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High rates of failure, exorbitant costs, and the sluggish pace of new drug discovery and development have led to a growing interest in repurposing "old" drugs to treat both common and rare diseases, particularly cancer. Cancer, a complex and heterogeneous disease, often necessitates a combination of different treatment modalities to achieve optimal outcomes. The intrinsic polygenicity of cancer, intricate biological signalling networks, and feedback loops make the inhibition of a single target frequently insufficient for achieving the desired therapeutic impact. As a result, addressing these complex or "smart" malignancies demands equally sophisticated treatment strategies. Combinatory treatments that target the multifaceted oncogenic signalling network hold immense promise. Repurposed drugs offer a potential solution to this challenge, harnessing known compounds for new indications. By avoiding the prohibitive costs and long development timelines associated with novel cancer drugs, this approach holds the potential to usher in more effective, efficient, and cost-effective cancer treatments. The pursuit of combinatory therapies through drug repurposing may hold the key to achieving superior outcomes for cancer patients. However, drug repurposing faces significant commercial, technological and regulatory challenges that need to be addressed. This review explores the diverse approaches employed in drug repurposing, delves into the challenges faced by the drug repurposing community, and presents innovative solutions to overcome these obstacles. By emphasising the significance of combinatory treatments within the context of drug repurposing, we aim to unlock the full potential of this approach for enhancing cancer therapy. The positive aspects of drug repurposing in oncology are underscored here; encompassing personalized treatment, accelerated development, market opportunities for shelved drugs, cancer prevention, expanded patient reach, improved patient access, multi-partner collaborations, increased likelihood of approval, reduced costs, and enhanced combination therapy.
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Antineoplásicos , Neoplasias , Humanos , Reposicionamento de Medicamentos , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Oncologia , Terapia CombinadaRESUMO
Infantile haemangioma (IH), the most common vascular tumour of infancy, is comprised of diverse cell types including endothelial cells, pericytes, fibroblasts and immune cells. IH is characterized by rapid proliferation followed by slow involution over 1 - 10 years. Most lesions regress spontaneously, but up to 10% can be disfiguring with complications that require further medical treatment. Recent research has revealed the biological characteristics of IH, highlighting the involvement of angiogenesis and vasculogenesis during tumour formation. Gene expression profiling has provided vital insights into these underlying biological processes, with some of the key IH-related pathways identified, including VEGF, RAAS, HIF-1α, Notch, PDGF, PI3K/Akt/mTOR, JAK/STAT, FGF, PPARγ, IGF. Further evidence suggests extracellular matrix factors and hormone receptors regulate IH progression. In this review, we explore the molecular mechanisms involved in the proliferating, plateau and involuting phases of IH. This involves identifying differentially expressed genes, targeted proteins, and key signalling pathways. This knowledge will increase the broader understanding of vascular development, tissue remodelling and angiogenesis.
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BACKGROUND: Colon cancer is the third most common cancer and second highest cause of cancer deaths worldwide. The aim of the study was to find new biomarkers for diagnosis, prognosis and therapeutic drug targets for this disease. METHODS: Four low-grade and four high-grade human colon adenocarcinoma tumours with patient-matched normal colon tissues were analysed. Additionally, tissue-derived primary cell lines were established from each tumour tissue. The cell lines were validated using DNA sequencing to confirm that they are a suitable in vitro model for colon adenocarcinoma based on conserved gene mutations. Label-free quantitation proteomics was performed to compare the proteomes of colon adenocarcinoma samples to normal colon samples, and of colon adenocarcinoma tissues to tissue-derived cell lines to find significantly differentially abundant proteins. The functions enriched within the differentially expressed proteins were assessed using STRING. Proteomics data was validated by Western blotting. RESULTS: A total of 4767 proteins were identified across all tissues, and 4711 across primary tissue-derived cell lines. Of these, 3302 proteins were detected in both the tissues and the cell lines. On average, primary cell lines shared about 70% of proteins with their parent tissue, and they retained mutations to key colon adenocarcinoma-related genes and did not diverge far genetically from their parent tissues. Colon adenocarcinoma tissues displayed upregulation of RNA processing, steroid biosynthesis and detoxification, and downregulation of cytoskeletal organisation and loss of normal muscle function. Tissue-derived cell lines exhibited increased interferon-gamma signalling and aberrant ferroptosis. Overall, 318 proteins were significantly up-regulated and 362 proteins significantly down-regulated by comparisons of high-grade with low-grade tumours and low-grade tumour with normal colon tissues from both sample types. CONCLUSIONS: The differences exhibited between tissues and cell lines highlight the additional information that can be obtained from patient-derived primary cell lines. DNA sequencing and proteomics confirmed that these cell lines can be considered suitable in vitro models of the parent tumours. Various potential biomarkers for colon adenocarcinoma initiation and progression and drug targets were identified and discussed, including seven novel markers: ACSL4, ANK2, AMER3, EXOSC1, EXOSC6, GCLM, and TFRC.
