice

World Heart Federation consensus on transthyretin amyloidosis cardiomyopathy (ATTR-CM)

COPYRIGHT: © 2023 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/ licenses/by/4.0/.Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients' perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients' perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis.info:eu-repo/semantics/publishedVersio

World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients’ perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients’ perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis

Solos das áreas-piloto do Projeto BiosBrasil (Conservation and Sustainable Management of Below-Ground Biodiversity: phase I), Município de Benjamin Constant, Estado do Amazonas.

Este trabalho relata a variação dos atributos físicos, químicos, morfológicos e mineralógicos dos solos descritos e coletados em seis áreas-piloto situadas no município de Benjamin Constant, região noroeste do estado do Amazonas. É parte integrante do projeto BiosBrasil (Conservation and sustainable management of below-ground biodiversity project: phase I), cujo objetivo principal é melhorar a percepção, o conhecimento e o entendimento da biodiversidade dos solos da Amazônia. Cada área-piloto, denominada de Janela no âmbito do projeto, caracteriza- se por apresentar uma extensão aproximada de nove hectares, com pontos eqüidistantes, estaqueados a cada 100 m, formando uma malha de amostragem onde foram realizados estudos físicos, químicos e, principalmente, biológicos do solo. As Janelas são áreas descontínuas, selecionadas em função do uso e cobertura do solo representativos da região. Estão inseridas no compartimento geológico da Formação Solimões, caracterizada por sedimentos flúvio-lacustres de idade terciária (argilitos vermelhos e cinzas, siltitos e arenitos, com camadas de conchas e de linhito). Seu relevo varia de plano, nos topos de morrotes curtos e alongados, e nas planícies aluviais, a suave ondulado e ondulado nas demais posições da paisagem. O tipo climático predominante é Af, segundo a classificação de Köppen, com temperatura e pluviosidade médias anuais de, respectivamente, 25,7 ºC e 2.562 mm. Cambissolos constituem os solos dominantes nas áreas estudadas, seguidos dos Gleissolos e Alissolos. Em comum, manifestam elevados e anormais teores de alumínio extraível, com valores que variam de 0,0 a 14,6 cmolc/kg de solo em superfície e de 0,0 a 25,2 cmolc/kg de solo em profundidade, podendo ou não apresentar elevados conteúdos de Ca e Mg, com valores médios em superfície de, respectivamente, 4,6 e 1,4 cmolc/kg de solo. A despeito do elevado conteúdo de Al extraído por KCl 1N, que pode ou não estar relacionado com a atividade do elemento em solução, a pequena profundidade do solum, os elevados teores de silte e presença de filossilicatos 2:1 evidenciam sua maior jovialidade em relação à grande maioria dos solos de terra firme já descritos e mapeados na bacia Amazônica, os quais influenciam sobremaneira suas propriedades morfológicas, químicas, físicas, hidro e biológicas, bem como seu comportamento frente aos diferentes usos e práticas de manejo.bitstream/CNPS-2010/14884/1/bpd67-2005-solos-area-piloto-projbios-br.pd

Levantamento pedológico de uma área-piloto relacionada ao Projeto BiosBrasil (Conservation and Sustainable Management of Below-Ground Biodiversity: Phase I), Município de Benjamin Constant (AM): janela 6.

Um pré-requisito decisivo para a seleção e implantação de áreas de pesquisa é o conhecimento preciso da distribuição dos solos na paisagem e de suas propriedades. Isso só é obtido com um levantamento pedológico. O presente trabalho é um relato dos solos identificados no levantamento pedológico de uma área-piloto denominada de Janela 6. É parte integrante de um projeto maior, cujo objetivo é melhorar a percepção, o conhecimento e o entendimento da biodiversidade dos solos da Amazônia. Abrangendo aproximadamente 9,3 hectares, a Janela 6 situase no município de Benjamin Constant, localizada a noroeste do Estado do Amazonas, entre as coordenadas geográficas (UTM) 9.514.396 e 9.514.076 m de latitude sul e 386.922 e 387.327 m de longitude oeste. Está inserida no compartimento geológico da Formação Solimões, caracterizada por sedimentos flúviolacustres de idade terciária (argilitos vermelhos e cinzas, siltitos e arenitos, com camadas de conchas e de linhito). O relevo varia de plano, nos topos de morrotes curtos e alongados, e nas planícies aluviais, a suave ondulado e forte ondulado, nas demais posições da paisagem. O tipo climático predominante é Af, segundo a classificação de Köppen, com temperatura e pluviosidade médias anuais de, respectivamente, 25,7ºC e 2.562 mm. Os Cambissolos e Gleissolos são as classes de solos detalhadamente descritas e mapeadas na área. As variações de relevo, drenagem interna do perfil, classe textural e associação com os Gleissolos permitiram separar os Cambissolos da área em seis unidades de mapeamento, as quais se distribuem por aproximadamente 95% de toda a Janela 6. Em comum, esses Cambissolos manifestam elevados e anormais teores de alumínio extraível, com valores que variam de 1,4 a 9,6 cmolc/kg de solo em superfície e de 4,7 a 15,3 cmolc/kg de solo em profundidade. Seus elevados teores de silte e presença de filossilicatos 2:1 evidenciam sua maior jovialidade em relação à grande maioria dos solos já descritos e mapeados na bacia Amazônica, os quais influenciam sobremaneira suas propriedades morfológicas, químicas, físicas, hidro e biológicas, bem como seu comportamento frente aos diferentes usos e práticas de manejo.bitstream/CNPS-2010/14883/1/bpd68-2005-area-piloto-proj-bios-br.pd

Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study

Bladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70-75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. TERT promoter mutations and FGFR3 hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor®, capable of detecting trace amounts of TERT promoter (c.1-124C > T and c.1-146C > T) and FGFR3 (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.info:eu-repo/semantics/publishedVersio

The management of cytotoxic chemotherapy extravasation: A systematic review of the literature to evaluate the evidence underpinning contemporary practice

Management of cytotoxic drug extravasation remains contentious, with differing views on the most effective management strategy. With the increasing drive to provide effective, evidence-based healthcare, while ensuring the patient experience of the treatment provided plays a significant part in the development of clinical practice guidelines, the purpose of this literature review was to both critically analyse the quality of evidence that underpins contemporary practice and to determine if the patient experience is taken into account. A literature search was undertaken sourcing publications from the 1960s to July 2014 identifying all studies detailing strategies aimed at preventing the need for surgical debridement and all studies evaluating extravasation management from the patient's perspective. No conclusive evidence was found to suggest one clinical strategy as more effective than the other. No studies were identified that evaluated outcome from the patient's perspective. It is therefore suggested that outcomes-based research should underpin contemporary extravasation management guidelines to determine what the final outcome or 'end result' is and how this impacts on the patient and that the current lack of research into the patient experience of extravasation management is an area that needs to be addressed