Exploratory analysis of radiomic as prognostic biomarkers in 18F-FDG PET/CT scan in uterine cervical cancer.

Objective: To evaluate the performance of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) radiomic features to predict overall survival (OS) in patients with locally advanced uterine cervical carcinoma. Methods: Longitudinal and retrospective study that evaluated 50 patients with cervical epidermoid carcinoma (clinical stage IB2 to IVA according to FIGO). Segmentation of the 18F-FDG PET/CT tumors was performed using the LIFEx software, generating the radiomic features. We used the Mann-Whitney test to select radiomic features associated with the clinical outcome (death), excluding the features highly correlated with each other with Spearman correlation. Subsequently, ROC curves and a Kaplan-Meier analysis were performed. A p-value < 0.05 were considered significant. Results: The median follow-up was 23.5 months and longer than 24 months in all surviving patients. Independent predictors for OS were found-SUVpeak with an AUC of 0.74, sensitivity of 77.8%, and specificity of 72.7% (p = 0.006); and the textural feature gray-level run-length matrix GLRLM_LRLGE, with AUC of 0.74, sensitivity of 72.2%, and specificity of 81.8% (p = 0.005). When we used the derived cut-off points from these ROC curves (12.76 for SUVpeak and 0.001 for GLRLM_LRLGE) in a Kaplan-Meier analysis, we can see two different groups (one with an overall survival probability of approximately 90% and the other with 30%). These biomarkers are independent of FIGO staging. Conclusion: By radiomic 18F-FDG PET/CT data analysis, SUVpeak and GLRLM_LRLGE textural feature presented the best performance to predict OS in patients with cervical cancer undergoing chemo-radiotherapy and brachytherapy.

Parkinson's disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein-induced changes in maturation and immune reactive properties.

SignificanceOur results demonstrate the existence of early cellular pathways and network alterations in oligodendrocytes in the alpha-synucleinopathies Parkinson's disease and multiple system atrophy. They further reveal the involvement of an immune component triggered by alpha-synuclein protein, as well as a connection between (epi)genetic changes and immune reactivity in multiple system atrophy. The knowledge generated in this study could be used to devise novel therapeutic approaches to treat synucleinopathies.

Characteristics of patients diagnosed with cervical cancer in Brazil: preliminary results of the prospective cohort EVITA study (EVA001/LACOG 0215).

OBJECTIVES: Cervical cancer is the fourth most common cancer in women worldwide. Epidemiological and quality of life (QoL) data in patients with cervical cancer from low- and middle-income countries are scarce. We aimed to describe sociodemographic and clinicopathological characteristics and quality of life of patients with cervical cancer at diagnosis in Brazil. METHODS: EVITA is a prospective cohort study of newly diagnosed patients with cervical cancer from May 2016 to December 2017, stages I-IVB, from 16 Brazilian sites representing the five Brazilian regions. At baseline, medical evaluation was performed and European Organization for Research and Treatment of Cancer (EORTC) QLQ-CX24/C30 questionnaires were administered. RESULTS: A total of 631 patients were included. Mean±SD age was 49.3±13.9 years; skin color was non-white in 65.3%, and 68.0% had ≤8 years of formal education. In total, 85.1% of patients had a Pap smear. The main reasons reported by patients for not having a Pap smear were: lack of interest (46.9%), shame or embarrassment (19.7%), lack of knowledge (19.7%), and difficulty with access (9.1%). Most patients were diagnosed with locally advanced or metastatic disease (FIGO clinical stage II-IV in 81.8%- stage II in 35.2%, stage III in 36.1%, and stage IV in 10.5%). Patients with clinical stage III-IV had worse physical functioning and role functioning. CONCLUSIONS: Cervical cancer in Brazil is usually diagnosed at an advanced stage. Most patients have low formal education and are unemployed. Lack of interest was identified as a main reason for not having a screening test, and limited access was reported as a reason by <10% of the patients. Awareness campaigns must be a governmental priority, specially focused on the needy population, along with wide access to treatment.

