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BACKGROUND: High-dose chemotherapy followed by stem cell transplant (HDCT) is potentially curative for patients with refractory germ cell tumors (rGCT). There is scarce real-world data supporting its implementation in low- and middle-income countries. We described the experience of our tertiary cancer center in Sao Paulo, Brazil. METHODS: We identified male patients ≥18 years-old with rGCT referred to HDCT after board discussion. Clinical data, including delays in HDCT protocol, were extracted from medical records, and survival outcomes were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazard were used to determine effects on overall survival (OS). RESULTS: From January 2013 to January 2023, 34 patients were referred and considered eligible to receive 2 cycles of HDCT. Most patients had primary testicular tumors (82%), nonseminomatous histology (88%), and poor International Germ Cell Collaborative Group (IGCCCG) (79%). Twenty-three patients received HDCT (1 cycle, n = 8; 2 cycles, n = 15). Main reasons for not receiving any HDCT were death due to progressive disease (n = 1), performance deterioration (n = 7), and failure of stem cell mobilization (n = 3). OS at 2 years was 36.7% for the eligible population, 56.1% for patients who underwent at least 1 HDCT, and 77.1% for those who had ≥2 cycles. The 2-year OS rate for patients not given HDCT was 0%. All patients had delays in protocol, and poor-risk patients had longer intervals from referral to protocol initiation (0.7 vs. 1.8 month, P < .01). CONCLUSION: Outcomes of patients who received ≥1 HDCT were encouraging; however, only 15 from 34 eligible patients were able to receive the planned 2 cycles of HDCT. Further strategies to minimize treatment delays in low- and middle-income countries are needed.
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Neoplasias Embrionárias de Células Germinativas , Centros de Atenção Terciária , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/patologia , Brasil , Adulto , Centros de Atenção Terciária/estatística & dados numéricos , Neoplasias Testiculares/terapia , Neoplasias Testiculares/patologia , Neoplasias Testiculares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto Jovem , Transplante Autólogo , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Transplante de Células-Tronco Hematopoéticas/métodos , Terapia Combinada , AdolescenteRESUMO
OBJECTIVE: To validate the Cancer of the Bladder Risk Assessment (COBRA) score in patients with urothelial variants. METHODS: Epidemiological, clinical, radiological, and anatomopathological data were collected from patients with urothelial carcinoma who underwent radical cystectomy at the Institute of Cancer of São Paulo between May 2008 and December 2022. Patients with the presence of at least 10% of any urothelial variants in the radical cystectomy specimens' anatomopathological exam were included in the study. The COBRA score and derivatives were applied and correlated with oncological outcomes. RESULTS: A total of 680 patients [482 men (70.9%) and 198 women (29.1%)]; 66 years (IQR 59-73) underwent radical cystectomy for bladder tumor, and of these patients, a total of 167 patients presented any type of urothelial variant. The median follow-up time was 28.77 months (IQR 12-85). The three most prevalent UV were squamous differentiation (50.8%), glandular differentiation (31.3%), and micropapillary differentiation (11.3%). The subtypes with the worst prognosis were sarcomatoid with a median survival of 8 months (HR 1.161; 95% CI 0.555-2.432) and plasmacytoid with 14 months (HR 1.466; 95% CI 0.528-4.070). The COBRA score for patients with micropapillary variants demonstrated good predictive accuracy for OS (log-rank P = 0.009; 95% IC 6.78-29.21) and CSS (log-rank P = 0.002; 95% IC 13.06-26.93). CONCLUSIONS: In our study, the COBRA score proved an effective risk stratification tool for urothelial histological variants, especially for the micropapillary urothelial variant. It may be helpful in the prognosis evaluation of UV patients after radical cystectomy.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Masculino , Humanos , Feminino , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células de Transição/patologia , Cistectomia , Estudos Retrospectivos , Brasil , Medição de RiscoRESUMO
Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m2) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m2) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (P < 0.001), and FBF and FVC responses were attenuated (P < 0.05). MAP was similar between the groups (P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (P > 0.05). MAP was lower in COVID-19 survivors (P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.
