RESUMEN
T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8+ T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer.
Asunto(s)
Linfocitos T CD8-positivos , Hepatocitos , Interleucina-6 , Factor de Transcripción STAT3 , Proteína Amiloide A Sérica , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/genética , Hepatocitos/metabolismo , Hepatocitos/inmunología , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Interleucina-6/metabolismo , Factor de Transcripción STAT3/metabolismo , Microambiente Tumoral/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Escape del Tumor , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Transducción de Señal , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Línea Celular TumoralRESUMEN
There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Vesículas Extracelulares/metabolismo , Neoplasias/diagnóstico , Animales , Biomarcadores de Tumor/sangre , Línea Celular , Proteínas del Choque Térmico HSC70/metabolismo , Humanos , Aprendizaje Automático , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Neoplasias/metabolismo , Proteoma/análisis , Proteoma/metabolismo , Proteómica/métodos , Sensibilidad y Especificidad , Tetraspanina 29/metabolismo , Proteínas de Unión al GTP rap/metabolismoRESUMEN
Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness' based on neoantigen similarity to known antigens4,5, and 'selfness' based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer.
Asunto(s)
Antígenos de Neoplasias , Supervivientes de Cáncer , Neoplasias Pancreáticas , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Linfocitos T/inmunología , Escape del Tumor/inmunologíaRESUMEN
Missense driver mutations in cancer are concentrated in a few hotspots1. Various mechanisms have been proposed to explain this skew, including biased mutational processes2, phenotypic differences3-6 and immunoediting of neoantigens7,8; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical 'free fitness' framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations. Focusing on TP53, the most mutated gene in cancer1, we present an inference of mutant p53 concentration and demonstrate that TP53 hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity. Our model anticipates patient survival in The Cancer Genome Atlas and patients with lung cancer treated with immunotherapy as well as the age of tumour onset in germline carriers of TP53 variants. The predicted differential immunogenicity between hotspot mutations was validated experimentally in patients with cancer and in a unique large dataset of healthy individuals. Our data indicate that immune selective pressure on TP53 mutations has a smaller role in non-cancerous lesions than in tumours, suggesting that targeted immunotherapy may offer an early prophylactic opportunity for the former. Determining the relative contribution of immunogenicity and oncogenic function to the selective advantage of hotspot mutations thus has important implications for both precision immunotherapies and our understanding of tumour evolution.
Asunto(s)
Carcinogénesis , Evolución Molecular , Neoplasias Pulmonares , Mutación , Carcinogénesis/genética , Carcinogénesis/inmunología , Conjuntos de Datos como Asunto , Genes p53 , Aptitud Genética , Genómica , Voluntarios Sanos , Humanos , Inmunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutación/genética , Mutación Missense , Reproducibilidad de los ResultadosRESUMEN
Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues1,2. Although ILC2s are found in cancers of these tissues3, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8+ T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1+ TILC2s and PD-1+ T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.
Asunto(s)
Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/inmunología , Linfocitos/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Células Dendríticas/inmunología , Femenino , Humanos , Inmunidad Innata/inmunología , Inmunoterapia , Interleucina-33/inmunología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T/inmunologíaRESUMEN
OBJECTIVE: To assess whether selective omission of operative drains after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) is associated with adverse perioperative outcomes. BACKGROUND: The routine use of operative drains after pancreatectomy is widely practiced; however, prospective randomized clinical trials and retrospective analyses have shown mixed results. METHODS: Patients who underwent PD or DP between November 2009 and May 2021 were reviewed and stratified by operative drain placement. Patient demographics, morbidity, the need for additional procedures, and mortality were compared between patients who did or did not develop a clinically relevant post-operative pancreatic fistula (CR-POPF). RESULTS: In total, 1,855 PD and 752 DP cases were analyzed. Among PD patients with a CR-POPF (N=259, 14%), 160 (62%) had an operative drain placed, of whom 141 (88%) required at least 1 additional procedure. Within this subgroup, grade ≥ 4 complications (7.5% vs. 11.1%, P=0.37), 90-day mortality (3.8% vs. 6.1%, P=0.54), length of stay (LOS) (median 12 vs. 13 d, P=0.19) and readmission rates (63.1% vs. 54.6%, P=0.19) were similar between drained and non-drained patients. Of note, drained PD patients without a CR-POPF had a longer hospital stay (8 vs. 7 d, respectively, P=0.004) and more thromboembolic events (2.4% vs. 1.1%, respectively, P=0.04) Among DP patients with a CR-POPF (n=129), 44 had an operative drain, with 37 (84%) requiring an additional procedure. Within this subgroup, grade ≥ 4 complications (4.6% vs. 5.9%, P>0.95), 90-day mortality (0%), LOS (median 7 d for both, P=0.88) and readmission rates (72.7% vs. 80%, P=0.38) were similar in drained and non-drained patients. CONCLUSION: This study confirms that selective omission of operative drains does not compromise perioperative outcomes, as initially reported in our prospective randomized trial.