Phase II study of the safety and efficacy of the anti-PD-1 antibody balstilimab in patients with recurrent and/or metastatic cervical cancer.

OBJECTIVE: This phase II clinical trial evaluated the safety and antitumor activity of balstilimab, an anti-PD-1 antibody, in patients with previously-treated, recurrent/metastatic cervical cancer. METHODS: Eligible patients were 18 years or older with recurrent and/or metastatic cervical cancer and who had relapsed after a prior platinum-based treatment regimen for advanced disease. Balstilimab was administered intravenously at 3 mg/kg once every two weeks, for up to 24 months. The primary endpoint was objective response rate (ORR, RECIST v1.1) as assessed by an independent review committee. RESULTS: At data cutoff, 161 women (median age, 53 years [range 25-81]) were enrolled and treated with balstilimab. Of these, 140 had measurable disease at baseline and one prior line of platinum-based therapy in the metastatic, persistent, or recurrent setting; these patients were included in the efficacy analyses. The ORR was 15% (95% CI, 10.0%-21.8%) and included 5 patients with a complete response and 16 with a partial response. The median duration of response was 15.4 months. In patients with PD-L1-positive tumors the ORR was 20%, however patients with PD-L1-negative tumors also responded to balstilimab (ORR, 7.9%). Responses were not restricted to tumors of squamous cell histology, and an ORR of 12.5% was seen in the subset of patients with cervical adenocarcinoma. The disease control rate was 49.3% (95% CI, 41.1%-57.5%). Immune-mediated enterocolitis (3.1%) and diarrhea (1.9%) were the most common grade 3 or higher treatment-related adverse events. CONCLUSION: Balstilimab demonstrated meaningful and durable clinical activity, with manageable safety, in patients with previously-treated, recurrent/metastatic cervical cancer.

Higher severity and risk of in-hospital mortality for COVID-19 patients with cancer during the year 2020 in Brazil: A countrywide analysis of secondary data.

BACKGROUND: Coronavirus disease 2019 (COVID-19) and cancer are serious public health problems worldwide. However, little is known about the risk factors of in-hospital mortality among COVID-19 patients with and without cancer in Brazil. The objective of this study was to evaluate the risk factors of in-hospital mortality among COVID-19 patients with and without cancer and to compare mortality according to gender and topography during the year 2020 in Brazil. METHODS: This was a secondary data study of hospitalized adult patients with a diagnosis of COVID-19 by real-time polymerase chain reaction testing in Brazil. The data were collected from the Influenza Epidemiological Surveillance Information System. RESULTS: This study analyzed data from 322,817 patients. The prevalence of cancer in patients with COVID-19 was 2.3%. COVID-19 patients with neurological diseases and cancer had the most lethal comorbidities in both sexes. COVID-19 patients with cancer were more likely to be older (median age, 67 vs 62 years; P < .001), to have a longer hospital stay (13.1 vs 11.5 days; P < .001), to be admitted to the intensive care unit (45.3% vs 39.6%; P < .001), to receive more invasive mechanical ventilation (27.1% vs 21.9%), and to have a higher risk of death (adjusted odds ratio [aOR], 1.94; 95% confidence interval [CI], 1.83-2.06; P < .001) than those without cancer. Patients with hematological neoplasia (aOR, 2.85; 95% CI, 2.41-3.38; P < .001) had a higher risk of mortality than those with solid tumors (aOR, 1.83; 95% CI, 1.72-1.95; P < .001) in both sexes. CONCLUSIONS: Brazilian COVID-19 patients with cancer have higher disease severity and a higher risk of mortality than those without cancer.

TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration.

