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Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages. Whether TRMs and monocyte-derived macrophages have district roles under differing pathologies is not understood. Here, we showed that a substantial portion of the macrophages that accumulated during pancreatitis and pancreatic cancer in mice had expanded from TRMs. Pancreas TRMs had an extracellular matrix remodeling phenotype that was important for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and death, due to impaired acinar cell survival and recovery. During pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.
Assuntos
Pâncreas , Pancreatite , Camundongos , Animais , Pâncreas/patologia , Macrófagos , Pancreatite/genética , Pancreatite/patologia , Fibrose , Neoplasias PancreáticasRESUMO
Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1-4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.
Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias , Humanos , Hipóxia Celular , Núcleo Celular , Cromatina/genética , Cromatina/metabolismo , Elementos Facilitadores Genéticos/genética , Epigênese Genética/genética , Transição Epitelial-Mesenquimal , Estrogênios/metabolismo , Perfilação da Expressão Gênica , Proteínas Ativadoras de GTPase/metabolismo , Metástase Neoplásica , Neoplasias/classificação , Neoplasias/genética , Neoplasias/patologia , Sequências Reguladoras de Ácido Nucleico/genética , Análise de Célula Única , Fatores de Transcrição/metabolismoRESUMO
Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling molecules in the extracellular matrix. Collectively, these findings uncover the heterogeneity of TAM origin and functions and could provide therapeutic insight for PDAC treatment.
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Carcinogênese , Carcinoma Ductal/imunologia , Macrófagos/imunologia , Pâncreas/patologia , Neoplasias Pancreáticas/imunologia , Animais , Carcinoma Ductal/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Matriz Extracelular/metabolismo , Desenvolvimento Fetal , Fibrose , Hematopoese , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Neoplasias Pancreáticas/patologia , Microambiente TumoralRESUMO
Single-cell RNA sequencing (scRNA-seq) is a powerful technology to investigate the transcriptional programs in stromal, immune, and disease cells, like tumor cells or neurons within the Alzheimer's Disease (AD) brain or tumor microenvironment (ME) or niche. Cell-cell communications within ME play important roles in disease progression and immunotherapy response and are novel and critical therapeutic targets. Though many tools of scRNA-seq analysis have been developed to investigate the heterogeneity and sub-populations of cells, few were designed for uncovering cell-cell communications of ME and predicting the potentially effective drugs to inhibit the communications. Moreover, the data analysis processes of discovering signaling communication networks and effective drugs using scRNA-seq data are complex and involve a set of critical analysis processes and external supportive data resources, which are difficult for researchers who have no strong computational background and training in scRNA-seq data analysis. To address these challenges, in this study, we developed a novel open-source computational tool, sc2MeNetDrug (https://fuhaililab.github.io/sc2MeNetDrug/). It was specifically designed using scRNA-seq data to identify cell types within disease MEs, uncover the dysfunctional signaling pathways within individual cell types and interactions among different cell types, and predict effective drugs that can potentially disrupt cell-cell signaling communications. sc2MeNetDrug provided a user-friendly graphical user interface to encapsulate the data analysis modules, which can facilitate the scRNA-seq data-based discovery of novel inter-cell signaling communications and novel therapeutic regimens.
Assuntos
Análise de Célula Única , Software , RNA-Seq , Análise de Sequência de RNA , Perfilação da Expressão Gênica , Transdução de Sinais/genéticaRESUMO
Cancer-derived extracellular vesicles (EVs) promote tumorigenesis, premetastatic niche formation, and metastasis via their protein cargo. However, the proteins packaged by patient tumors into EVs cannot be determined in vivo because of the presence of EVs derived from other tissues. We therefore developed a cross-species proteomic method to quantify the human tumor-derived proteome of plasma EVs produced by patient-derived xenografts of four cancer types. Proteomic profiling revealed individualized packaging of novel protein cargo, and machine learning accurately classified the type of the underlying tumor.
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Vesículas Extracelulares , Neoplasias , Humanos , Proteômica , Vesículas Extracelulares/metabolismo , Neoplasias/metabolismo , Comunicação Celular , Proteoma/metabolismoRESUMO
The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/terapia , Melanoma/diagnóstico , Melanoma/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Estadiamento de Neoplasias , Oncologia/normas , Oncologia/métodosRESUMO
BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS. METHODS: From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at seven academic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR), time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed. RESULTS: Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLR recurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation. CONCLUSION: For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.
