RESUMEN
OBJECTIVES: Although systemic chemotherapy for pancreatic ductal adenocarcinoma (PDAC) has made progress, ensuring long-term survival remains difficult. There are several reports on the usefulness of neutrophil-to-lymphocyte ratio (NLR) in predicting the prognosis of PDAC, but few reports in systemic chemotherapy. We hereby investigated the usefulness of NLR in systemic chemotherapy for PDAC. MATERIALS AND METHODS: A retrospective study was conducted on patients with advanced PDAC treated with first-line systemic chemotherapy. Cox regression hazards models were performed to analyze the association between baseline patient characteristics and the initial treatment response, and overall survival (OS). RESULTS: A total of 60 patients with PDAC were enrolled. At baseline, there were significant differences in NLR and carbohydrate antigen 19-9 (CA19-9), as well as the selection rate of combination chemotherapy, between patients with partial response or stable disease and those with progressive disease. Univariate and multivariate analysis showed that NLR < 3.10, combination chemotherapy, and CA19-9 < 1011 U/mL were significant and independent predictive factors of the initial treatment response. Meanwhile, NLR < 3.10 and combination chemotherapy were independently associated with longer OS. Moreover, OS was significantly prolonged in patients with NLR < 3.10, regardless of whether combination chemotherapy or monotherapy. Patients with NLR < 3.10 at baseline had a significantly higher conversion rate to third-line chemotherapy and a longer duration of total chemotherapy. CONCLUSIONS: This study suggests that NLR may be a useful marker for predicting the initial treatment response to first-line chemotherapy and the prognosis for patients with advanced PDAC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Linfocitos , Neutrófilos , Neoplasias Pancreáticas , Humanos , Femenino , Masculino , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Estudios Retrospectivos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Persona de Mediana Edad , Anciano , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Antígeno CA-19-9/sangre , Recuento de Linfocitos , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Modelos de Riesgos Proporcionales , Anciano de 80 o más Años , Gemcitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Resultado del TratamientoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis. The current challenge remains the absence of predictive biomarkers. Cytokines are crucial factors in the pathogenesis and prognosis of PDAC. Furthermore, there is growing interest in differentiating between molecular subtypes of PDAC. The aim of our study is to evaluate the association between the analyzed cytokines and the molecular subtypes of PDAC and to determine their prognostic value. Cytokine levels were measured in 73 patients, and molecular subtypes were analyzed in 34 of these patients. Transforming Growth Factor Beta 2 (TGF-ß2) levels were independently associated with the basal-like and null subtypes. In patients with locally advanced and metastatic PDAC, elevated levels of interleukin (IL)-1α, IL-1ß, IL-6, IL-8, IL-9, and IL-15 were associated with a higher risk of progression during first-line treatment, and increased levels of IL-1ß, IL-6, IL-8, IL-9, and IL-15 were related to increased mortality. Furthermore, a significant association was observed between higher percentiles of IL-6 and IL-8 and shorter progression-free survival (PFS) during first-line treatment, and between higher percentiles of IL-8 and shorter overall survival (OS). In the multivariate analysis, only elevated levels of IL-8 were independently associated with a higher risk of progression during first-line treatment and mortality. In conclusion, the results of our study suggest that cytokine expression varies according to the molecular subtype of PDAC and that cytokines also play a relevant role in patient prognosis.