Here, we examine the cellular changes triggered by tumor necrosis factor alpha (TNF-α) and different alpha-synuclein (αSYN) species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNF-α display a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the nuclear factor κB (NF-κB) pathway, and release of pro-inflammatory cytokines, whereas those treated with high-molecular-weight αSYN fibrils acquire a reactive antigen (cross)-presenting phenotype with upregulation of major histocompatibility complex (MHC) genes and increased human leukocyte antigen (HLA) molecules at the cell surface. Surprisingly, the cell surface location of MHC proteins is abrogated by larger F110 fibrillar polymorphs, despite the upregulation of MHC genes. Interestingly, TNF-α and αSYN fibrils compete to drive the astrocyte immune reactive response. The astrocyte immune responses are accompanied by an impaired mitochondrial respiration, which is exacerbated in Parkinson's disease (PD) astrocytes. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.

QTest: A new way to easily sample, store, and ship samples to perform Q fever PCR analysis on bulk tank milk.

Bulk tank milk (BTM) is an easy, inexpensive, and representative sample for detection of Coxiella burnetii infections (Q fever) in dairy herds using real-time PCR. Bulk tank milk PCR can be performed either for initial herd screening or for monitoring the effectiveness of preventive measures. However, one major limitation under field conditions is the need to deliver BTM samples in adequate condition (quickly, safely, and under refrigeration) to a qualified laboratory. In addition, sending non-inactivated biological samples via normal mail may be prohibited. We developed an innovative, easy, and accurate diagnostic tool (QTest) for Q fever to support veterinarians and farmers in overcoming these constraints. The farmer or veterinarian simply places some drops of BTM on a Whatman FTA Elute Micro Card (FTA card) and lets the card dry before mailing it to the laboratory. In a 2-step study, we tested the hypotheses that (1) BTM samples stored on FTA cards are stable over time and at different temperatures, and (2) PCR results obtained via FTA cards are consistent with those obtained from raw BTM samples. The stability of C. burnetii DNA in milk preserved on an FTA card was maintained for at least 29 d at room temperature or 37°C to mimic field conditions. In our field study, of the original 70 positive BTM samples (when tested on raw BTM just after sampling), 58 samples were positive (on either raw BTM or FTA card) by the time of the direct comparison study (10 to 14 d later). Of these 58 samples, 45 raw BTM samples still tested positive after aging, and 53 FTA card BTM samples tested positive, indicating that detection was higher using FTA cards (91.4%) than raw milk (77.6%). Therefore, with inactivation and shipping advantages, this technique facilitates an easier and more practical approach to diagnosis of Q fever at the herd level and would support Q fever control strategies, especially in countries lacking adequate and close laboratory facilities.

Intervenção comunitária recovery: Impacto na qualidade de vida, suporte social e satisfação de necessidades da pessoa com doença mental / Community intervention & recovery: Impact on quality of life, social support and needs' satisfaction of the person with mental illness / Intervención comunitaria & recuperación: Impacto en la calidad de vida, soporte social y satisfación de las necesidades de la persona con enfermedad mental

CONTEXTO: O recovery é entendido como um processo subjetivo que pressupõe as dimensões clínica e pessoal. Os programas de intervenção comunitária na promoção do recovery devem basear-se em aspetos importantes como a qualidade de vida, suporte social e necessidades. OBJETIVOS: Avaliar o impacto de um programa de intervenção individualizado na qualidade de vida, suporte social e satisfação das necessidades, em pessoas com doença mental. MÉTODOS: Estudo quase-experimental com desenho antes-após de grupo único, com três momentos de avaliação com 16 sessões implementadas durante 4 meses. A amostra é constituída por 25 pessoas com doença mental selecionadas a partir da alta clínica de um hospital psiquiátrico da região Norte de Portugal. Utilizaram-se como instrumentos: Questionário de Avaliação Sociodemográfica e Clínica; Instrumento de Avaliação de Necessidades, construídos pelos investigadores; EQ-5D e; Escala de Satisfação com o Suporte Social. A Investigação foi aprovada pela Comissão de Ética da instituição onde foram recolhidos os dados. Foi utilizado o SPSS, versão 25.0, com recurso a medidas descritivas e testes de diferenças de médias não paramétricos - Friedman e de Wilcoxon - com um valor de significância de p<.05. RESULTADOS: Verificou-se uma evolução positiva relativamente às variáveis avaliadas, com diferenças estatisticamente significativas ao longo dos três momentos de avaliação para: qualidade de vida - EQ-5D; Dimensão Doença do IAN, e Dimensão Ambiente. CONCLUSÕES: Intervir no recovery da pessoa com doença mental é uma intervenção morosa e exigente, mas com resultados positivos desde que a intervenção seja direcionada às necessidades das pessoas.

