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1.
Biochim Biophys Acta Rev Cancer ; 1876(2): 188631, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34606974

RESUMO

Receptor tyrosine kinases play an important role in many cellular processes, and their dysregulation leads to diseases, most importantly cancer. One such receptor tyrosine kinase is c-Kit, a type-III receptor tyrosine kinase, which is involved in various intracellular signaling pathways. The role of different mutant isoforms of c-Kit has been established in several types of cancers. Accordingly, promising c-Kit inhibition results have been reported for the treatment of different cancers (e.g., gastrointestinal stromal tumors, melanoma, acute myeloid leukemia, and other tumors). Therefore, lots of effort has been put to target c-Kit for the treatment of cancer. Here, we provide a comprehensive compilation to provide an insight into c-Kit inhibitor discovery. This compilation provides key information regarding the structure, signaling pathways related to c-Kit, and, more importantly, pharmacophores, binding modes, and SAR analysis for almost all small-molecule heterocycles reported for their c-Kit inhibitory activity. This work could be used as a guide in understanding the basic requirements for targeting c-Kit, and how the selectivity and efficacy of the molecules have been achieved till today.


Assuntos
Neoplasias/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Humanos , Neoplasias/fisiopatologia , Transdução de Sinais
2.
Biochim Biophys Acta Rev Cancer ; 1876(2): 188641, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34695533

RESUMO

Aminopeptidase N (APN/CD13) is a multifunctional glycoprotein that acts as a peptidase, receptor, and signalling molecule in a tissue-dependent manner. The activities of APN have been implicated in the progression of many cancers, pointing toward significant therapeutic potential for cancer treatment. However, despite the tumour-specific functions of this protein that have been uncovered, the ubiquitous nature of its expression in normal tissues as generally reported remains a limitation to the potential utility of APN as a target for cancer therapeutics and drug discovery. With this in mind, we have extensively explored the literature, and present a comprehensive review that for the first-time provides evidence to support the suggestion that tumour-expressed APN may in fact be unique in structure, function, substrate specificity and activity, contrary to its nature in normal tissues. The review also focuses on the biology of APN, and its "moonlighting" functional roles in both normal physiology and cancer development. Several APN-targeting approaches that have been explored over recent decades as therapeutic strategies in cancer treatment, including APN-targeting agents reported both in preclinical and clinical studies, are also extensively discussed. This review concludes by posing critical questions about APN that remain unanswered and unexplored, hence providing opportunities for further research.


Assuntos
Antígenos CD13/metabolismo , Neoplasias/fisiopatologia , Peptídeo Hidrolases/metabolismo , Humanos
3.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502188

RESUMO

Cripto-1 is an essential protein for human development that plays a key role in the early phase of gastrulation in the differentiation of an embryo as well as assists with wound healing processes. Importantly, Cripto-1 induces epithelial to mesenchymal transition to turn fixed epithelial cells into a more mobile mesenchymal phenotype through the downregulation of epithelial adhesion molecules such as E-cadherin, occludins, and claudins, and the upregulation of mesenchymal, mobile proteins, such as N-cadherin, Snail, and Slug. Consequently, Cripto-1's role in inducing EMT to promote cell motility is beneficial in embryogenesis, but detrimental in the formation, progression and metastasis of malignant tumors. Indeed, Cripto-1 is found to be upregulated in most cancers, such as breast, lung, gastrointestinal, hepatic, renal, cervical, ovarian, prostate, and skin cancers. Through its role in EMT, Cripto-1 can remodel cancer cells to enable them to travel through the extracellular matrix as well as blood and lymphatic vessels to metastasize to different organs. Additionally, Cripto-1 promotes the survival of cancer stem cells, which can lead to relapse in cancer patients.