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Recidiva Local de Neoplasia , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia , Idoso , Estados Unidos/epidemiologia , Sarcoma/patologia , Sarcoma/mortalidade , Sarcoma/cirurgia , Sarcoma/terapia , Taxa de Sobrevida , Adulto , Seguimentos , Prognóstico , Idoso de 80 Anos ou mais , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/cirurgia , Neoplasias de Tecidos Moles/terapiaRESUMO
BACKGROUND: Radiographic calcifications and cystic morphology are associated with higher and lower tumor grade, respectively, in pancreatic neuroendocrine tumors (PNETs). Whether calcifications and/or cystic morphology could be used preoperatively to predict post-resection survival in patients with PNETs remains elusive. METHODS: Patients undergoing curative-intent resection of well-differentiated PNETs from 2000 to 2017 at eight academic institutions participating in the US Neuroendocrine Tumor Study Group were identified. Preoperative cross-sectional imaging reports were reviewed to identify the presence of calcifications and of a cystic component occupying >50% of the total tumor area. Clinicopathologic characteristics and recurrence-free survival (RFS) were compared. RESULTS: Of 981 patients studied, 18% had calcifications and 17% had cystic tumors. Tumors with calcifications were more commonly associated with Ki-67 ≥3% (47% vs. 33%; p = 0.029), lymph node metastasis (36% vs. 24%; p = 0.011), and distant metastasis (13% vs. 4%; p < 0.001). In contrast, cystic tumors were less commonly associated with lymph node metastasis (12% vs. 30%; p < 0.001). Five-year RFS after resection was most favorable for cystic tumors without calcifications (91%), intermediate for solid tumors without calcifications (77%), and least favorable for any calcified PNET (solid 69%, cystic 67%; p = 0.043). Calcifications remained an independent predictor of RFS on multivariable analysis (p = 0.043) controlling for nodal (p < 0.001) and distant metastasis (p = 0.001). CONCLUSIONS: Easily detectable radiographic features, such as calcifications and cystic morphology, can be used preoperatively to stratify prognosis in patients with PNETs and possibly inform the decision to operate or not, as well as guide the extent of resection and potential use of neoadjuvant therapy.
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Calcinose , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/cirurgia , Metástase Linfática , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Pancreatectomia , Calcinose/diagnóstico por imagem , Calcinose/cirurgia , Tumores Neuroectodérmicos Primitivos/cirurgiaRESUMO
BACKGROUND: An increasing number of hepatic artery infusion (HAI) programs have been established worldwide. Practice patterns for this complex therapy across these programs have not been reported. This survey aimed to identify current practice patterns in HAI therapy with the long-term goal of defining best practices and performing prospective studies. METHODS: Using SurveyMonkeyTM, a 28-question survey assessing current practices in HAI was developed by 12 HAI Consortium Research Network (HCRN) surgical oncologists. Content analysis was used to code textual responses, and the frequency of categories was calculated. Scores for rank-order questions were generated by calculating average ranking for each answer choice. RESULTS: Thirty-six (72%) HCRN members responded to the survey. The most common intended initial indications for HAI at new programs were unresectable colorectal liver metastases (uCRLM; 100%) and unresectable intrahepatic cholangiocarcinoma (uIHC; 56%). Practice patterns evolved such that uCRLM (94%) and adjuvant therapy for CRLM (adjCRLM; 72%) have become the most common current indications for HAI at established centers. Referral patterns for pump placement differed between uCRLM and uIHC, with most patients referred while receiving second- and first-line therapy, respectively, with physicians preferring to evaluate patients for HAI while receiving first-line therapy for CRLM. Concern for extrahepatic disease was ranked as the most important factor when considering a patient for HAI. CONCLUSIONS: Indication and patient selection factors for HAI therapy are relatively uniform across most HCRN centers. The increasing use of adjuvant HAI therapy and overall consistency of practice patterns among HCRN centers provides a robust environment for prospective data collection and randomized clinical trials.
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Cancer models are indispensable research tools for elucidating the mechanisms involved in tumor onset, progression and treatment resistance. They are key in evaluating therapeutics prior clinical trials. In this editorial, we invite contributions for a BMC Cancer's Collection of articles addressing 'Advances in pre-clinical cancer models' towards relivable outcomes at the preclinical stage.