RESUMEN
BACKGROUND: Early-Onset (EO) pancreatic neuroendocrine tumor (PanNET) is a rare disease, but whether it is clinically different from late-onset (LO) PanNET is unknown. Our study aimed to evaluate clinical differences and disease outcomes between EO-PanNET and LO-PanNET and to compare sporadic EO-PanNET with those with a hereditary syndrome. METHODS: Patients with localized PanNET who underwent pancreatectomy at Memorial Sloan Kettering between 2000 and 2017 were identified. Those with metastatic disease and poorly differentiated tumors were excluded. EO-PanNET was defined as <50 and LO-PanNET >50 years of age at the time of diagnosis. Family history and clinical and pathology characteristics were recorded. RESULTS: Overall 383 patients were included, 107 (27.9%) with EO-PanNET. Compared with LO-PanNET, EO-PanNET were more likely to have a hereditary syndrome (2.2% vs. 16%, P <0.001) but had similar pathology features such as tumor grade ( P =0.6), size (2.2 Vs. 2.3 cm, P =0.5) and stageof disease ( P =0.8). Among patients with EO-PanNET, those with hereditary syndrome had more frequently a multifocal disease (65% vs. 3.3%, P <0.001). With a median follow-up of 70 months (range 0-238), the 5-year cumulative incidence of recurrence after curative surgery was 19% (95% CI 12%-28%) and 17% (95% CI 13%-23%), in EO-PanNET and LO-PanNET ( P =0.3). Five-year disease-specific survival was 99% (95% CI 98%-100%) with no difference with respect to PanNET onset time ( P =0.26). CONCLUSIONS: In this surgical cohort, we found that EO-PanNET is associated with hereditary syndromes but has pathologic characteristics and oncological outcomes similar to LO-PanNET. These findings suggest that patients with EO-PanNET can be managed similarly to those with LO-PanNET.
Asunto(s)
Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Pancreatectomía , IncidenciaRESUMEN
OBJECTIVE: To identify risk factors associated with the progression of pancreatic cysts in patients undergoing surveillance. BACKGROUND: Previous studies of intraductal papillary mucinous neoplasms (IPMNs) rely on surgical series to determine malignancy risk and have inconsistently identified characteristics associated with IPMN progression. METHODS: We conducted a retrospective review of 2197 patients presenting with imaging concerning for IPMN from 2010 to 2019 at a single institution. Cyst progression was defined as resection or pancreatic cancer development. RESULTS: The median follow-up time was 84 months from the presentation. The median age was 66 years, and 62% were female. Ten percent had a first-degree relative with pancreatic cancer, and 3.2% had a germline mutation or genetic syndrome associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). Cumulative incidence of progression was 17.8% and 20.0% at 12 and 60 months postpresentation, respectively. Surgical pathology for 417 resected cases showed noninvasive IPMN in 39% of cases and PDAC with or without associated IPMN in 20%. Only 18 patients developed PDAC after 6 months of surveillance (0.8%). On multivariable analysis, symptomatic disease [hazard ratio (HR)=1.58; 95% CI: 1.25-2.01], current smoker status (HR=1.58; 95% CI: 1.16-2.15), cyst size (HR=1.26; 95% CI: 1.20-1.33), main duct dilation (HR=3.17; 95% CI: 2.44-4.11), and solid components (HR=1.89; 95% CI: 1.34-2.66) were associated with progression. CONCLUSIONS: Worrisome features on imaging at presentation, current smoker status, and symptomatic presentation are associated with IPMN progression. Most patients progressed within the first year of presentation to Memorial Sloan Kettering Cancer Center (MSKCC). Further investigation is necessary to develop personalized cyst surveillance strategies.