Assuntos
Transição Epitelial-Mesenquimal , Proteínas Ligadas por GPI/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo , Neoplasias/fisiopatologia , Transdução de Sinais
4.
Sci Rep ; 11(1): 17510, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471193

RESUMO

Cerebral small vessel diseases (cSVDs) affect the prognosis of various types of ischemic stroke. Therefore, we evaluated the association between cSVD and the prognosis of cryptogenic stroke patients with active cancer. We enrolled patients diagnosed with cryptogenic stroke and active cancer from 2010 to 2016. Early neurological deterioration (END) was defined as a ≥ 2-point increase in the total NIHSS score or a ≥ 1-point increase in the motor NIHSS score within the first 72 h. We defined an unfavorable outcome as the modified Rankin Scale (mRS) score ≥ 3 points. We analyzed cSVD separately for each subtype including white matter hyperintensity (WMH), silent brain infarct (SBI), and cerebral microbleed (CMB). A total of 179 cryptogenic stroke patients with active cancer were evaluated. In the multivariable analysis, SBI was significantly associated with END (adjusted odds ratio = 3.97, 95% confidence interval: 1.53-10.33). This close relationship between SBI and END increased proportionally with an increase in SBI burden. However, WMH and CMB showed no significant association with END. None of the cSVD subtypes showed a statistically significant relationship with the 3-month unfavorable outcome. SBI was the only parameter closely associated with END in cryptogenic stroke patients with active cancer.


Assuntos
Infarto Encefálico/patologia , Doenças de Pequenos Vasos Cerebrais/complicações , AVC Isquêmico/complicações , Neoplasias/fisiopatologia , Índice de Gravidade de Doença , Idoso , Infarto Encefálico/etiologia , Estudos Transversais , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco
5.
Arch Biochem Biophys ; 712: 109040, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34555372

RESUMO

BACKGROUND: Epigenetic modifiers, such as methyltransferases, play crucial roles in the regulation of many biological processes, including development, cancer and multiple physiopathological conditions. SUMMARY: The Su(Var)3-9, Enhancer-of-zeste and Trithorax (SET) and Myeloid, Nervy, and DEAF-1 (MYND) domain-containing (SMYD) protein family consists of five members in humans and mice (i.e. SMYD1, SMYD2, SMYD3, SMYD4 and SMYD5), which are known or predicted to have methyltransferase activity on histone and non-histone substrates. The abundance of information concerning SMYD2 and SMYD3 is of note, whereas the other members of the SMYD family have not been so thoroughly studied CONCLUSION: Here we review the literature regarding SMYD proteins published in the last five years, including basic molecular biology mechanistic studies using in vitro systems and animal models, as well as human studies with a more translational or clinical approach.


Assuntos
Histona-Lisina N-Metiltransferase/fisiologia , Animais , Doenças Cardiovasculares/fisiopatologia , Diferenciação Celular/fisiologia , Coração/fisiologia , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Músculo Esquelético/fisiologia , Mutação , Neoplasias/fisiopatologia
6.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361078

RESUMO

Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, playing many other key roles as signaling platforms that regulate cell metabolism, proliferation, death and immunological response. As key regulators, mitochondria, when dysfunctional, are involved in the pathogenesis of a wide range of metabolic, neurodegenerative, immune and neoplastic disorders. Far more recently, mitochondria attracted renewed attention from the scientific community for their ability of intercellular translocation that can involve whole mitochondria, mitochondrial genome or other mitochondrial components. The intercellular transport of mitochondria, defined as horizontal mitochondrial transfer, can occur in mammalian cells both in vitro and in vivo, and in physiological and pathological conditions. Mitochondrial transfer can provide an exogenous mitochondrial source, replenishing dysfunctional mitochondria, thereby improving mitochondrial faults or, as in in the case of tumor cells, changing their functional skills and response to chemotherapy. In this review, we will provide an overview of the state of the art of the up-to-date knowledge on intercellular trafficking of mitochondria by discussing its biological relevance, mode and mechanisms underlying the process and its involvement in different pathophysiological contexts, highlighting its therapeutic potential for diseases with mitochondrial dysfunction primarily involved in their pathogenesis.


Assuntos
Doenças Metabólicas/fisiopatologia , Mitocôndrias/fisiologia , Dinâmica Mitocondrial , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Animais , Humanos , Doenças Metabólicas/terapia , Neoplasias/terapia
7.
Nutrients ; 13(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34444902

