A phase II/III randomized clinical trial of CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative chemotherapy versus immediate resection in patIents with resecTable BiliarY Tract Cancers (BTC) at high risk for recurrence: PURITY study.

BACKGROUND: Biliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1-3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20-40% and recurrence rates are up to ~ 75%(4-6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4-6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8). METHODS: PURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study. Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: Considering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients' outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery. TRIAL REGISTRATION: PURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023-503295-25-00).

Examination of Wnt signaling as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using a pancreatic tumor organoid library (PTOL).

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.

Effectiveness of nirmatrelvir-ritonavir versus azvudine for adult inpatients with severe or critical COVID-19.

BACKGROUND: In China, both nirmatrelvir-ritonavir (Paxlovid) and azvudine have been granted approval to treat adult SARS-CoV-2-infected patients with moderate symptoms. Information about the clinical effect of the two available agents among inpatients with severe or critical COVID-19 is scarce. PURPOSE: To compare the clinical outcomes of Paxlovid and azvudine among adult inpatients with severe or critical COVID-19. METHOD: We conducted a retrospective cohort study in two large medical centres after the epidemic control measures were lifted in China. A new propensity score matched-inverse probability of treatment weighting cohort was constructed to evaluate the in-hospital all-cause mortality, hospital length of stay, Sequential Organ Failure Assessment (SOFA) score and safety. RESULTS: A total of 955 individuals were in the cohort. The antiviral therapy strategies were decided by the senior physician and the supplies of the pharmacy. A total of 451 patients were in the Paxlovid group, and 504 patients were in the azvudine group. Compared with Paxlovid, the effects of azvudine on in-hospital all-cause mortality were not significantly different, and the OR (95% CI) was 1.084 (0.822 to 1.430), and the average hospital length of stay of patients discharged alive was also similar in the azvudine group, and the difference (day) and (95% CI) was 0.530 (-0.334 to 1.393). After 7 days of therapy, the degree of decline in the SOFA score was greater in the Paxlovid group than in the azvudine group (p<0.001). The change in glomerular filtration rate was not significantly different (p=0.824). CONCLUSION: Paxlovid and azvudine had similar effectiveness on in-hospital all-cause mortality and hospital length of stay. Compared with the azvudine group, after 7 days of therapy, the degree of decline in SOFA score was significantly higher in the Paxlovid group. These findings need to be verified in larger prospective studies or randomised controlled trials.

Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses.

PURPOSE: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma: A case report.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with limited effective treatment especially after first-line chemotherapy. The human epidermal growth factor receptor 2 (HER-2) immunohistochemistry (IHC) positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC. CASE SUMMARY: We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn't have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment. A novel combination therapy PRaG 3.0 of RC48 (HER2-antibody-drug conjugate), radiotherapy, PD-1 inhibitor, granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month. She had not developed any grade 2 or above treatment-related adverse events at any point. Percentage of peripheral CD8+Temra and CD4+Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy. CONCLUSION: PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

The Natural Product Parthenolide Inhibits Both Angiogenesis and Invasiveness and Improves Gemcitabine Resistance by Suppressing Nuclear Factor κB Activation in Pancreatic Cancer Cell Lines.

We previously established pancreatic cancer (PaCa) cell lines resistant to gemcitabine and found that the activity of nuclear factor κB (NF-κB) was enhanced upon the acquisition of gemcitabine resistance. Parthenolide, the main active ingredient in feverfew, has been reported to exhibit antitumor activity by suppressing the NF-κB signaling pathway in several types of cancers. However, the antitumor effect of parthenolide on gemcitabine-resistant PaCa has not been elucidated. Here, we confirmed that parthenolide significantly inhibits the proliferation of both gemcitabine-resistant and normal PaCa cells at concentrations of 10 µM and higher, and that the NF-κB activity is significantly inhibited, even by 1 µM parthenolide. In Matrigel invasion assays and angiogenesis assays, the invasive and angiogenic potentials were higher in gemcitabine-resistant than normal PaCa cells and were inhibited by a low concentration of parthenolide. Furthermore, Western blotting showed suppressed MRP1 expression in gemcitabine-resistant PaCa treated with a low parthenolide concentration. In a colony formation assay, the addition of 1 µM parthenolide improved the sensitivity of gemcitabine-resistant PaCa cell lines to gemcitabine. These results suggest that parthenolide may be used as a novel therapeutic agent for the treatment of gemcitabine-resistant PaCa.

Low albumin combined with low-molecular-weight heparin as risk factors for liver injury using azvudine: Evidence from an analysis of COVID-19 patients in a national prospective pharmacovigilance database.