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COVID-19 , Força da Mão , Adulto , Humanos , Pessoa de Meia-Idade , Pressão Sanguínea/fisiologia , Hemodinâmica , Exercício Físico/fisiologia , Frequência Cardíaca/fisiologia , Sistema Nervoso Simpático , Antebraço/irrigação sanguínea , Músculo Esquelético/inervaçãoRESUMO
Objectives: This study aimed to evaluate the functional results of the treatment protocol for the treatment of transolecranon fracture-dislocation, by surgical reduction and osteosynthesis with plate and screws, in patients attended at a referral hospital for orthopedic trauma, with a minimum follow-up period of six months. Methods: Twenty-five individuals treated surgically from January 2014 to November 2018 were selected for a primary observational longitudinal study using questionnaires to assess upper limb and elbow function (DASH and MEPS), quality of life (SF-12), pain (visual analog scale - VAS), and radiographic evaluation in anteroposterior and lateral views of the elbow. Results: Fifteen patients were male, and the mean age was 46.8 years. All participants had their fractures consolidated, with no radiolgraphic signs of implant failure, or degenerative arthritis. Mean range of motion was reduced relative to the contralateral limb: 102.6º for flexion-extension and 132.8º for pronation-supination. The mean MEPS and DASH scores were 89.6 and 16.5 respectively. There was no residual pain in 84% of the cases according to the VAS. Conclusion: The surgical treatment proposed for transolecranon fracture-dislocations showed satisfactory results according to MEPS, DASH scores and quality of life measures. Evidence Level IV; Retrospective observational study.
Objetivo: Avaliar os resultados funcionais do protocolo de tratamento da fratura-luxação transolecraniana, por redução cirúrgica e osteossíntese com placa e parafusos, nos pacientes atendidos em hospital de referência para trauma ortopédico, com seguimento mínimo de seis meses. Métodos: vinte e cinco indivíduos tratados cirurgicamente de janeiro de 2014 a novembro de 2018 foram selecionados para um estudo longitudinal observacional primário, utilizando questionários para avaliar a função do membro superior e cotovelo (DASH e MEPS), qualidade de vida (SF-12), dor (visual escala analógica - EVA), e avaliação radiográfica nas incidências anteroposterior e perfil do cotovelo. Resultados: Quinze pacientes eram do sexo masculino e a média de idade foi de 46,8 anos. Todos os participantes tiveram suas fraturas consolidadas, sem sinais radiográficos de falha do implante ou artrite degenerativa. A amplitude média do movimento foi reduzida em relação ao membro contralateral: 102,6º para flexo-extensão e 132,8º para pronossupinação. Os escores médios de MEPS e DASH foram 89,6 e 16,5, respectivamente. Não houve dor residual em 84% dos casos de acordo com a EAV. Conclusão: O tratamento cirúrgico proposto para a fratura-luxação transolecraniana apresentou resultados satisfatórios de acordo com MEPS, escores DASH e medidas de qualidade de vida. Nível de evidência IV; Estudo observacional retrospectivo.
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Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti-PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.
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Antineoplásicos Fitogênicos , Neuralgia , Ratos , Humanos , Camundongos , Animais , Receptor de Morte Celular Programada 1 , Antineoplásicos Fitogênicos/efeitos adversos , Ratos Sprague-Dawley , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Paclitaxel , Analgésicos/efeitos adversosRESUMO
Objectives: To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations. Design: Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions. Methods: Clinicopathological features were retrieved from the patient's charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths. Results: Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297-0.597vs 0.607, IQR: 0.445-0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs. Conclusions: CTNNB1: mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/ß-catenin pathway and telomere biology in the pathogenesis of aCPs.
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Craniofaringioma , Telômero , beta Catenina , Adolescente , Criança , Craniofaringioma/genética , Estudos Transversais , Humanos , Mutação , Estudos Retrospectivos , Telômero/ultraestrutura , Via de Sinalização Wnt , beta Catenina/genéticaRESUMO
Resumen OBJETIVO: Comparar el índice neutrófilo-linfocito, la relación plaquetas-linfocito y la distribución de la anchura del eritrocito de mujeres con preeclampsia con o sin criterios de severidad y los de mujeres sin ésta. MATERIALES Y MÉTODOS: Estudio retrospectivo, de casos y controles, efectuado en mujeres con y sin preeclampsia atendidas entre enero y diciembre de 2019. RESULTADOS: Se estudiaron 70 mujeres con preeclampsia y 70 con embarazo sin esta complicación. El índice neutrófilo-linfocito fue significativamente mayor en las mujeres con preeclampsia (4.11 ± 2.76; IC95%: 3.47-4.75) que en las mujeres sin esta complicación (2.99 ± 1.6; IC95%: 2.62-3.36; p = 0.004), similar a la relación plaquetas-linfocitos (117.61 ± 47.53; IC95%:106.48-128.24 vs 97.64 ± 43.67; IC95%: 87.41-107.87; p = 0.006) y para la distribución de la anchura del eritrocito (14.46 ± 1.9; IC95%: 14.02-14.9 vs 13.56 ± 1.38; IC95%: 13-13.72; p = 0.0002). Ninguno de estos parámetros logró discriminar entre las pacientes con preeclampsia con o sin criterios de severidad. CONCLUSIÓN: Un índice neutrófilo-linfocito ≥ 5.1 y una relación plaquetas-linfocito ≥ 113.1 son capaces de discriminar de manera adecuada entre preeclampsia con o sin criterios de severidad.