RESUMO

BACKGROUND AND AIMS: Muscle mass reduction (MMR) is one of the three etiologic criteria in the Global Leadership Initiative on Malnutrition (GLIM) framework. This study aimed to evaluate the value of MMR in GLIM criteria among ambulatory cancer patients. METHODS: A single-center prospective cross-sectional study was conducted. All participants underwent calf circumference (CC) measurement and body composition measurement by bioelectrical impedance analysis (BIA). MMR was identified by CC, fat-free mass index (FFMI), appendicular skeletal muscle index (ASMI), or combinations of the above three indicators. Patients-generated Subjective Global Assessment (PG-SGA) was used as the comparator. RESULTS: A total of 562 cancer patients receiving intravenous treatment were evaluated. Of the participants, 62.8% (355/562) were male. The median age of the patients was 59.0 years (range, 21-82 y). The median BMI was 22.8 kg/m2 (range, 14.6-34.5 kg/m2). A total of 41.8% of patients were evaluated as malnutrition (PG-SGA ≥ 4), and 11.9% were diagnosed with severe malnutrition (PG-SGA ≥ 9). For the GLIM criteria, the prevalence of malnutrition was 26.9%, and severe malnutrition was 12.3%. For all criteria combinations of GLIM together versus PG-SGA, sensitivity was 60.4% (53.8-66.7), specificity was 97.9% (95.4-99.1), while the accordance between GLIM and PG-SGA was moderate (κ = 0.614). The performance of the GLIM worsened when MMR was excluded (κ = 0.515), with reduced sensitivity (50.2% (43.7-56.8)) and the same specificity (97.9% (95.4-99.1)). Including FFMI and ASMI by BIA can further improve the performance of GLIM than using CC alone (κ = 0.614 vs. κ = 0.565). CONCLUSIONS: It is important to include MMR in the GLIM framework. Using body composition measurement further improves the performance of the GLIM criteria than using anthropometric measurement alone.


Assuntos
Antropometria , Composição Corporal , Desnutrição/diagnóstico , Neoplasias/fisiopatologia , Avaliação Nutricional , Adulto , Idoso , Assistência Ambulatorial/estatística & dados numéricos , Estudos Transversais , Impedância Elétrica , Feminino , Humanos , Masculino , Desnutrição/etiologia , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Neoplasias/complicações , Estado Nutricional , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto Jovem
8.
Lancet Oncol ; 22(9): 1333-1340, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34399096

RESUMO

BACKGROUND: Kidney function assessment by estimated glomerular filtration rate (eGFR) equations, such as the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, is important to determine dosing and eligibility for anticancer drugs. Inclusion of race in eGFR equations calculates a higher eGFR at a given serum creatinine concentration for Black patients versus non-Black patients. We aimed to characterise the effect of removing race from the CKD-EPI equation on dosing and eligibility of anticancer drugs with kidney function cutoffs. METHODS: We did a retrospective analysis of patients enrolled in phase 1 studies sponsored by the Cancer Therapy Evaluation Program between January, 1995, and October, 2010. eGFR based on creatinine (eGFRCr) was calculated by the CKD-EPI equation and a version of the CKD-EPI equation without the race term (CKD-EPIwithout race). Estimated creatinine clearance (eClCr) was calculated by the Cockcroft-Gault equation. Dosing simulations based on each assessment of kidney function were done for ten anticancer drugs with kidney function cutoffs for dosing (oxaliplatin, capecitabine, etoposide, topotecan, fludarabine, and bleomycin) or eligibility (cisplatin, pemetrexed, bendamustine, and mitomycin) based on labelling approved by the US Food and Drug Administration or consensus guidelines. The absolute proportion of patients eligible or in each renal dosing range was calculated for each drug. Eligibility and dosing discordance rates were also calculated. FINDINGS: Demographics and laboratory values from 340 Black patients (172 men and 168 women) were used. Median age was 57 years (IQR 47-64), median bodyweight was 78·1 kg (67·0-89·8), median body surface area was 1·91 m2 (1·77-2·09), and median serum creatinine concentration was 0·9 mg/dL (0·8-1·1). Median eGFRCr or eClCr was 103 mL/min (85-122) calculated by CKD-EPI, 89 mL/min (73-105) by CKD-EPIwithout race, and 90 mL/min (72-120) by Cockcroft-Gault. Black patients were recommended to receive dose reductions or were rendered ineligible to receive drug more frequently when using CKD-EPIwithout race than when using CKD-EPI, but at a similar rate as when using Cockcroft-Gault. The number of patients ineligible for therapy or recommended to receive any renal dose adjustment when CKD-EPIwithout race versus CKD-EPI was used increased by 72% (from 25 of 340 to 43 of 340 patients) for cisplatin, by 120% (from five to 11) for pemetrexed, by 67% (from three to five) for bendamustine, by 150% (from ten to 25) for capecitabine, by 150% (from ten to 25) for etoposide, by 67% (from three to five) for topotecan, by 61% (from 74 to 119) for fludarabine, and by 163% (from eight to 21) for bleomycin. Up to 18% of patients had discordant recommendations using CKD-EPIwithout race versus CKD-EPI. INTERPRETATION: Removing race from the CKD-EPI equation will calculate a lower eGFR for Black patients and exclude more patients from receiving anticancer therapy, which could lead to undertreatment of Black patients with cancer and adversely affect their outcomes. FUNDING: National Institutes of Health.


