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Maintenance of the proteasome requires oxidative phosphorylation (ATP) and mitigation of oxidative damage, in an increasingly dysfunctional relationship with aging. SLC3A2 plays a role on both sides of this dichotomy as an adaptor to SLC7A5, a transporter of branched-chain amino acids (BCAA: Leu, Ile, Val), and to SLC7A11, a cystine importer supplying cysteine to the synthesis of the antioxidant glutathione. Endurance in mammalian muscle depends in part on oxidation of BCAA; however, elevated serum levels are associated with insulin resistance and shortened lifespans. Intriguingly, the evolution of modern birds (Neoaves) has entailed the purging of genes including SLC3A2, SLC7A5, -7, -8, -10, and SLC1A4, -5, largely removing BCAA exchangers and their interacting Na+/Gln symporters in pursuit of improved energetics. Additional gene purging included mitochondrial BCAA aminotransferase (BCAT2), pointing to reduced oxidation of BCAA and increased hepatic conversion to triglycerides and glucose. Fat deposits are anhydrous and highly reduced, maximizing the fuel/weight ratio for prolonged flight, but fat accumulation in muscle cells of aging humans contributes to inflammation and senescence. Duplications of the bidirectional α-ketoacid transporters SLC16A3, SLC16A7, the cystine transporters SLC7A9, SLC7A11, and N-glycan branching enzymes MGAT4B, MGAT4C in Neoaves suggests a shift to the transport of deaminated essential amino acid, and stronger mitigation of oxidative stress supported by the galectin lattice. We suggest that Alfred Lotka's theory of natural selection as a maximum power organizer (PNAS 8:151,1922) made an unusually large contribution to Neoave evolution. Further molecular analysis of Neoaves may reveal novel rewiring with applications for human health and longevity.
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Aves , Evolução Molecular , Longevidade , Animais , Humanos , Aminoácidos de Cadeia Ramificada/metabolismo , Cistina/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Fígado/metabolismo , Longevidade/genética , Aves/genética , Aves/metabolismo , Cadeia Pesada da Proteína-1 Reguladora de Fusão/genética , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Seleção GenéticaRESUMO
OBJECTIVE: The aim of the present study was to compare the effect of radiotherapy (RT) on abdominal recurrence-free survival (ARFS) in patients with primary retroperitoneal sarcoma treated in the EORTC-STBSG-62092 (STRASS) phase 3 randomized controlled trial (STRASS cohort) and off-trial (STREXIT cohort) and to pool STRASS and STREXIT data to test the hypothesis that RT improves ARFS in patients with liposarcoma. BACKGROUND: The STRASS trial did not show any difference in ARFS between patients treated with preoperative radiotherapy+surgery (RT+S) versus surgery alone (S). METHODS: All consecutive adult patients not enrolled in STRASS and underwent curative-intent surgery for a primary retroperitoneal sarcoma with or without preoperative RT between 2012 and 2017 (STRASS recruiting period) among ten STRASS-recruiting centres formed the STREXIT cohort. The effect of RT in STREXIT was explored with a propensity score (PS)-matching analysis. Primary endpoint was ARFS defined as macroscopically incomplete resection or abdominal recurrence or death of any cause, whichever occurred first. RESULTS: STRASS included 266 patients, STREXIT included 831 patients (727 after excluding patients who received preoperative chemotherapy, 202 after 1:1 PS-matching). The effect of RT on ARFS in STRASS and 1:1 PS-matched STREXIT cohorts, overall and in patients with liposarcoma, was similar. In the pooled cohort analysis, RT administration was associated with better ARFS in patients with liposarcoma [N=321, hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.42-0.89]. In particular, patients with well-differentiated liposarcoma and G1-2 dedifferentiated liposarcoma (G1-2 DDLPS, n=266) treated with RT+S had better ARFS (HR, 0.63; 95% CI, 0.40-0.97) while patients with G3 DDLPS and leiomyosarcoma had not. At the current follow-up, there was no association between RT and overall survival or distant metastases-free survival. CONCLUSIONS: In this study, preoperative RT was associated with better ARFS in patients with primary well-differentiated liposarcoma and G1-2 DDLPS.