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Neoplasias , Humanos , Neoplasias/patologia , Modelos BiológicosRESUMO
BACKGROUND: The benefit of adjuvant therapy (AT) after curative resection of distal cholangiocarcinoma (DCC) remains unclear. The objective of the current study was to investigate the impact of AT on long-term survival of patients who underwent curative-intent resection for DCC. METHODS: Patients who underwent curative-intent resection for DCC between 2000 and 2020 were identified from a multi-institutional database. The primary outcomes included overall (OS) and recurrence-free survival (RFS). RESULTS: Among 245 patients, 150 (61.2%) patients received AT (chemotherapy alone: n = 43; chemo- and radiotherapy: n = 107) after surgical resection, whereas 95 (38.8%) patients underwent surgery only. Patients who received AT were younger, and more likely to have an advanced tumor with the presence of perineural invasion (PNI), lymph node metastasis (LNM), lymph-vascular invasion, and higher T categories (all p < 0.05). Overall, there was no difference in OS (median, surgery + AT 25.5 vs. surgery alone 24.5 months, p = 0.27) or RFS (median, surgery + AT 15.8 vs. surgery alone 18.9 months, p = 0.24) among patients who did versus did not receive AT. In contrast, AT was associated with improved long-term survival among patients with PNI (median OS, surgery + AT 25.9 vs. surgery alone 17.8 months, p = 0.03; median RFS, surgery + AT 15.9 vs. surgery alone 11.9 months, p = 0.04) and LNM (median, surgery + AT 20.0 vs. surgery alone 17.8 months, p = 0.03), but not among patients with no PNI or LNM (all p > 0.1). CONCLUSIONS: AT was commonly utilized among patients with DCC. Patients with more advanced disease, including the presence of PNI or LNM, benefited the most from AT with improved long-term outcomes among this subset of patients.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/cirurgia , Terapia Combinada , Metástase Linfática/patologia , Ductos Biliares Intra-Hepáticos/patologia , Estudos Retrospectivos , PrognósticoRESUMO
BACKGROUND: This study aimed to define how utilization of plastic surgical reconstruction (PSR) affects perioperative outcomes, locoregional recurrence-free survival (LRRFS), and overall survival (OS) after radical resection of extremity and truncal soft tissue sarcoma (ETSTS). The secondary aim was to determine factors associated with PSR. METHODS: Patients who underwent resection of ETSTS between 2000 and 2016 were identified from a multi-institutional database. PSR was defined as complex primary closure requiring a plastic surgeon, skin graft, or tissue-flap reconstruction. Outcomes included PSR utilization, postoperative complications, LRRFS, and OS. RESULTS: Of 2750 distinct operations, 1060 (38.55%) involved PSR. Tissue-flaps (854, 80.57%) were most commonly utilized. PSR was associated with a higher proportion of R0 resections (83.38% vs. 74.42%, p < 0.001). Tissue-flap PSR was associated with local wound complications (odds ratio: 1.81, confidence interval: 1.21-2.72, p = 0.004). Neither PSR nor postoperative complications were independently associated with LRRFS or OS. High-grade tumors (1.60, 1.13-2.26, p = 0.008) and neoadjuvant radiation (1.66, 1.20-2.30, p = 0.002) were associated with the need for PSR. CONCLUSION: Patients with ETSTS undergoing resection with PSR experienced acceptable rates of complications and a higher rate of negative margins, which were associated with improved LRRFS and OS. High tumor grade and neoadjuvant radiation were associated with requirement of PSR.
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Procedimentos de Cirurgia Plástica , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Extremidades/cirurgia , Extremidades/patologia , Tronco/cirurgia , Tronco/patologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/cirurgia , Sarcoma/patologia , Neoplasias de Tecidos Moles/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: Proton pump inhibitors (PPIs) are effective in reducing marginal ulcers after pancreatoduodenectomy. However, their impact on perioperative complications has not been defined. METHODS: We retrospectively analyzed the effect of postoperative PPIs on 90-day perioperative outcomes in all patients who underwent pancreatoduodenectomy at our institution from April 2017 to December 2020. RESULTS: 284 patients were included; 206 (72.5%) received perioperative PPIs, 78 (27.5%) did not. The two cohorts were similar in demographics and operative variables. Postoperatively, the PPI cohort had significantly higher rates of overall complications (74.3% vs. 53.8%) and delayed gastric emptying (28.6% vs. 11.5%), p < 0.05. However, no differences in infectious complications, postoperative pancreatic fistula, or anastomotic leaks were seen. On multivariate analysis, PPI was independently associated with a higher risk of overall complications (OR 2.46, CI 1.33-4.54) and delayed gastric emptying (OR 2.73, CI 1.26-5.91), p = 0.011. Four patients developed marginal ulcers within 90-days postoperatively; all were in the group who received PPIs. CONCLUSION: Postoperative proton pump inhibitor use was associated with a significantly higher rate of overall complications and delayed gastric emptying after pancreatoduodenectomy.