Assuntos
Antineoplásicos/uso terapêutico , Taxa de Filtração Glomerular/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/etnologia , Grupo com Ancestrais do Continente Africano , Ensaios Clínicos Fase I como Assunto , Creatinina/sangue , Cálculos da Dosagem de Medicamento , Definição da Elegibilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Neoplasias/fisiopatologia , Estudos Retrospectivos , Estados Unidos
9.
Medicine (Baltimore) ; 100(29): e26202, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34397999

RESUMO

INTRODUCTION: Previous research indicates that the platelet-to-lymphocyte ratio (PLR) may be an indicator of poor prognosis in many tumor types. However, the PLR is rarely described in patients undergoing neoadjuvant chemotherapy (NAC) for solid tumors. Thus, we performed a meta-analysis to investigate the prognostic value of this ratio for patients with solid tumors treated by NAC. METHODS: A comprehensive search of the literature was conducted using the PubMed, EMBASE, Cochrane Library, and Web of Science databases, followed by a manual search of references from the retrieved articles. Pooled hazard ratios (HRs) with 95% confidence interval (CIs) were used to evaluate the association between PLR and 3 outcomes, namely, overall survival, disease-free survival, and pathological complete response rate after NAC. RESULTS: Eighteen studies published no earlier than 2014 were included in our study. A lower PLR was associated with better overall survival (HR = 1.46, 95% CI, 1.11-1.92) and favorable disease-free survival (HR = 1.81, 95% CI, 1.27-2.59). A PLR that was higher than a certain cutoff was associated with a lower pathological complete response rate in patients with cancer who received NAC (Odds ratio = 1.93, 95% CI, 1.40-2.87). CONCLUSION: Elevated PLR is associated with poor prognosis in various solid tumors. PLR may be a useful biomarker in delineating those patients with poorer prognoses who may benefit from neoadjuvant therapies.


Assuntos
Contagem de Linfócitos/normas , Terapia Neoadjuvante/métodos , Neoplasias/patologia , Contagem de Plaquetas/normas , Prognóstico , Plaquetas/classificação , Plaquetas/patologia , Humanos , Contagem de Linfócitos/métodos , Linfócitos/classificação , Linfócitos/patologia , Neoplasias/fisiopatologia , Neoplasias/terapia , Contagem de Plaquetas/métodos
10.
Nutrients ; 13(8)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34444741

RESUMO

Gut microbiota has emerged as a major metabolically active organ with critical functions in both health and disease. The trillions of microorganisms hosted by the gastrointestinal tract are involved in numerous physiological and metabolic processes including modulation of appetite and regulation of energy in the host spanning from periphery to the brain. Indeed, bacteria and their metabolic byproducts are working in concert with the host chemosensory signaling pathways to affect both short- and long-term ingestive behavior. Sensing of nutrients and taste by specialized G protein-coupled receptor cells is important in transmitting food-related signals, optimizing nutrition as well as in prevention and treatment of several diseases, notably obesity, diabetes and associated metabolic disorders. Further, bacteria metabolites interact with specialized receptors cells expressed by gut epithelium leading to taste and appetite response changes to nutrients. This review describes recent advances on the role of gut bacteria in taste perception and functions. It further discusses how intestinal dysbiosis characteristic of several pathological conditions may alter and modulate taste preference and food consumption via changes in taste receptor expression.