Asunto(s)
Carcinoma Ductal Pancreático , Citocinas , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Femenino , Masculino , Citocinas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/metabolismo , Pronóstico , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor , Anciano de 80 o más Años , AdultoRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) are rarely used to treat advanced pancreatic ductal adenocarcinoma (PDAC) due to marginal efficacy. PATIENTS AND METHODS: This study included 92 consecutive patients diagnosed with advanced or recurrent PDAC who received nivolumab-based treatment. Univariate and multivariate analyses were used to identify prognostic factors. A control group of 301 patients with PDAC who achieved disease control with palliative chemotherapy but without ICIs was selected for comparison using propensity score matching (PSM). RESULTS: The median overall survival (OS) since nivolumab treatment was 15.8 (95% confidence interval [CI], 12.5-19.0), 2.4 (95% CI 1.2-3.6), and 1.1 (95% CI 1.0-1.2) months in patients who received add-on nivolumab after achieving disease control with chemotherapy, in those who received concomitant nivolumab and chemotherapy without prerequisite confirmation of disease control, and in those who received nivolumab without concomitant chemotherapy, respectively (P < 0.001). After PSM, the median overall survival (OS) since initiation of the concomitant chemotherapy that achieved disease control was significantly longer (P = 0.026) in patients who received add-on nivolumab (19.8 months; 95% CI 14.5-25.1) than in those who received chemotherapy alone (13.8 months; 95% CI 10.8-16.9). The immune profiling of the tumors in resected patients revealed higher scores of CD8+ T cells to Tregs in patients with add-on nivolumab comparing to those who received chemotherapy alone. CONCLUSION: Adding-on nivolumab was associated with improved OS in patients with advanced PDAC who achieved disease control following chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Nivolumab , Neoplasias Pancreáticas , Humanos , Masculino , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Nivolumab/uso terapéutico , Nivolumab/administración & dosificación , Femenino , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Anciano , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pronóstico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adulto , Anciano de 80 o más Años , Estudios RetrospectivosRESUMEN
INTRODUCTION: Pancreatic adenocarcinoma (PDAC) is becoming a public health issue with a 5-years survival rate around 10%. Patients with PDAC are often sarcopenic, which impacts postoperative outcome. At the same time, overweight population is increasing and adipose tissue promotes tumor related-inflammation. With several studies supporting independently these data, we aimed to assess if they held an impact on survival when combined. METHODS: We included 232 patients from two university hospitals (CHU de Lille, Institut Paoli Calmette), from January 2011 to December 2018, who underwent Pancreaticoduodenectomy (PD) for resectable PDAC. Preoperative CT scan was used to measure sarcopenia and visceral fat according to international cut-offs. Neutrophil to lymphocyte (NLR) and platelet to lymphocyte ratios (PLR) were used to measure inflammation. For univariate and multivariate analyses, the Cox proportional-hazard model was used. P-values below 0.05 were considered significant. RESULTS: Sarcopenic patients with visceral obesity were less likely to survive than the others in multivariate analysis (OS, HR 1.65, p= 0.043). Cutaneous obesity did not influence survival. We also observed an influence on survival when we studied sarcopenia with visceral obesity (OS, p= 0.056; PFS, p = 0.014), sarcopenia with cutaneous obesity (PFS, p= 0.005) and sarcopenia with PLR (PFS, p= 0.043). This poor prognosis was also found in sarcopenic obese patients with high PLR (OS, p= 0.05; PFS, p= 0.01). CONCLUSION: Sarcopenic obesity was associated with poor prognosis after PD for PDAC, especially in patients with systemic inflammation. Pre operative management of these factors should be addressed in pancreatic cancer patients.
