RESUMEN
BACKGROUND & AIMS: Previous studies have shown an increasing incidence of pancreatic cancer (PC), especially in younger women; however, this has not been externally validated. In addition, there are limited data about contributing factors to this trend. We report age and sex-specific time-trend analysis of PC age-adjusted incidence rates (aIRs) using the National Program of Cancer Registries database without Surveillance Epidemiology and End Results data. METHODS: PC aIR, mortality rates, annual percentage change, and average annual percentage change (AAPC) were calculated and assessed for parallelism and identicalness. Age-specific analyses were conducted in older (≥55 years) and younger (<55 years) adults. PC incidence based on demographics, tumor characteristics, and mortality were evaluated in younger adults. RESULTS: A total of 454,611 patients were diagnosed with PC between 2001 and 2018 with significantly increasing aIR in women (AAPC = 1.27%) and men (AAPC = 1.14%) without a difference (P = .37). Similar results were seen in older adults. However, in younger adults (53,051 cases; 42.9% women), women experienced a greater increase in aIR than men (AAPCs = 2.36%, P < .001 vs 0.62%, P = 0.62) with nonparallel trends (P < .001) and AAPC difference of 1.74% (P < .001). This AAPC difference appears to be due to rising aIR in Blacks (2.23%; P < .001), adenocarcinoma histopathologic subtype (0.89%; P = .003), and location in the head-of-pancreas (1.64%; P < .001). PC mortality was found to be unchanged in women but decreasing in counterpart men (AAPC difference = 0.54%; P = .001). CONCLUSION: Using nationwide data, covering ≈64.5% of the U.S. population, we externally validate a rapidly increasing aIR of PC in younger women. There was a big separation of the incidence trend between women and men aged 15-34 years between 2001 and 2018 (>200% difference), and it did not show slowing down.
Asunto(s)
Neoplasias Pancreáticas , Masculino , Humanos , Femenino , Estados Unidos/epidemiología , Anciano , Incidencia , Sistema de Registros , Neoplasias Pancreáticas/epidemiología , Páncreas , Neoplasias PancreáticasRESUMEN
BACKGROUND & AIMS: The stroma in pancreatic ductal adenocarcinoma (PDAC) contributes to its immunosuppressive nature and therapeutic resistance. Herein we sought to modify signaling and enhance immunotherapy efficacy by targeting multiple stromal components through both intracellular and extracellular mechanisms. METHODS: A murine liver metastasis syngeneic model of PDAC was treated with focal adhesion kinase inhibitor (FAKi), anti-programmed cell death protein 1 (PD-1) antibody, and stromal hyaluronan (HA) degradation by PEGylated recombinant human hyaluronidase (PEGPH20) to assess immune and stromal modulating effects of these agents and their combinations. RESULTS: The results showed that HA degradation by PEGPH20 and reduction in phosphorylated FAK expression by FAKi leads to improved survival in PDAC-bearing mice treated with anti-PD-1 antibody. HA degradation in combination with FAKi and anti-PD-1 antibody increases T-cell infiltration and alters T-cell phenotype toward effector memory T cells. FAKi alters the expression of T-cell modulating cytokines and leads to changes in T-cell metabolism and increases in effector T-cell signatures. HA degradation in combination with anti-PD-1 antibody and FAKi treatments reduces granulocytes, including granulocytic- myeloid-derived suppressor cells and decreases C-X-C chemokine receptor type 4 (CXCR4)-expressing myeloid cells, particularly the CXCR4-expressing granulocytes. Anti-CXCR4 antibody combined with FAKi and anti-PD-1 antibody significantly decreases metastatic rates in the PDAC liver metastasis model. CONCLUSIONS: This represents the first preclinical study to identify synergistic effects of targeting both intracellular and extracellular components within the PDAC stroma and supports testing anti-CXCR4 antibody in combination with FAKi as a PDAC treatment strategy.
Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Ratones , Animales , Neoplasias Pancreáticas/patología , Adenocarcinoma/patología , Hialuronoglucosaminidasa/farmacología , Hialuronoglucosaminidasa/uso terapéutico , Ácido Hialurónico , Carcinoma Ductal Pancreático/genética , Neoplasias Hepáticas/tratamiento farmacológico , Proteína-Tirosina Quinasas de Adhesión Focal , Citocinas/farmacología , Muerte Celular , Polietilenglicoles/uso terapéutico , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
INTRODUCTION: The efficacy and safety of combined immunotherapy and transarterial radioembolization (TARE) were suggested in preclinical and early-phase trials, but these were limited by small sample sizes. We sought to compare the efficacy of combined therapy and immunotherapy alone in patients with advanced hepatocellular carcinoma (HCC). METHODS: The National Cancer Database was used to identify patients with advanced HCC diagnosed between January 1, 2017, and December 31, 2019. We included patients who received combined therapy or immunotherapy alone as first-line treatment. Multivariable logistic regression was conducted to determine predictors of combined therapy. Kaplan-Meier and Cox regression approaches were used to identify predictors of overall survival and to compare hazards of mortality between the patients who received combined therapy and immunotherapy alone. RESULTS: Of 1,664 eligible patients with advanced-stage HCC, 142 received combined TARE/immunotherapy and 1,522 received immunotherapy alone. Receipt of combination therapy was associated with care at an academic center and inversely associated with racial/ethnic minority status (Hispanic and Black individuals). The median overall survival was significantly higher in the combination group than in the immunotherapy alone group (19.8 vs 9.5 months). In multivariable analysis, combined therapy was independently associated with reduced mortality (adjusted hazard ratio 0.50, 95% confidence interval: 0.36-0.68, P < 0.001). Results were consistent across subgroups and in sensitivity analyses using propensity score matching and inverse probability of treatment weighting. DISCUSSION: The combination of TARE and immunotherapy was associated with improved survival compared with immunotherapy alone in patients with advanced-stage HCC. Our findings underly the importance of large clinical trials evaluating combination therapy in these patients.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Etnicidad , Estudios Retrospectivos , Grupos Minoritarios , Inmunoterapia , Resultado del TratamientoRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor survival. The dense desmoplastic stroma in PDAC contributes to treatment resistance. Among the components comprising the tumor stroma, hyaluronan (HA) has been demonstrated to play a critical role in tumor progression and survival. Previous preliminary studies have suggested differences in HA expression in primary and metastatic foci of PDAC. However, the effects of treatment and location of HA expression as a biomarker signature remain unknown; this study sought to compare HA expression in primary and metastatic sites of PDAC. METHODS: Tissue from primary and metastatic PDACs were obtained from Cedars-Sinai Medical Center along with associated clinical data. Tissue slides were stained for H&E, HA, and CD44. Associations between HA levels and the evaluated variables were examined including progression free survival and overall survival. RESULTS: HA score was significantly higher in primary PDACs compared to sites of metastases (p = 0.0148). Within the metastases, HA score was significantly higher in liver metastases compared to metastases at other sites (p = 0.0478). In the treatment-naive liver metastasis cohort, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status (p = 0.0032 and p = 0.0478, respectively). CONCLUSIONS: HA score is variable between primary PDAC, PDAC metastatic to the liver, and PDAC metastatic to other sites. Within liver metastases, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status. HA levels can serve as a potential biomarker to guide pancreatic cancer treatments and trial design for agents targeting the stroma.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Ácido Hialurónico/metabolismo , Neoplasias Pancreáticas/diagnóstico , Adyuvantes Inmunológicos , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Humanos , Neoplasias Hepáticas , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Neoplasias PancreáticasRESUMEN
Despite advances in cancer therapeutics, pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, with a poor prognosis at time of diagnosis. Research in PDAC has suggested that adaptive signaling in the tumor microenvironment may promote tumor proliferation and survival. Several FGFR fusion genes-specifically FGFR2-are involved with the creation and progression of cancer. These mutations are found in a variety of cancer types. This report presents a unique case of a young patient with stage IV PDAC with a known FGFR2 fusion. This molecular alteration afforded a remarkable response to FGFR inhibitor therapy, erdafitinib, after the patient experienced disease progression on multiple chemotherapy regimens.
Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pirazoles , Quinoxalinas , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/uso terapéutico , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Pancreatic metastasis of primary lung adenocarcinoma is a rare occurrence, accounting for <0.3% of all pancreatic malignancies. Given that the prognosis and treatment options for primary pancreatic cancer differ greatly from pancreatic metastases from a primary site, an accurate diagnosis is critical. This report presents a unique case of a 65-year-old man who was admitted with significant unintentional weight loss, fatigue, abdominal pain, and jaundice, and found to have a pancreatic mass initially thought to be primary pancreatic adenocarcinoma and subsequently diagnosed as an EGFR-mutated lung adenocarcinoma with metastases to the pancreas via early application of next-generation sequencing (NGS). The use of NGS early in the patient's clinical course not only changed the treatment strategy but also drastically altered the prognosis. Although metastatic pancreatic adenocarcinoma has a poor prognosis and survival rate, treatment of EGFR-mutated non-small cell lung cancer with EGFR tyrosine kinase inhibitors is associated with high response rates. Importantly, our case demonstrates that timely application of NGS very early in the disease course is paramount to the diagnosis, management, and prognosis of solid malignancies.
Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Pancreáticas , Masculino , Humanos , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Neoplasias PancreáticasAsunto(s)
Carcinoma Ductal Pancreático , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Mutación de Línea Germinal , Neoplasias Pancreáticas , Humanos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Neoplasias Pancreáticas/genética , Pruebas Genéticas/métodos , Carcinoma Ductal Pancreático/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Fenotipo , Valor Predictivo de las Pruebas , Biomarcadores de Tumor/genética , Adulto , Análisis Mutacional de ADNRESUMEN
PURPOSE: There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA. METHODS: We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5-1, >1-2, or >2 mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS). RESULTS: Among all margins, PM clearance up to 2 mm was prognostic of DFS (p = 0.01) and OS (p = 0.01). Dichotomizing the PM at 2 mm revealed it to be an independent predictor of local recurrence-free survival [hazard ratio HR] 0.20, 95% confidence interval [CI] 0.048-0.881, p = 0.033), DFS (HR 0.46, 95% CI 0.22-0.96, p = 0.03), and OS (HR 0.31, 95% CI 0.14-0.74, p = 0.008). A margin status of >2 mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11-0.89, p = 0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10-1.58, p = 0.19). CONCLUSION: These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2 mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2 mm.
Asunto(s)
Adenocarcinoma/mortalidad , Carcinoma Ductal Pancreático/mortalidad , Quimioradioterapia Adyuvante/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adenocarcinoma/terapia , Anciano , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Recurrencia Local de Neoplasia/terapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/terapia , Pronóstico , Tasa de SupervivenciaRESUMEN
Although recent advances in cancer treatment significantly improved the prognosis of patients, drug resistance remains a major challenge. Targeting programmed cell death is a major approach of antitumor drug development. Deregulation of programmed cell death (PCD) contributes to resistance to a variety of cancer therapeutics. Yes-associated protein (YAP) and its paralog TAZ, the main downstream effectors of the Hippo pathway, are aberrantly activated in a variety of human malignancies. The Hippo-YAP pathway, which was originally identified in Drosophila, is well conserved in humans and plays a defining role in regulation of cell fate, tissue growth and regeneration. Activation of YAP signaling has emerged as a key mechanism involved in promoting cancer cell proliferation, metastasis, and drug resistance. Understanding the role of YAP/TAZ signaling network in PCD and drug resistance could facilitate the development of effective strategies for cancer therapeutics.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Neoplasias , Humanos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAP , Neoplasias/metabolismo , Resistencia a Medicamentos , Apoptosis/genéticaRESUMEN
Liver cancer remains a challenge of global health, being the 4th leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is usually precipitated by chronic viral infections (hepatitis B and C), non-alcoholic steatohepatitis, heavy alcohol use, and other factors which may lead to chronic inflammation and cirrhosis of the liver. There have been significant advances in the systemic treatment options for HCC over the past decades, with several approvals of both immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with preserved liver function. These advances have led to improvement in survival outcomes, with expected survival of greater than 18 months, in those with sensitive tumors, adequate liver function, and those functionally fit to receive sequential therapies. Several ongoing and promising trials are now evaluating combinational strategies with novel systemic agents and combinations of systemic therapy with locoregional therapy. In view of these trials, further advances in the treatment of HCC are foreseen in the near future.