Asunto(s)
Carcinoma Ductal Pancreático , Quiste Pancreático , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Humanos , Femenino , Anciano , Masculino , Neoplasias Intraductales Pancreáticas/patología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/cirugía , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/epidemiología , Carcinoma Ductal Pancreático/cirugía , Factores de Riesgo , Quiste Pancreático/diagnóstico por imagen , Quiste Pancreático/cirugía , Estudios RetrospectivosRESUMEN
Inactivating alterations in the SWItch/Sucrose Non-Fermentable (SWI/SNF) Chromatin Remodeling Complex subunits have been described in multiple tumor types. Recent studies focused on SMARC subunits of this complex to understand their relationship with tumor characteristics and therapeutic opportunities. To date, pancreatic cancer with these alterations has not been well-studied, although isolated cases of undifferentiated carcinomas have been reported. Herein, we screened 59 pancreatic undifferentiated carcinomas for alterations in SWI/SNF complex-related [SMARCB1 (BAF47/INI1), SMARCA4 (BRG1), SMARCA2 (BRM)] proteins and/or genes using immunohistochemistry (IHC) and/or next-generation sequencing (NGS). Cases with alterations in SWI/SNF complex-related proteins/genes were compared to cases without alterations, as well as to 96 conventional pancreatic ductal adenocarcinomas (PDAC). In all tumor groups, MMR and PD-L1 protein expression were also evaluated. Thirty of 59 (51%) undifferentiated carcinomas had a loss of SWI/SNF complex-related protein expression or gene alteration. Twenty-seven of 30 (90%) SWI/SNF-deficient undifferentiated carcinomas had rhabdoid morphology [vs. 9/29 (31%) SWI/SNF-retained undifferentiated carcinomas; p < 0.001] and all expressed cytokeratin, at least focally. Immunohistochemically, SMARCB1 protein expression was absent in 16/30 (53%) cases, SMARCA2 in 4/30 (13%), and SMARCA4 in 4/30 (13%); both SMARCB1 and SMARCA2 protein expressions were absent in 1/30 (3%). Five of 8 (62.5%) SWI/SNF-deficient undifferentiated carcinomas that displayed loss of SMARCB1 protein expression by IHC were found to have corresponding SMARCB1 deletions by NGS. Analysis of canonical driver mutations for PDAC in these cases showed KRAS (2/5) and TP53 (2/5) abnormalities. Median CPS for PD-L1 (E1L3N) was significantly higher in the undifferentiated carcinomas with/without SWI/SNF deficiency compared to the conventional PDACs (p < 0.001). SWI/SNF-deficient undifferentiated carcinomas were larger (p < 0.001) and occurred in younger patients (p < 0.001). Patients with SWI/SNF-deficient undifferentiated carcinoma had worse overall survival compared to patients with SWI/SNF-retained undifferentiated carcinoma (p = 0.004) and PDAC (p < 0.001). Our findings demonstrate that SWI/SNF-deficient pancreatic undifferentiated carcinomas are frequently characterized by rhabdoid morphology, exhibit highly aggressive behavior, and have a negative prognostic impact. The ones with SMARCB1 deletions appear to be frequently KRAS wild-type. Innovative developmental therapeutic strategies targeting this genomic basis of the SWI/SNF complex and the therapeutic implications of EZH2 inhibition (NCT03213665), SMARCA2 degrader (NCT05639751), or immunotherapy are currently under investigation.
