RESUMEN

Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.

Asunto(s)

Vacunas contra el Cáncer , Desoxicitidina , Resistencia a Antineoplásicos , Gemcitabina , Inmunoterapia , Nanopartículas , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/farmacología , Animales , Inmunoterapia/métodos , Resistencia a Antineoplásicos/efectos de los fármacos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Nanopartículas/química , Ratones , Humanos , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos C57BL , Femenino , Imidazoles/farmacología , Imidazoles/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Nanovacunas

RESUMEN

Cholangiocarcinoma (CCA) is an extremely aggressive malignancy arising from the epithelial cells lining the bile ducts. It presents a substantial global health issue, with the highest incidence rates, ranging from 40­100 cases/100,000 individuals, found in Southeast Asia, where liver fluke infection is endemic. In Europe and America, incidence rates range from 0.4­2 cases/100,000 individuals. Globally, mortality rates range from 0.2­2 deaths/100,000 person­years and are increasing in most countries. Chemotherapy is the primary treatment for advanced CCA due to limited options from late­stage diagnosis, but its efficacy is hindered by drug­resistant phenotypes. In a previous study, proteomics analysis of drug­resistant CCA cell lines (KKU­213A­FR and KKU­213A­GR) and the parental KKU­213A line identified cullin 3 (Cul3) as markedly overexpressed in drug­resistant cells. Cul3, a scaffold protein within CUL3­RING ubiquitin ligase complexes, is crucial for ubiquitination and proteasome degradation, yet its role in drug­resistant CCA remains to be elucidated. The present study aimed to elucidate the role of Cul3 in drug­resistant CCA cell lines. Reverse transcription­quantitative PCR and western blot analyses confirmed significantly elevated Cul3 mRNA and protein levels in drug­resistant cell lines compared with the parental control. Short interfering RNA­mediated Cul3 knockdown sensitized cells to 5­fluorouracil and gemcitabine and inhibited cell proliferation, colony formation, migration and invasion. In addition, Cul3 knockdown induced G0/G1 cell cycle arrest and suppressed key cell cycle regulatory proteins, cyclin D, cyclin­dependent kinase (CDK)4 and CDK6. Bioinformatics analysis of CCA patient samples using The Cancer Genome Atlas data revealed Cul3 upregulation in CCA tissues compared with normal bile duct tissues. STRING analysis of upregulated proteins in drug­resistant CCA cell lines identified a highly interactive Cul3 network, including COMM Domain Containing 3, Ariadne RBR E3 ubiquitin protein ligase 1, Egl nine homolog 1, Proteasome 26S Subunit Non­ATPase 13, DExH­box helicase 9 and small nuclear ribonucleoprotein polypeptide G, which showed a positive correlation with Cul3 in CCA tissues. Knocking down Cul3 significantly suppressed the mRNA expression of these genes, suggesting that Cul3 may act as an upstream regulator of them. Gene Ontology analysis revealed that the majority of these genes were categorized under binding function, metabolic process, cellular anatomical entity, protein­containing complex and protein­modifying enzyme. Taken together, these findings highlighted the biological and clinical significance of Cul3 in drug resistance and progression of CCA.

Asunto(s)

Neoplasias de los Conductos Biliares , Proliferación Celular , Colangiocarcinoma , Proteínas Cullin , Resistencia a Antineoplásicos , Humanos , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Proteínas Cullin/metabolismo , Proteínas Cullin/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Fenotipo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Gemcitabina , Movimiento Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Antineoplásicos/farmacología