Assuntos
Fenômenos Fisiológicos Bacterianos , Microbioma Gastrointestinal/fisiologia , Intestinos/microbiologia , Percepção Gustatória , Animais , Antineoplásicos/uso terapêutico , Cirurgia Bariátrica , COVID-19/fisiopatologia , Dieta , Disbiose/fisiopatologia , Comportamento Alimentar , Hormônios/metabolismo , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Receptores Acoplados a Proteínas G/metabolismo , Paladar , Papilas Gustativas/fisiologia , Receptores Toll-Like/metabolismo
11.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445197

RESUMO

The term "cachexia" is derived from the Greek words kakos (bad) and hexis (habit). Cachexia is a malnutrition associated with chronic diseases such as cancer, chronic heart failure, chronic renal failure, and autoimmune diseases, and is characterized by decreased skeletal muscle mass. Cancer cachexia is quite common in patients with advanced cancer. Weight loss is also a characteristic symptom of cancer cachexia, along with decreased skeletal muscle mass. As nutritional supplementation alone cannot improve cachexia, cytokines and tumor-derived substances have been attracting attention as its relevant factors. Cancer cachexia can be also associated with reduced chemotherapeutic effects, increased side effects and treatment interruptions, and even poorer survival. In 2011, a consensus definition of cachexia has been proposed, and the number of relevant research reports has increased significantly. However, the pathogenesis of cachexia is not fully understood, and there are currently few regulatory-approved standard treatments for cachexia. The main reason for this is that multiple etiologies are involved in the development of cachexia. In this review, we will outline the current status of cachexia, the mechanisms of which have been elucidated in recent years, especially from the perspective of advanced cancer.


Assuntos
Caquexia/etiologia , Neoplasias/complicações , Anilidas/uso terapêutico , Animais , Caquexia/diagnóstico , Caquexia/fisiopatologia , Caquexia/terapia , Suplementos Nutricionais , Gerenciamento Clínico , Humanos , Hidrazinas/uso terapêutico , Neoplasias/fisiopatologia , Oligopeptídeos/uso terapêutico
12.
Sci Rep ; 11(1): 16321, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381065

RESUMO

Vascular bypass surgery in children differs significantly from adults. It is a rarely performed procedure in the setting of trauma and tumor surgery. Besides technical challenges to reconstruct the small and spastic vessels, another concern in bypass grafting is the adequate limb length growth over time. The primary aim of this study was to assess long-term outcome after pediatric bypass grafting, in a single academic center, focusing on potential effects on limb development. In this retrospective cohort analyses we included all pediatric patients undergoing vascular bypass grafting at our department between 2002 and 2017. All patients ≤ 18 years suffered a traumatic injury or underwent a tumor resection of the lower or upper limb. The youngest female patient was 0.4 years, the youngest male patient was 3.5 years. During the observation period, 33 pediatric patients underwent vascular repair, whereby 15 patients underwent bypass grafting. Median overall follow-up was 4.7 years (IQR ± 9). 8 patients (53%) had a traumatic injury (traumatic surgery group) and 7 patients had a planned orthopedic tumor resection (orthopedic surgery group). In 13/15 (87%) a great saphenous vein (GSV) graft and in 2/15 (13%) a Gore-Tex graft was used for bypassing. Both Gore-Tex grafts showed complete occlusion 12 and 16 years after implantation. No patient died in the early postoperative phase (< 30 days), however 3/7 (43%) in the orthopedic group died during follow-up. Revision surgery had to be performed in 1/15 (7%) patients. A functional use of the extremity was reported in all patients. Normal limb length growth according to the contralateral site, and therefore bypass growth, could be documented in 14/15 patients. Children are surgically challenging. In our study, surgery by a specialized vascular surgery team using GSV grafts led to adequate limb length and bypass growth, and we observed no functional restrictions.


Assuntos
Oclusão de Enxerto Vascular/fisiopatologia , Neoplasias/fisiopatologia , Criança , Feminino , Oclusão de Enxerto Vascular/cirurgia , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Neoplasias/cirurgia , Politetrafluoretileno/química , Estudos Retrospectivos , Veia Safena/fisiopatologia , Veia Safena/cirurgia , Resultado do Tratamento , Extremidade Superior/fisiopatologia , Enxerto Vascular/métodos , Grau de Desobstrução Vascular/fisiologia , Procedimentos Cirúrgicos Vasculares/métodos
13.
PLoS Med ; 18(8): e1003728, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34464384