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ABSTRACT: The mastoid process, a pneumatized prominence of the temporal bone with air-filled air cells, grows with age. We present here a series of 4 patients with bilateral mastoid hypertrophy associated with severe trismus from different etiologies, and discuss the possible explanation of this observation.
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Processo Mastoide , Trismo , Humanos , Hipertrofia , Processo Mastoide/diagnóstico por imagem , Osso Temporal , Trismo/etiologiaRESUMO
BACKGROUND: Propranolol is the preferred treatment for problematic proliferating infantile hemangioma (IH) by targeting the renin-angiotensin system (RAS) expressed by IH endothelium. (Pro)renin receptor (PRR) is a major component of the RAS associated with the canonical wnt signaling pathway. We proposed that activation of PRR by renin causes proliferation of IH. METHODS: The expression of PRR in IH tissue samples was investigated using immunohistochemical (IHC) staining and NanoString analysis. NanoString analysis was also used to confirm transcriptional expression of PRR in CD34-sorted proliferating IH-derived primary cell lines. MTT assay was utilized to determine the effect of exogenous renin on the number of viable IH cells. RT-qPCR was used to determine the effect of renin on the stem cell gene expression. RESULTS: NanoString analysis and IHC staining confirmed transcriptional and translational expression of PRR, which was localized to the non-endothelial and the endothelial IH cell populations. MTT assay demonstrated an increased number of viable IH cells by administration of renin and the effect was negated by the wnt receptor blocker dickkopf-1. CONCLUSION: Our results present a model for renin-induced increased proliferation of IH cells through PRR acting via the wnt signaling pathway, which may account for accumulation of cells in IH during the proliferative phase of the tumor.
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Células Endoteliais/citologia , Hemangioma Capilar/metabolismo , Receptores de Superfície Celular/metabolismo , Renina/metabolismo , Antígenos CD34/metabolismo , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Células Endoteliais/metabolismo , Feminino , Perfilação da Expressão Gênica , Hemangioma Capilar/patologia , Humanos , Imuno-Histoquímica , Lactente , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Propranolol/farmacologia , Sistema Renina-Angiotensina , Células-Tronco/citologia , Células-Tronco/metabolismo , Via de Sinalização Wnt , Receptor de Pró-ReninaRESUMO
AIM: We investigated the expression of neuropeptide Y (NPY), NPY receptor 1 (NPYR1) and NPY receptor 2 (NPYR2) in infantile haemangiomas (IHs). METHODS: Immunohistochemical (IHC) staining was performed on proliferating IHs from six patients aged 4-13 (mean 8.7) months and involuted IHs from six patients aged 5-59 (mean 18.7) years, for the expression of NPY, NPYR1 and NPYR2. Protein and messenger ribonucleic acid expression corresponding to these proteins was investigated by Western blotting and NanoString analysis, respectively. RESULTS: IHC staining, Western blotting and NanoString analysis demonstrated the presence of NPYR1, but not NPYR2, within proliferating and involuted IHs. IHC staining showed NPYR1 was expressed by B and T lymphocytes expressing CD45 and mast cells expressing tryptase. IHC staining demonstrated the presence of NPY on the NPYR1+ cells, but it was not detected by Western blotting or NanoString analysis. CONCLUSION: NPYR1, but not NPYR2, was present in IHs. The localisation of NPYR1 to B and T lymphocytes and mast cells suggests its role in the biology of IHs. The demonstration of NPY on the NPYR1+ cells, without active transcription, suggests that NPY was not being produced within IHs.