BACKGROUND: Recovery is understood as a subjective process that presupposes clinical and personal dimensions. Community intervention programs in the promotion of recovery should be based on important aspects such as their needs, quality of life and social support. AIM: To evaluate the impact of an individualized intervention program on quality of life, social support and needs satisfaction in people with mental illness. METHODS:Quasi-experimental study with before-after design of single group, with three evaluation moments with 16 sessions implemented during 4 months. The sample consists of 25 people with mental illness selected from the high clinic of a psychiatric hospital in the Northern region of Portugal. The sociodemographic and clinical evaluation questionnaire, the Needs Assessment Instrument (NAI)., constructed by the researchers, the EQ-5D and the Social Support Satisfaction Scale were used as instruments. The investigation was approved by the Ethics Committee of the institution where the data were collected. SPSS, version 25.0 was used, using descriptive measures and tests of non-parametric mean differences - Friedman and Wilcoxon - with a significance level of p<.05. RESULTS: There was a positive evolution regarding the evaluated variables, with statistically significant differences during the three evaluation moments for: quality of life - EQ-5D; Dimension Disease of the NAI, and Environment Dimension. CONCLUSIONS: Intervening in the recovery of the person with mental illness is a time-consuming and demanding intervention, but with positive results if the intervention is directed to the needs of the people.

CONTEXTO:La recuperación es un proceso subjetivo que presupone las dimensiones clínica y personal. Los programas de intervención comunitaria en la recuperación deben basarse en la calidad de vida, el apoyo social y las necesidades. OBJETIVOS: Evaluar el impacto de un programa de intervención individualizado en la calidad de vida, apoyo social y satisfacción de las necesidades, en personas con enfermedad mental. METODOLOGÍA: Estudio casi experimental con diseño antes-después de grupo único, con tres momentos de evaluación con 16 sesiones implementadas durante 4 meses. La muestra se compone de 25 personas con enfermedad mental seleccionados a partir del alta clínica de un hospital psiquiátrico en el norte de Portugal.Se utilizaron como instrumentos un cuestionario sociodemográfico y clínico, el Instrumento de Evaluación de Necesidades, construidos por los investigadores, el EQ-5D y la Escala de Satisfacción con el soporte social. La investigación fue aprobada por la Comisión de Ética de la institución donde se recogieron los datos. Se utilizó el SPSS, versión 25.0, con medidas descriptivas y pruebas de diferencias de promedios no paramétricos - Friedman y Wilcoxon - con un valor de significancia de p<.05. RESULTADOS: Se observó una evolución positiva con respecto a las variables evaluadas, con diferencias estadísticamente significativas a lo largo de los tres momentos de evaluación para: calidad de vida - EQ-5D; Dimensión de la enfermedad del IAN, y la dimensión ambiental. CONCLUSIONES: Intervenir en la recuperación de la persona con enfermedad mental es algo moroso y exigente, pero con resultados positivos desde que la intervención se dirija a las necesidades de las personas.

Generation of an induced pluripotent stem cell line (CSC-32) from a patient with Parkinson's disease carrying a heterozygous variation p.A53T in the SNCA gene.