Asunto(s)
Adenocarcinoma , Pancreatectomía , Neoplasias Pancreáticas , Sarcopenia , Humanos , Sarcopenia/complicaciones , Sarcopenia/mortalidad , Sarcopenia/patología , Sarcopenia/etiología , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/complicaciones , Masculino , Femenino , Anciano , Tasa de Supervivencia , Pancreatectomía/mortalidad , Pancreatectomía/efectos adversos , Pronóstico , Persona de Mediana Edad , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Adenocarcinoma/complicaciones , Estudios de Seguimiento , Estudios Retrospectivos , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/mortalidad , Pancreaticoduodenectomía/efectos adversos , Pancreaticoduodenectomía/mortalidad , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/complicacionesRESUMEN
INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is currently the third-leading cause of cancer-related death in the United States. African Americans (AAs) with PDAC have worse survival in comparison to other racial groups. The COVID-19 pandemic caused significant stress to the healthcare system. We aim to evaluate the pandemic's impact on already known disparities in newly diagnosed patients with PDAC in Florida. METHODS: This is a retrospective analysis of newly diagnosed patients with PDAC in the OneFlorida+ Data Trust based upon date of diagnosis: Pre-pandemic (01/01/2017- 09/30/2019), Transition (10/01/2019-02/28/2020), and Pandemic (03/1/2020-10/31/2020). Primary endpoints are time to treatment initiation and rate of surgery and secondary endpoint is survival time. Disparities due to age, sex, race, and income were also evaluated. Chi-squared or Fisher's exact test when necessary, Kruskal-Wallis test, and Kaplan-Meier analysis with log-rank test were performed to compare the differences between the comparative groups for categorical, quantitative, and survival outcomes, respectively. Multivariable regression analyses were conducted to estimate the effects of cofactors. RESULTS: 934 patients with a median age of 67 years were included. There were 47.8% females and 52.2% males; 19.4% AA, 70.2% Caucasian, 10.4% Other race; median income was $53,551. While we observed a significant reduction in the diagnosis rate of new PDAC cases during the pandemic, there were no significant differences in demographic distributions among the three cohorts. Time to treatment did not significantly change from the pre-pandemic to the pandemic, and no difference was observed across all demographics. Rate of surgery increased significantly from the pre-pandemic (35.8%) to the pandemic (55.6%). AAs in the pre-pandemic cohort had a significantly lower rate of surgery of 25.0% compared to 41.7% in Caucasians. AAs, patients ≥ 67 years, and income < $53,000 had significantly higher hazards to death and shorter median survival time (mST). CONCLUSIONS: While no differences in time to initial treatment are observed among the newly diagnosed PDAC patients, there remain significant disparities in the rate of surgery and overall survival. Observing a significant reduction in diagnosis rate and analyzing disparities can provide insight into the effect of a resource-restricting pandemic for patients with newly diagnosed PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Disparidades en Atención de Salud , Neoplasias Pancreáticas , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Negro o Afroamericano/estadística & datos numéricos , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/etnología , COVID-19/epidemiología , Florida/epidemiología , Disparidades en Atención de Salud/etnología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/etnología , Pandemias , Estudios Retrospectivos , Blanco/estadística & datos numéricosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal tumor with increasing incidence, presenting numerous clinical challenges. The histopathological examination of novel, unexplored biomarkers offers a promising avenue for research, with significant translational potential for improving patient outcomes. In this study, we evaluated the prognostic significance of ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian clock regulators (CLOCK, BMAL1, PER1, PER2), and KLOTHO in a retrospective cohort of 41 patients deceased by PDAC. Immunohistochemical techniques (IHC) and multiple statistical analyses (Kaplan-Meier curves, correlograms, and multinomial linear regression models) were performed. Our findings reveal that ferroptosis markers are directly associated with PDAC mortality, while circadian regulators and KLOTHO are inversely associated. Notably, TFRC emerged as the strongest risk marker associated with mortality (HR = 35.905), whereas CLOCK was identified as the most significant protective marker (HR = 0.01832). Correlation analyses indicate that ferroptosis markers are positively correlated with each other, as are circadian regulators, which also positively correlate with KLOTHO expression. In contrast, KLOTHO and circadian regulators exhibit inverse correlations with ferroptosis markers. Among the clinical variables examined, only the presence of chronic pathologies showed an association with the expression patterns of several proteins studied. These findings underscore the complexity of PDAC pathogenesis and highlight the need for further research into the specific molecular mechanisms driving disease progression.