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Linfócitos B/metabolismo , Hemangioma/imunologia , Mastócitos/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Linfócitos T/metabolismo , Adolescente , Adulto , Western Blotting , Contagem de Células , Criança , Pré-Escolar , Expressão Gênica , Hemangioma/metabolismo , Hemangioma/patologia , Humanos , Imuno-Histoquímica , Adulto JovemRESUMO
A 19-year-old male with a port wine stain on the base of his neck presented with a 5-month history of gradual thickening of the involved skin which interfered with clothing and caused repeated bleeding. The lesion was excised and histopathologic examination revealed angiolymphoid hyperplasia with eosinophilia (ALHE) arising from the pre-existing port wine stain - a rare finding with only one previously reported case. Additionally the lesion was associated with elevated serum renin levels which virtually normalized following excision of the lesion. We further demonstrated the expression of angiotensin converting enzyme and angiotensin II receptors 1 and 2 by the lesion and discuss the possible role of the renin-angiotensin system in this condition.
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Hiperplasia Angiolinfoide com Eosinofilia/diagnóstico , Mancha Vinho do Porto/diagnóstico , Mancha Vinho do Porto/patologia , Hiperplasia Angiolinfoide com Eosinofilia/metabolismo , Hiperplasia Angiolinfoide com Eosinofilia/cirurgia , Humanos , Masculino , Pescoço/patologia , Peptidil Dipeptidase A/biossíntese , Mancha Vinho do Porto/metabolismo , Mancha Vinho do Porto/cirurgia , Receptor Tipo 1 de Angiotensina/biossíntese , Receptor Tipo 2 de Angiotensina/biossíntese , Renina/sangue , Adulto JovemRESUMO
BACKGROUND: Recent description of hemangioblastic blood islands within pyogenic granuloma (PG) has led us to investigate the expression of embryonic stem cell (ESC) markers in this tumor. METHODS: In this study we examined the expression of ESC markers, OCT4, SOX2, STAT3 and NANOG in PG samples from 11 patients, by immunohistochemical (IHC) staining, NanoString analysis and in situ hybridization (ISH). RESULTS: IHC staining demonstrated the expression of pSTAT3, OCT4, SOX2 and NANOG by the endothelium of the microvessels in PG whilst pSTAT3, SOX2 and NANOG were also expressed by cells in the interstitium, outside of the microvessels. NanoString and ISH analysis showed mRNA expression for STAT3, OCT4 and NANOG in PG. CONCLUSIONS: The expression of the ESC markers, OCT4, SOX2, pSTAT3 and NANOG, suggests the endothelium of PG displays a primitive phenotype. Cells in the interstitium expressing pSTAT3, SOX2 and NANOG may represent a more downstream derivative of the primitive endothelium, or a separate population. The primitive nature of the endothelium and cells in the interstitium reveals novel insights into the biology of PG. To the best of our knowledge, this is the first demonstration of the expression of ESC markers in PG, implying the presence of a hematopoietic stem cell population.
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Células-Tronco Embrionárias/patologia , Granuloma Piogênico/patologia , Dermatopatias/patologia , Biomarcadores/análise , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Hibridização In Situ , TranscriptomaRESUMO
UNLABELLED: PHACE syndrome comprises a spectrum of anomalies including posterior fossa malformations, haemangioma, arterial anomalies, cardiac defects and eye anomalies. PHACE should be considered in any patient with a large facial segmental infantile haemangioma (IH), and multidisciplinary management is crucial. Low-dose propranolol is effectively for the treatment of IH associated with PHACE syndrome. Recent evidence suggests IH is comprised of mesoderm-derived haemogenic endothelium. CONCLUSION: The embryonic developmental anomaly nature of IH provides an insight into the origin of PHACE syndrome.