Here, we describe the generation of an induced pluripotent stem cell (iPSC) line, from a male patient diagnosed with Parkinson's disease (PD). The patient carries a heterozygous variation p.A53T in the SNCA gene. Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver OCT3/4, SOX2, c-MYC and KLF4 factors. The generated iPSC line (CSC-32) preserved the mutation, displayed expression of common pluripotency markers, differentiated into derivatives of the three germ layers, and exhibited a normal karyotype. The clone CSC-32B is presented thereafter; it can be used to study the mechanisms underlying PD pathogenesis.

Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene.

Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson's disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1Q811R) variant midbrain dopaminergic neuron-containing spheroids (MDNS) from a female patient who developed early-onset PD, and compared them to cultures derived from a healthy control of the same gender. Both POLG1 variant and control MDNS contained functional midbrain regionalized TH/FOXA2-positive dopaminergic neurons, capable of releasing dopamine. Western blot analysis identified the presence of high molecular weight oligomeric alpha-synuclein in POLG1Q811R MDNS compared to control cultures. In order to assess POLG1Q811R-related cellular alterations within the MDNS, we applied mass-spectrometry based quantitative proteomic analysis. In total, 6749 proteins were identified, with 61 significantly differentially expressed between POLG1Q811R and control samples. Pro- and anti-inflammatory signaling and pathways involved in energy metabolism were altered. Notably, increased glycolysis in POLG1Q811R MDNS was suggested by the increase in PFKM and LDHA levels and confirmed using functional analysis of glycolytic rate and oxygen consumption levels. Our results validate the use of iPSCs to assess cellular alterations in relation to PD pathogenesis, in a unique PD patient carrying a novel p.Q811R variation in POLG1, and identify several altered pathways that may be relevant to PD pathogenesis.

PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons.

The protein parkin, encoded by the PARK2 gene, is vital for mitochondrial homeostasis, and although it has been implicated in Parkinson's disease (PD), the disease mechanisms remain unclear. We have applied mass spectrometry-based proteomics to investigate the effects of parkin dysfunction on the mitochondrial proteome in human isogenic induced pluripotent stem cell-derived neurons with and without PARK2 knockout (KO). The proteomic analysis quantified nearly 60% of all mitochondrial proteins, 119 of which were dysregulated in neurons with PARK2 KO. The protein changes indicated disturbances in oxidative stress defense, mitochondrial respiration and morphology, cell cycle control, and cell viability. Structural and functional analyses revealed an increase in mitochondrial area and the presence of elongated mitochondria as well as impaired glycolysis and lactate-supported respiration, leading to an impaired cell survival in PARK2 KO neurons. This adds valuable insight into the effect of parkin dysfunction in human neurons and provides knowledge of disease-related pathways that can potentially be targeted for therapeutic intervention.

Canine Rabies in the Brazil-Bolivia Border Region from 2006 to 2014.

BACKGROUND: After 2006 the cross-border region between the state of Mato Grosso do Sul (Brazil) and the Germán Busch Province (Bolivia) became risk areas for canine rabies antigenic variant 1, previously unknown in the Brazilian territory. OBJECTIVES: To perform a descriptive analysis of canine rabies from 2006 to 2014, analyzing the database of the official rabies diagnostic laboratory of the State Agency of Animal and Plant Health Protection of Mato Grosso do Sul. METHODS: A descriptive analysis of canine rabies from 2006 to 2014 was performed using the database of the official rabies diagnostic laboratory of the State Agency of Animal and Plant Health Protection of Mato Grosso do Sul. Location, time and residence status of the animals were analyzed. Monthly frequencies were calculated as the ratio of the number of positive samples to the total of sent samples and were then statistically compared. FINDINGS: In the period, 539 samples of nervous system from dogs and cats were sent for rabies diagnosis, of which 37 (6.9%; CI95% 5.0-9.3) canine and no positive feline samples were found positive. Twenty-four (64.9%, CI95% 48.8-78.2) positive samples were from Bolivia and 13 (31.1%, CI95% 21.8-51.2) from Brazil. Most positive animals were owned. The years 2008 and 2009 showed the highest occurrence of canine rabies, with 18 cases recorded in 2008 and 6 in 2009 (17 in Bolivia and 7 in Brazil). Annual samples sent in Brazil presented a decreasing trend (R2 = 0.53) and, over the months, a higher concentration of samples was observed between May and August (R2 = 0.69). No annual or monthly trends were observed for Bolivian samples (R2 < 0.003). CONCLUSIONS: AgV1 canine rabies due to antigenic variant 1 is still considered an endemic disease in the Brazil-Bolivia border region, requiring an international One Health Approach to mitigate canine rabies in Latin America.