RESUMEN

OBJECTIVE: The prognosis of extra-nodal NK/T cell lymphoma (ENKTL) is poor, and the optimal therapy remains controversial. This study aims to evaluate the safety and efficacy of a new combined modality therapy. METHODS: Phase-2 study of pegaspargase, etoposide and gemcitabine (PEG) combined with involved field radiation therapy (IFRT) in newly-diagnosed patients with early-stage ENKTL. Patients received 4 course of PEG followed by IFRT. The primary endpoints were complete response (CR), partial response (PR), and objective response rate (ORR) after IFRT. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: 34 consecutive patients with Ann Arbor stage I/II were enrolled. 3 patients progressed on PEG, while the remaining 31 received IFRT. The ORR was 88.2% (30/34), included 28 (82.4%) complete and 2 (5.8%) partial responses. With a median follow-up of 56.0 months (Interquartile Range [IQR], 36.0-66.9 months), the estimated 5-year PFS and OS were 87.4% (95% Confidence Interval [CI],69.5%-94.8%) and 97.1% (95%CI, 80.1%-99.6%), respectively. Most adverse events were hematological and easily managed. CONCLUSIONS: PEG followed by IFRT is a safe and effective initial therapy for early-stage ENKTL, demonstrating impressive PFS and OS rates. This promising approach warrants further validation in a randomized controlled trial (Registered at Clinicaltrials.gov NCT02705508).Trial registration: ClinicalTrials.gov identifier: NCT02705508.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Asparaginasa , Desoxicitidina , Etopósido , Gemcitabina , Linfoma Extranodal de Células NK-T , Polietilenglicoles , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Linfoma Extranodal de Células NK-T/radioterapia , Linfoma Extranodal de Células NK-T/mortalidad , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/terapia , Masculino , Femenino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Asparaginasa/administración & dosificación , Asparaginasa/uso terapéutico , Asparaginasa/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Etopósido/uso terapéutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Estadificación de Neoplasias , Resultado del Tratamiento

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 Tratamiento

RESUMEN

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5-year survival rate of 5%-15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12-14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab-paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%-53%) compared to NPT (56%-69%) or GemCis (37%-58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell-derived xenografts (67%-90%). PDX studies revealed TE's marked inhibition of tumour growth (40%-73%) compared to GemCis (80%-86%) or NPT (57%-76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy.

Asunto(s)

Neoplasias de los Conductos Biliares , Colangiocarcinoma , Triptófano Hidroxilasa , Ensayos Antitumor por Modelo de Xenoinjerto , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Colangiocarcinoma/metabolismo , Animales , Triptófano Hidroxilasa/metabolismo , Triptófano Hidroxilasa/antagonistas & inhibidores , Humanos , Línea Celular Tumoral , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Ratones , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Proliferación Celular/efectos de los fármacos , Gemcitabina , Cisplatino/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sinergismo Farmacológico , Modelos Animales de Enfermedad , Serotonina/metabolismo , Femenino

RESUMEN

Liposomes are applied to various anticancer treatments as representative drug delivery carriers. However, liposomes do not have their own targeting properties; therefore, there are limitations in drug delivery to specific tissues or cells. High targetability in drug delivery is an important factor in improving bioavailability and drug efficacy and reducing side effects; recent research has been actively investigated to modify the surface of liposomes to give them specific functions. In this study, we studied a drug delivery system for anticancer treatment that enhances targeting ability through fusion with exosomes on the surface of liposomes. We designed exosome-liposome hybrid nanoparticles loaded with a gemcitabine prodrug as a treatment for pancreatic ductal adenocarcinoma (PDAC). Membrane fusion with exosomes shows excellent targeting ability to pancreatic cancer cells due to intrinsic targeting ability and expansion of the macropinocytosis pathway.

Asunto(s)

Carcinoma Ductal Pancreático , Desoxicitidina , Ensayos de Selección de Medicamentos Antitumorales , Vesículas Extracelulares , Gemcitabina , Liposomas , Nanopartículas , Neoplasias Pancreáticas , Tamaño de la Partícula , Profármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacología , Profármacos/química , Profármacos/farmacología , Humanos , Liposomas/química , Nanopartículas/química , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Proliferación Celular/efectos de los fármacos , Ensayo de Materiales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Antineoplásicos/química , Antineoplásicos/farmacología