RESUMEN
BACKGROUND: A post-hoc analysis of ABC trials included 34 patients with liver-confined unresectable intrahepatic cholangiocarcinoma (iCCA) who received systemic chemotherapy with gemcitabine and cisplatin (gem-cis). The median overall survival (OS) was 16.7 months and the 3-year OS was 2.8%. The aim of this study was to compare patients treated with systemic gem-cis versus hepatic arterial infusion pump (HAIP) chemotherapy for liver-confined unresectable iCCA. METHODS: We retrospectively collected consecutive patients with liver-confined unresectable iCCA who received gem-cis in two centers in the Netherlands to compare with consecutive patients who received HAIP chemotherapy with or without systemic chemotherapy in Memorial Sloan Kettering Cancer Center. RESULTS: In total, 268 patients with liver-confined unresectable iCCA were included; 76 received gem-cis and 192 received HAIP chemotherapy. In the gem-cis group 42 patients (55.3%) had multifocal disease compared with 141 patients (73.4%) in the HAIP group (p = 0.023). Median OS for gem-cis was 11.8 months versus 27.7 months for HAIP chemotherapy (p < 0.001). OS at 3 years was 3.5% (95% confidence interval [CI] 0.0-13.6%) in the gem-cis group versus 34.3% (95% CI 28.1-41.8%) in the HAIP chemotherapy group. After adjusting for male gender, performance status, baseline hepatobiliary disease, and multifocal disease, the hazard ratio (HR) for HAIP chemotherapy was 0.27 (95% CI 0.19-0.39). CONCLUSIONS: This study confirmed the results from the ABC trials that survival beyond 3 years is rare for patients with liver-confined unresectable iCCA treated with palliative gem-cis alone. With HAIP chemotherapy, one in three patients was alive at 3 years.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Masculino , Gemcitabina , Cisplatino , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica , Colangiocarcinoma/tratamiento farmacológico , Desoxicitidina , Hígado , Conductos Biliares Intrahepáticos , Bombas de Infusión , Resultado del TratamientoRESUMEN
BACKGROUND: Management of intrahepatic cholangiocarcinoma (IHC) has advanced in recent decades, including randomized trial evidence supporting systemic therapy in the palliative and adjuvant setting. Mounting observational evidence suggests resection of IHC with multifocal disease (IHC-MF) or lymph node metastasis (IHC-LNM) should be limited. It is unknown how real-world practice has evolved in light of research advances. This study characterizes trends in management and outcomes of IHC without distant metastasis. METHODS: We queried the National Cancer Database (NCDB) for patients treated for IHC without distant metastasis (M0) and identified subgroups with lymph node (cN1) or multifocal hepatic involvement (cT2b). Two-sided Cochran-Armitage tests evaluated trends in initial treating modality and perioperative chemotherapy. Logistic regression evaluated associations with choice of initial treating modality. Overall survival (OS) was evaluated by using Kaplan-Meier methods. RESULTS: Between 2004 and 2020, 11,368 patients were treated for IHC without extrahepatic metastasis. Forty-three percent underwent resection. Initial management shifted from resection towards radiation or systemic therapy in IHC-MF and IHC-LNM. Use of perioperative chemotherapy increased from 39% pre-2010 to 70% in 2018-2020 (p < 0.001), most often delivered postoperatively. Across the entire cohort, median OS improved from 16 (95% confidence interval [CI] 15-18) to 27 months (95% CI 26-29). More modest improvements were observed in IHC-MF and IHC-LNM. CONCLUSIONS: Use of perioperative chemotherapy has been widely adopted, predating randomized trial evidence in the adjuvant setting. Initial management of IHC-MF and IHC-LNM has shifted from resection to systemic and/or radiation therapy. While OS has improved overall, outcomes of IHC-MF and IHC-LNM remain poor, warranting further investigation.