Generation of an induced pluripotent stem cell line (CSC-46) from a patient with Parkinson's disease carrying a novel p.R301C mutation in the GBA gene.

Mutations in the glucocerebrosidase (GBA) gene have been associated with the development of Parkinson's disease (PD). An induced pluripotent stem cell (iPSC) line was generated from a 60-year old patient diagnosed with PD and carrying a new mutation variant p.R301C in GBA. Using non-integrating Sendai virus-based technology, we utilized OCT3/4, SOX2, c-MYC and KLF4 transcription factors to reprogram skin fibroblasts into iPSCs. The generated iPSC line retained the mutation, displayed expression of common pluripotency markers, differentiated into the three germ layers, and exhibited normal karyotype. The iPSC line can be further used for studying PD pathogenesis.

Padrões de tratamento, uso de recursos e custo do câncer de pulmão de não pequenas células avançado em instituições brasileiras privadas / Treatment patterns, resource use and cost-of-illness of advanced non-small lung cancer in Brazilian private institutions

Objetivo: No Brasil, dados clínicos e custos econômicos do câncer de pulmão de não pequenas células (CPNPC) são escassos. Portanto, conduzimos este estudo para coletar dados de mundo real sobre padrões de tratamento e uso de recursos para CPNPC avançado (CPNPCa) em pacientes em instituições privadas brasileiras. Métodos: Coletamos dados de prontuários de seis instituições privadas no Brasil. Os pacientes elegíveis tinham diagnóstico de CPNPC avançado ou recorrente (estágios IIIB e IV) entre janeiro de 2011 e julho de 2014, e haviam recebido pelo menos duas linhas de quimioterapia. Dados foram resumidos usando estatísticas descritivas e os custos foram estimados pela abordagem bottom-up. Resultados: Dos 430 pacientes selecionados, 152 foram elegíveis para coleta de dados. A idade mediana dos pacientes foi de 62 anos e 55,9% eram do sexo masculino. Entre os pacientes, 57,2% e 31,6% receberam três e quatro linhas de tratamento, respectivamente. Dezesseis e vinte regimes foram utilizados como tratamentos de primeira e segunda linha. Bevacizumabe carboplatina + paclitaxel (n = 32; 21,1%) foi o mais frequente na primeira linha, enquanto docetaxel isolado (n = 36; 23,7%) foi o regime mais comum de segunda linha. Hospitalizações e visitas ao pronto-socorro foram registradas em 52% e 25% dos pacientes, respectivamente. O custo total da coorte foi de R$ 47.692.195,1 (US$ 14.803.425,4). Conclusões: Os padrões de tratamento para pacientes com CPNPCa em instituições privadas brasileiras são heterogêneos. O alto uso e custos de recursos observados entre os pacientes da CPNPCa têm um impacto econômico significativo para o sistema de saúde privado brasileiro.