Abstract OBJECTIVE: To compare the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and erythrocyte width distribution, of women with preeclampsia with or without severity criteria and those of women without. MATERIALS AND METHODS: Retrospective case-control study in 70 women with preeclampsia and 70 with normal pregnancy between January and December 2019. RESULTS: Seventy women with preeclampsia and 70 with pregnancy without this complication were studied. The neutrophil-lymphocyte ratio was significantly higher in women with preeclampsia (4.11 ± 2.76; 95%CI: 3.47-4.75), than in women with normal pregnancies (2.99 ± 1.6; 95%CI: 2.62-3.36; p = 0.004); which is similar for the platelet-lymphocyte ratio (117.61 ± 47.53, 95%CI: 106.48-128.24 vs 97.64 ± 43.67; 95%CI: 87.41-107.87; p = 0.006) and for the distribution of the width of the erythrocyte; (14.46 ± 1.9, CI95%: 14.02-14.9 vs 13.56 ± 1.38; CI95%: 13-13.72; p = 0.0002). None of these parameters was able to discriminate between patients with preeclampsia with or without severity criteria. A neutrophil-lymphocyte ratio ≥ 5.1 discriminates between women with a normal pregnancy and those with preeclampsia with or without severity criteria [area under the curve of 0.746, (95%CI: 0.664-0.827)], sensitivity 42%, specificity 91%, positive predictive value 82%, negative predictive value 60% and Odds Ratio 7.1 (95%CI: 2.7-18.6, p = 0.001). The platelet-lymphocyte ratio ≥ 113.4 can discriminate between women with a normal pregnancy and preeclampsia with or without severity criteria, with an area under the curve of 0.617 (95% CI 0.525-0.709). CONCLUSION: A neutrophil-lymphocyte ratio ≥ 5.1, and a platelet-lymphocyte ratio ≥ 113.1 are able to adequately discriminate between patients with normal pregnancy and those with preeclampsia with or without severity criteria.
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BACKGROUND: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. METHODS: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. RESULTS: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. CONCLUSIONS: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.
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CONTEXT: Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. OBJECTIVE: To develop a prediction model of therapeutic response of acromegaly to fg-SRL. METHODS: Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). RESULTS: A total of 153 patients were analyzed. Controlled patients were older (Pâ =â .002), had lower GH at diagnosis (Pâ =â .01), had lower pretreatment GH and IGF-I (Pâ <â .001), and more frequently harbored tumors that were densely granulated (Pâ =â .014) or highly expressed SST2 (Pâ <â .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. CONCLUSION: We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.
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Acromegalia/tratamento farmacológico , Regras de Decisão Clínica , Monitoramento de Medicamentos/métodos , Aprendizado de Máquina , Receptores de Somatostatina/administração & dosagem , Acromegalia/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Queratinas , Ligantes , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Receptores de Somatostatina/sangue , Resultado do Tratamento , Adulto JovemRESUMO
The ability of communities to react to risks and disturbances is for their balance, development, and sustainability. The concept of resilience provides a way to think about policies and actions for future changes in socioeconomic and ecological-environmental systems. This paper analyzes, in the context of mining, the perception of the resilience of Canaã dos Carajás population in Pará State, Brazilian Amazon. The methodology involved face-to-face interviews based on a structured questionnaire conducted on a sample of 140 residents stratified from 11 social actors in the Canaã community. This approach allowed the evaluation of resilience perception using 26 interview statements derived from six resilience theories. Our multivariate analysis found that the level of residents' perception of resilience was reasonable (with an average score of 3.04 ± 0.22 using a Likert scale, with a Cronbach's alpha of 0.788). The interviewees pointed out one positive and five negative factors that influenced the level of resilience in Canaã. According to residents' perceptions, the resilience of Canaã dos Carajás was moderate but could have been improved with more economic diversification, more infrastructure, and less inequality in access to services and participation in decision-making. The considered most relevant themes were problems caused by mining in the municipality, quality of life issues, difficulties dealing with change after the arrival of mining, and economic problems. This study contributes to the literature because it used theories as a conceptual orientation for the development of a resilience scale to measure resilience at the community level in the context of large-scale mining.