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Gastroparesia , Úlcera Péptica , Humanos , Inibidores da Bomba de Prótons/efeitos adversos , Pancreaticoduodenectomia/efeitos adversos , Gastroparesia/etiologia , Gastroparesia/prevenção & controle , Estudos Retrospectivos , Úlcera Péptica/induzido quimicamente , Complicações Pós-Operatórias/etiologia , Esvaziamento GástricoRESUMO
BACKGROUND: The impact of neighborhood deprivation on outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) is not well-described and represents an area to improve disparities. METHODS: We retrospectively queried our prospectively maintained database of patients with PDAC (2014-2022). Patients were grouped by Area Deprivation Index (ADI) and rural-urban commuting area (RUCA) codes. Cox proportional hazards models and logistic regressions were used to investigate effect on overall survival (OS) and adjuvant therapy administration. RESULTS: 536 patients were included. High ADI patients (more disadvantaged, n = 184) were more likely to identify as non-Hispanic Black (17.9% vs. 4.8%, p < 0.01) and were more likely to be from rural areas (49.5% vs. 18.5%, p < 0.01). High ADI was independently associated with decreased OS (HR (95% CI): 1.31 (1.01-1.69), p = 0.04). Urban high ADI patients were 3.5 times more likely to receive adjuvant therapy than rural high ADI patients (OR [95% CI]: 3.48 [1.26-9.61], p = 0.02). CONCLUSION: Patients from the most disadvantaged neighborhoods have decreased OS. Access to adjuvant therapy likely contributes to this disparity in rural areas. Investigation into sources of this OS disparity and identification of barriers to adjuvant therapy will be crucial to improve outcomes in underserved patients with PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Terapia Combinada , Neoplasias PancreáticasRESUMO
BACKGROUND: Decreased preoperative physical fitness and low physical activity have been associated with preoperative functional reserve and surgical complications. We sought to evaluate daily step count as a measure of physical activity and its relationship with post-pancreatectomy outcomes. METHODS: Patients undergoing pancreatectomy were given a remote telemonitoring device to measure their preoperative levels of physical activity. Patient activity, demographics, and perioperative outcomes were collected and compared in univariate and multivariate logistic regression analysis. RESULTS: 73 patients were included. 45 (61.6%) patients developed complications, with 17 (23.3%) of those patients developing severe complications. These patients walked 3437.8 (SD 1976.7) average daily steps, compared to 5918.8 (SD 2851.1) in patients without severe complications (p < 0.001). In logistic regression analysis, patients who walked less than 4274.5 steps had significantly higher odds of severe complications (OR = 7.5 (CI 2.1, 26.8), p = 0.002). CONCLUSION: Average daily steps below 4274.5 before surgery are associated with severe complications after pancreatectomy. Preoperative physical activity levels may represent a modifiable target for prehabilitation protocols.
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Pancreatectomia , Complicações Pós-Operatórias , Humanos , Pancreatectomia/efeitos adversos , Fatores de Risco , Complicações Pós-Operatórias/etiologiaRESUMO
BACKGROUND: Frailty is associated with postoperative mortality, but its significance after hepatectomy for colorectal liver metastases (CRLM) is poorly defined. This study evaluated the impact of frailty after hepatectomy for CRLM. METHODS: The study identified 8477 patients in National Surgical Quality Improvement Program databases from 2014 to 2019 and stratified them by frailty score using the risk analysis index as very frail (>90th percentile), frail (75th-90th percentile), or non-frail (< 75th percentile). Multivariate regression models determined the impact of frailty on perioperative outcomes, including by the extent of hepatectomy. RESULTS: The procedures performed were 2752 major hepatectomies (left hepatectomy, right hepatectomy, trisectionectomy) and 5725 minor hepatectomies (≤2 segments) for 870 (10.3%) very frail, 1680 (19.8%) frail, and 5927 (69.9%) non-frail patients. Postoperatively, the very frail and frail patients experienced more complications (very frail [41.8%], frail [35.1%], non-frail [31.0%]), which resulted in a longer hospital stay (very-frail [5.7 days], frail [5.8 days], non-frail [5.1 days]), a higher 30-day mortality (very-frail [2.2%], frail [1.3%], non-frail [0.5%]), and more discharges to a facility (very frail [6.8%], frail [3.7%], non-frail [2.6%]) (p < 0.05) although they underwent similarly extensive (major vs. minor) hepatectomies. In the multivariate analysis, frailty was independently associated with complications (very-frail [odds ratio {OR}, 1.70], frail [OR, 1.25]) and 30-day mortality (very-frail [OR, 4.24], frail [OR, 2.41]) (p < 0.05). After minor hepatectomy, the very frail and frail patients had significantly higher rates of complications and 30-day mortality than the non-frail patients, and in the multivariate analysis, frailty was independently associated with complications (very frail [OR, 1.97], frail [OR, 1.27]) and 30-day mortality (very frail [OR, 6.76], frail [OR, 3.47]) (p < 0.05) after minor hepatectomy. CONCLUSIONS: Frailty predicted significantly poorer outcomes after hepatectomy for CRLM, even after only a minor hepatectomy.
