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OBJECTIVE: To compare the efficacy and safety of high-intensity focused ultrasound (HIFU) and radical surgery for non-metastatic pancreatic cancer (PC). MATERIALS AND METHODS: We retrospectively analyzed 89 stage I/II/III PC patients who underwent HIFU (n = 43) or surgery (n = 46) at the Third Xiangya Hospital from January 2020 to December 2021. Pain relief, Karnofsky Performance Scale (KPS), overall survival (OS), treatment-related complications and risk factors for OS were assessed. RESULTS: There was no significant difference in the pain relief rate at 30 days post-treatment between the two groups. However, compared with the surgery group, the HIFU group showed significantly lower post-treatment VAS scores (p = 0.019). In the surgery group, the KPS at 30 days post-treatment was lower than pretreatment KPS (70 vs 80; p = 0.015). This relationship was reversed in the HIFU group (80 vs 70; p = 0.024). Median OS favored surgery over HIFU (23 vs 10 months; p < 0.001), with a higher 1-year OS rate (69.57% vs 32.6%; p < 0.001). However, there was no significant difference in OS between the two groups for stage III patients (p = 0.177). Complications rated ≥ grade III were 2.33% in the HIFU group and 32.6% in the surgery group. Multivariate analyses showed that age, KPS, and treatment methods were independent prognostic factors for OS. CONCLUSION: HIFU demonstrates advantages over surgery in terms of early KPS, VAS improvements, and safety for pancreatic cancer; however, long-term outcomes favor surgery. For III-stage disease, HIFU was noninferior to surgery in overall survival.
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Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , AdultoRESUMEN
This article presents updates in the surgical management of non-functional sporadic pancreas neuroendocrine tumors NET, including considerations for assessment of biologic behavior to support decision-making, indications for surgery, and surgical approaches tailored to the unique nature of neuroendocrine tumors.
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Tumores Neuroendocrinos , Pancreatectomía , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/diagnóstico , Pancreatectomía/métodos , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/terapia , Tumores Neuroendocrinos/diagnósticoRESUMEN
The majority of patients diagnosed with pancreatic cancer already have metastatic disease at the time of presentation, which results in a 5-year survival rate of only 13%. However, multiagent chemotherapy regimens can stabilize the disease in select patients with limited metastatic disease. For such patients, a combination of curative-intent therapy and systemic therapy may potentially enhance outcomes compared to using systemic therapy alone. Of note, the evidence supporting this approach is primarily derived from retrospective studies and may carry a significant selection bias. Looking ahead, ongoing prospective trials are exploring the efficacy of curative-intent therapy in managing oligometastatic pancreatic cancer and the implementation of treatment strategies based on specific biomarkers. The emergence of these trials, coupled with the development of less invasive therapeutic modalities, provides hope for patients with oligometastatic pancreatic cancer.
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Pancreatectomía , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Pancreatectomía/métodos , Metástasis de la Neoplasia , Terapia CombinadaRESUMEN
While pancreatic adenocarcinoma requires surgical resection definitive cure, treatment paradigms are shifting toward a neoadjuvant approach to systemic therapy. Rationale is twofold: micro-metastatic disease is likely present in a majority of patients, reinforcing the importance of systemic therapy regardless of resectability; moreover, systemic therapy is well-tolerated and improves surgical outcomes when delivered preoperatively. Second, a neoadjuvant approach allows for selection of biology and patients most likely to benefit from potentially morbid surgery. This review examines the increasing body of evidence in support of empiric neoadjuvant therapy in pancreatic adenocarcinoma.