RESUMEN

Pancreatic cancer (PC) is a highly malignant solid tumor whose resistance to gemcitabine (GEM) chemotherapy is a major cause of poor patient prognosis. Although PC is known to thrive on malnutrition, the mechanism underlying its chemotherapy resistance remains unclear. The current study analyzed clinical tissue sample databases using bioinformatics tools and observed significantly upregulated expression of the deubiquitinase STAMBP in PC tissues. Functional experiments revealed that STAMBP knockdown remarkably increases GEM sensitivity in PC cells. Multiple omics analyses suggested that STAMBP enhances aerobic glycolysis and suppresses mitochondrial respiration to increase GEM resistance in PC both in vitro and in vivo. STAMBP knockdown decreased PDK1 levels, an essential regulator of the aerobic glycolytic process, in several cancers. Mechanistically, STAMBP promoted the PDK1-mediated Warburg effect and chemotherapy resistance by modulating E2F1 via direct binding to E2F1 and suppressing its degradation and ubiquitination. High-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified the FDA drug entrectinib as a potent GEM sensitizer and STAMBP inhibitor, augmenting the antitumor effect of GEM in a patient-derived xenograft (PDX) model. Overall, we established a novel mechanism, via the STAMBP-E2F1-PDK1 axis, by which PC cells become chemoresistant in a nutrient-poor tumor microenvironment.

Asunto(s)

Desoxicitidina , Resistencia a Antineoplásicos , Gemcitabina , Neoplasias Pancreáticas , Microambiente Tumoral , Animales , Humanos , Ratones , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Factor de Transcripción E2F1 , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

PURPOSE: To evaluate the long-term efficacy and safety of GP and TPF sequential chemotherapy regimens in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: From 2005 to 2016, a total of 408 LA-NPC patients treated with GP or TPF sequential chemoradiotherapy were retrospectively included. Propensity Score Matching (PSM) was employed to balance the baseline variables. Survival outcomes and acute toxicities were compared between both groups. RESULTS: A total of 230 patients were selected by 1:1 PSM. At a median follow-up of 91 months, no significant differences were observed between the matched GP and TPF groups regarding 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregionally relapse-free survival (83.4% vs. 83.4%, P = 0.796; 75.6% vs. 68.6%, P = 0.301; 86.7% vs. 81.1%, P = 0.096; and 87.4% vs. 87.2%, P = 0.721). Notable disparities in adverse effects were identified, with higher incidences of grade 3/4 thrombocytopenia in the GP group while grade 3/4 leukopenia and neutropenia in the TPF group. Though not recorded in our cohort, combined with the FAERS database, thrombotic adverse reactions are a concern for the GP regimen, while the TPF regimen requires vigilance for life-threatening adverse reactions such as septic shock, acute respiratory distress syndrome, and laryngeal edema. CONCLUSION: No significant difference in long-term outcomes was observed between the GP and TPF sequential chemotherapy regimens for LA-NPC. Differences in adverse effects should be noted when choosing the regimen.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Quimioradioterapia , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Puntaje de Propensión , Humanos , Masculino , Femenino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/tratamiento farmacológico , Persona de Mediana Edad , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/mortalidad , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano , Resultado del Tratamiento , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Cisplatino/efectos adversos , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Gemcitabina , Estudios de Seguimiento , Compuestos Organoplatinos

RESUMEN

Intravesical therapy (IT) is widely used to tackle various urological diseases. However, its clinical efficacy is decreased by the impermeability of various barriers presented on the bladder luminal surface, including the urinary mucus layer and the densely packed tissue barrier. In this study, we report a mucoadhesive-to-penetrating nanomotors-in-hydrogel system for urothelium-oriented intravesical drug delivery. Upon intravesical instillation, its poloxamer 407 (PLX) hydrogel gelated and adhered to the urothelium to prolong its intravesical retention. The urea afterwards diffused into the hydrogel, thus generating a concentration gradient. Urease-powered membrane nanomotors (UMN) without asymmetric surface engineering could catalyze the urea and migrate down this concentration gradient to deeply and unidirectionally penetrate the urothelial barrier. Moreover, the intravesical hybrid system-delivered gemcitabine could effectively inhibit the bladder tumor growth without inducing any side effect. Therefore, our mucoadhesive-to-penetrating nanomotors-in-hydrogel system could serve as an alternative to IT to meet the clinical need for more efficacious therapeutics for urological diseases.