Asunto(s)
Carcinoma Hepatocelular , Hepatitis B , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/complicaciones , Cirrosis Hepática/complicaciones , Hepatitis B/complicacionesRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) has extremely poor prognosis, with a 5-year survival rate of approximately 11 %. Yes-associated protein (YAP) is a major downstream effector of the Hippo-YAP pathway and plays a pivotal role in regulation of cell proliferation and organ regeneration and tumorigenesis. Activation of YAP signaling has been associated with PDAC progression and drug resistance. Verteporfin (VP) is a photosensitizer used for photodynamic therapy and previous work showed that it can function as a YAP inhibitor. The efficacy of VP on human cancer are being tested in several trials. In this study, we examined the effect of VP on reactive oxygen species (ROS) and lipid peroxidation in pancreatic cancer cells, by using fluorescent molecular probes and by measuring the levels of malondialdehyde, a metabolic byproduct and marker of lipid peroxidation. We found that VP causes rapid increase of both overall ROS and lipid peroxide levels, independent of light activation. These effects were not dependent on YAP, as knockdown of YAP did not cause ROS or lipid peroxidation or enhance VP-induced ROS production. Temoporfin, another photodynamic drug, did not show similar activities. In addition, VP treatment led to loss of cell membrane integrity and reduction of viability. Notably, the activity of VP to induce lipid peroxidation was neutralized by ferroptosis inhibitors ferrostatin-1 or liproxstatin-1. VP treatment also reduced the levels of glutathione peroxidase 4 (GPX4), an enzyme that protects against lipid peroxidation. These results indicate that VP can induce lipid peroxidation and ferroptosis in the absence of light activation. Our findings reveal a novel mechanism by which VP inhibits tumor growth and provide insights into development of new therapeutic strategies for the treatment of pancreatic cancer.
Asunto(s)
Carcinoma Ductal Pancreático , Ferroptosis , Neoplasias Pancreáticas , Humanos , Verteporfina/farmacología , Verteporfina/uso terapéutico , Peroxidación de Lípido , Especies Reactivas de Oxígeno , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genéticaRESUMEN
OBJECTIVES: Adenocarcinomas of the biliary tract frequently present diagnostic challenges because of their histologic overlap with benign and preinvasive lesions. The molecular profiles of biliary adenocarcinomas vary by anatomical location. Variations in IDH1/2, common in intrahepatic cholangiocarcinoma, can lead to defective production of 5-hydroxymethylcytosine (5-hmC). Limited ancillary studies are available for biliary adenocarcinomas, and loss of 5-hmC staining could serve as a helpful ancillary diagnostic tool for biliary tract malignancies. METHODS: We evaluated 93 cases-20 benign biliary lesions, 15 preinvasive biliary neoplasms, 46 invasive biliary carcinomas, and 12 pancreatic adenocarcinomas-for 5-hmC staining. Preoperative biopsies from 16 cases of biliary carcinoma were also stained. Sixteen nonneoplastic/reactive bile duct biopsies served as controls. RESULTS: Loss of 5-hmC was seen in 41 of 46 (89.1%) biliary malignancies vs 0 of 20 benign tumors (P < .001), for a sensitivity and specificity of 89.1% and 100%, respectively. Intrahepatic cholangiocarcinoma showed loss of 5-hmC in 11 of 13 (84.6%) cases, similar to the 30 of 33 (90.9%) cases in other biliary adenocarcinomas (P = .61). Similarly, 5-hmC loss was more frequent in distal bile duct adenocarcinomas than in pancreatic ductal adenocarcinomas, at 15 of 17 (88.2%) vs 4 of 12 (33.3%), respectively (P = .0045). There was no difference in the frequency of 5-hmC loss in patients that received neoadjuvant therapy vs those who did not (90.9% vs 88.6%, P > .99). 5-hmC immunohistochemistry in preoperative biopsies was concordant with the resection specimen in 81.3% (13/16) of cases. CONCLUSIONS: Loss of 5-hmC is not unique to intrahepatic cholangiocarcinoma among biliary carcinomas, but is a useful diagnostic marker differentiating malignancies of the biliary tree from benign mimics.