RESUMO

BACKGROUND: Unexpected weight loss (UWL) is a presenting feature of cancer in primary care. Existing research proposes simple combinations of clinical features (risk factors, symptoms, signs, and blood test data) that, when present, warrant cancer investigation. More complex combinations may modify cancer risk to sufficiently rule-out the need for investigation. We aimed to identify which clinical features can be used together to stratify patients with UWL based on their risk of cancer. METHODS AND FINDINGS: We used data from 63,973 adults (age: mean 59 years, standard deviation 21 years; 42% male) to predict cancer in patients with UWL recorded in a large representative United Kingdom primary care electronic health record between January 1, 2000 and December 31, 2012. We derived 3 clinical prediction models using logistic regression and backwards stepwise covariate selection: Sm, symptoms-only model; STm, symptoms and tests model; Tm, tests-only model. Fifty imputations replaced missing data. Estimates of discrimination and calibration were derived using 10-fold internal cross-validation. Simple clinical risk scores are presented for models with the greatest clinical utility in decision curve analysis. The STm and Tm showed improved discrimination (area under the curve ≥ 0.91), calibration, and greater clinical utility than the Sm. The Tm was simplest including age-group, sex, albumin, alkaline phosphatase, liver enzymes, C-reactive protein, haemoglobin, platelets, and total white cell count. A Tm score of 5 balanced ruling-in (sensitivity 84.0%, positive likelihood ratio 5.36) and ruling-out (specificity 84.3%, negative likelihood ratio 0.19) further cancer investigation. A Tm score of 1 prioritised ruling-out (sensitivity 97.5%). At this threshold, 35 people presenting with UWL in primary care would be referred for investigation for each person with cancer referred, and 1,730 people would be spared referral for each person with cancer not referred. Study limitations include using a retrospective routinely collected dataset, a reliance on coding to identify UWL, and missing data for some predictors. CONCLUSIONS: Our findings suggest that combinations of simple blood test abnormalities could be used to identify patients with UWL who warrant referral for investigation, while people with combinations of normal results could be exempted from referral.


Assuntos
Análise Custo-Benefício , Testes Hematológicos/instrumentação , Neoplasias/diagnóstico , Fatores de Risco , Perda de Peso , Estudos de Coortes , Registros Eletrônicos de Saúde , Neoplasias/etiologia , Neoplasias/fisiopatologia , Atenção Primária à Saúde , Estudos Retrospectivos , Reino Unido
14.
PLoS One ; 16(8): e0252781, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34403429

RESUMO

PURPOSE: Evaluation of symptoms and signs for the management of neuropathic cancer pain (NCP) is challenging. This study aimed to identify clinical predictors of NCP and symptoms and signs most relevant of those in Korean patients. METHODS: This nationwide, descriptive, cross-sectional, multicenter, observational study included 2,003 cancer patients aged ≥20 years who reported a visual analog scale (VAS) score ≥1 for pain and provided informed consent for participation. The Douleur Neuropathic (DN4) questionnaire (score ≥4) was used to determine symptoms and signs as well as the presence of NCP. RESULTS: The prevalence of NCP was associated with age <65 years [OR, 1.57; 95% CI, 1.270-1.934], disease duration >6 months (OR, 1.57; 95% CI, 1.232-2.012), stage IV cancer (OR, 0.75; 95% CI, 0.593-0.955), history of chemotherapy (OR, 1.74; 95% CI, 1.225-2.472), and moderate-to-severe cancer pain (OR, 2.05; 95% CI, 1.671-2.524) after multivariate analysis. The most common descriptive symptoms of NCP were tingling, electric shock, and pins and needles. For NCP patients in the presence or absence of the clinical predictors, pins and needles (p = 0.001) and painful cold (p<0.001) symptoms were significantly frequent in patients with moderate-to-severe pain. Tingling, numbness, and touch hypoesthesia (p = 0.022, 0.033, 0.024, respectively) were more frequent in those with longer cancer duration and hyperesthesia (p = 0.024) was more frequent in young patients. CONCLUSION: Age <65 years, disease duration >6 months, stage IV cancer, history of chemotherapy, and moderate-to-severe cancer pain, were identified as predictors of NCP. Some symptoms and signs of NCP were associated with these predictors. Further studies are warranted on the pathogenesis and management of NCP with respect to the symptoms and signs, and factors associated with pain severity in Korean patients.