Asunto(s)
Carcinoma Ductal Pancreático , Ferroptosis , Proteínas Klotho , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Femenino , Masculino , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Ferroptosis/genética , Pronóstico , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Relojes Circadianos/genética , Estudios Retrospectivos , Regulación Neoplásica de la Expresión Génica , Glucuronidasa/genética , Glucuronidasa/metabolismoRESUMEN
BACKGROUND: Previous studies have identified the hemoglobin (Hb) to red blood cell distribution width (RDW) ratio (HRR) is associated with the prognosis of a variety of malignant tumors. However, the relationship between HRR and pancreatic ductal adenocarcinoma (PDAC) prognosis remains unexplored. This study aims to ascertain the prognostic significance of HRR in PDAC patients. METHODS: In a retrospective analysis, 128 PDAC patients undergoing initial surgical resection at Ningbo Medical Center Lihuili Hospital between January 2016 and September 2021 were included. Based on receiver operating characteristic curve-derived cut-off values, participants were categorized into low and high HRR groups. The correlation between HRR and patient prognosis was subsequently examined. RESULTS: Significant disparities in age, Hb levels, RDW, tumor locality, surgical intervention, and postoperative chemotherapy were observed between the two groups (P < 0.05). Notably, the low HRR cohort exhibited inferior disease-free survival (DFS) and overall survival (OS) rates (P = 0.002 for both). Univariate analysis indicated that male gender, adjacent tissue invasion, TNM stages III/IV, non-O blood types, low HRR, and lack of postoperative chemotherapy were linked to adverse DFS and OS outcomes (P < 0.05). Multivariate analysis further delineated low HRR as an independent predictor of poor DFS and OS outcomes (HR: 1.520, 95% CI: 1.028-2.247, P = 0.036; HR: 1.537, 95% CI: 1.034-2.284, P = 0.034, respectively). CONCLUSION: Our findings suggest that a lower HRR is indicative of poorer DFS and OS in PDAC patients, underscoring its potential utility as a prognostic biomarker for this population.
Asunto(s)
Carcinoma Ductal Pancreático , Índices de Eritrocitos , Hemoglobinas , Neoplasias Pancreáticas , Humanos , Masculino , Femenino , Estudios Retrospectivos , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/cirugía , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Persona de Mediana Edad , Hemoglobinas/análisis , Pronóstico , Anciano , Supervivencia sin Enfermedad , AdultoRESUMEN
BACKGROUND: Pancreatic cancer is anatomically divided into pancreatic head and body/tail cancers, and some studies have reported differences in prognosis. However, whether this discrepancy is induced from the difference of tumor biology is hotly debated. Therefore, we aimed to evaluate the differences in clinical outcomes and tumor biology depending on the tumor location. METHODS: In this retrospective cohort study, we identified 800 patients with pancreatic ductal adenocarcinoma who had undergone upfront curative-intent surgery. Cox regression analysis was performed to explore the prognostic impact of the tumor location. Among them, 153 patients with sufficient tumor tissue and blood samples who provided informed consent for next-generation sequencing were selected as the cohort for genomic analysis. RESULTS: Out of the 800 patients, 500 (62.5%) had pancreatic head cancer, and 300 (37.5%) had body/tail cancer. Tumor location in the body/tail of the pancreas was not identified as a significant predictor of survival outcomes compared to that in the head in multivariate analysis (hazard ratio, 0.94; 95% confidence interval, 0.77-1.14; P = 0.511). Additionally, in the genomic analyses of 153 patients, there were no significant differences in mutational landscapes, distribution of subtypes based on transcriptomic profiling, and estimated infiltration levels of various immune cells between pancreatic head and body/tail cancers. CONCLUSIONS: We could not find differences in prognosis and tumor biology depending on tumor location in pancreatic ductal adenocarcinoma. Discrepancies in prognosis may represent a combination of lead time, selection bias, and clinical differences, including the surgical burden between tumor sites.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/mortalidad , Pronóstico , Genómica/métodos , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: The aim of this study was to investigate the patterns of recurrence and their associated risk factors in patients who underwent resection for pancreatic carcinoma. METHODS: This retrospective study included 272 patients, who underwent Ro/R1-resection of PDAC from 2005 to 2020 at the University Hospital Erlangen. Risk factors for different recurrence patterns and the prognostic value of recurrence pattern on the overall survival after recurrence were evaluated. RESULTS: 61 % of the patients experienced recurrence, mostly within the first 12 postoperative months (62 %) and in the form of metastases (87 %). The median overall survival from recurrence was 9.2 months. The preoperative absence of diabetes and the presence of lymph node metastasis were independent risk factors for recurrence and a preoperative CA19-9 exceeding 97 U/ml for early recurrence. Additionally, lymph node metastases were associated with a higher risk of metastatic recurrence. Early recurrence, but not the site of recurrence, was identified as an independent prognostic factor for worse overall survival from recurrence. CONCLUSION: The occurrence of recurrence and especially of early and metastatic recurrence are associated with a worse overall survival. Patients lacking preoperative diabetes, having high preoperative CA19-9 values and lymph node metastases are particularly at risk for (early) recurrence.