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Mineração , Qualidade de Vida , Brasil , Ecossistema , PercepçãoRESUMO
BACKGROUND: Previous data have reported that the growth of established tumors may be facilitated by postsepsis disorder through changes in the microenvironment and immune dysfunction. However, the influence of postsepsis disorder in initial carcinogenesis remains elusive. METHODS: In the present work, the effect of postsepsis on inflammation-induced early carcinogenesis was evaluated in an experimental model of colitis-associated colorectal cancer (CAC). We also analyzed the frequency and role of intestinal T regulatory cells (Treg) in CAC carcinogenesis. RESULTS: The colitis grade and the tumor development rate were evaluated postmortem or in vivo through serial colonoscopies. Sepsis-surviving mice (SSM) presented with a lower colonic DNA damage, polyp incidence, reduced tumor load, and milder colitis than their sham-operated counterparts. Ablating Treg led to restoration of the ability to develop colitis and tumor polyps in the SSM, in a similar fashion to that in the sham-operated mice. On the other hand, the growth of subcutaneously inoculated MC38luc colorectal cancer cells or previously established chemical CAC tumors was increased in SSM. CONCLUSION: Our results provide evidence that postsepsis disorder has a dual effect in cancer development, inhibiting inflammation-induced early carcinogenesis in a Treg-dependent manner, while increasing the growth of previously established tumors.
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Colite/complicações , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Inflamação/complicações , Sepse/complicações , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Animais , Colite/imunologia , Colite/patologia , Neoplasias do Colo/etiologia , Citocinas/metabolismo , Feminino , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Sepse/imunologia , Sepse/patologia , Transdução de SinaisRESUMO
CONTEXT: Lipodystrophy syndromes are rare disorders characterized by the selective loss of adipose tissue. We aimed to report a case of acquired generalized lipodystrophy possibly associated with nivolumab. CASE DESCRIPTION: A woman was referred to our Endocrinology Department for uncontrolled diabetes mellitus. At 50 years of age, she was diagnosed with type 2 diabetes after a routine laboratory test and her diabetes was well controlled with low doses of metformin. In 2010, she was diagnosed with clear cell renal carcinoma. The cancer progressed in the following years, leading to the initiation of treatment with nivolumab in 2017. Two months later she presented with facial lipoatrophy, with loss of the buccal fat pads and prominent zygomatic arch. Her neck, shoulders, arms, and buttocks were also affected. Her diabetes control worsened. She received maximal doses of metformin and pioglitazone and was administered 1.5 units/kg/d insulin. Subcutaneous biopsy of medial surface of the arm revealed chronic lobular panniculitis. Despite nivolumab's possible involvement in the onset of lipodystrophy, the maintenance of nivolumab therapy was justified by the observed reduction in the progression of the cancer, combined with the lack of an alternative chemotherapy. The therapy was withdrawn after 8 months of treatment because of grade 3 hepatitis. CONCLUSION: Anti-PD1 therapy has great potential. Early recognition of the onset of unusual collateral effects is important to improve decision making regarding the treatment of patients with tumors.
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Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Lipodistrofia/induzido quimicamente , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Neutrophils and inflammatory monocytes control sepsis by migration to the site of infection via their chemokine receptors. CCR5 is a chemokine receptor that is not expressed on neutrophils and inflammatory monocytes under homeostatic conditions. However, it has been demonstrated that CCR5 can become expressed on these cells during different models of inflammation. In the present study, we investigated if CCR5 is also expressed on neutrophil and inflammatory monocytes during sepsis, exerting an important role in the migration of these cells to the infectious focus. Using cecal ligation and puncture model to induce polymicrobial sepsis, we demonstrated that the expression of CCR5 is induced on CD11bLy6GLy6C inflammatory monocytes, but not on neutrophils (CD11bLy6GLy6C). Furthermore, CCR5 plays an important role for the migration of the inflammatory monocytes to infection focus during sepsis. CCR5-expressing inflammatory monocytes migrate from the bone marrow to the circulation and then into the site of infection, where they phagocytize and kill the bacteria. Consequently, CCR5 mice showed increased systemic inflammatory response and mortality compared to wild-type mice. These data therefore demonstrate a hitherto unrecognized protective role of CCR5 in sepsis.