OBJECTIVE: Azvudine is an effective treatment for patients infected with common COVID-19. However, physicians have reported a series of adverse reactions, including multiple cases of liver injury, caused by azvudine in clinical practice. This study assessed the incidence, clinical features, and associated risk factors of liver injury induced by azvudine in real-world settings, offering guidance for safe clinical use. MATERIALS AND METHODS: This study utilized the Chinese Hospital Pharmacovigilance System (CHPS) to retrospectively analyze the treatment of COVID-19 patients with azvudine at Changsha Central Hospital from December 19, 2022, to June 6, 2023. A case-control study was conducted to analyze the occurrence of azvudine-induced liver injury in COVID-19 patients who triggered a CHPS alert compared to normal COVID-19 patients. RESULTS: Among the total of 2,141 COVID-19 patients, 31 (1.45%) developed azvudine-induced liver injury, which is classified as an occasional adverse reaction. Liver injury was observed in 93.55% of patients between days 4 and 12 of the azvudine treatment, with elevated transaminases as the primary clinical manifestation. Univariate and binary logistic regression analyses indicated that low albumin levels and co-administration of low-molecular-weight heparin were statistically significant risk factors (p < 0.05). CONCLUSION: This study represents the first investigation of azvudine-induced liver injury and high-risk patients using the CHPS. The findings provide valuable insights to promote the safety of anti-COVID-19 drugs, serving as an important reference for future drug safety measures.

IFN­Î³ induces apoptosis in gemcitabine­resistant pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent and aggressive form of pancreatic cancer. Gemcitabine (GEM), the first­line treatment for PDAC, which alleviates symptoms and enhances the quality of life of patients. However, it is prone to lead to the development of drug resistance during treatment. Interferon (IFN)­Î³ exhibits antitumor and immunomodulatory properties. The present study aimed to explore the impact of IFN­Î³ on the viability, migration and apoptosis of GEM­resistant pancreatic cancer cells. Firstly, a GEM­resistant pancreatic cancer cell line, named PANC­1/GEM, was constructed. Hematoxylin and eosin staining analyzed the cell morphology, whereas reverse transcription­quantitative PCR (RT­qPCR) assessed the expression levels of the drug­resistance genes multidrug resistance­associated protein (MRP) and breast cancer resistance protein (BCRP). The MTT assay and cell counting techniques were used to determine the appropriate concentration of IFN­y and its effects on cell viability. The IFN­Î³­induced apoptosis of PANC­1/GEM cells was assessed using an Apoptosis Detection Kit, whereas the impact of IFN­Î³ on the migration of these cells was evaluated using a wound­healing assay. The MTT assay revealed a resistance index of 22.4 in the PANC­1/GEM cell line. RT­qPCR indicated that, compared with in wild­type cells, the PANC­1/GEM resistant strain exhibited lower MRP and higher BCRP mRNA expression levels. The optimal concentration of IFN­Î³ for affecting PANC­1/GEM cells was determined to be 0.3 µg/ml. At this concentration, IFN­Î³ induced PANC­1/GEM cell apoptosis, along with a notable reduction in migration. Following treatment of PANC­1/GEM cells with IFN­Î³, MRP expression increased whereas BCRP mRNA expression decreased, indicating a reversal in their drug­resistance gene expression. In conclusion, IFN­Î³ exhibited antitumor immune properties by upregulating MRP and downregulating BCRP expression, reversing drug­resistance gene expression, and reducing cell viability and migration, while promoting apoptosis in PANC­1/GEM cells. IFN­Î³ could potentially serve as a treatment option for patients with GEM­resistant pancreatic cancer.

Gemcitabine Modulates HLA-I Regulation to Improve Tumor Antigen Presentation by Pancreatic Cancer Cells.

Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine increased pancreatic cancer cells' HLA-I mRNA transcripts, total protein, surface expression, and surface stability. Temperature-dependent assay results indicated that the increased HLA-I stability may be due to reduced binding of low affinity peptides. Mass spectrometry analysis confirmed changes in the HLA-I-presented peptide pool post-treatment, and computational predictions suggested improved affinity and immunogenicity of peptides displayed solely by gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were derived from unique source proteins, with a notable overrepresentation of translation-related proteins. Gemcitabine also increased expression of select immunoproteasome subunits, providing a plausible mechanism for its modulation of the HLA-I-bound peptidome. Our work supports continued investigation of immunotherapies, including peptide-based vaccines, to be used with gemcitabine as new combination treatment modalities for pancreatic cancer.

Novel silicene-mesoporous silica nanoparticles conjugated gemcitabine induced cellular apoptosis via upregulating NF-κB p65 nuclear translocation suppresses pancreatic cancer growthin vitroandin vivo.