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Adenocarcinoma , Terapia Neoadyuvante , Pancreatectomía , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/cirugía , Terapia Neoadyuvante/métodos , Adenocarcinoma/terapia , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Pancreatectomía/métodos , Quimioterapia Adyuvante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Pancreatic cancer, renowned for its aggressive nature and poor prognosis, necessitates the optimization of treatment strategies. The sequence of procedures in clinical trials is critical, such as evaluating the potential benefits of preoperative chemo-radio-therapy for pancreatic cancer. Nevertheless, we might not be aware of other temporal sequences which have an effect on therapy response or the general outcome. Extracting transitive sequential patterns from patients' medical trajectories allows researchers to identify temporal characteristics for complex diseases. We illustrate how such sequential patterns can be discovered and might be utilized in pancreatic cancer research as well as patient care.
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Minería de Datos , Neoplasias Pancreáticas , Neoplasias Pancreáticas/terapia , HumanosRESUMEN
BACKGROUND: Prognostic implications of peritoneal washing cytology (CY) in patients with localized pancreatic ductal adenocarcinoma (PDAC) undergoing surgical resection following preoperative chemoradiotherapy (CRT) remain unclear. This study aimed to elucidate the prognostic significance and predictors of a positive CY status (CY+) after preoperative CRT. METHODS: Clinical data from 141 patients with localized PDAC who underwent curative-intent resection after preoperative CRT were retrospectively analyzed to examine the association between CY+ and clinicopathological factors and survival. RESULTS: CY+ was observed in six patients (4.3%). The CY+ group exhibited significantly higher preoperative serum levels of CA19-9 and a substantially greater incidence of tumor location in the pancreatic body or tail, along with pathological invasion to the anterior pancreatic capsule, than the CY- group. The CY+ group had a significantly higher incidence of peritoneal recurrence compared with the CY- group (83.3% vs. 18.5%, p = 0.002). Overall survival (OS) and recurrence-free survival (RFS) after surgery were significantly shorter in the CY+ group than in the CY- group (CY+ vs. CY-: 18.3 vs. 46.2 months, p = 0.001, and 8.9 vs. 17.7 months, p = 0.009, respectively). Multivariate analyses identified CY+ as an independent prognostic factor for worse OS (hazard ratio 5.00, 95% confidence interval 1.03-12.31) and RFS (hazard ratio 2.58, 95% confidence interval 1.04-6.43). Local invasion grade on imaging before CRT, limited histological response to CRT, and absence of adjuvant chemotherapy were independent predictors of worse OS and RFS. CONCLUSION: Despite the relatively low incidence of CY+ after preoperative CRT, it emerged as an independent prognostic factor in patients with localized PDAC undergoing curative-intent resection following preoperative CRT.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Femenino , Masculino , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Anciano , Persona de Mediana Edad , Pronóstico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/cirugía , Estudios Retrospectivos , Quimioradioterapia , Adulto , Anciano de 80 o más Años , Lavado Peritoneal/métodos , Citodiagnóstico/métodos , Recurrencia Local de Neoplasia/patología , CitologíaRESUMEN
OBJECTIVES: Pancreatic cancer with peritoneal metastasis presents a challenging prognosis, with limited effective treatment options available. This study aims to evaluate the efficacy and safety of combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as a treatment strategy for this patient group. METHODS: A retrospective analysis was conducted on patients with peritoneal metastasis of pancreatic cancer who underwent CRS + HIPEC treatment at Beijing Shijitan Hospital from March 2017 to December 2023. The study focused on assessing clinical features, the incidence of sever adverse events (SAEs), and overall survival (OS). RESULTS: A total of 10 patients were enrolled in this study. The median OS was 24.2 months, suggesting an improvement over traditional therapies. While SAEs were noted, including two cases of severe complications necessitating additional surgical interventions, no perioperative fatalities were recorded. The overall survival time for patients with CC0/1 was not significantly different from that of patients with CC2/3, and no prognostic predictors were identified. CONCLUSIONS: The combination of CRS and HIPEC appears to be a viable and promising treatment modality for patients with peritoneal metastasis of pancreatic cancer, offering an improved survival rate with manageable safety concerns. Further research is needed to refine patient selection criteria and to explore the long-term benefits of this approach.