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Células da Medula Óssea/imunologia , Movimento Celular/imunologia , Monócitos/imunologia , Receptores CCR5/imunologia , Sepse/imunologia , Animais , Células da Medula Óssea/patologia , Movimento Celular/genética , Camundongos , Camundongos Knockout , Monócitos/patologia , Receptores CCR5/genética , Sepse/genética , Sepse/patologiaRESUMO
Heregulins (HRGs) bind to the receptors HER3 or HER4, induce receptor dimerization, and trigger downstream signaling that leads to tumor progression and resistance to targeted therapies. Increased expression of HRGs has been associated with worse clinical prognosis; therefore, attempts to block HRG-dependent tumor growth have been pursued. This manuscript summarizes the function and signaling of HRGs and review the preclinical evidence of its involvement in carcinogenesis, prognosis, and treatment resistance in several malignancies such as colorectal cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. Agents in preclinical development and clinical trials of novel therapeutics targeting HRG-dependent signaling are also discussed, including anti-HER3 and -HER4 antibodies, anti-metalloproteinase agents, and HRG fusion proteins. Although several trials have indicated an acceptable safety profile, translating preclinical findings into clinical practice remains a challenge in this field, possibly due to the complexity of downstream signaling and patterns of HRG, HER3 and HER4 expression in different cancer subtypes. Improving patient selection through biomarkers and understanding the resistance mechanisms may translate into significant clinical benefits in the near future.
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This study estimated the reference evapotranspiration rate (ETo) for the Itacaiúnas River Watershed (IRW), Eastern Amazonia, and measured the accuracy of eight empirical equations: Penman-Monteith (PM), Priestley-Taylor (PT), Hargreaves and Samani (HS), Camargo (CAM), Thornthwaite (TH), Hamon (HM), Kharrufa (KF) and Turc (TC) using monthly data from 1980 to 2013. In addition, it verifies the regional applicability to the IRW using a for the Marabá-PA station. The methods TC and PM (FAO56) presented the best results, which demonstrate that radiation and higher temperatures are the dominant drivers in the Evapotranspiration process, while relative humidity and wind speed have a much smaller impact. The temporal and spatial variability of ETo for IRW show has strong seasonality, increasing during the dry season and decreasing during the rainy season. The statistical analyses at 1% level of significance, indicates that there is no correlation of the residuals between the dry and rainy seasons, and test of the physical parameters such as mean temperature, solar radiation and relative air humidity explains the variations of ETo.
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OPINION STATEMENT: Colorectal cancer (CRC) is the third leading cancer diagnosed globally and an important cause of cancer-related mortality. Of interest, while we have witnessed a declining incidence trend over the past few decades in the older population, incidence rates for adolescents and young adults have been increasing steadily. Several factors may well explain this apparent epidemic in the young, namely a lack of routine screening and emerging lifestyle issues such as obesity, lack of exercise, and dietary factors. It is known that both environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility is associated with the most striking increases in risk, and must always be considered in a young patient with CRC, the majority of CRCs are in fact sporadic rather than familial. Early-onset CRC is a truly heterogeneous disease, with mounting evidence to suggest that this patient population has a distinctive molecular profile, very different to late-onset CRC cases. Currently, both younger and older patients with CRC are treated in essentially the same manner, but with a better understanding of the molecular mechanisms underlying CRC in the young, we will have the opportunity to specifically tailor screening and clinical management strategies in this unique patient population in an effort to improve outcomes. The aim of this review is to outline our current knowledge of the distinguishing features of early-onset CRC, the ongoing research efforts, and the evolving evidence in this field.