Asunto(s)

Sistemas de Liberación de Medicamentos , Hidrogeles , Poloxámero , Neoplasias de la Vejiga Urinaria , Urotelio , Urotelio/metabolismo , Animales , Hidrogeles/química , Sistemas de Liberación de Medicamentos/métodos , Administración Intravesical , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Ratones , Poloxámero/química , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/administración & dosificación , Gemcitabina , Vejiga Urinaria/metabolismo , Humanos , Femenino , Línea Celular Tumoral , Adhesividad

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is almost entirely resistant to conventional chemotherapy and radiation therapy. A significant factor in this resistance appears to be the dense desmoplastic stroma, which contains various cancer-associated fibroblast (CAF) populations. However, our understanding of the communication between tumor cells and CAFs that contributes to this aggressive malignancy is still developing. Recently, we used an advanced three-dimensional heterospecies, heterospheroid co-culture model to investigate the signaling between human pancreatic tumor Panc1 cells and mouse pancreatic stellate cells (mPSCs) through global expression profiling. Upon discovering that CCN1 was significantly upregulated in Panc1 cells during co-culture, we decided to explore the role of CCN1 using CRISPR-Cas9 knockout technology. Panc1 cells lacking CCN1 showed reduced differentiation and decreased sensitivity to gemcitabine, primarily due to lower expression of genes involved in gemcitabine transport and metabolism. Additionally, we observed that stimulation with TGF-ß1 and lysophosphatidic acid increased CCN1 expression in Panc1 cells and induced a shift in mPSCs towards a more myofibroblastic CAF-like phenotype.

Asunto(s)

Técnicas de Cocultivo , Proteína 61 Rica en Cisteína , Desoxicitidina , Gemcitabina , Neoplasias Pancreáticas , Células Estrelladas Pancreáticas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Proteína 61 Rica en Cisteína/metabolismo , Proteína 61 Rica en Cisteína/genética , Humanos , Células Estrelladas Pancreáticas/metabolismo , Células Estrelladas Pancreáticas/efectos de los fármacos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Ratones , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Lisofosfolípidos/metabolismo , Lisofosfolípidos/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos

RESUMEN

PURPOSE: In high-risk non-muscle-invasive bladder cancer (NMIBC), intravesical Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy post-transurethral resection of bladder tumor (TURBT). Intravesical gemcitabine, used as an alternative or second-line therapy amid BCG shortages, lacks outcome studies in the Korean population. MATERIALS AND METHODS: Patients who received weekly intravesical gemcitabine for 6 weeks after TURBT from 2019 to 2022 were retrospectively investigated. Based on the American Urological Association risk classification, patients with high- or very high-risk NMIBC who refused cystectomy were included. Maintenance treatment was performed depending on their risk. Recurrence was defined as histologic confirmation on subsequent cystoscopic biopsies or TURBT. Disease free survival (DFS) was evaluated by the Kaplan-Meier method. RESULTS: The study included 60 patients, comprising 45 high-risk (group 1) patients with a median age of 76 years and 15 very high-risk (group 2) patients with a median age of 68 years. Among them, 28 patients had previously received intravesical BCG. Over a median follow-up of 22 months, recurrence occurred in 31 patients in group 1 and 11 in group 2. The DFS rates of the high-risk group and the very high-risk group were 57.8% versus 40% at 1 year, 20.7% versus 21.3% at 2 years and 20.7% versus 21.3% at 3 years, respectively (p=0.831). Tis stage (p=0.042) and prostatic urethra invasion (p=0.028) were significant predictors of DFS. Cancer-specific mortality rates were 2.2% in group 1 and 6.7% in group 2 (p=0.441). CONCLUSIONS: Similar DFS outcome between high-risk and very high-risk patients were observed based on short-term results in Korea. This finding is crucial for clinical practice; however, studies analyzing more patients and long-term outcomes are needed.