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Coartação Aórtica , Anormalidades do Olho , Síndromes Neurocutâneas , Antagonistas Adrenérgicos beta/uso terapêutico , Coartação Aórtica/tratamento farmacológico , Coartação Aórtica/embriologia , Anormalidades do Olho/tratamento farmacológico , Anormalidades do Olho/embriologia , Feminino , Humanos , Lactente , Síndromes Neurocutâneas/tratamento farmacológico , Síndromes Neurocutâneas/embriologiaAssuntos
Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Hemangioma/metabolismo , Neoplasias Hepáticas/metabolismo , Comunicação Parácrina , alfa-Fetoproteínas/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Técnicas de Cocultura , Hemangioma/patologia , Células Hep G2 , Humanos , Lactente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Fatores de Tempo , Células Tumorais Cultivadas , alfa-Fetoproteínas/genéticaRESUMO
AIMS: Propranolol, now the preferred treatment for problematic proliferating infantile haemangioma (IH), at an empirical cardiovascular dosage of 2-3 mg/kg/day is associated with variable complication rates. A meta-analysis shows complications in 31% of patients at a mean dosage of 2.12 mg/kg/day. This study reports on the minimal dosage and duration of treatment to achieve accelerated involution and side effects using a stepwise escalation regimen. METHODS: Consecutive patients with problematic proliferating IH treated with propranolol were identified from our vascular anomalies database. Propranolol was commenced at 0.5 mg/kg/day in two divided doses and increased to 1 mg/kg/day after 24 h. The patients were reviewed after 1 week, and the dosage was increased to 1.5 mg/kg/day. The dosage was further increased by 0.5 mg/kg/day, if necessary, to achieve accelerated involution. RESULTS: Forty-four patients, aged 3 weeks to 11 months (mean, 3.8 months), received propranolol therapy for problematic proliferating IH. The minimal dosage required to achieve accelerated involution was 1.5-2 mg/kg/day. Treatment was maintained for an average of 9.3 months and discontinued at an average age of 14.2 months. Rebound growth occurred in the first patient of this series when propranolol was withdrawn at 7.5 months of age, requiring reinstitution of treatment. Slight rebound growth following cessation of treatment was observed in four other patients, but reinstitution of propranolol was not required. Minor complications were observed in three (6.8%) patients. CONCLUSIONS: Propranolol at 1.5-2 mg/kg/day, administered in divided doses with stepwise escalation, is safe and effective for treating problematic proliferating IH. Treatment is continued to an average age of 14.2 months.
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Antagonistas Adrenérgicos beta/administração & dosagem , Hemangioma Capilar/tratamento farmacológico , Propranolol/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Administração Oral , Antagonistas Adrenérgicos beta/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Propranolol/uso terapêutico , Resultado do TratamentoRESUMO
The authors present a case of PHACE(S) (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies, and sternal cleft or supraumbilical raphe) syndrome with a right-sided segmental infantile hemangioma, and describe in detail, the associated absent ipsilateral intracranial internal carotid artery and anomalous Circle of Willis. Propranolol therapy led to accelerated, complete involution. Nadolol may reduce the theoretical risk of treating PHACE(S) patients with ß-blockers.
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Anormalidades Múltiplas/diagnóstico , Encéfalo/anormalidades , Artéria Carótida Interna/anormalidades , Círculo Arterial do Cérebro/anormalidades , Imageamento por Ressonância Magnética/métodos , Feminino , Humanos , Lactente , Síndrome , Tomografia Computadorizada por Raios XRESUMO
Cutaneous squamous cell carcinoma (cSCC) constitutes the most common cancer capable of metastasis. While the latest version of the American Joint Committee on Cancer guidelines represents a significant step forward in accurate staging of cSCC, several proven independent risk factors remain excluded. We review the current literature on the incidence and proven independent risk factors of metastasis for cSCC and proposes their full inclusion in the staging system for primary lesions.