Asunto(s)
Carcinoma Ductal Pancreático , Recurrencia Local de Neoplasia , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Masculino , Femenino , Factores de Riesgo , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/mortalidad , Recurrencia Local de Neoplasia/epidemiología , Anciano , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Persona de Mediana Edad , Metástasis Linfática , Pronóstico , Anciano de 80 o más Años , Adulto , Análisis de Supervivencia , Antígeno CA-19-9/sangre , PancreatectomíaRESUMEN
BACKGROUND: Systemic inflammation and altered metabolism are essential hallmarks of cancer. We hypothesized that the rapid turnover protein transthyretin (TTR) (half-life: 2-3 days), compared with the conventional marker albumin (21 days), better reflects the inflammatory/metabolic dynamics of pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and is a useful prognostic marker. METHODS: Serum TTR and albumin levels were measured in 104 consecutive post-NAT PDAC patients before curative resection. The associations of preoperative TTR and albumin levels with overall survival (OS) after pancreatectomy were retrospectively analyzed. RESULTS: The mean (SD) TTR and albumin levels were 21.6 (6.4) mg/dL (normal range: ≥22.0 mg/dL) and 3.9 (0.55) g/dL. A low (<22.0 mg/dL) post-NAT TTR level was associated with an advanced tumor stage and higher CEA and CRP levels. Patients with low TTR levels showed significantly worse OS compared with normal levels (3-year OS 39 % vs. 54 %, P = 0.037), although albumin levels did not. We modified prognostic biomarkers of systemic inflammation/metabolism, such as GPS, PNI, and CONUT scores, using the serum TTR instead of albumin level and successfully showed that modified scores were better associated with OS compared with original scores using serum albumin level. CONCLUSIONS: Our data suggest that the TTR level is a promising prognostic biomarker for PDAC patients after NAT.
Asunto(s)
Biomarcadores de Tumor , Carcinoma Ductal Pancreático , Terapia Neoadyuvante , Neoplasias Pancreáticas , Prealbúmina , Humanos , Prealbúmina/metabolismo , Prealbúmina/análisis , Masculino , Femenino , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/terapia , Anciano , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Biomarcadores de Tumor/sangre , Estudios Retrospectivos , Pronóstico , Análisis de Supervivencia , Albúmina Sérica/análisis , Albúmina Sérica/metabolismo , Anciano de 80 o más Años , Pancreatectomía , AdultoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at metastatic stage and typically treated with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Few patients benefit from this treatment. Molecular subtypes are prognostic in particularly resectable PDAC and might predict treatment response. This study aims to correlate molecular subtypes in metastatic PDAC with FOLFIRINOX responses using real-world data, providing assistance in counselling patients. We collected 131 RNA-sequenced metastatic biopsies and applied a network-based meta-analysis using published PDAC classifiers. Subsequent survival analysis was performed using the most suitable classifier. For validation, we developed an immunohistochemistry (IHC) classifier using GATA6 and keratin-17 (KRT17), and applied it to 86 formalin-fixed paraffin-embedded samples of advanced PDAC. Lastly, GATA6 knockdown models were generated in PDAC organoids and cell lines. We showed that the PurIST classifier was the most suitable classifier. With this classifier, classical tumors had longer PFS and OS than basal-like tumors (PFS: 216 vs. 78 days, p = 0.0002; OS: 251 vs. 195 days, p = 0.049). The validation cohort showed a similar trend. Importantly, IHC GATA6low patients had significantly shorter survival with FOLFIRINOX (323 vs. 746 days, p = 0.006), but no difference in non-treated patients (61 vs. 54 days, p = 0.925). This suggests that GATA6 H-score predicts therapy response. GATA6 knockdown models did not lead to increased FOLFIRINOX responsiveness. These data suggest a predictive role for subtyping (transcriptomic and GATA6 IHC), though no direct causal relationship was found between GATA6 expression and chemoresistance. GATA6 immunohistochemistry should be seamlessly added to current diagnostics and integrated into upcoming clinical trials.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Fluorouracilo , Factor de Transcripción GATA6 , Irinotecán , Leucovorina , Oxaliplatino , Neoplasias Pancreáticas , Transcriptoma , Humanos , Leucovorina/uso terapéutico , Oxaliplatino/uso terapéutico , Irinotecán/uso terapéutico , Fluorouracilo/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor de Transcripción GATA6/genética , Factor de Transcripción GATA6/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Estudios de Cohortes , Anciano , Línea Celular Tumoral , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/mortalidad , Metástasis de la Neoplasia , Resultado del TratamientoRESUMEN
KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.