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Procedimientos Quirúrgicos de Citorreducción , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Pancreáticas , Neoplasias Peritoneales , Humanos , Neoplasias Peritoneales/terapia , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/mortalidad , Procedimientos Quirúrgicos de Citorreducción/métodos , Procedimientos Quirúrgicos de Citorreducción/mortalidad , Masculino , Femenino , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Quimioterapia Intraperitoneal Hipertérmica/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Tasa de Supervivencia , Terapia Combinada , Pronóstico , Anciano , Estudios de Seguimiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , AdultoRESUMEN
Extracellular vesicles play an important role in the progression of pancreatic adenocarcinoma (PAAD) through the transfer of proteins, mRNAs, and long noncoding RNAs (lncRNAs). However, the intricate interplay between extracellular vesicles-related lncRNAs and the tumor microenvironment (TME) remains poorly elucidated. Consequently, our investigation aimed to delineate the association between extracellular vesicles-related lncRNAs and the PAAD microenvironment. Initially, we identified differentially expressed lncRNAs (DELs) from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) project datasets. Subsequently, we validated the expression of these DELs within extracellular vesicles and assessed their prognostic implications in PAAD using the GSE133684 and TCGA datasets. Multiomics data were analyzed comprehensively, including genomic landscape, functional annotation, immune profiles, and therapeutic responses. Differential expression of selected lncRNAs in both cellular and exosomal fractions of PAAD was further confirmed through quantitative polymerase chain reaction (qPCR). Eight DELs were identified from TCGA and GTEx datasets, and two exosomal lncRNAs exhibited a significant correlation with overall survival, warranting further investigation. Specifically, elevated expression of LINC00996 correlated positively with immune infiltration and enhanced response to immunotherapy. Conversely, heightened expression of TRHED-AS1 was associated with compromised immune cell infiltration and diminished responsiveness to immunotherapy. Our study establishes a compelling link between two extracellular vesicles-related gene signatures, prognosis, and immune infiltration in PAAD. Notably, these signatures serve as robust prognostic indicators for PAAD patients, offering valuable insights for the strategic selection of immunotherapeutic interventions.
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Adenocarcinoma , Vesículas Extracelulares , Neoplasias Pancreáticas , ARN Largo no Codificante , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Vesículas Extracelulares/metabolismo , Microambiente Tumoral/inmunología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Adenocarcinoma/inmunología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Pronóstico , Regulación Neoplásica de la Expresión GénicaRESUMEN
Outcomes from pancreatic ductal adenocarcinoma (PDAC) remain poor and better methods of prognostication and therapeutic approaches are needed. Recent advances in cancer genomics have led to the development of molecular subtypes of PDAC associated with clinical outcomes. Current evidence also suggests that the subtypes have differential response to first-line chemotherapy regimens. PDAC is also characterized by different stroma and immune environments. Further work is needed to confirm the utility of these subtypes to predicting response to different systemic therapies.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/diagnóstico , Perfilación de la Expresión Génica , Biomarcadores de Tumor/genética , PronósticoAsunto(s)
Neoplasias Intestinales , Tumores Neuroendocrinos , Nomogramas , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/terapia , Neoplasias Intestinales/mortalidad , Neoplasias Intestinales/terapia , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/terapia , Estudios de Cohortes , Femenino , MasculinoRESUMEN
Pancreatic cancer comprises different subtypes, where most cases include ductal adenocarcinoma (PDAC). It is one of the deadliest tumor types, with a poor prognosis. In the majority of patients, the disease has already spread by the time of diagnosis, making full recovery unlikely and increasing mortality risk. Despite developments in its detection and management, including chemotherapy, radiotherapy, and targeted therapies as well as advances in immunotherapy, only in about 13% of PDAC patients does the overall survival exceed 5 years. This may be attributed, at least in part, to the highly desmoplastic tumor microenvironment (TME) that acts as a barrier limiting perfusion, drug delivery, and immune cell infiltration and contributes to the establishment of immunologically 'cold' conditions. Therefore, there is an urgent need to unravel the complexity of the TME that promotes PDAC progression and decipher the mechanisms of pancreatic tumors' resistance to immunotherapy. In this review, we provide an overview of the major cellular and non-cellular components of PDAC TME, as well as their biological interplays. We also discuss the current state of PDAC therapeutic treatments and focus on ongoing and future immunotherapy efforts and multimodal treatments aiming at remodeling the TME to improve therapeutic efficacy.