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Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/etiologia , Estadiamento de Neoplasias/normas , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/etiologia , Carcinoma de Células Escamosas/classificação , Carcinoma de Células Escamosas/secundário , Humanos , Incidência , Nova Zelândia/epidemiologia , Prognóstico , Fatores de Risco , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/patologiaRESUMO
The renin-angiotensin system (RAS) is increasingly being recognized to play a role in the tumor microenvironment, promoting tumor growth. Studies blocking a single part of the RAS have shown mixed results, possibly due to the existence of different bypass pathways and redundancy within the RAS. As such, multimodal blockade of the RAS has been developed to exert more complete inhibition of the RAS. The aim of the present study was to assess the safety of multimodal RAS blockade in dogs. Five dogs (four with appendicular osteosarcoma, one with oral malignant melanoma) were treated with atenolol, benazepril, curcumin, meloxicam, and metformin. The dogs underwent clinical examination, blood pressure measurement, and hematology and serum biochemistry tests performed at 0, 1, 3, 6, 9, and 12 weeks, then every 3 months thereafter. End-of-life decisions were made by the owners. None of the dogs developed hypotension. One dog had intermittent vomiting during the 64 weeks it was on the trial. One dog had a one-off increase in serum SDMA(symmetrical dimethylarginine) concentration. Dogs were euthanized at weeks 3 (osteosarcoma), 10 (osteosarcoma), 17 (osteosarcoma), and 26 (oral malignant melanoma), and one dog was still alive at the end of the trial at 64 weeks (osteosarcoma). This is the first assessment of multimodal blockade of the RAS in dogs, and the results suggest it causes only mild adverse effects in some animals. The efficacy of the treatment was not assessed due to the small number of dogs. This pilot study allows for future larger studies assessing multimodal RAS blockade for the treatment of canine cancer.
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BACKGROUND: Verrucous hemangioma (VH) presents clinically as a vascular malformation but has similar histopathologic features to infantile hemangioma. This study characterized the cell population within VH. MATERIAL AND METHODS: Paraffin-embedded sections from two male patients with VH were processed for immunohistochemistry. The expression of SMA, CD34, glucose transporter-1 (Glut-1), D2-40, brachyury, angiotensin converting enzyme (ACE), Oct-4, hemoglobin ζ chain (HBZ), Wilms tumor protein (WT-1) and CD45 was examined. RESULTS: The lymphatic marker, D2-40, was not expressed in VH, whereas Glut-1 was widely expressed in infantile hemangioma, it was only focally expressed by the endothelium of VH. The endothelium of VH expressed the primitive markers, Oct-4, brachyury and ACE. The primitive marker, WT-1, was expressed predominantly on the pericyte layer of both VH and infantile hemangioma. However, HBZ was only expressed in infantile hemangioma. CD45, a mature hematopoetic marker, was expressed by cells within the interstitium, away from the endothelium of VH and infantile hemangioma. DISCUSSION: The expression of the primitive markers, Oct-4, brachyury and ACE on the endothelium, and WT-1 predominantly on the pericyte layer of VH shows a primitive microvascular phenotype similar to infantile hemangioma. However, the absence of the embryonic marker, HBZ, expressed only in first trimester placenta and in proliferating infantile hemangioma, suggests a different cellular origin. HBZ could be used to distinguish between the two conditions.