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Lipossarcoma , Neoplasias Retroperitoneais , Sarcoma , Adulto , Humanos , Sarcoma/radioterapia , Sarcoma/cirurgia , Lipossarcoma/radioterapia , Lipossarcoma/cirurgia , Neoplasias Retroperitoneais/radioterapia , Neoplasias Retroperitoneais/cirurgia , Espaço Retroperitoneal , Modelos de Riscos Proporcionais , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: Retroperitoneal sarcoma (RPS)-specific nomograms provide estimates of survival and recurrence risk following resection in the individual patient. The effect of preoperative treatment on nomogram performance has not been previously examined. Our aim was to evaluate the predictive accuracy of existing RPS-specific nomograms in patients managed at our center, where the majority of patients received preoperative radiation. PATIENTS AND METHODS: All patients who underwent curative treatment for primary RPS at Mount Sinai Hospital/Princess Margaret Hospital between 1996 and 2016 were identified. The performance of four previously published nomograms was assessed by measuring the agreement between nomogram-predicted and observed outcomes using Harrell's C-Index and level of calibration. Outcomes included in each of the nomograms [overall survival (OS), disease-free survival (DFS), disease-specific death (DSD), local recurrence (LR), distant recurrence (DR)] at each of the specified post-resection timepoints were examined. RESULTS: In total, 253 patients were included. When observed outcomes were compared with those predicted by each of the four nomograms, the C-Index ranged from 0.60 to 0.81, representing a wide range of predictive accuracy. The lowest C-Index was for prediction of LR. Calibration plots revealed that the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram predicted a 5-year LR of 45%, whereas the observed LR was 24%. Overprediction of LR was detected in patients who had undergone preoperative radiotherapy, but not in patients treated with surgery alone. CONCLUSIONS: Preoperative radiotherapy appeared to preclude the use of the LR component of existing nomograms for primary RPS. Updated nomograms should be created to reflect this variable, particularly in light of the recently published STRASS trial results.
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Neoplasias Retroperitoneais , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Recidiva Local de Neoplasia/cirurgia , Nomogramas , Neoplasias Retroperitoneais/cirurgia , Sarcoma/cirurgiaRESUMO
Prior to the COVID-19 pandemic, patients attending ambulatory clinics at cancer centers in Ontario completed the Edmonton Symptom Assessment Scale (ESAS) at each visit. At our center, completion was via touchpad, with assistance from clinic volunteers. As of March 2020, clinic appointments were conducted virtually when possible and touch pads removed. We anticipated a negative impact on the collection of patient-reported outcomes (PROs) and the recognition of severe symptoms. METHODS: We performed a prospective cross-sectional cohort study to investigate remote ESAS completion by patients with appointments at a weekly surgical oncology clinic. Patients in the initial study cohort were asked to complete and return the ESAS virtually (V). Given low completion rates, the ensuing cohort was asked to complete a hard-copy (HC) ESAS. For the final cohort, we provided remote, personal mentorship by a member of the care team to support virtual electronic ESAS completion (virtual-mentored (VM) cohort). RESULTS: Between May and July 2020, a total of 174 patient encounters were included in the study. For the V cohort, 20/46 patients (44%) successfully completed and returned the electronic ESAS, compared to 49/50 (98%) for the HC cohort. For the VM cohort, the overall completion rate was 74% (58/78); however, 12 of these 58 patients did not independently complete a virtual ESAS. Virtual questionnaire completion was not predicted by age, sex, or tumor site, although patients who completed the ESAS were more likely to be in active management rather than surveillance (p = 0.04). Of all completed forms, 42% revealed a depression score of ≥2, and 27% an anxiety score of ≥4. CONCLUSIONS: We identified significant barriers to the virtual completion of ESAS forms, with a lack of predictive variables. The severe degree of psychological distress reported by ~50% of respondents demonstrates the need for ongoing regular collection/review of these data. Innovative solutions are required to overcome barriers to the virtual collection of PROs.