Asunto(s)

Antimetabolitos Antineoplásicos , Desoxicitidina , Gemcitabina , Invasividad Neoplásica , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/cirugía , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Masculino , Administración Intravesical , Anciano , Femenino , República de Corea/epidemiología , Estudios Retrospectivos , Persona de Mediana Edad , Antimetabolitos Antineoplásicos/administración & dosificación , Resultado del Tratamiento , Factores de Tiempo , Anciano de 80 o más Años , Neoplasias Vesicales sin Invasión Muscular

RESUMEN

Purpose: Erythrocytes and fibroblasts in the pancreatic cancer tumor microenvironment promote tumor cell growth and invasion by providing nutrients and promoting immunosuppression. Additionally, they form a barrier against the penetration of chemotherapeutic drugs. Therefore, the search for diversified tumor-targeting materials plays an essential role in solving the above problems. Methods: Physicochemical characterization of Graphene fluorescent nanoparticles (GFNPs) and nanomedicines were analyzed by transmission electron microscopy (TEM), elemental analyzers and ultraviolet fluorescence (UV/FL) spectrophotometer. Localization of GFNPs in cell and tissue sections imaged with laser confocal microscope, fluorescence scanner and small animal in vivo imager. Qualitative detection and quantitative detection of GFNPs and GFNPs-GEM were performed using High performance liquid chromatography (HPLC). Results: Based on the 3 nm average dimensions, GFNPs penetrate vascular endothelial cells and smooth muscle cells, achieve up to label 30% tumor cells and 60% cancer-associated fibroblasts (CAFs) cells, and accurately label mature red blood cells in the tumor microenvironment. In orthotopic transplanted pancreatic cancer models, the fluorescence intensity of GFNPs in tumors showed a positive correlation with the cycle size of tumor development. The differential spatial distribution of GFNPs in three typical clinical pancreatic cancer samples demonstrated their diagnostic potential. To mediate the excellent targeting properties of GFNPs, we synthesized a series of nanomedicines using popular chemotherapeutic drugs, in which complex of GFNPs and gemcitabine (GFNPs-GEM) possessed stability in vivo and exhibited effective reduction of tumor volume and fewer side effects. Conclusion: GFNPs with multiple targeting tumor microenvironments in pancreatic cancer possess diagnostic efficiency and therapeutic potential.

Asunto(s)

Desoxicitidina , Gemcitabina , Grafito , Nanopartículas , Neoplasias Pancreáticas , Microambiente Tumoral , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Nanopartículas/química , Línea Celular Tumoral , Humanos , Ratones , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacología , Desoxicitidina/administración & dosificación , Microambiente Tumoral/efectos de los fármacos , Grafito/química , Nanomedicina , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Modelos Animales de Enfermedad

RESUMEN

Nerve invasion (NI) is a characteristic feature of pancreatic cancer. Traditional dichotomous statements on the presence of NI are unreasonable because almost all cases exhibit NI when sufficient pathological sections are examined. The critical implications of NI in pancreatic cancer highlight the need for a more effective criterion. This study included 511 patients, who were categorized into a training group and a testing group at a ratio of 7:3. According to the traditional definition, NI was observed in 91.2 % of patients using five pathological slides in our study. The prevalence of NI increased as more pathological slides were used. The criterion of 'two points of intraneural (endoneural) invasion in the case of four pathological slides' has the highest receiver operating characteristic (ROC) score. Based on this new criterion, NI was proved to be an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) and was also correlated with tumor recurrence (P = 0.004). Interestingly, gemcitabine-based chemotherapy regimen is an independent favorable factor for patients with high NI. In the high NI group, patients who received a gemcitabine-based regimen exhibited a better prognosis than those who did not receive the gemcitabine-based regimen for OS (P = 0.000) and DFS (P = 0.001). In conclusion, this study establishes assessment criteria to evaluate the severity of NI in order to predict patient outcomes.