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Biomarcadores Tumorais/metabolismo , Hemangioma/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Transportador de Glucose Tipo 1/metabolismo , Hemangioma/patologia , Hemangioma/cirurgia , Hemoglobinas Anormais/metabolismo , Humanos , Masculino , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgiaRESUMO
Non-melanocytic skin cancers (NMSCs) account for five times the incidence of all other cancers combined and cost US $6 billion annually. These are the most frequent specimens encountered in community pathology practice in many Western countries. Lack of standardised structured pathology reporting protocols (SPRPs) can result in omission of critical information or miscommunication leading to suboptimal patient management. The lack of standardised data has significant downstream public health implications, including insufficient data for reliable development of prognostic tools and health-economy planning. The Royal College of Pathologists of Australasia has developed an NMSC SPRP. A multidisciplinary expert committee including pathologists, surgeons, dermatologists, and radiation and medical oncologists from high volume cancer centres was convened. A systematic literature review was performed to identify evidence for including elements as mandatory standards or best practice guidelines. The SPRP and accompanying commentary of evidence, definitions and criteria was peer reviewed by external stakeholders. Finally, the protocol was revised following feedback and trialled in multiple centres prior to implementation. Some parameters utilised clinically for determining management and prognosis including tumour depth, lymphovascular invasion or distance to the margins lack high level evidence in NMSC. Dermatologists, surgeons, and radiation oncologists welcomed the SPRP. Pathologists indicated that the variety of NMSC specimens ranging from curettes to radical resections as well as significant differences in the biological behaviour of different tumours covered by the NMSC umbrella made use of a single protocol difficult. The feedback included that using a SPRP for low risk NMSC was neither clinically justified nor compensated adequately by the Australian Medicare Reimbursement Schedule. Following stakeholder feedback, the SPRP implementation was restricted to excision specimens of head and neck NMSC; and low-risk NMSC, such as superficial basal cell carcinoma, were excluded. Implementing NMSC SPRP fulfils an unmet clinical need. Unlike other cancers, NMSCs generate a range of specimen types and are reported in a wide range of pathology practices. Limiting use of SPRP to NMSC at higher risk of progression and providing formatted templates for easy incorporation into laboratory information systems were essential to successful deployment. In the future, further consideration should be given to implementing the SPRP to include all relevant specimens, including non-head and neck and low-risk NMSC specimens.
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Carcinoma Basocelular , Neoplasias Cutâneas , Idoso , Humanos , Austrália , Programas Nacionais de Saúde , Neoplasias Cutâneas/patologia , Carcinoma Basocelular/patologia , Risco , Revisões Sistemáticas como AssuntoRESUMO
BACKGROUND: Cutaneous squamous cell carcinoma (cSCC), the most common cancer capable of metastasis, has variable reported metastatic rates and the impact of individual risk factors for metastasis is unknown. METHODS: This study examined pathology records of excised cSCC over a 10-year period. Uni-variate and multi-variate analyses including patient demographics, maximum clinical diameter (MCD), anatomical sub-site, histological differentiation, perineural invasion (PNI), and lymphovascular invasion (LVI) of the lesion were performed. The primary endpoint was time to metastasis. RESULTS: Six thousand one hundred sixty four patients (median age 74 years) underwent excision of 8,997 primary cSCC. During the median follow-up of 70 months, the metastatic rate of cSCC was 1.9-2.6%. Multi-variate analysis showed that MCD (hazards ratio 1.41 [95% CI 1.25-1.60] P < 0.001), PNI (5.29; P < 0.0001), poor histological differentiation (4.26; P < 0.0001), location in the ear and retro-auricular area (3.31 [1.17-9.33]; P = 0.0024), cheek (3.18 [1.15-8.81]; P = 0.026), and lip (4.84; P = 0.009) increased the risk of metastasis. CONCLUSIONS: We show a 1.9-2.6% metastatic rate for cSCC with MCD, histologic differentiation, PNI, and certain anatomical sub-sites being independent risk factors for metastasis. A prospective study on our proposed risk stratification scheme based on these parameters may lead to identification of high-risk lesions that would benefit from more intensive treatment and/or routine post-operative follow-up.Inc.