Asunto(s)
Carcinoma Ductal Pancreático , Mutación , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/mortalidad , Animales , Ratones , Transición Epitelial-Mesenquimal/genética , Pronóstico , Masculino , Femenino , FN-kappa B/metabolismo , FN-kappa B/genética , Transducción de Señal/genética , Persona de Mediana Edad , Organoides/patología , Movimiento Celular/genética , AncianoRESUMEN
Background: pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a very poor prognosis and a complex tumor microenvironment, which plays a key role in tumor progression and treatment resistance. Glycosylation plays an important role in processes such as cell signaling, immune response and protein stability. Materials and methods: single-cell RNA sequencing data and spatial transcriptome data were obtained from GSE197177 and GSE224411, respectively, and RNA-seq data and survival information were obtained from UCSC Xena and TCGA. Multiple transcriptomic data were comprehensively analyzed to explore the role of glycosylation processes in tumor progression, and functional experiments were performed to assess the effects of MGAT1 overexpression on PDAC cell proliferation and migration. Results: In PDAC tumor samples, the glycosylation level of macrophages was significantly higher than that of normal samples. MGAT1 was identified as a key glycosylation-related gene, and its high expression was associated with better patient prognosis. Overexpression of MGAT1 significantly inhibited the proliferation and migration of PDAC cells and affected intercellular interactions in the tumor microenvironment. Conclusion: MGAT1 plays an important role in PDAC by regulating glycosylation levels in macrophages, influencing tumor progression and improving prognosis.MGAT1 is a potential therapeutic target for PDAC and further studies are needed to develop targeted therapeutic strategies against MGAT1 to improve clinical outcomes.
Asunto(s)
Carcinoma Ductal Pancreático , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Glicosilación , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Proliferación Celular/genética , Microambiente Tumoral/genética , Línea Celular Tumoral , Movimiento Celular/genética , Pronóstico , Macrófagos/metabolismo , Macrófagos/inmunología , Biomarcadores de Tumor/genéticaRESUMEN
The notion that technically resectable pancreatic ductal adenocarcinoma presents as localized disease is now known to be inaccurate. Evidence supports that most patients have subclinical systemic dissemination at the time of diagnosis. It is now widely accepted that both a local and systemic component of disease coexist, each requiring treatment of improved survival and potential cure. The advent of multiagent chemotherapy regimens has resulted in a modest improvement in survival. Consequently, this article will emphasize the expanding potential and significance of circulating tumor cells in the prognostication and management of patients with pancreatic cancer.