Asunto(s)
5-Metilcitosina , Neoplasias del Sistema Biliar , Biomarcadores de Tumor , Colangiocarcinoma , Humanos , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/análisis , 5-Metilcitosina/metabolismo , Biomarcadores de Tumor/análisis , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias del Sistema Biliar/diagnóstico , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/metabolismo , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patología , Colangiocarcinoma/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Adulto , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/patología , Anciano de 80 o más Años , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/diagnósticoRESUMEN
INTRODUCTION: Pancreatic ductal adenocarcinoma is associated with significant morbidity and mortality as most patients present with advanced disease. The development of ascites has been associated with poor outcomes and further characterization and contemporary management strategies are needed. METHODS: A total of 437 patients enrolled in the Gastrointestinal Biobank at Cedars-Sinai Medical Center who had epithelial pancreatic malignancy were included in the prospective cohort group. Overall, 41.7% of patients included in this study developed ascites. Most patients with ascites (>80%) had high serum-ascites albumin gradient ascites. In both univariate and multivariate analysis, a history of ≥1 form of chemotherapy was significantly associated with ascites. Estimated median overall survival in patients with ascites was significantly lower than in patients without ascites, 473 days vs 573 days, and ascites had a hazard ratio of 1.37. RESULTS: Patients with ascites who received diuretics and indwelling peritoneal catheter had an estimated median survival of 133 days from diagnosis of ascites, and those who received only the indwelling peritoneal catheter without diuretics had an estimated median survival of only 54 days. The estimated median survival from the diagnosis of ascites was 92 days, and the median time to puncture was 7 days. The median time from first tap to death was 45 days. DISCUSSION: The use of diuretics is lower than would be expected for patients with pancreatic ductal adenocarcinoma with elevated serum-ascites albumin gradient. Other therapies such as beta blockers should be investigated in this subset of patients. The etiology of ascites in these patients is poorly understood, and further research is needed to establish treatment guidelines and improve outcomes.
Asunto(s)
Ascitis , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Ascitis/etiología , Masculino , Femenino , Estudios Prospectivos , Anciano , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/diagnóstico , Pronóstico , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/complicaciones , Carcinoma Ductal Pancreático/patología , Diuréticos/uso terapéutico , Albúmina Sérica/análisis , Albúmina Sérica/metabolismo , Anciano de 80 o más Años , Catéteres de Permanencia/efectos adversosRESUMEN
Purpose: The role of preoperative stereotactic body radiation therapy (SBRT) in pancreatic cancer is controversial, and questions regarding the optimal dose and radiation treatment field remain. To better inform future investigations of SBRT dose and radiation fields, we evaluated the patterns of failure in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC) after preoperative chemotherapy and SBRT in patients who underwent surgical resection. Methods and Materials: We performed a single-institution retrospective review of consecutive patients treated from September 2017 to January 2022 with BR/LAPC. Patients who underwent preoperative chemotherapy and SBRT followed by surgical resection were reviewed. SBRT was delivered to a dose of 33 Gy in 5 fractions. Kaplan-Meier overall survival and progression-free survival estimates were calculated. Results: In total, 18 patients (12 BRPC, 6 LAPC) were included. Median age was 69 years (range 41-84 years). Median follow-up was 30 months (range 13-59 months). Seventeen patients (94%) had a R0 resection and 13 (72%) underwent vascular reconstruction. Median overall survival and progression-free survival was 42 months (range 13-59 months) and 23 months (range 1-45 months), respectively. In total, 61% (11/18) patients experienced progression at any point during follow-up. Of the patients who experienced recurrence, 27% (3/11) experienced local progression as component of their first recurrence, whereas 100% (11/11) experienced distant progression as a component of their first recurrence. When examining all recurrences that occurred at any point in follow-up, 28% (5/18) of patients experienced local or locoregional recurrence and 61% (11/18) experienced distant progression. Conclusions: Local control and margin negative resection rates were excellent with preoperative chemotherapy and nondose-escalated SBRT in surgically resected patients with BR/LAPC. Distant recurrence was the predominant site of failure with lower incidences of isolated locoregional recurrences. Additional research is needed to determine the ideal treatment volume and patients who may benefit from dose escalation.