RESUMEN
OBJECTIVE: To determine whether the morphologic features of the main pancreatic duct (MPD) of main-duct-involved-intraductal papillary mucinous neoplasm (IPMN) (ie, main duct or mixed main duct/side branch) have implications for the risk of malignancy and extent of resection. BACKGROUND: International consensus guidelines acknowledge the presence of various MPD morphologies (ie, diffuse vs segmental main-duct-involved-IPMN) without a precise definition of each entity and with limited data to guide treatment strategy. METHODS: All consecutive main-duct-involved-IPMN patients (2005-2019) with a MPD diameter ≥5 mm by cross-sectional imaging were reviewed from a prospective institutional database. Morphologic features of the MPD were correlated with the identification of high-grade dysplasia or pancreatic ductal adenocarcinoma (HGD/PDAC) by logistic regression modeling. In patients who underwent partial pancreatectomy, preoperative MPD morphologic features were correlated with the future development of HGD/PDAC in the pancreatic remnant by Cox hazards modeling. RESULTS: In a cohort of 214 main-duct-involved-IPMN patients, the overall rate of HGD/PDAC was 54.2%. MPD morphologic characteristics associated with HGD/PDAC included: maximal MPD diameter (5-10 mm: 29.8%; 10-14 mm: 59.0%; 15-19 mm: 78.6%; ≥20 mm: 95.8%; P <0.001), segmental extent of maximal dilation (<25%: 28.2%; 25%-49%: 54.9%; 50%-74%: 63.1%; ≥75%: 67.9%; P =0.002), and nonsegmental MPD diameter (<5 mm: 21.5% vs ≥5 mm: 78.5%, P <0.001). Diffuse MPD dilation involving ≥90% extent was rare (5.6%). After a median follow-up of 50 months, 7 (7.2%) patients who underwent partial pancreatectomy for IPMN without associated PDAC developed HGD/PDAC in the pancreatic remnant. Maximal MPD diameter, segmental extent of maximal dilation, or nonsegmental MPD diameter were not associated with the development of HGD/PDAC in the pancreatic remnant. However, a mural nodule on preoperative imaging was associated with the development of HGD/PDAC in the pancreatic remnant. CONCLUSIONS: "Diffuse" involvement with homogenous dilation of the MPD was rare. For the majority of patients with segmental main-duct-involved-IPMN, the MPD morphology conferred malignancy risk. Duct morphology was not predictive for the development of HGD or invasive disease in the pancreatic remnant, implying the safety of limited pancreatic resection for initial surgical management.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Humanos , Neoplasias Intraductales Pancreáticas/cirugía , Neoplasias Intraductales Pancreáticas/patología , Estudios Prospectivos , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Conductos Pancreáticos/patología , Modelos Logísticos , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
OBJECTIVE: The aim of this study was to describe the surgeon's ability to accurately predict the margin following resection of colorectal liver metastases (CRLM). SUMMARY BACKGROUND DATA: The decision to resect CRLM is based on the surgeon's ability to predict tumor free resection margins. However, to date, no study has evaluated the accuracy of surgeon margin prediction. METHODS: In this single-institution prospective study, the operating attending and fellow independently completed a preoperative and postoperative questionnaire describing their expected resection margin in 100 consecutive cases (200 assessments) of colorectal liver metastasis resections. In cases with multiple metastases, the closest margin was assessed as the margin of interest for the primary outcome. Surgeon assessments were compared to the gold-standard histopathologic assessment. RESULTS: After excluding aborted cases, 190 preoperative and 190 postoperative assessments from 95 cases were included in the analysis. The pathologic margin was noted to be wide (≥1 cm), 1 mm to 1 cm, narrow (<1 mm), and positive in 28 (29.5%), 55 (57.9%), 5 (5.3%), and 7 (7.4%) cases, respectively. The 88 cases with negative margins were all predicted to be negative. None of the cases with positive margins were predicted to be positive. Ninety-one (48%) preoperative and 104 (55%) postoperative predictions were accurate. The sensitivity of predicting a margin <1 mm was 8.3% preoperatively and 16.7% postoperatively. The positive predictive value for preoperative and postoperative predictions of margin <1 mm was 18.2% and 26.7%, respectively. CONCLUSIONS: Surgeons are inaccurate at predicting positive and close surgical margins following resection of CRLM. A predicted close margin should not necessarily preclude resection.
RESUMEN
INTRODUCTION: Patients who recur in the first year after resection of colorectal liver metastases (CRLM) do poorly. The aim of our study was to predict treatment failure in patients undergoing upfront resection with a nomogram. METHODS: Data from patients resected between 1991 and 2019 were randomly split (70:30) into two cohorts. Treatment failure was defined as any recurrence or death within 12 months. A nomogram was constructed using multivariable logistic regression on the training cohort and validated using the testing cohort. RESULTS: Overall, 783 patients were included. Primary tumor characteristics included 50% left-sided: 75.2% T3/4 and 56.5% node-positive. The median disease-free interval was 10 months, median number of metastases was 1 (1-50), and with a median size of 3.6 cm (0.2-22); 222 (28.3%) patients recurred within 1 year. Recurrence was mostly extrahepatic with or without liver involvement (150/222, 67.6%). Curative-intent treatment was possible in 37.8% of these patients. Primary location, T-stage and node status, disease-free interval, and number and size of metastases were associated with treatment failure. The area under the curve from the validation of the model was 0.6 (95% confidence interval 0.52-0.68). Patients with a high-risk of treatment failure (≥40%) had a worse survival from the landmark time of 12 months from surgery compared with those with low-risk (2-years: 82% vs. 70%; p = 0.0002). CONCLUSIONS: Primary location, T stage, node status, disease-free interval, and number and size of metastases are associated with treatment failure. The survival of patients with a probability of treatment failure ≥40% is unfavorable. Future trials investigating the role of neoadjuvant therapy in these high-risk patients are warranted.
Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/patología , Predicción , Hepatectomía , Neoplasias Hepáticas/secundario , Pronóstico , Estudios Retrospectivos , Insuficiencia del TratamientoRESUMEN
BACKGROUND: For some patients with colorectal liver metastases (CRLMs), surgical resection of all visible disease can lead to long-term survival and even cure. When complete resection is not feasible, microwave ablation (MWA) can help achieve hepatic disease control. As modern 2.45-GHz MWA generators gain popularity, the characteristics of tumors most likely to benefit from this method remain unclear. This study aimed to evaluate local recurrence (LR) rates, patterns of recurrence, and factors contributing to treatment failure after 2.45-GHz MWA of CRLM. METHODS: Patients with CRLM who underwent operative 2.45-GHz MWA between 2011 and 2019 were identified in a prospectively maintained single-institution database. Recurrence outcomes were ascertained for each lesion by imaging review. Factors associated with LR were analyzed. RESULTS: The study enrolled 184 patients bearing 416 ablated tumors. Most of the patients (65.8%) had high clinical risk scores (3-5), and 165 (90%) underwent concurrent liver resection. The median tumor size was 10 mm. After a median follow-up period of 28.8 months, LR was observed in 45 tumors, and the cumulative incidence of LR at 24 months was 10.9% (95% confidence interval [CI], 8.0-14.3%]. In 7%, LR was the first recurrence site, often combined with recurrence elsewhere. The cumulative incidence of LR at 24 months was 6.8% (95% CI 3.8-11.0%) for tumors 10 mm in size or smaller, 12.4% (95% CI 7.8-18.1%) for tumors 11 to 20 mm in size, and 30.2% (95% CI 14.2-48.0%) for tumors larger than 20 mm. In the multivariable analysis, tumors larger than 20 mm with a subcapsular location were significantly associated with increased LR risk. CONCLUSIONS: Treatment of CRLM with 2.45-GHz MWA offers excellent local control at 2 years and is most successful for small tumors deep within the parenchyma.
Asunto(s)
Ablación por Catéter , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Microondas/uso terapéutico , Ablación por Catéter/métodos , Neoplasias Hepáticas/secundario , Neoplasias Colorrectales/patología , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
PURPOSE: Chemotherapy-naive patients with unresectable colorectal liver metastases (CRLM) have been the best responders to hepatic arterial infusion (HAI) therapy. The current treatment paradigm has drifted away from HAI in the first-line setting. We aimed to analyze outcomes of combined first-line systemic therapy with HAI therapy (HAI+SYS) in the modern era. METHODS: We conducted a retrospective study of consecutive chemotherapy-naive patients with unresectable CRLM who received HAI+SYS between 2003 and 2019. Patients were selected from a prospectively maintained database. Outcomes included radiological response rate, conversion to resection (CTR) rate, and overall survival (OS). RESULTS: Fifty-eight chemotherapy-naive patients were identified out of 546 patients with unresectable CRLM managed with HAI. After induction treatment, 4 patients (7%) had a complete radiological response, including two durable responses. In total, 32 patients (55%) underwent CTR. CTR or complete response without resection was achieved after seven cycles of systemic therapy and four cycles of HAI therapy. Median OS for the whole cohort was 53.0 months (95% confidence interval 23.0-82.9). Three- and 5-year OS in patients who achieved CTR or complete response versus patients who did not was 88% and 72% versus 27% and 0% respectively. Of patients who underwent CTR, complete and major pathological response (no and <10% viable tumor cells, respectively) was observed in 7 (22%) and 12 patients (38%). CONCLUSIONS: Combined HAI+SYS in chemotherapy-naive patients resulted in durable and substantial response in a large proportion of patients. Nearly two-thirds of patients achieved a complete response or proceeded to conversion surgery, which was associated with prolonged survival.
Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/patología , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Hepáticas/cirugía , Bombas de Infusión , Infusiones Intraarteriales , Arteria Hepática/patología , Fluorouracilo , Resultado del TratamientoRESUMEN
Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells. We estimate these components using the relative MHC binding affinity of each neoantigen to its wild type and a nonlinear dependence on sequence similarity of neoantigens to known antigens. To describe the evolution of a heterogeneous tumour, we evaluate its fitness as a weighted effect of dominant neoantigens in the subclones of the tumour. Our model predicts survival in anti-CTLA-4-treated patients with melanoma and anti-PD-1-treated patients with lung cancer. Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumours and rapidly evolving pathogens.
Asunto(s)
Antígenos de Neoplasias/inmunología , Inmunoterapia , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Melanoma/inmunología , Melanoma/terapia , Modelos Inmunológicos , Presentación de Antígeno , Antígenos de Neoplasias/genética , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/inmunología , Estudios de Cohortes , Evolución Molecular , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Activación de Linfocitos , Melanoma/genética , Melanoma/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Análisis de Supervivencia , Linfocitos T/inmunologíaRESUMEN
Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.
Asunto(s)
Antígenos de Neoplasias/inmunología , Proteínas Bacterianas/inmunología , Supervivientes de Cáncer , Reacciones Cruzadas/inmunología , Neoplasias Pancreáticas/inmunología , Linfocitos T Citotóxicos/inmunología , Adenocarcinoma/sangre , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Antígenos de Neoplasias/genética , Proteínas Bacterianas/sangre , Proteínas Bacterianas/genética , Antígeno Ca-125/genética , Antígeno Ca-125/inmunología , Simulación por Computador , Reacciones Cruzadas/genética , Humanos , Inmunoterapia , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/genética , Pronóstico , Análisis de Supervivencia , Linfocitos T Citotóxicos/citología , Secuenciación del ExomaRESUMEN
BACKGROUND: Recurrence-free survival has been used as a surrogate endpoint for overall survival in trials involving patients with resected colorectal liver metastases. We aimed to assess the correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases to determine the adequacy of this surrogate endpoint. METHODS: In this retrospective study and meta-analysis, we compiled an institutional cohort of consecutive patients who had complete resection of colorectal liver metastases from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) prospective database. Patients were eligible for inclusion if they were aged 18 years or older, and underwent hepatectomy, with or without operative ablation, between Jan 1, 1991, and April 30, 2019. We estimated overall survival and recurrence-free survival probabilities at various timepoints using the Kaplan-Meier method, and we assessed pairwise associations between these endpoints using Spearman's rank correlation. We also did a meta-analysis of adjuvant phase 3 clinical trials for colorectal liver metastases to assess the correlation between hazard ratios (HRs) for recurrence-free survival and overall survival. We searched MEDLINE for articles of phase 3 randomised controlled trials analysing adjuvant treatment strategies for resected colorectal metastases from database inception to Jan 1, 2022. The titles and abstracts of identified studies were screened before full-text screening and summary data were either recalculated or extracted manually from the published Kaplan-Meier curves (depending on data availability). FINDINGS: Data were available for 3299 patients in the institutional database, of whom 2983 were eligible for inclusion in our cohort. Median follow-up was 8·4 years (95% CI 7·9-9·1) , during which time there were 1995 (67%) disease recurrences and 1684 (56%) deaths. Median recurrence-free survival was 1·3 years (95% CI 1·3-1·4) and median overall survival was 5·2 years (95% CI 5·0-5·5). 1428 (85%) of 1684 deaths were preceded by recurrence, and median time from recurrence to death was 2·0 years (IQR 1·0-3·4). Pairwise correlations between recurrence-free survival and overall survival were low to moderate, with a correlation estimate ranging from 0·30 (SD 0·17) to 0·56 (0·13). In the meta-analysis of adjuvant clinical trials, the Spearman's correlation coefficient between recurrence-free survival HR and overall survival HR was r=0·20 (p=0·71). INTERPRETATION: We found a minimal correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases. Recurrence-free survival is an inadequate surrogate endpoint for overall survival in this disease setting. FUNDING: US National Cancer Institute.