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COVID-19 , Neoplasias , Estudos Transversais , Humanos , Neoplasias/psicologia , Pandemias , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Avaliação de SintomasRESUMO
INTRODUCTION: Surgeons may choose an open approach to locally advanced colon cancer (LACC) because of the elevated conversion rate (minimally invasive to open) in these patients (resulting in part from a judgment of the technical feasibility of a minimally invasive approach). Poorer outcomes have been suggested in those requiring conversion from a minimal access to an open approach; however, the influence of conversion has not been studied in LACC. We sought to compare perioperative outcomes in patients with T4aN2 colon cancer undergoing minimally invasive surgery (MIS), planned open (PO), and converted (CN) procedures to evaluate the influence of conversion in this subgroup. METHODS: A retrospective cohort study was conducted using the NSQIP database. Patients with T4aN2 colon cancer undergoing elective resection were included; rectal/unknown tumor location, and T4b disease were excluded (to ensure homogeneity in surgical management). Patients were divided into cohorts based on approach: PO, MIS, and CN. Summary statistics were compared between groups. Multivariable analysis was conducted for mortality and morbidity outcomes. RESULTS: 1286 cases were included (313 PO, 842 MIS, 131 CN); 10.2% underwent conversion. Those undergoing MIS had a shorter length of stay than those undergoing PO or CN (p < 0.0001). On univariable analysis, CN resulted in increased rates of any complication (p < 0.0001). CN also had a greater rate of anastomotic leak (p = 0.0046) and death (p = 0.05). On multivariable analysis, significant predictors of any complication included age, ASA class, M stage, and approach; however, CN did not increase the risk of complication compared with MIS, whereas PO nearly doubled the risk of complication (OR = 1.98, p = 0.0083). The only significant predictor of mortality on multivariable analysis was age (HR = 1.09, p = 0.0002)-approach was not associated with mortality. CONCLUSION: PO confers the greatest risk of suffering any complication. Surgical approach was not associated with death. Results of our study challenge the notion that conversion is associated with the worst perioperative outcomes and an MIS approach should be considered in patients with LACC.
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Neoplasias do Colo , Laparoscopia , Neoplasias Retais , Procedimentos Cirúrgicos Robóticos , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Procedimentos Cirúrgicos Eletivos/métodos , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Tempo de Internação , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Neoplasias Retais/cirurgia , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do TratamentoRESUMO
BACKGROUND: This study aimed to investigate changes in treatment strategy and outcome for patients with primary retroperitoneal sarcoma (RPS) undergoing resection at referral centers during a recent period. METHODS: The study enrolled consecutive adult patients with primary non-metastatic RPS who underwent resection with curative intent between 2002 and 2017 at 10 referral centers. The patients were grouped into three periods according to date of surgery: t1 (2002-2006), t2 (2007-2011), and t3 (2012-2017). Five-year overall survival (OS), disease-specific survival (DSS), and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were calculated. Multivariable analyses for OS and DSS were performed. RESULTS: The study included 1942 patients. The median follow-up period after resection varied from 130 months (interquartile range [IQR], 124-141 months) in t1 to 37 months (IQR, 35-39 months) in t3. The 5-year OS was 61.2% (95% confidence interval [CI], 56.4-66.3%) in t1, 67.0% (95 CI, 63.2-71.0%) in t2, and 71.9% (95% CI, 67.7-76.1%) in t3. The rate of macroscopically incomplete resection (R2) was 7.1% in t1 versus 4.7% in t3 (p = 0.066). The median number of resected organs increased over time (p < 0.001). In the multivariable analysis resection during t3 was associated with better OS and DSS. The 90-day postoperative mortality improved over time (4.3% in t1 to 2.3% in t3; p = 0.031). The 5-year CCI of LR and DM did not change significantly over time. CONCLUSIONS: The long-term survival of patients who underwent resection for primary RPS has increased during the past 15 years. This increased survival is attributable to better patient selection for resection, quality of surgery, and perioperative patient management.