Pancreatic cancer's high fatality rates stem from its resistance to systemic drug delivery and aggressive metastasis, limiting the efficacy of conventional treatments. In this study, two-dimensional ultrathin silicene nanosheets were initially synthesized and near-infrared-responsive two-dimensional silicene-mesoporous silica nanoparticles (SMSNs) were successfully constructed to load the clinically-approved conventional pancreatic cancer chemotherapeutic drug gemcitabine. Experiments on nanoparticle characterization show that they have excellent photothermal conversion ability and stability. Then silicene-mesoporous silica nanoparticles loaded with gemcitabine nanoparticles (SMSN@G NPs) were employed in localized photothermal therapy to control pancreatic tumor growth and achieve therapeutic effects. Our research confirmed the functionality of SMSN@G NPs through immunoblotting and apoptotic assays, demonstrating its capacity to enhance the nuclear translocation of the NF-κB p65, further affect the protein levels of apoptosis-related genes, induce the apoptosis of tumor cells, and ultimately inhibit the growth of the tumor. Additionally, the study assessed the inhibitory role of SMSN@G NPs on pancreatic neoplasm growthin vivo, revealing its excellent biocompatibility. SMSN@G NPs have a nice application prospect for anti-pancreatic tumors.

First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma.

Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating ß1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Following in vivo screening of three asTF-proficient human PDAC cell lines, we chose to make use of KRAS G12V-mutant human PDAC cell line PaCa-44, which yields aggressive primary orthotopic tumors with spontaneous spread to PDAC-relevant anatomical sites, along with concomitant severe leukocytosis. The experimental design featured orthotopic tumors formed by luciferase labeled PaCa-44 cells; administration of hRabMab1 alone or in combination with gemcitabine/paclitaxel (gem/PTX); and the assessment of the treatment outcomes on the primary tumor tissue as well as systemic spread. When administered alone, hRabMab1 exhibited poor penetration of tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX, which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNA-seq analysis of primary tumors showed that the addition of hRabMab1 to gem/PTX enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. We here demonstrate for the first time that hRabMab1 may help suppress metastasis in PDAC. hRabMab1's ability to improve the efficacy of chemotherapy is significant and warrants further investigation.

[Gemcitabine long-term maintenance chemotherapy benefits patients with survival: a multicenter, real-world study of advanced breast cancer treatment in China].

Objective: This study collected a real-world data on survival and efficacy of gemcitabine-containing therapy in advanced breast cancer. Aimed to find the main reasons of affecting the duration of gemcitabine-base therapy in advanced breast cancer patients. Methods: Advanced breast cancer patients who received gemcitabine-base therapy from January 2017 to January 2019 were enrolled(10 hospitals). The clinicopathological data, the number of chemotherapy cycles and the reasons for treatment termination were collected and analyzed. To identify the reasons related with continuous treatment for advanced breast cancer and the factors which affect the survival and efficacy. Results: A total of 224 patients with advanced breast cancer were enrolled in this study, with a median age of 52 years (26-77 years), 55.4%(124/224) was postmenopausal. Luminal type were 83 cases, TNBC were 97 cases, and human epidermal growth factor receptor 2 (HER's-2) overexpression were 44. At the analysis, 224 patients who received the gemcitabine-based regimens were evaluated, included 5 complete reponse (CR), 77 partial response (PR), 112 stable disease (SD) and 27 progressive disease (PD). The objective response rate (ORR) was 36.6%(82/224). Seventy patients had serious adverse diseases, including leukopenia (9), neutrophilia (49), thrombocytopenia (15), and elevated transaminase (2). The median follow-up time was 41 months (26~61 months), and the median PFS was 5.6 months. The reasons of termination treatment were listed: disease progression were 90 patients; personal reasons were 51 patients; adverse drug reactions were 18 patients; completed treatment were 65 patients. It was found that progression-free survival (PFS) was significantly longer in patients receiving >6 cycles than that in patients with ≤6 cycles (8.2 months vs 5.4 months, HR=2.474, 95% CI: 1.730-3.538, P＜0.001). Conclusions: Gemcitabine-based regimen is generally well tolerated in the Chinese population and has relatively ideal clinical efficacy in the real world. The median PFS is significantly prolonged when the number of treatment cycles are appropriately increased.

Electrospun nanofibrous mats loaded with gemcitabine and cisplatin suppress bladder tumor growth by improving the tumor immune microenvironment.

The perplexing issues related to positive surgical margins and the considerable negative consequences associated with systemic chemotherapy have posed ongoing challenges for clinicians, especially when it comes to addressing bladder cancer treatment. The current investigation describes the production of nanocomposites loaded with gemcitabine (GEM) and cisplatin (CDDP) through the utilization of electrospinning technology. In vitro and in vivo studies have provided evidence of the strong effectiveness in suppressing tumor advancement while simultaneously reducing the accumulation of chemotherapy drugs within liver and kidney tissues. Mechanically, the GEM and CDDP-loaded electrospun nanocomposites could effectively eliminate myeloid-derived suppressor cells (MDSCs) in tumor tissues, and recruit CD8+ T cells and NKp46+ NK cells to kill tumor cells, which can also effectively inhibit tumor microvascular formation. Our investigation into the impact of localized administration of chemotherapy through GEM and CDDP-loaded electrospun nanocomposites on the tumor microenvironment will offer novel insights for tackling tumors.