Asunto(s)

Invasividad Neoplásica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Adulto , Supervivencia sin Enfermedad , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Gemcitabina , Curva ROC , Anciano de 80 o más Años , Pronóstico

RESUMEN

PURPOSE: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) of gemcitabine and oxaliplatin (GEMOX) plus systemic gemcitabine chemotherapy (GEM-SYS) in combination with lenvatinib and programmed cell death protein-1 (PD-1) inhibitor for patients with large unresectable intrahepatic cholangiocarcinoma (uICC). METHODS: From November 2019 to December 2022, 21 large uICC patients who underwent GEMOX-HAIC (Day 1) and GEM-SYS (Day 8) (3w/cycle) combined with lenvatinib and PD-1 inhibitor were retrospectively enrolled. Local tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were analyzed. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. AEs were evaluated by the common terminology criteria for adverse events (CTCAE) version 5.0. RESULTS: After a median follow-up duration of 16.0 months (range 5-43.5 months), 17 patients had died. The median OS was 19.5 months (range 9-43.5 months), and the median PFS was 6.0 months (range 2.5-38.5 months). The 1-, 2-, and 3-year OS rates were 71.4 %, 42.9 %, and 19.0 %, respectively. The 1-, 2-, and 3-year PFS rates were 33.3 %, 19.0 %, and 9.5 %, respectively. Complete response, partial response, stable disease, and progressive disease were observed in 0 (0 %), 11 (52.3 %), 5 (23.8 %), and 5 (23.8 %) patients, respectively. The disease control rate and objective response rate were 76.1 % and 52.3 %, respectively. None of the enrolled patients experienced grade 5 AEs. CONCLUSIONS: GEMOX-HAIC plus GEM-SYS in combination with lenvatinib and PD-1 inhibitor was effective and well tolerated for patients with large uICC.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Desoxicitidina , Gemcitabina , Compuestos de Fenilurea , Quinolinas , Humanos , Masculino , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/mortalidad , Femenino , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Persona de Mediana Edad , Anciano , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/mortalidad , Estudios Retrospectivos , Infusiones Intraarteriales , Oxaliplatino/uso terapéutico , Oxaliplatino/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Arteria Hepática , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Compuestos Organoplatinos

RESUMEN

Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm with an aggressive clinical course and a poor response to conventional chemotherapy. Currently, no standard treatment paradigms are available. Herein, we present a case of de novo HS treated with pembrolizumab combined with a GDP regimen (gemcitabine, cisplatin, and dexamethasone) that resulted in sustained complete remission with progression-free survival exceeding 4 years. Immunohistochemical analysis demonstrated significant overexpression of programmed death ligand 1 (PD-L1) on biopsy samples. Additionally, fluorescence in situ hybridization (FISH) with a JAK-2 probe indicated 9p24.1 amplification, suggesting reliance on the JAK-STAT pathway. Polymerase chain reaction (PCR) analysis did not reveal any BRAF-V600 mutations. Consequently, an immune checkpoint inhibitor (ICI) was administered alongside chemotherapy, resulting in sustained complete remission and progression-free survival for over 4 years. Our findings suggest that a combination of ICI and chemotherapy could represent a promising therapeutic approach for HS.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Desoxicitidina , Dexametasona , Gemcitabina , Sarcoma Histiocítico , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Sarcoma Histiocítico/tratamiento farmacológico , Sarcoma Histiocítico/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Cisplatino/uso terapéutico , Cisplatino/administración & dosificación , Inducción de Remisión , Masculino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Persona de Mediana Edad , Supervivencia sin Progresión , Femenino

RESUMEN

Drug resistance is a major challenge in the treatment of advanced cholangiocarcinoma (CCA). Understanding the mechanisms of drug resistance can aid in identifying novel prognostic biomarkers and therapeutic targets to improve treatment efficacy. This study established 5-fluorouracil- (5-FU) and gemcitabine-resistant CCA cell lines, KKU-213FR and KKU-213GR, and utilized comparative proteomics to identify differentially expressed proteins in drug-resistant cells compared to parental cells. Additionally, bioinformatics analyses were conducted to explore the biological and clinical significance of key proteins. The drug-resistant phenotypes of KKU-213FR and KKU-213GR cell lines were confirmed. In addition, these cells demonstrated increased migration and invasion abilities. Proteomics analysis identified 81 differentially expressed proteins in drug-resistant cells, primarily related to binding functions, biological regulation, and metabolic processes. Protein-protein interaction analysis revealed a highly interconnected network involving MET, LAMB1, ITGA3, NOTCH2, CDH2, and NDRG1. siRNA-mediated knockdown of these genes in drug-resistant cell lines attenuated cell migration and cell invasion abilities and increased sensitivity to 5-FU and gemcitabine. The mRNA expression of these genes is upregulated in CCA patient samples and is associated with poor prognosis in gastrointestinal cancers. Furthermore, the functions of these proteins are closely related to the epithelial-mesenchymal transition (EMT) pathway. These findings elucidate the potential molecular mechanisms underlying drug resistance and tumor progression in CCA, providing insights into potential therapeutic targets.