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Neoplasias Ósseas , Neoplasias Retroperitoneais , Sarcoma , Adulto , Seguimentos , Humanos , Recidiva Local de Neoplasia/cirurgia , Neoplasias Retroperitoneais/cirurgia , Estudos Retrospectivos , Sarcoma/cirurgia , Taxa de SobrevidaRESUMO
BACKGROUND: Retroperitoneal soft tissue sarcomas comprise a heterogeneous group of rare tumors of mesenchymal origin that include several well-defined histologic subtypes. In 2015, the Transatlantic Australasian RPS Working Group (TARPSWG) published consensus recommendations for the best management of primary retroperitoneal sarcoma (RPS). Since then, through international collaboration, new evidence and knowledge have been generated, creating the need for an updated consensus document. METHODS: The primary aim of this study was to critically evaluate the current evidence and develop an up-to-date consensus document on the approach to these difficult tumors. The resulting document applies to primary RPS that is non-visceral in origin, with exclusion criteria as previously described. The relevant literature was evaluated and an international group of experts consulted to formulate consensus statements regarding the best management of primary RPS. A level of evidence and grade of recommendation were attributed to each new/updated recommendation. RESULTS: Management of primary RPS was considered from diagnosis to follow-up. This rare and complex malignancy is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, and an individualized management plan should be made based on the 29 consensus statements included in this article, which were agreed upon by all of the authors. Whenever possible, patients should be enrolled in prospective trials and studies. CONCLUSIONS: Ongoing international collaboration is critical to expand upon current knowledge and further improve outcomes of patients with RPS. In addition, prospective data collection and participation in multi-institution trials are strongly encouraged.
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Neoplasias Ósseas , Neoplasias Retroperitoneais , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Consenso , Humanos , Neoplasias Retroperitoneais/cirurgia , Sarcoma/terapiaAssuntos
Nefrectomia/métodos , Neoplasias Retroperitoneais/cirurgia , Sarcoma/cirurgia , Fatores Etários , Idoso , Tomada de Decisão Clínica , Taxa de Filtração Glomerular , Humanos , Pessoa de Meia-Idade , Nefrectomia/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/terapia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal , Neoplasias Retroperitoneais/complicações , Estudos Retrospectivos , Fatores de Risco , Sarcoma/complicaçõesRESUMO
BACKGROUND: Studies comparing conversion from laparoscopic to open approaches to colectomy have found an association between conversion and morbidity, mortality, and length of stay, suggesting that certain patients may benefit from an open approach "up-front." AIM: The objective of this study was to use machine learning algorithms to develop a model enabling the prediction of which patients are likely to require conversion. METHODS AND RESULTS: We used ACS NSQIP data to identify patients undergoing colectomy (2014-2019). We included patients undergoing elective colectomy for colorectal neoplasm via a minimally invasive approach or a converted approach. The outcome of interest was conversion. Variables were included in the model based on their correlation with conversion by logistic regression (p < .05). Two models were used: weighted logistic regression with regularization, and Random Forest classifier. The data was randomly split into training (70%) and test (30%) cohorts, and prediction performance was calculated. 24 327 cases were included (17 028 training, 7299 test). When applied to the test cohort, the models had an accuracy of 0.675 (range 0.65-0.70) in predicting conversion; c-index ranged from 0.62-0.63. This machine learning model achieved a moderate area under the curve and a high negative predictive value, but a low positive predictive value; therefore, this model can predict (with 95% accuracy) whether a colectomy for neoplasm can be successfully completed using a minimally invasive approach. CONCLUSION: This model can be used to reassure surgeons of the appropriateness of a minimally invasive approach when planning for an elective colectomy.
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Neoplasias Colorretais , Humanos , Estudos Retrospectivos , Neoplasias Colorretais/cirurgia , Modelos Logísticos , ColectomiaRESUMO
INTRODUCTION: Retroperitoneal sarcomas (RPS) are rare mesenchymal tumors that account for only 0.1-0.2% of all malignancies. Management of this disease is challenging, and resection remains the cornerstone of treatment. Ongoing international collaboration has expanded our knowledge of this disease, allowing for a more personalized approach to RPS patients resulting in improved survival over time. Due to the heterogeneity of RPS, with differing recurrence patterns and sensitivities to neoadjuvant therapies based on histology and grade, management of RPS should be tailored to the individual patient. AREAS COVERED: Our review focuses on a histology-driven approach in the management of primary RPS. We searched relevant articles from 1993 to 2023 that investigated prognostic factors and treatment of patients with RPS and summarized recent advances and future directions in the field. EXPERT OPINION: Deeper understanding of the role of neoadjuvant radiotherapy and ongoing trials investigating the role of neoadjuvant chemotherapy will potentially contribute to the development of individualized treatment pathways.