Asunto(s)
Carcinoma Ductal Pancreático , Células Neoplásicas Circulantes , Neoplasias Pancreáticas , Humanos , Células Neoplásicas Circulantes/patología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/cirugía , PronósticoRESUMEN
There is a significant difference in prognosis and response to chemotherapy between basal and classical subtypes of pancreatic ductal adenocarcinoma (PDAC). Further biomarkers are required to identify subtypes of PDAC. We selected candidate biomarkers via review articles. Correlations between these candidate markers and the PDAC molecular subtype gene sets were analyzed using bioinformatics, confirming the biomarkers for identifying classical and basal subtypes. Subsequently, 298 PDAC patients were included, and their tumor tissues were immunohistochemically stratified using these biomarkers. Survival data underwent analysis, including Cox proportional hazards modeling. Our results indicate that the pairwise and triple combinations of KRT5/KRT17/S100A2 exhibit a higher correlation coefficient with the basal-like subtype gene set, whereas the corresponding combinations of GATA6/HNF4A/TFF1 show a higher correlation with the classical subtype gene set. Whether analyzing unmatched or propensity-matched data, the overall survival time was significantly shorter for the basal subtype compared with the classical subtype (p < .001), with basal subtype patients also facing a higher risk of mortality (HR = 4.017, 95% CI 2.675-6.032, p < .001). In conclusion, the combined expression of KRT5, KRT17, and S100A2, in both pairwise and triple combinations, independently predicts shorter overall survival in PDAC patients and likely identifies the basal subtype. Similarly, the combined expression of GATA6, HNF4A, and TFF1, in the same manner, may indicate the classical subtype. In our study, the combined application of established biomarkers offers valuable insights for the prognostic evaluation of PDAC patients.
Asunto(s)
Biomarcadores de Tumor , Carcinoma Ductal Pancreático , Queratina-17 , Queratina-5 , Neoplasias Pancreáticas , Proteínas S100 , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Masculino , Femenino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Persona de Mediana Edad , Proteínas S100/genética , Proteínas S100/metabolismo , Queratina-5/genética , Queratina-5/metabolismo , Anciano , Queratina-17/genética , Queratina-17/metabolismo , Pronóstico , Factor de Transcripción GATA6/genética , Factor de Transcripción GATA6/metabolismo , Regulación Neoplásica de la Expresión Génica , Adulto , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Factores QuimiotácticosRESUMEN
While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.
Asunto(s)
Biomarcadores de Tumor , Carcinoma Ductal Pancreático , ADN Tumoral Circulante , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Femenino , Masculino , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mutación , Supervivencia sin Progresión , Metástasis de la NeoplasiaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy with known disparities in outcomes across ethnicities. Studies specifically investigating PDAC in Asian populations are sparse, overlooking the rich diversity within this group. This research seeks to fill that gap by examining survival differences across the broad spectrum of Asian ethnicities, acknowledging the complexity and varied experiences within these communities. Utilizing the National Cancer Database from 2004 to 2019, we categorized patients into East Asian, Southeast Asian, South Asian, and Pacific Islander groups. Non-Asians or Pacific Islanders were excluded. Overall survival was analyzed using a Cox hazards model. The study consisted of 13,254 patients. Most patients were East Asian (59.4%, n = 7,866). Southeast Asians exhibited the poorest survival in unadjusted analysis (HR, 1.32; 95% confidence interval, 1.23-1.42; P < 0.001) compared with South Asians who exhibited the best survival. Multivariable analysis revealed significantly worse survival for East Asians and Pacific Islanders relative to South Asians, whereas Southeast Asians' results were not significantly different. Asian subgroup differences notably affect PDAC outcomes. Research on genetic and cultural aspects, especially in Southeast Asians, and tackling health disparities are crucial for enhancing survival in this diverse disease. SIGNIFICANCE: This study highlights the significant survival disparities among Asian subgroups with pancreatic cancer, utilizing a large national database. By differentiating among East Asian, Southeast Asian, South Asian, and Pacific Islander groups, it underscores the need for tailored research and healthcare approaches. Addressing these differences is essential for developing culturally sensitive interventions and potentially improving outcomes in a disease that uniquely affects these diverse populations.