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Neoplasias Colorretais , Fragilidade , Neoplasias Hepáticas , Neoplasias Colorretais/complicações , Neoplasias Colorretais/cirurgia , Fragilidade/complicações , Hepatectomia , Humanos , Tempo de Internação , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Morbidade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Recurrence after curative-intent surgery can occur in more than 50% of gastric cancer (GC) patients. We sought to identify predictors of very early recurrence (VER) among GC patients who underwent curative-intent surgery. METHODS: A multi-institutional database of GC patients undergoing curative-intent surgery between 2000 and 2020 at 8 major institutions was queried. VER was defined as local or distant tumor recurrence within 6 months from surgery. Univariable Cox proportional hazard models were used to evaluate the predictive value of clinical-pathological features on VER. A regularized Cox regression model was employed to build a predictive model of VER and recurrence within 12 months. The discriminant ability of the Cox regularized models was evaluated by reporting a ROC curve together with the calibration plot, considering 200 runs. RESULTS: Among 1133 patients, 65 (16.0%) patients experienced a VER. Preoperative symptoms (HR 1.198), comorbidities (HR 1.289), tumor grade (HR 1.043), LNR (HR 4.339) and T stage (HR 1.639) were associated with an increased likelihood of VER. Model performance was very good at predicting VER at 6 months (AUC of 0.722) and 12 months (AUC 0.733). Two nomograms to predict 6-month and 12-month VER were built based on the predictive model. A higher nomogram score was associated with worse prognosis. There was good prediction between observed and estimated VER with minimal evidence of overfitting and good performance on internal bootstrapping validation. CONCLUSION: One in 6 patients experienced VER following curative-intent surgery for GC. Nomograms to predict risk of VER performed well on internal validation, and stratified patients into distinct prognostic groups relative to 6- and 12-months recurrence.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/patologia , Nomogramas , Adenocarcinoma/cirurgia , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: We sought to define the association of the systemic immune inflammation index (SII) with prognosis and adjuvant therapy benefit among patients undergoing resection of extrahepatic cholangiocarcinoma (eCCA). METHODS: The impact of SII on overall (OS) and recurrence-free survival (RFS) following resection of eCCA was assessed and compared with other inflammatory markers and traditional prognostic factors. Propensity score matching (PSM) was used to determine the impact of adjuvant therapy (AT) on OS and RFS relative to low versus high SII. RESULTS: Patients with high versus low SII had worse 5-year OS (15.9% vs. 27.9%) and RFS (12.4% vs. 20.9%) (both p < 0.01). On multivariate analysis, high SII remained associated with worse OS (HR = 1.50, 95% CI 1.20-1.87) and RFS (HR = 1.46, 95% CI 1.18-1.81). Patients with T1/2 disease and a high-SII had worse 5-year OS versus individuals with T3/4 disease and low-SII (5-year OS: T1/2 & low-SII 35.6%, T1/2 & high-SII 16.4%, T3/4 & low-SII 22.1%, T3/4 & high-SII 15.6%, p < 0.01). Similarly, 5-year OS was comparable among individuals with N0 and high-SII versus N1 and low-SII (5-year OS: N0 & high-SII 23.2%, N1 and low-SII 19.8%, p = 0.95). On PSM, AT improved OS and RFS among patients with high SII (5-year OS: 22.5% vs. 12.3%, p < 0.01, 5-year RFS: 19.0% vs. 12.5%; p = 0.01) but not individuals with low SII (5-year OS: 22.9% vs. 26.9%; p = 0.98, 5-year RFS: 18.5% vs. 19.9%; p = 0.94). CONCLUSIONS: SII was independently associated with postoperative OS and RFS following curative-intent resection of eCCA. High SII up-staged patients relative T- and N-categories and identified patients with high SII as the most likely to benefit from AT.