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Neoplasias Retroperitoneais , Sarcoma , Humanos , Estudos Retrospectivos , Sarcoma/patologia , Neoplasias Retroperitoneais/patologia , Terapia Neoadjuvante , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/patologiaRESUMO
PURPOSE OF REVIEW: Supportive and palliative care services have been an important component of the overall COVID-19 pandemic response. However, significant changes in the provision and models of care were needed in order to optimize the care delivered to vulnerable cancer patients. This review discusses the evolution of palliative and supportive care service in response to the pandemic, and highlights remaining challenges. RECENT FINDINGS: Direct competition for resources, as well as widespread implementation of safety measures resulted in major shifts in the mode of assessment and communication with cancer patients by supportive care teams. Telemedicine/virtual consultation and follow-up visits became an integral strategy, with high uptake and satisfaction amongst patients, families and providers. However, inequities in access to the required technologies were sometimes exposed. Hospice/palliative care unit (PCU) bed occupancy declined markedly because of restrictive visitation policies. Collection of patient-reported outcome (PRO) data was suspended in many cancer centers, with resulting under-recognition of anxiety and depression in ambulatory patients. As in many other areas, disparities in delivery of supportive and palliative care were magnified by the pandemic. SUMMARY: Virtual care platforms have been widely adopted and will continue to be used to include a wider circle of family/friends and care providers in the provision of palliative and supportive care. To facilitate equitable delivery of supportive care within a pandemic, further research and resources are needed to train and support generalists and palliative care providers. Strategies to successfully collect PROs from all patients in a virtual manner must be developed and implemented.
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COVID-19 , Neoplasias , Telemedicina , COVID-19/epidemiologia , Humanos , Oncologia , Neoplasias/epidemiologia , Neoplasias/terapia , Cuidados Paliativos/métodos , PandemiasRESUMO
Tumor budding (TB) and poorly differentiated clusters (PDCs) are powerful prognostic factors in colorectal cancer (CRC). Despite their morphologic and biological overlap, TB and PDC are assessed separately and are distinguished by an arbitrary cutoff for cell cluster size. This cutoff can be challenging to apply in practice and its biological significance remains unclear. We developed a novel scoring system that incorporates TB and PDC into a single parameter ("Combined Score"; CS), eliminating the need for such cutoffs and allowing the prognostic value of PDC to be captured alongside TB. In a cohort of 481 stage I-III CRC resections, CS was significantly associated with American Joint Committee on Cancer (AJCC) stage, T-stage, N-stage, histologic grade, tumor deposits, lymphovascular invasion, and perineural invasion ( P <0.0001). In addition, CS was significantly associated with decreased 5-year recurrence-free survival, overall survival, and disease-specific survival ( P <0.0001). TB and PDC showed similar associations with oncologic outcomes, with hazard ratios consistently lower than for CS. The association between CS and oncologic outcomes remained significant in subgroup analyses stratified by AJCC stage, anatomic location (rectum/colon) and neoadjuvant therapy status. On multivariable analysis, CS retained its significant association with oncologic outcomes ( P =0.0002, 0.005, and 0.009) for recurrence-free survival, disease-specific survival, and overall survival, respectively. In conclusion, CS provides powerful risk stratification in CRC which is at least equivalent to that of TB and PDC assessed individually. If validated elsewhere, CS has practical advantages and a biological rationale that may make it an attractive alternative to assessing these features separately.
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Neoplasias Colorretais , Neuroblastoma , Neoplasias Colorretais/patologia , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Neuroblastoma/patologia , Prognóstico , Estudos RetrospectivosRESUMO
Gastric adenocarcinoma, commonly known as stomach cancer, has a predilection for metastasis to the peritoneum, which portends limited survival. The peritoneal metastatic cascade remains poorly understood, and existing models fail to recapitulate key elements of the interaction between cancer cells and the peritoneal layer. To explore the underlying cellular and molecular mechanisms of peritoneal metastasis, we developed an ex vivo human peritoneal explant model. Fresh peritoneal tissue samples were suspended, mesothelial layer down but without direct contact, above a monolayer of red-fluorescent dye stained AGS human gastric adenocarcinoma cells for 24 h, then washed thoroughly. Implantation of AGS cells within the explanted peritoneum and invasion beyond the mesothelial layer were examined serially using real-time confocal fluorescence microscopy. Histoarchitecture of the explanted peritoneum was preserved over 5 days ex vivo. Both implantation and invasion were suppressed by restoration of functional E-cadherin through stable transfection of AGS cells, demonstrating sensitivity of the model to molecular manipulation. Thus, our ex vivo human peritoneal explant model permits meaningful investigation of the pathways and mechanism that contribute to peritoneal metastasis. The model will facilitate screening of new therapies that target peritoneal dissemination of gastric, ovarian and colorectal cancer.