RESUMEN
In previous studies, a significant increase in the incidence of pancreatic cancer among younger women compared to men in the United States was noted. However, the specific histopathologic characteristics were not delineated. This population-based study aimed to assess whether this disproportionate rise in pancreatic cancer in younger women was contributed by pancreatic ductal adenocarcinoma (PDAC) or pancreatic neuroendocrine tumors (PanNET). The United States Cancer Statistics (USCS) database was used to identify patients with pancreatic cancer between 2001 and 2018. The results showed that, in younger adults, the incidence of PDAC has increased in women [average annual percentage change (AAPC) = 0.62%], while it has remained stable in men (AAPC = -0.09%). The PDAC incidence rate among women increased at a greater rate compared to men with a statistically significant difference in AAPC (p < 0.001), with neither identical nor parallel trends. In contrast, cases of PanNET did not demonstrate a statistically significant sex-specific AAPC difference. In conclusion, this study demonstrated that the dramatic increase in the incidence rate of PDAC explains the disproportionate rise in pancreatic cancer incidence in younger women. This prompts further prospective studies to investigate the underlying reasons for these sex-specific disparities in PDAC.
RESUMEN
Contemporary analyses focused on a limited number of clinical and molecular biomarkers have been unable to accurately predict clinical outcomes in pancreatic ductal adenocarcinoma. Here we describe a precision medicine platform known as the Molecular Twin consisting of advanced machine-learning models and use it to analyze a dataset of 6,363 clinical and multi-omic molecular features from patients with resected pancreatic ductal adenocarcinoma to accurately predict disease survival (DS). We show that a full multi-omic model predicts DS with the highest accuracy and that plasma protein is the top single-omic predictor of DS. A parsimonious model learning only 589 multi-omic features demonstrated similar predictive performance as the full multi-omic model. Our platform enables discovery of parsimonious biomarker panels and performance assessment of outcome prediction models learning from resource-intensive panels. This approach has considerable potential to impact clinical care and democratize precision cancer medicine worldwide.
Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/genética , Adenocarcinoma/cirugía , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirugía , Multiómica , Inteligencia Artificial , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirugía , InteligenciaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of less than 10% due to its late diagnosis, rapid metastasis, and chemotherapeutic resistance. For a small proportion (10-20%) of early-stage patients however, surgical resection of the pancreatic tumor offers the best chance for survival but the effect of surgery on disease dissemination is unknown. The primary objective of this study was to characterize cellular and acellular blood-based analytes in portal and peripheral blood before pancreatic manipulation, during tumor dissection and immediately after surgical resection to determine the effects of the surgery. This study used the non-enriching third generation High-Definition Single Cell Assay (HDSCA3.0) workflow to investigate heterogeneous circulating rare cell population in the blood. Blood from both sites taken before surgical manipulation of the pancreas had significantly greater incidence of total rare cellular and acellular analytes than normal donor samples. Post-surgery portal and peripheral blood had significantly greater incidence of specific cellular and acellular subtypes compared to the matched pre- and during-surgery samples. Our results reveal that in patients with PDAC liquid biopsy analytes are increased in both the portal and peripheral blood; portal blood contains a higher frequency of analytes than in the peripheral blood; total analytes in the portal and peripheral blood samples were significantly associated with the tumor volume and pathological T stage; and the surgical procedure increased the blood levels of circulating cellular and acellular analytes, but not Epi.CTCs or Mes.CTCs. This study demonstrates liquid biopsy's utility in monitoring patients with PDAC with surgically resectable disease.