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Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Colangiocarcinoma , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/patologia , Humanos , Inflamação , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: We sought to derive and validate a prediction model of survival and recurrence among Western patients undergoing resection of gastric cancer. METHODS: Patients who underwent curative-intent surgery for gastric cancer at seven US institutions and a major Italian center from 2000 to 2020 were included. Variables included in the multivariable Cox models were identified using an automated model selection procedure based on an algorithm. Best models were selected using the Bayesian information criterion (BIC). The performance of the models was internally cross-validated via the bootstrap resampling procedure. Discrimination was evaluated using the Harrell's Concordance Index and accuracy was evaluated using calibration plots. Nomograms were made available as online tools. RESULTS: Overall, 895 patients met inclusion criteria. Age (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.17-1.84), presence of preoperative comorbidities (HR 1.66, 95% CI 1.14-2.41), lymph node ratio (LNR; HR 1.72, 95% CI 1.42-2.01), and lymphovascular invasion (HR 1.81, 95% CI 1.33-2.45) were associated with overall survival (OS; all p < 0.01), whereas tumor location (HR 1.93, 95% CI 1.23-3.02), T category (Tis-T1 vs. T3: HR 0.31, 95% CI 0.14-0.66), LNR (HR 1.82, 95% CI 1.45-2.28), and lymphovascular invasion (HR 1.49; 95% CI 1.01-2.22) were associated with disease-free survival (DFS; all p < 0.05) The models demonstrated good discrimination on internal validation relative to OS (C-index 0.70) and DFS (C-index 0.74). CONCLUSIONS: A web-based nomograms to predict OS and DFS among gastric cancer patients following resection demonstrated good accuracy and discrimination and good performance on internal validation.
Assuntos
Nomogramas , Neoplasias Gástricas , Teorema de Bayes , Intervalo Livre de Doença , Gastrectomia , Humanos , Prognóstico , Estudos Retrospectivos , Software , Neoplasias Gástricas/cirurgiaRESUMO
BACKGROUND: Prognostic nomograms for patients with resected extremity soft tissue sarcoma (STS) include the Sarculator and Memorial Sloan Kettering (MSKCC) nomograms. We sought to validate these two nomograms within a large, modern, multi-institutional cohort of resected primary extremity STS patients. METHODS: Resected primary extremity STS patients from 2000 to 2017 were identified across nine high-volume U.S. institutions. Predicted 5- and 10-year overall survival (OS) and distant metastases cumulative incidence (DMCI), and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated with Sarculator and MSKCC nomograms, respectively. Predicted survival probabilities stratified in quintiles were compared in calibration plots to observed survival assessed by Kaplan-Meier estimates. Cumulative incidence was estimated for DMCI. Harrell's concordance index (C-index) assessed discriminative ability of nomograms. RESULTS: A total of 1326 patients underwent resection of primary extremity STS. Common histologies included: undifferentiated pleomorphic sarcoma (35%), fibrosarcoma (13%), and leiomyosarcoma (9%). Median tumor size was 8.0 cm (IQR 4.5-13.0). Tumor grade distribution was: Grade 1 (13%), Grade 2 (9%), Grade 3 (78%). Median OS was 172 months, with estimated 5- and 10-year OS of 70% and 58%. C-indices for 5- and 10-year OS (Sarculator) were 0.72 (95% CI 0.70-0.75) and 0.73 (95% CI 0.70-0.75), and 0.72 (95% CI 0.69-0.75) for 5- and 10-year DMCI. C-indices for 4-, 8-, and 12-year DSS (MSKCC) were 0.71 (95% CI 0.68-0.75). Calibration plots showed good prognostication across all outcomes. CONCLUSIONS: Sarculator and MSKCC nomograms demonstrated good prognostic ability for survival and recurrence outcomes in a modern, multi-institutional validation cohort of resected primary extremity STS patients. External validation of these nomograms supports their ongoing incorporation into clinical practice.