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Adenocarcinoma , Neoplasias Peritoneais , Neoplasias Gástricas , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Peritoneais/secundário , Peritônio/patologia , Neoplasias Gástricas/patologiaRESUMO
PURPOSE: The aim of this study was to create and validate dynamic nomograms to predict overall survival (OS) and disease-free survival (DFS) at different time points during follow-up in patients who had undergone resection of primary retroperitoneal sarcoma (RPS). METHODS: Patients with primary RPS operated upon between 2002 and 2017 at four and six referral centres comprised the development and external validation cohorts, respectively. Landmark analysis and multivariable Cox models were used to develop dynamic nomograms. Variables were selected using two backward procedures based on the Akaike information criterion. The prediction window was fixed at 5 years. Nomogram performances were tested in terms of calibration and discrimination on the development and validation cohorts. RESULTS: Development and validation cohorts totalled 1357 and 487 patients (OS analysis), and 1309 and 452 patients (DFS analysis), respectively. The final OS model included age, landmark time (TLM), tumour grade, completeness of resection and occurrence of local/distant recurrence. The final DFS model included TLM, histologic subtype, tumour size, tumour grade, multifocality and the interaction terms between TLM and size, grade and multifocality. For OS, Harrell C indices were higher than 0.7 in both cohorts, indicating very good discriminative capability. For DFS, Harrell C indices were between 0.64 and 0.72 in the development cohort and 0.62 and 0.68 in the validation cohort. Calibration plots showed good agreement between predicted and observed outcomes. CONCLUSION: Validated nomograms are available to predict the 5-year OS and DFS probability at different time points throughout the first 5 years of follow-up in RPS survivors.
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Sobreviventes de Câncer/estatística & dados numéricos , Recidiva Local de Neoplasia/epidemiologia , Nomogramas , Neoplasias Retroperitoneais/mortalidade , Sarcoma/mortalidade , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Neoplasias Retroperitoneais/cirurgia , Sarcoma/cirurgia , Adulto JovemRESUMO
Polo like kinase 4 (Plk4) is a tightly regulated serine threonine kinase that governs centriole duplication. Increased Plk4 expression, which is a feature of many common human cancers, causes centriole overduplication, mitotic irregularities, and chromosomal instability. Plk4 can also promote cancer invasion and metastasis through regulation of the actin cytoskeleton. Herein we demonstrate physical interaction of Plk4 with FAM46C/TENT5C, a conserved protein of unknown function until recently. FAM46C localizes to centrioles, inhibits Plk4 kinase activity, and suppresses Plk4-induced centriole duplication. Interference with Plk4 function by FAM46C was independent of the latter's nucleotidyl transferase activity. In addition, FAM46C restrained cancer cell invasion and suppressed MDA MB-435 cancer growth in a xenograft model, opposing the effect of Plk4. We demonstrate loss of FAM46C in patient-derived colorectal cancer tumor tissue that becomes more profound with advanced clinical stage. These results implicate FAM46C as a tumor suppressor that acts by inhibiting Plk4 activity.
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Genes Supressores de Tumor , Nucleotidiltransferases/metabolismo , Animais , Linhagem Celular Tumoral , Centríolos/metabolismo , Neoplasias Colorretais/patologia , Sequência Conservada , Humanos , Camundongos Nus , Fosforilação , Ligação Proteica , Domínios Proteicos , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Curative treatment of RPS is predicated on complete macroscopic resection, but this is not appropriate in all cases, for a variety of tumour-, patient- and/or treatment-related reasons. Here we review the available literature to glean data that can guide patient selection for major extirpative surgery with its attendant risks or for palliative-intent management that emphasizes quality of life.