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Inmunoterapia , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Inmunoterapia/métodos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , AnimalesRESUMEN
Cancer is a complex disease intrinsically associated with cellular processes and gene expression. With the development of techniques such as single-cell sequencing and sequential fluorescence in situ hybridization (seqFISH), it was possible to map the location of cells based on their gene expression with more precision. Moreover, in recent years, many tools have been developed to analyze these extensive datasets by integrating machine learning and artificial intelligence in a comprehensive manner. Since these tools analyze sequencing data, they offer the chance to analyze any tissue regardless of its origin. By applying this to cancer settings, spatial transcriptomic analysis based on artificial intelligence may help us understand cell-cell communications within the tumor microenvironment. Another advantage of this analysis is the identification of new biomarkers and therapeutic targets. The integration of such analysis with other omics data and with routine exams such as magnetic resonance imaging can help physicians with the earlier diagnosis of tumors as well as establish a more personalized treatment for pancreatic cancer patients. In this review, we give an overview description of pancreatic cancer, describe how spatial transcriptomics and artificial intelligence have been used to study pancreatic cancer and provide examples of how integrating these tools may help physicians manage pancreatic cancer in a more personalized approach.
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Inteligencia Artificial , Neoplasias Pancreáticas , Transcriptoma , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Transcriptoma/genética , Perfilación de la Expresión Génica/métodos , Biomarcadores de Tumor/genética , Microambiente Tumoral/genética , Manejo de la Enfermedad , Aprendizaje AutomáticoRESUMEN
BACKGROUND: Despite calls for regionalizing pancreatic cancer (PC) care to high-volume centers (HVCs), many patients with PC elect to receive therapy closer to their home or at multiple institutions. In the context of cross-institutional PC care, the challenges associated with coordinating care are poorly understood. METHODS: In this qualitative study we conducted semi-structured interviews with oncology clinicians from a HVC (n = 9) and community-based hospitals (n = 11) to assess their perspectives related to coordinating the care of and treating PC patients across their respective institutions. Interviews were transcribed, coded, and analyzed using deductive and inductive approaches to identify themes related to cross-institutional coordination challenges and to note improvement opportunities. RESULTS: Clinicians identified challenges associated with closed-loop communication due, in part, to not having access to a shared electronic health record. Challenges with patient co-management were attributed to patients receiving inconsistent recommendations from different clinicians. To address these challenges, participants suggested several improvement opportunities such as building rapport with clinicians across institutions and updating tumor board processes. The opportunity to update tumor board processes was reportedly multi-dimensional and could involve: (1) designating a tumor board coordinator; (2) documenting and disseminating tumor board recommendations; and (3) using teleconferencing to facilitate community-based clinician engagement during tumor board meetings. CONCLUSIONS: In light of communication barriers and challenges associated with patient co-management, enabling the development of relationships among PC clinicians and improving the practices of multidisciplinary tumor boards could potentially foster cross-institutional coordination. Research examining how multidisciplinary tumor board coordinators and teleconferencing platforms could enhance cross-institutional communication and thereby improve patient outcomes is warranted.