Asunto(s)
Carcinoma Ductal Pancreático , Nativos de Hawái y Otras Islas del Pacífico , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/etnología , Carcinoma Ductal Pancreático/mortalidad , Femenino , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Neoplasias Pancreáticas/etnología , Neoplasias Pancreáticas/mortalidad , Masculino , Anciano , Persona de Mediana Edad , Pueblo Asiatico/estadística & datos numéricos , Disparidades en el Estado de Salud , Pueblos Isleños del PacíficoRESUMEN
BACKGROUND: The introduction of the 1 mm cut-off for resection margin according to the Leeds Pathology Protocol has transformed the concept of surgical radicality. Its impact on nodal-positive resected pancreatic ductal adenocarcinoma patients is unclear. The aim of this study was to analyse the effect of margin clearance on survival among resected, nodal-positive pancreatic ductal adenocarcinoma patients whose specimens were analysed according to the Leeds Pathology Protocol. METHODS: Data were collected retrospectively from multicentre clinical databases. Resected patients with nodal involvement were included. Overall survival and disease-free survival were analysed according to minimum reported margin clearances of 0, 0.5, 1, and 2 mm. The results are reported separately for patients who had not undergone venous resection and for patients for whom data were available regarding the superior mesenteric vein-facing margin or the vein specimen. The eighth edition of TNM classification by the AJCC was used. RESULTS: The study comprised 290 stage IIB patients and 215 stage III patients without venous resection. The superior mesenteric vein margin analysis comprised 127 stage IIB patients and 198 stage III patients. The different resection margin distances were not associated with overall survival and disease-free survival among patients without venous resection (P > 0.050). Receiving adjuvant therapy was associated with longer overall survival among stage IIB patients (P = 0.034) and stage III patients (P = 0.003) and with longer disease-free survival among stage III patients (P < 0.001). CONCLUSIONS: In this study, a margin clearance greater than 1 mm showed no clear effect on overall survival in pancreatic ductal adenocarcinoma patients with nodal involvement, whereas adjuvant therapy was confirmed to be essential to ensure longer overall survival.
Asunto(s)
Carcinoma Ductal Pancreático , Márgenes de Escisión , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Masculino , Femenino , Anciano , Persona de Mediana Edad , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Supervivencia sin Enfermedad , Estadificación de Neoplasias , Pancreatectomía , Metástasis Linfática , Venas Mesentéricas/patología , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Anciano de 80 o más Años , AdultoRESUMEN
Importance: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven. Objective: To compare the survival of patients with surveillance-detected PDAC with US national data. Design, Setting, and Participants: This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023. Exposures: Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment. Main Outcomes and Measures: Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted. Results: A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%]). Conclusions and Relevance: These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Programa de VERF , Humanos , Femenino , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patología , Masculino , Anciano , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/epidemiología , Persona de Mediana Edad , Detección Precoz del Cáncer , Estados Unidos/epidemiología , Factores de Riesgo , Imagen por Resonancia Magnética , Estadificación de NeoplasiasRESUMEN
Although sequence-based studies show that basal-like features lead to worse prognosis and chemotherapy-resistance compared to the classical subtype in advanced pancreatic ductal adenocarcinoma (PDAC), a surrogate biomarker distinguishing between these subtypes in routine diagnostic practice remains to be identified. We aimed to evaluate the utility of immunohistochemistry (IHC) expression subtypes generated by unsupervised hierarchical clustering based on staining scores of four markers (CK5/6, p63, GATA6, HNF4a) applied to endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) materials. EUS-FNAB materials taken from 190 treatment-naïve advanced PDAC patients were analyzed, and three IHC patterns were established (Classical, Transitional, and Basal-like pattern). Basal-like pattern (high co-expression of CK5/6 and p63 with low expression of GATA6 and HNF4a) was significantly associated with squamous differentiation histology (p < 0.001) and demonstrated the worst overall survival among our cohort (p = 0.004). IHC expression subtype (Transitional, Basal vs Classical) was an independent poor prognosticator in multivariate analysis [HR 1.58 (95% CI 1.01-2.38), p = 0.047]. Furthermore, CK5/6 expression was an independent poor prognostic factor in histological glandular type PDAC [HR 2.82 (95% CI 1.31-6.08), p = 0.008]. Our results suggest that IHC expression patterns successfully predict molecular features indicative of the Basal-like subgroup in advanced PDAC. These results provide the basis for appropriate stratification for therapeutic selection and prognostic estimation of advanced PDAC in a simplified manner.