Asunto(s)

Neoplasias de los Conductos Biliares , Colangiocarcinoma , Biología Computacional , Desoxicitidina , Resistencia a Antineoplásicos , Fluorouracilo , Gemcitabina , Proteómica , Colangiocarcinoma/genética , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Humanos , Resistencia a Antineoplásicos/genética , Proteómica/métodos , Línea Celular Tumoral , Biología Computacional/métodos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Fluorouracilo/farmacología , Pronóstico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Movimiento Celular/genética , Movimiento Celular/efectos de los fármacos , Mapas de Interacción de Proteínas/genética

RESUMEN

Fucoidan-coated pH sensitive liposomes were designed for targeted delivery of gemcitabine (FU-GEM PSL) to treat pancreatic cancer (PC). FU-GEM PSL had a particle size of 175.3 ± 4.9 nm, zeta potential of -19.0 ± 3.7 mV, encapsulation efficiency (EE) of 74.05 ± 0.17 %, and drug loading (DL) of 21.27 ± 0.05 %. Cell experiments in vitro showed that FU-GEM PSL could increase the release of GEM and drug concentration, and could inhibit tumor cell proliferation by affecting the cell cycle. FU-GEM PSL entered cells through macropinocytosis and caveolin-mediated endocytosis to exert effects. Meanwhile, the expression of P-selectin was detected in human tissues, demonstrating the feasibility of targeting FU. Moreover, combined with animal experiments in vivo, FU-GEM PSL could inhibit the development of PC. Furthermore, anti-tumor experiments in vivo carried on BALB/c mice indicated that FU-GEM PSL had tumor suppression abilities and safety. Therefore, FU-GEM PSL is a promising formulation for PC therapy.

Asunto(s)

Proliferación Celular , Desoxicitidina , Gemcitabina , Liposomas , Neoplasias Pancreáticas , Polisacáridos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/química , Desoxicitidina/administración & dosificación , Animales , Polisacáridos/química , Polisacáridos/farmacología , Liposomas/química , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos BALB C , Liberación de Fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Sistemas de Liberación de Medicamentos , Endocitosis/efectos de los fármacos

RESUMEN

A 49-year-old man underwent an open cholecystectomy for advanced gallbladder cancer in 2021. Three months after surgery, the patient underwent an additional resection, which showed no malignant findings, but 12 months after surgery, contrast-enhanced CT and MRI showed a new mass lesion in segment 8 of the liver, and the patient was diagnosed with postoperative hepatic metastatic recurrence of gallbladder cancer. After referral to our institution, he received 1 course of gemcitabine+cisplatin(GC)therapy and 8 courses of gemcitabine+cisplatin+durvalumab(GCD)therapy. Contrast- enhanced CT and MRI showed that the metastases had shrunk, and PET scan showed no FDG accumulation. Two months after completion of chemotherapy, there was no evidence of metastatic enlargement and new metastasis including distant metastasis, and the patient was referred to our department. Since curative resection was expected, a laparoscopic partial hepatectomy of segment 8 of the liver was performed. Pathological diagnosis revealed no residual tumor. If the metastases could be well controlled by systemic chemotherapy, hepatectomy for hepatic metastases of biliary tract cancer could be a treatment option.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Desoxicitidina , Neoplasias de la Vesícula Biliar , Gemcitabina , Hepatectomía , Neoplasias Hepáticas , Recurrencia , Humanos , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/cirugía , Neoplasias de la Vesícula Biliar/patología , Masculino , Persona de Mediana Edad , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Cisplatino/administración & dosificación