RESUMEN
Background and Aims: The change in hepatocellular carcinoma (HCC) care continuum during the coronavirus disease 2019 (COVID-19) pandemic remains unknown at a national level in the United States. We sought to determine the impact of the pandemic on incident HCC cases, clinical characteristics, and treatment in the United States. Methods: Using the National Cancer Database, we analyzed incident HCC cases from 2010 to 2020. The incidence rate was calculated using the population data for each year from the census bureau. Joinpoint regression analysis was applied for trend analysis, and a polynomial regression model estimated the number of projected HCC cases in 2020 according to the trend of rates from 2010 to 2019. The distribution of cancer stage and treatment modality were assessed. Results: The pandemic led to a significant reduction in reported HCC cases, from 19,597 in 2019 to 16,188 in 2020. The projected number of HCC for 2020 was 19,011, corresponding to a 14.8% reduction in 2020. Extent of reduction in the number of incident HCC cases relative to estimated cases remains consistent in racial and ethnic subgroups. Despite underdiagnosis of HCC in 2020, proportion of patients with early tumor stage (30.5% for Tumour, Node, Metastasis stage 1) and curative treatment receipt (9.1% for surgical resection, 13% for ablation, 4.2% for liver transplant) for HCC remained stable in the first year of the COVID-19 pandemic. Conclusion: There was a significant reduction in HCC cases in 2020 compared to pre-COVID years. While tumor stage and proportion of patients receiving curative treatment remained stable, continued follow-up is needed to assess potential changes during subsequent years.
RESUMEN
Due to the challenge for intratumoral administration, innate agonists have not made it beyond preclinical studies for efficacy testing in most tumor types. Pancreatic ductal adenocarcinoma (PDAC) has a hostile tumor microenvironment that renders T cells dysfunctional. Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment. Using a transplant mouse model with spontaneously formed liver metastasis, a genetically engineered KPC mouse model that spontaneously develops PDAC, and a human patient-derived xenograft model, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. Flow cytometry, Nanostring, and cytokine assays were used to evaluate local and systemic immune responses. This study demonstrated that administration of STING agonist systemically via intramuscular injection is equivalent to its intratumoral injection in inducing both effector T cell response and antitumor efficacy. Compared to intratumoral administration, T cell exhaustion and immunosuppressive signals induced by systemic administration were attenuated. Nonetheless, either intratumoral or systemic treatment of STING agonist was associated with increased expression of CTLA-4 on tumor-infiltrating T cells. However, the combination of a-PD-1 and anti-CTLA-4 antibody with systemic STING agonist demonstrated the antitumor efficacy in the KPC mouse spontaneous PDAC model. The mouse pancreatic and liver orthotopic model of human patient-derived xenograft reconstituted with PBMC also showed that antitumor and abscopal effects of both intratumoral and intramuscular STING agonist are equivalent. Taken together, this study supports the clinical development of innate agonists via systemic administration for treating PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Proteínas de la Membrana , Neoplasias Pancreáticas , Animales , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Humanos , Ratones , Proteínas de la Membrana/agonistas , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Inyecciones Intralesiones , Ensayos Antitumor por Modelo de Xenoinjerto , Microambiente Tumoral/efectos de los fármacos , Línea Celular TumoralRESUMEN
Radiotherapy is hypothesized to have an immune-modulating effect on the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) to sensitize it to anti-PD-1 antibody (a-PD-1) treatment. We collected paired pre- and posttreatment specimens from a clinical trial evaluating combination treatment with GVAX vaccine, a-PD-1, and stereotactic body radiation (SBRT) following chemotherapy for locally advanced PDACs (LAPC). With resected PDACs following different neoadjuvant therapies as comparisons, effector cells in PDACs were found to skew toward a more exhausted status in LAPCs following chemotherapy. The combination of GVAX/a-PD-1/SBRT drives TME to favor antitumor immune response including increased densities of GZMB+CD8+ T cells, TH1, and TH17, which are associated with longer survival, however increases immunosuppressive M2-like tumor-associated macrophages (TAMs). Adding SBRT to GVAX/a-PD-1 shortens the distances from PD-1+CD8+ T cells to tumor cells and to PD-L1+ myeloid cells, which portends prolonged survival. These findings have guided the design of next radioimmunotherapy studies by targeting M2-like TAM in PDACs.