Assuntos
Dor do Câncer , Neoplasias , Neuralgia , Medição da Dor , Inquéritos e Questionários , Fatores Etários , Idoso , Dor do Câncer/diagnóstico , Dor do Câncer/epidemiologia , Dor do Câncer/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Neoplasias/fisiopatologia , Neuralgia/diagnóstico , Neuralgia/epidemiologia , Neuralgia/fisiopatologia , Prevalência
15.
Eur J Cancer ; 156: 24-34, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34411849

RESUMO

BACKGROUND: Previous reports highlight the greater number of side effects that women experience during cancer treatment, but little is known about sex differences in symptoms and functioning in long-term survivors. METHODS: We investigated sex differences in the prevalence of physical (EORTC QLQ-C30) and emotional symptoms (Hospital Anxiety and Depression Scale) and loss of functioning (EORTC QLQ-C30) in 5339 cancer survivors (55% males). General linear models were computed to assess the differences in symptoms and functioning between female and male cancer survivors and between survivors and an age-matched reference population. RESULTS: The direct comparison between female and male cancer survivors identified more symptoms, such as nausea and vomiting (M = 5.0 versus. 3.2), insomnia (M = 26.1 versus. 15.9), anxiety (M = 5.2 versus. 4.2), and lower physical (M = 77.5 versus. 82.5) and emotional functioning (M = 83.4 versus. 86.3), in female survivors. However, comparison with an age-matched reference population demonstrated that several symptoms, such as fatigue, dyspnea, anxiety and depression, appeared to be more frequent in male patients. The investigation of functioning domains - compared with a reference population - highlighted further sex-specific differences. Female survivors experienced a moderate net loss in physical and cognitive functioning (-6.1 [95% CI = -8.1; -4,1] and -5.2 respectively [95% CI = -7; -3.5]), whereas male survivors displayed a significant net loss in role and social functioning compared to the reference population (-9.9 [95% CI = -11.2; -8.6] and -7.7 [95% CI = -9.6; -7.6] respectively). CONCLUSION: To adequately capture sex differences in symptoms and functioning in long-term cancer survivors, a comparison with a reference population should always be considered. In our study population, this adjustment highlighted a significant and unexpected long-term impact on male patients. Role and social functioning were especially impacted in male patients, emphasizing the need to further investigate these gendered domains.


Assuntos
Sobreviventes de Câncer , Estado Funcional , Neoplasias/diagnóstico , Qualidade de Vida , Avaliação de Sintomas , Adulto , Idoso , Estudos Transversais , Emoções , Feminino , Disparidades nos Níveis de Saúde , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/fisiopatologia , Neoplasias/psicologia , Países Baixos/epidemiologia , Medidas de Resultados Relatados pelo Paciente , Sistema de Registros , Fatores Sexuais , Interação Social
16.
Nutrients ; 13(6)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207529

RESUMO

Nutritional status in oncological patients may differ according to several modifiable and non-modifiable factors. Knowledge of the epidemiology of malnutrition/cachexia/sarcopenia may help to manage these complications early in the course of treatment, potentially impacting patient quality of life, treatment intensity, and disease outcome. Therefore, this narrative review aimed to critically evaluate the current evidence on the combined impact of tumor- and treatment-related factors on nutritional status and to draw some practical conclusions to support the multidisciplinary management of malnutrition in cancer patients. A comprehensive literature search was performed from January 2010 to December 2020 using different combinations of pertinent keywords and a critical evaluation of retrieved literature papers was conducted. The results show that the prevalence of weight loss and associated symptoms is quite heterogeneous and needs to be assessed with recognized criteria, thus allowing a clear classification and standardization of therapeutic interventions. There is a large range of variability influenced by age and social factors, comorbidities, and setting of cures (community-dwelling versus hospitalized patients). Tumor subsite is one of the major determinants of malnutrition, with pancreatic, esophageal, and other gastroenteric cancers, head and neck, and lung cancers having the highest prevalence. The advanced stage is also linked to a higher risk of developing malnutrition, as an expression of the relationship between tumor burden, inflammatory status, reduced caloric intake, and malabsorption. Finally, treatment type influences the risk of nutritional issues, both for locoregional approaches (surgery and radiotherapy) and for systemic treatment. Interestingly, personalized approaches based on the selection of the most predictive malnutrition definitions for postoperative complications according to cancer type and knowledge of specific nutritional problems associated with some new agents may positively impact disease course. Sharing common knowledge between oncologists and nutritionists may help to better address and treat malnutrition in this population.