Objective: In Brazil, data on clinical and economic burden of non-small cell lung cancer (NSCLC) are scarce. Therefore, we conducted this study to gather real-world data on treatment patterns and resource use for advanced NSCLC (aNSCLC) patients in Brazilian private institutions. Methods: We collected data from medical charts from six private institutions in Brazil. Eligible patients were diagnosed with advanced or recurrent NSCLC (stages IIIB and IV) between January 2011 and July 2014, and had received at least two lines of chemotherapy. Data were summarized using descriptive statistics and costs estimated by bottom-up approach. Results: Out of 430 charts screened, 152 were eligible for data collection. Patients' median age was 62 years, 55.9% were male. Among patients, 57.2% and 31.6% had received three and four treatment lines, respectively. Sixteen and twenty regimens were used as first and second-line treatments, respectively. Bevacizumab + carboplatin + paclitaxel (n = 32; 21.1%) was the most frequent first-line regimens, while docetaxel (n = 36; 23.7%) the most common second-line regimen. Hospitalizations and ER visits were recorded from 52% and 25% of the patients, respectively. Total cohort costs were R$ 47,692,195.1 (US$ 14,803,425.4). Conclusions: Treatment patterns for patients with aNSCLC in Brazilian private institutions are heterogeneous. The observed high resource use and costs among aNSCLC patients have a significant economic impact to the Brazilian private healthcare system.

Phase II trial of neoadjuvant chemotherapy followed by chemoradiation in locally advanced cervical cancer.

OBJECTIVE: Cervical cancer is a global public health challenge. Since 1999, platin based chemoradiation (CRT) is the standard treatment for those patients with locally advanced disease. However, this population still has a dismal prognosis and, alternatives approaches such as adjuvant chemotherapy are controversial, especially because of increased toxicity. Neoadjuvant chemotherapy (NACT) could be an option for more intensive treatment with manageable toxicity. METHODS: A phase II, prospective, non-randomized trial was conducted at a reference center in Recife, Brazil. Locally advanced cervical cancer patients (Ib2-IVa) were treated with neoadjuvant cisplatin 35mg/m2 and gemcitabine 1000mg/m2 D1 and D8, for 2cycles. Then, they received CRT (50.4Gy) with weekly cisplatin 40mg/m2 followed by brachytherapy. Response rate (RR) and toxicity were the primary endpoints. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. RESULTS: Between Sep/2013 and Oct/2015, 50 patients were initiated on NACT and CRT. RR was 81% at the end of treatment. Hematological and gastrointestinal toxicity were most common. Grade 3/4 toxicity was 20% during NACT and 44% during CRT. Late adverse events were present in 20% of patients. PFS at 1 and 3-years were 73.4% (IC 58.7-83.6) and 53.9% (IC 36.9-68.3), respectively; and, OS at 1 and 3-years were 93.9% (IC 82.4-98.0) and 71.3% (IC 53.3-83.3), respectively. CONCLUSION: In our hands NACT in locally advanced cervical cancer patients did not show a meaningful improvement in ORR. Nevertheless, we believe it should be further explored in prospective trials.

Derivation of mouse embryonic stem cell lines from tyrosine hydroxylase reporter mice crossed with a human SNCA transgenic mouse model of Parkinson's disease.

Mouse embryonic stem cell (mESC) lines were derived by crossing heterozygous transgenic (tg) mice expressing green fluorescent protein (GFP) under the control of the rat tyrosine hydroxylase (TH) promoter, with homozygous alpha-synuclein (aSYN) mice expressing human mutant SNCAA53T under the control of the mouse Prion promoter (MoPrP), or wildtype (WT) mice. The expression of GFP and human aSYN was validated by immunocytochemistry in midbrain neuron cultures upon differentiation of mESC lines using stromal cell-derived inducing activity. These mESC lines can help to study the impact of human aSYN expression in neurons and oligodendrocytes, and also trace GFP-expressing midbrain neurons.

Reporting on methods to generate and purify rodent and human oligodendrocytes from different sources.

Oligodendrocytes are part of the glial cells located in the central nervous system, capable of providing trophic support to neurons and ensheathing their axons. These cells can become dysfunctional under pathologic condition. Rodent and human pluripotent stem cells are inexhaustible sources for producing oligodendrocytes that can be used for disease modeling and cell replacement therapy studies. They also offer many opportunities to model the contribution of oligodendrocytes in non-genetic disorders such as multiple system atrophy. In this method article, we provide robust and reproducible differentiation protocols to obtain oligodendrocyte progenitor cells and purify them using fluorescence activated cell sorting.