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Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/secundário , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Cutâneas/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/terapia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapia , Adulto JovemRESUMO
Cells exhibiting embryonic stem cell (ESC) characteristics have been demonstrated in vascular anomalies (VAs), cancer, and fibroproliferative conditions, which are commonly managed by plastic surgeons and remain largely unsolved. The efficacy of the mTOR inhibitor sirolimus, and targeted therapies that block the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways in many types of cancer and VAs, further supports the critical role of ESC-like cells in the pathogenesis of these conditions. ESC-like cells in VAs, cancer, and fibroproliferative conditions express components of the renin-angiotensin system (RAS) - a homeostatic endocrine signaling cascade that regulates cells with ESC characteristics. ESC-like cells are influenced by the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways, which directly regulate cellular proliferation and stemness, and interact with the RAS at multiple points. Gain-of-function mutations affecting these pathways have been identified in many types of cancer and VAs, that have been treated with targeted therapies with some success. In cancer, the RAS promotes tumor progression, treatment resistance, recurrence, and metastasis. The RAS modulates cellular invasion, migration, proliferation, and angiogenesis. It also indirectly regulates ESC-like cells via its direct influence on the tissue microenvironment and by its interaction with the immune system. In vitro studies show that RAS inhibition suppresses the hallmarks of cancer in different experimental models. Numerous epidemiological studies show a reduced incidence of cancer and improved survival outcomes in patients taking RAS inhibitors, although some studies have shown no such effect. The discovery of ESC-like cells that express RAS components in infantile hemangioma (IH) underscores the paradigm shift in the understanding of its programmed biologic behavior and accelerated involution induced by ß-blockers and angiotensin-converting enzyme inhibitors. The findings of SOX18 inhibition by R-propranolol suggests the possibility of targeting ESC-like cells in IH without ß-adrenergic blockade, and its associated side effects. This article provides an overview of the current knowledge of ESC-like cells and the RAS in VAs, cancer, and fibroproliferative conditions. It also highlights new lines of research and potential novel therapeutic approaches for these unsolved problems in plastic surgery, by targeting the ESC-like cells through manipulation of the RAS, its bypass loops and converging signaling pathways using existing low-cost, commonly available, and safe oral medications.
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Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)-a small population of highly tumorigenic cancer cells with pluripotency and self-renewal properties, at the apex of a cellular hierarchy. CSCs drive metastasis and treatment resistance and are sustained by a dynamic tumor microenvironment (TME). Numerous pathways mediate communication between CSCs and/or the surrounding TME. These include a paracrine renin-angiotensin system and its convergent signaling pathways, the immune system, and other signaling pathways including the Notch, Wnt/ß-catenin, and Sonic Hedgehog pathways. Appreciation of the mechanisms underlying metastasis and treatment resistance, and the pathways that regulate CSCs and the TME, is essential for developing a durable treatment for cancer. Pre-clinical and clinical studies exploring single-point modulation of the pathways regulating CSCs and the surrounding TME, have yielded partial and sometimes negative results. This may be explained by the presence of uninhibited alternative signaling pathways. An effective treatment of cancer may require a multi-target strategy with multi-step inhibition of signaling pathways that regulate CSCs and the TME, in lieu of the long-standing pursuit of a 'silver-bullet' single-target approach.
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Glioblastoma, a grade IV astrocytoma, is regarded as the most aggressive primary brain tumour with an overall median survival of 16.0 months following the standard treatment regimen of surgical resection, followed by radiotherapy and chemotherapy with temozolomide. Despite such intensive treatment, the tumour almost invariably recurs. This poor prognosis has most commonly been attributed to the initiation, propagation, and differentiation of cancer stem cells. Despite the unprecedented advances in biomedical research over the last decade, the current in vitro models are limited at preserving the inter- and intra-tumoural heterogeneity of primary tumours. The ability to understand and manipulate complex cancers such as glioblastoma requires disease models to be clinically and translationally relevant and encompass the cellular heterogeneity of such cancers. Therefore, brain cancer research models need to aim to recapitulate glioblastoma stem cell function, whilst remaining amenable for analysis. Fortunately, the recent development of 3D cultures has overcome some of these challenges, and cerebral organoids are emerging as cutting-edge tools in glioblastoma research. The opportunity to generate cerebral organoids via induced pluripotent stem cells, and to perform co-cultures with patient-derived cancer stem cells (GLICO model), has enabled the analysis of cancer development in a context that better mimics brain tissue architecture. In this article, we review the recent literature on the use of patient-derived glioblastoma organoid models and their applicability for drug screening, as well as provide a potential workflow for screening using the GLICO model. The proposed workflow is practical for use in most laboratories with accessible materials and equipment, a good first pass, and no animal work required. This workflow is also amenable for analysis, with separate measures of invasion, growth, and viability.