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Neoplasias Colorretais/epidemiologia , Adulto , Fatores Etários , Idade de Início , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/terapia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Gerenciamento Clínico , Detecção Precoce de Câncer/métodos , Predisposição Genética para Doença , Humanos , Incidência , Vigilância da População , Fatores de Risco , Adulto JovemRESUMO
ABSTRACT This study estimated the reference evapotranspiration rate (ETo) for the Itacaiúnas River Watershed (IRW), Eastern Amazonia, and measured the accuracy of eight empirical equations: Penman-Monteith (PM), Priestley-Taylor (PT), Hargreaves and Samani (HS), Camargo (CAM), Thornthwaite (TH), Hamon (HM), Kharrufa (KF) and Turc (TC) using monthly data from 1980 to 2013. In addition, it verifies the regional applicability to the IRW using a for the Marabá-PA station. The methods TC and PM (FAO56) presented the best results, which demonstrate that radiation and higher temperatures are the dominant drivers in the Evapotranspiration process, while relative humidity and wind speed have a much smaller impact. The temporal and spatial variability of ETo for IRW show has strong seasonality, increasing during the dry season and decreasing during the rainy season. The statistical analyses at 1% level of significance, indicates that there is no correlation of the residuals between the dry and rainy seasons, and test of the physical parameters such as mean temperature, solar radiation and relative air humidity explains the variations of ETo.
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BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare neoplasm of vascular origin that typically arises from the skin or soft tissues as a solitary tumor. The optimal therapy for this disease is still unknown. We report the case of an adult patient presenting with metastatic KHE of the spleen, who had a partial response after treatment with paclitaxel. CASE PRESENTATION: A 36-year-old man presented in November 2012 with a nontraumatic rupture of the spleen. A splenectomy was performed, and the pathology was consistent with a nonspecific vascular proliferation. Follow-up scans revealed lytic bone lesions and liver metastasis. A biopsy of the liver was performed and confirmed KHE. The decision was made to proceed with treatment with gemcitabine and docetaxel, which was discontinued due to myelotoxicity. The patient was then transferred to our institution, and a pathology review supported the diagnosis of metastatic KHE. His disease remained stable until February 2014, when he developed progression in the liver. Chemotherapy was restarted with paclitaxel, and a partial response was documented after 3 cycles. Unfortunately, disease progression occurred after 24 weeks, and subsequent treatments included prednisone, doxorubicin, interferon-α, gemcitabine, and ifosfamide, without any response. The patient developed Kasabach-Merritt phenomenon and passed away 1 week later due to a major gastrointestinal bleeding. CONCLUSIONS: This case report suggests that paclitaxel could be considered as a treatment option for advanced KHE, a rare condition for which no standard treatment exists.
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PURPOSE: Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis. METHODS: A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion. RESULTS: Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1ß contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis. CONCLUSIONS: IL-1ß, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/análogos & derivados , Fluoruracila/efeitos adversos , Enteropatias/induzido quimicamente , Mucosite/induzido quimicamente , Camptotecina/efeitos adversos , Citocinas/metabolismo , Humanos , Enteropatias/metabolismo , Enteropatias/patologia , Irinotecano , Mucosite/metabolismo , Mucosite/patologia , Receptores de Citocinas/efeitos dos fármacos , Receptores de Citocinas/metabolismoRESUMO
Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortality rate. Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role in counteracting invading microorganisms during infection. The aim of this study was to evaluate systemic NETs formation, their participation in host bacterial clearance and their contribution to organ dysfunction in sepsis. C57Bl/6 mice were subjected to endotoxic shock or a polymicrobial sepsis model induced by cecal ligation and puncture (CLP). The involvement of cf-DNA/NETs in the physiopathology of sepsis was evaluated through NETs degradation by rhDNase. This treatment was also associated with a broad-spectrum antibiotic treatment (ertapenem) in mice after CLP. CLP or endotoxin administration induced a significant increase in the serum concentrations of NETs. The increase in CLP-induced NETs was sustained over a period of 3 to 24 h after surgery in mice and was not inhibited by the antibiotic treatment. Systemic rhDNase treatment reduced serum NETs and increased the bacterial load in non-antibiotic-treated septic mice. rhDNase plus antibiotics attenuated sepsis-induced organ damage and improved the survival rate. The correlation between the presence of NETs in peripheral blood and organ dysfunction was evaluated in 31 septic patients. Higher cf-DNA concentrations were detected in septic patients in comparison with healthy controls, and levels were correlated with sepsis severity and organ dysfunction. In conclusion, cf-DNA/NETs are formed during sepsis and are associated with sepsis severity. In the experimental setting, the degradation of NETs by rhDNase attenuates organ damage only when combined with antibiotics, confirming that NETs take part in sepsis pathogenesis. Altogether, our results suggest that NETs are important for host bacterial control and are relevant actors in the pathogenesis of sepsis.