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Cuidados Paliativos/métodos , Neoplasias Retroperitoneais/terapia , Sarcoma/terapia , Tomada de Decisões , Feminino , Humanos , Masculino , Neoplasias Retroperitoneais/patologia , Sarcoma/patologiaRESUMO
INTRODUCTION: The evaluation of lymph nodes and the role of groin dissection for groin sarcomas has been controversial where there have not been previous studies or guidelines published. In this study, we aim to first formulate a clinical approach in the evaluation of regional lymph nodal metastases. Second, we aim to also evaluate the role of regional lymphadenectomy in the setting of pathologically involved regional lymph nodes for groin sarcomas. MATERIALS AND METHODS: In total, 43 consecutive patients with groin sarcomas underwent treatment at the National Cancer Centre Singapore between 2002 and 2015. Univariate comparisons were performed using the log-rank test. A Cox multivariate analysis was performed for disease-specific survival to identify independent prognostic factors. RESULTS: The median disease-free survival was 18 months (range, 1 to 180 mo). The median overall survival (OS) was 28 months (range, 3 to 180 mo). In total, 28 patients underwent a groin dissection. Of the 28 patients who underwent groin dissections, 15 had negative lymph node involvement, 7 had positive lymph node involvement and 6 had lymphovascular invasion.On univariate analysis, grade (P=0.047) and clinical and/or radiological involvement (P=0.039) were significant for regional lymph nodal metastases.The 5-year OS for patients with positive lymph nodes was 31%. CONCLUSIONS: Our study suggests that the evaluation of lymph nodes via groin dissections in groin sarcomas in the Asian population should be based primarily on clinical and radiologic evidence. Regional lymph node dissection seems to confer OS benefit in patients with these high-risk tumors and can improve local control of disease.
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Neoplasias Ósseas/secundário , Condrossarcoma/patologia , Virilha/patologia , Sarcoma de Células Claras/secundário , Neoplasias Cutâneas/secundário , Adulto , Neoplasias Ósseas/cirurgia , Condrossarcoma/cirurgia , Feminino , Seguimentos , Virilha/cirurgia , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Sarcoma de Células Claras/cirurgia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/cirurgia , Taxa de SobrevidaRESUMO
INTRODUCTION: Currently, factors such as size, mitotic rate, and degree of necrosis have been shown to influence survival in patients with solitary fibrous tumors (SFTs); however, there remains no consensus regarding the associations between tumor characteristics and the malignant nature of these tumors. The aim of this article was to identify factors that would help in prognosticating SFTs and to validate the MD Anderson Cancer Center (MDACC) SFT nomogram in the largest known series of SFTs treated in an Asian population. METHODS: A retrospective review of all patients with a diagnosis of SFT treated surgically in our institution between 2005 and 2015 was carried out. Basic demographics, clinicopathological, and surgical factors were analyzed for association with clinical outcomes. Factors that predicted for distant recurrence (DR) and poor survival were identified as high-risk features. The MDACC nomogram was validated by assessing the extent of discrimination, quantified using Harrell's concordance index (C-index). RESULTS: Fifty-nine patients were included in analysis. Significant univariate associations for DR were found for mitotic rate ( P = .05) and presence of necrosis ( P = .04). Significant univariate associations for overall survival were found for presence of recurrence ( P = .035), presence of necrosis ( P = .072), and mitotic rate ( P = .033). The C-index associated with the nomogram was 0.75. CONCLUSION: There is a negative association for DR and overall survival, with the mitotic rate and presence of necrosis. We propose that SFTs with these features should be regarded as high risk. The MDACC nomogram generally predicts well for patients in an Asian population.
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Nomogramas , Tumores Fibrosos Solitários/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Tumores Fibrosos Solitários/mortalidade , Adulto JovemRESUMO
Carotid body tumours (CBT) are extremely rare neoplasms that arise from chemoreceptor cells at the bifurcation of the carotid artery. This rarity poses a challenge for the anaesthetist when dealing with surgeries for the removal of CBT. Reports of associated perioperative morbidity range from twenty to forty percent. This paper reviews the perioperative anaesthetic management of CBT patients and challenges in our institution's 20 year experience on 13 surgical CBT resections.