Assuntos
Caquexia/etiologia , Desnutrição/etiologia , Neoplasias/complicações , Estado Nutricional , Sarcopenia/etiologia , Caquexia/epidemiologia , Humanos , Desnutrição/epidemiologia , Oncologia/estatística & dados numéricos , Neoplasias/fisiopatologia , Avaliação Nutricional , Prevalência , Fatores de Risco , Sarcopenia/epidemiologia
17.
Clin Ter ; 172(4): 305-314, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34247213

RESUMO

Introduction: Background The aim of the paper is related to our experience defining the diagnostic accuracy of breast elastosonog-raphy. Objective: The aim of our study is therefore to define the diagnostic accuracy of breast elastosonography in the differential diagnosis of nodular breast neoformations to improve the characterization of the solid lesion and reduce the number of needle aspiration unnecessary for benign formations. Material and methods: A total of 88 patients were enrolled, who came to the Department with an ultrasound diagnosis of a breast lesion. Each lesion was subjected to mammography and B-mode ultrasonogra-phy with an evaluation of size, echogenicity, and vascularization pres-ence or absence. The use of the ultrasound machine and the respective probe has made it possible to make the measurements. All nodules were subjected to ultrasound-guided FNAC. These data were compared with the results of elastosonographic examination. Results: FNAC results were as follows: CIN 1 in 18 nodules, CIN 2 in 22 nodules, CIN 3 in 36 nodules, CIN 4 in 6 nodules, and CIN 5 in 6 nodules. The sensitivity and specificity of elastosonography found in our case series reported values in line with data reported in the literature, confirming the method's high reliability. Conclusions: The elastosonography could become a complemen-tary technique to mammography and ultrasonography in the future, reducing the costs and risks of additional examinations. Therefore, we believe it is essential to contribute with this additional finding to increasingly accredit this pathway and reduce the discomfort to patients of more invasive methods.


Assuntos
Biópsia por Agulha Fina/métodos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/fisiopatologia , Neoplasias/diagnóstico , Neoplasias/fisiopatologia , Ultrassonografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
18.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299300

RESUMO

Erythropoietin (EPO) is a glycoprotein cytokine known for its pleiotropic effects on various types of cells and tissues. EPO and its receptor EPOR trigger signaling cascades JAK2/STAT5, MAPK, and PI3K/AKT that are interconnected and irreplaceable for cell survival. In this article, we describe the role of the MAPK and PI3K/AKT signaling pathways during red blood cell formation as well as in non-hematopoietic tissues and tumor cells. Although the central framework of these pathways is similar for most of cell types, there are some stage-specific, tissue, and cell-lineage differences. We summarize the current state of research in this field, highlight the novel members of EPO-induced PI3K and MAPK signaling, and in this respect also the differences between erythroid and non-erythroid cells.


Assuntos
Eritropoese/fisiologia , Eritropoetina/fisiologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases , Modelos Biológicos , Neoplasias/fisiopatologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores da Eritropoetina/fisiologia , Transdução de Sinais
19.
Nat Rev Cancer ; 21(9): 592-604, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34239104

RESUMO

Collective cancer invasion with leader-follower organization is increasingly recognized as a predominant mechanism in the metastatic cascade. Leader cells support cancer invasion by creating invasion tracks, sensing environmental cues and coordinating with follower cells biochemically and biomechanically. With the latest developments in experimental and computational models and analysis techniques, the range of specific traits and features of leader cells reported in the literature is rapidly expanding. Yet, despite their importance, there is no consensus on how leader cells arise or their essential characteristics. In this Perspective, we propose a framework for defining the essential aspects of leader cells and provide a unifying perspective on the varying cellular and molecular programmes that are adopted by each leader cell subtype to accomplish their functions. This Perspective can lead to more effective strategies to interdict a major contributor to metastatic capability.


Assuntos
Invasividade Neoplásica , Neoplasias/fisiopatologia , Animais , Movimento Celular , Humanos , Neoplasias/patologia , Células Neoplásicas Circulantes , Microambiente Tumoral
20.
Biomolecules ; 11(7)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209658

RESUMO

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds ß-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM's role in EMT may reveal additional therapeutic opportunities.


Assuntos
Molécula de Adesão da Célula Epitelial/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Linhagem Celular Tumoral , Molécula de Adesão da Célula Epitelial/genética , Molécula de Adesão da Célula Epitelial/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Proteínas com Homeodomínio LIM/metabolismo , Proteínas Musculares/metabolismo , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Células Neoplásicas Circulantes/metabolismo , Células-Tronco Neoplásicas/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo
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