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Neoplasias Pancreáticas , Investigación Cualitativa , Humanos , Neoplasias Pancreáticas/terapia , Entrevistas como Asunto , Actitud del Personal de Salud , Masculino , Femenino , Continuidad de la Atención al Paciente/organización & administración , Hospitales Comunitarios/organización & administraciónRESUMEN
Immune checkpoint inhibitor-based cancer immunotherapy has shown promise as a potential treatment in the clinic. It has been reported that anti-PD-L1 combined with cisplatin treatment can improve the antitumor effect. However, the therapeutic outcome is limited due to the abundance of tumor stroma in pancreatic cancer (PC), which prevented the penetration of cisplatin and anti-PD-L1 into tumor regions, thus impeding the effectiveness in the treatment of PC. In this study, a nanocarrier-mediated codelivery system of hyaluronidase and cisplatin was constructed, which can degrade the stroma and promote cisplatin and anti-PD-L1 to penetrate the tumor stroma into the deep tumor, so as to suppress PC effectively. When combined the cisplatin nanocarrier system BPEI-SS-Pt/HAase@CaP (BSP/H@CaP) with an immune checkpoint inhibitor to overcome the poor therapeutic outcome of PC, the results indicated that the therapeutic effect of BSP/H@CaP combined with anti-PD-L1 was better than that of BSP/H@CaP and single anti-PD-L1 group. Because the stroma is degrading, a higher amount of BPEI-SS-Pt and anti-PD-L1 can enter the tumor stroma and reach the inner depths of the tumor for immune stimulation, leading to a synergistically augmented chemotherapy and immunotherapy for PC. The above combination therapy is useful for clinical translation to overcome the treatment resistance of matrix-rich PC.
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Antígeno B7-H1 , Cisplatino , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pancreáticas , Cisplatino/farmacología , Cisplatino/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Animales , Humanos , Ratones , Línea Celular Tumoral , Portadores de Fármacos/química , Nanopartículas , Inmunoterapia/métodos , Hialuronoglucosaminidasa , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Femenino , Ratones Endogámicos BALB CRESUMEN
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.
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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) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and type I interferon-mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8+ T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon-driven innate and adaptive immune response with durable antitumor efficacy against PDAC.
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Carcinoma Ductal Pancreático , Inmunidad Innata , Nanopartículas , Neoplasias Pancreáticas , Receptor Toll-Like 4 , Microambiente Tumoral , Animales , Inmunidad Innata/efectos de los fármacos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Humanos , Nanopartículas/química , Microambiente Tumoral/efectos de los fármacos , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/terapia , Ratones , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/agonistas , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Interferón Tipo I/metabolismo , Línea Celular Tumoral , Inmunoterapia/métodos , Senescencia Celular/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacosRESUMEN
Neoadjuvant therapy (NAT) for early-stage pancreatic ductal adenocarcinoma (PDA) has recently gained prominence. We investigated the clinical significance of mucin 5 AC (MUC5AC), which exists in two major glycoforms, a less-glycosylated immature isoform (IM) and a heavily glycosylated mature isoform (MM), as a biomarker in resected PDA. Immunohistochemistry was performed on 100 resected PDAs to evaluate the expression of the IM and MM of MUC5AC using their respective monoclonal antibodies, CLH2 (NBP2-44455) and 45M1 (ab3649). MUC5AC localization (cytoplasmic, apical, and extra-cellular (EC)) was determined, and the H-scores were calculated. Univariate and multivariate (MVA) Cox regression models were used to estimate progression-free survival (PFS) and overall survival (OS). Of 100 resected PDA patients, 43 received NAT, and 57 were treatment-naïve with upfront surgery (UpS). In the study population (n = 100), IM expression (H-scores for objective response vs. no response vs. UpS = 104 vs. 152 vs. 163, p = 0.01) and MM-MUC5AC detection rates (56% vs. 63% vs. 82%, p = 0.02) were significantly different. In the NAT group, MM-MUC5AC-negative patients had significantly better PFS according to the MVA (Hazard Ratio: 0.2, 95% CI: 0.059-0.766, p = 0.01). Similar results were noted in a FOLFIRINOX sub-group (n = 36). We established an association of MUC5AC expression with treatment response and outcomes.