Tauroursodeoxycholic Acid Protects Against Mitochondrial Dysfunction and Cell Death via Mitophagy in Human Neuroblastoma Cells.

Mitochondrial dysfunction has been deeply implicated in the pathogenesis of several neurodegenerative diseases. Thus, to keep a healthy mitochondrial population, a balanced mitochondrial turnover must be achieved. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in various neurodegenerative disease models; however, the mechanisms involved are still incompletely characterized. In this study, we investigated the neuroprotective role of TUDCA against mitochondrial damage triggered by the mitochondrial uncoupler carbonyl cyanide m-chlorophelyhydrazone (CCCP). Herein, we show that TUDCA significantly prevents CCCP-induced cell death, ROS generation, and mitochondrial damage. Our results indicate that the neuroprotective role of TUDCA in this cell model is mediated by parkin and depends on mitophagy. The demonstration that pharmacological up-regulation of mitophagy by TUDCA prevents neurodegeneration provides new insights for the use of TUDCA as a modulator of mitochondrial activity and turnover, with implications in neurodegenerative diseases.

Estudo de fase II avaliando a segurança e eficácia da quimioterapia neoadjuvante em pacientes com câncer de colo de útero localmente avançado / Phase II trial of neoadjuvant chemotherapy followed by chemoradiation in locally advanced cervical cancer

Introdução: o câncer de colo de útero é um problema de saúde pública no mundo. Desde 1999, radioterapia concomitante a quimioterapia baseada em platina constitui o tratamento padrão para pacientes com neoplasia localmente avançada. Entretanto, o prognóstico dessas pacientes permanece sombrio e abordagens alternativas, como por exemplo, a quimioterapia adjuvante ainda são controversas, especialmente pelo importante aumento de toxicidade. Quimioterapia neoadjuvante (QT neo) pode ser uma alternativa de intensificar o tratamento com melhor perfil de toxicidade. Métodos: foi realizado um estudo prospectivo, não-randomizado de fase II em um centro de referência de tratamento de câncer em Recife, Brasil. Pacientes com diagnóstico de carcinoma escamoso de colo de útero localmente avançado Ib2-IVa, foram submetidas a QT neo com cisplatina 35mg∕m2 e gencitabina 1000 mg∕m2 no D1 e D8, por dois ciclos. Em seguida, as pacientes realizavam radioterapia em pelve (50,4Gy) concomitante a cisplatina 40mg/m2, seguido de braquiterapia. Os objetivos primários foram taxa de resposta e toxicidade. A sobrevida livre de progressão e a sobrevida global foram objetivos secundários. Resultados: entre setembro/2013 e outubro/2015, 50 pacientes foram incluídas e completaram a QT neo seguida de quimioradioterapia...

Purpose: Cervical cancer is a global public health challenge. Since 1999, platin based chemoradiation (CRT) is the standard treatment for those patients with locally advanced disease. However, this population still has a dismal prognosis and, alternatives approaches such as adjuvant chemotherapy are controversial, especially because of increased toxicity. Neoadjuvant chemotherapy (NACT) could be an option for more intensive treatment with manageable toxicity. Methods: A phase II, prospective, non-randomized trial was conducted at a reference center in Recife, Brazil. Locally advanced cervical cancer patients (Ib2 - IVa) were treated with neoadjuvant cisplatin 35mg∕m2 and gemcitabine 1000 mg∕m2 D1 and D8, for 2 cycles. Then, they received CRT (50.4Gy) with weekly cisplatin 40mg∕m2 followed by brachytherapy. Response rate (RR) and toxicity were the primary endpoints. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Results: Between Sep/2013 and Oct/2015, 50 patients were initiated on NACT and CRT. RR was 81% at the end of treatment. Haematological and gastrointestinal toxicity were most common. Grade 3/4 toxicity was 20% during NACT and 44% during CRT...