RESUMEN

For triple-negative breast cancer (TNBC), the most aggressive subset of breast cancer, immune cell infiltrates have prognostic implications. The presence of myeloid-derived suppressor cells supports tumor progression, while tumor-infiltrating lymphocytes (TILs) correlate with improved survival and responsiveness to immunotherapy. Manipulating the abundance of these populations may enhance tumor immunity. Gemcitabine (GEM), a clinically employed chemotherapeutic, is reported to be systemically myeloablative, and thus it is a potentially useful adjunct therapy for promoting anti-tumor immunity. However, knowledge about the immunological effects of GEM intratumorally is limited. Thus, we directly compared the impact of systemic GEM on immune cell presence and functionality in the tumor microenvironment (TME) to its effects in the periphery. We found that GEM is not myeloablative in the TME; rather, we observed sustained, significant reductions in TILs and dendritic cells-crucial components in initiating an adaptive immune response. We also performed bulk-RNA sequencing to identify immunological alterations transcriptionally induced by GEM. While we found evidence of upregulation in the interferon-gamma (IFN-γ) response pathway, we determined that GEM-mediated growth control is not dependent on IFN-γ. Overall, our findings yield new insights into the tissue- and temporal-dependent immune ablative effects of GEM, contrasting the paradigm that this therapy is specifically myeloablative.

Asunto(s)

Desoxicitidina , Gemcitabina , Linfocitos Infiltrantes de Tumor , Microambiente Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Femenino , Animales , Línea Celular Tumoral , Ratones , Interferón gamma/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo

RESUMEN

OBJECTIVE: To evaluate the efficiency of pemetrexed cisplatin in comparison with gemcitabine cisplatin and to validate the EORTC (European Organisation for Research and Treatment of Cancer) prognostic score in combination chemotherapy treatment for malignant pleural mesothelioma. STUDY DESIGN:  An observational study. Place and Duration of the Study: Department of Oncology, Dicle University Hospital, Diyarbakir, Turkiye, from October 2000 to November 2017. METHODOLOGY: Malignant pleural mesothelioma (MPM) patients with EORTC score 0- were recruited. Factors affecting the prognosis of the disease and the effectiveness of first-line treatment were retrospectively analysed. EORTC prognostic score was calculated with a cut-off and survival analyses were used by the Kaplan-Meier method. Log-rank and univariable Cox regression tests were used to search for prognostic factors' impact on survival. RESULTS: Patients who received gemcitabine cisplatin treatment had a median progression-free survival (PFS) of 9 months, while those who received pemetrexed cisplatin therapy had a median PFS of 7 months. Median overall survival (OS) was 17 months in the gemcitabine cisplatin group and 18 months in the pemetrexed cisplatin group (p = 0.051). When the low-risk group was compared with the high-risk group, the median OS was found to be statistically significant (p = 0.009). CONCLUSION: The EORTC prognostic score, which is used for prognostic prediction in the period when pemetrexed is not utilised in the treatment of MPM, accurately predicts prognosis subsequent to the administration of pemetrexed in treatment. In the context of first-line treatment, cisplatin in combination with gemcitabine and cisplatin in combination with pemetrexed demonstrated comparable efficacy with respect to both overall survival and progression-free survival. KEY WORDS: Chemotherapy, Mesothelioma, Prognosis, Gemcitabine, Progression-free survival.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Desoxicitidina , Gemcitabina , Mesotelioma Maligno , Pemetrexed , Neoplasias Pleurales , Humanos , Masculino , Femenino , Estudios Retrospectivos , Pemetrexed/uso terapéutico , Pemetrexed/administración & dosificación , Cisplatino/uso terapéutico , Cisplatino/administración & dosificación , Persona de Mediana Edad , Mesotelioma Maligno/tratamiento farmacológico , Pronóstico , Anciano , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Adulto , Supervivencia sin Progresión