Comparison of neoadjuvant treatment and surgery first for resectable or borderline resectable pancreatic carcinoma: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Current treatment recommendations for resectable or borderline pancreatic carcinoma support upfront surgery and adjuvant therapy. However, neoadjuvant therapy (NT) seems to increase prognosis of pancreatic carcinoma and come to everyone's attention gradually. Randomized controlled trials offering comparison with the NT are lacking and optimal neoadjuvant treatment regimen still remains uncertain. This study aims to compare both treatment strategies for resectable or borderline resectable pancreatic cancer. METHODS: The PRISMA checklist was used as a guide to systematically review relevant peer-reviewed literature reporting primary data analysis. We searched PubMed, Medline, EMBASE, Cochrane Datebase and related reviews for randomized controlled trials comparing neoadjuvant therapy with surgery first for resectable or borderline resectable pancreatic carcinoma. We estimated relative hazard ratios (HRs) for median overall survival and ratios risks (RRs) for microscopically complete (R0) resection among different neoadjuvant regimens and major complications. We assessed the effects of neoadjuvant therapy on R0 resection rate and median overall survival with Bayesian analysis. RESULTS: Thirteen eligible articles were included. Eight studies performed comparison neoadjuvant therapy with surgery first, and R0 resection rate was recorded in seven studies. Compared with surgery first, neoadjuvant therapy did increase the R0 resection rate (RR = 1.53, I2 = 0%, P< 0.00001), there was a certain possibility that gemcitabine + cisplatin (Gem+Cis) + Radiotherapy was the most favorable in terms of the fact that there was no significant difference concerning the results from the individual studies. In direct comparison, four studies were included and estimated that Neoadjuvant therapy improved mOS compared with upfront surgery (HR 0.68, 95% CI 0.58-0.92; P = 0.012; I2 = 15%), after Bayesian analysis it seemed that regimen with Cisplatin/ Epirubicin then Gemcitabine/ Capecitabine (PEXG) was most likely the best with a relatively small sample size. The rate of major surgical complications was available for six studies and ranged from 11% to 56% with neoadjuvant therapy and 11% to 45% with surgery first. There was no significant difference between neoadjuvant therapy and surgery first, also with a high heterogeneity (RR = 0.96, 95%CI = 0.65-1.43; P = 0.85; I2 = 46%). CONCLUSION: In conclusion neoadjuvant therapy might offer benefit over up-front surgery. Neoadjuvant therapy increased the R0 resection rate with gemcitabine + cisplatin + Radiotherapy that was the most favorable and improved mOS with Cisplatin/ Epirubicin then Gemcitabine/ Capecitabine (PEXG) that was most likely the best.

Biodistribution and therapeutic efficacy of a gold nanoparticle-based targeted drug delivery system against pancreatic cancer.

Pancreatic cancer is characterized by desmoplasia; crosstalk between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) leads to the deposition of extracellular matrix proteins in the tumor environment resulting in poor vascularity. Targeting either PCCs or PSCs individually has produced mixed results, and there is currently no effective strategy to target both cell types simultaneously. Previously, we demonstrated, through in vitro cell culture experiments, that a specific gold nanoparticle-based nanoformulation containing the anti-EGFR antibody cetuximab (C225) as a targeting agent and gemcitabine as a chemotherapeutic agent effectively targets both PCCs and PSCs simultaneously. Herein, we extend our studies to test the ability of these in vitro tested nano formulations to inhibit tumor growth in an orthotopic co-implantation model of pancreatic cancer in vivo. Orthotopic tumors were established by co-implantation of equal numbers of PCCs and PSCs in the mouse pancreas. Among the various formulations tested, 5 nm gold nanoparticles coated with gemcitabine, cetuximab and poly-ethylene glycol (PEG) of molecular weight 1000 Da, which we named ACGP441000, demonstrated optimal efficacy in inhibiting tumor growth. The current study reveals an opportunity to target PCCs and PSCs simultaneously, by exploiting their overexpression of EGFR as a target, in order to inhibit pancreatic cancer growth.

Systems pharmacodynamic model of combined gemcitabine and trabectedin in pancreatic cancer cells. Part I.Çô Effects on signal transduction pathways related to tumor growth.

Pancreatic ductal adenocarcinoma (PDAC) is often chemotherapy-resistant, and novel drug combinations would fill an unmet clinical need. Previously we reported synergistic cytotoxic effects of gemcitabine and trabectedin on pancreatic cancer cells, but underlying protein-level interaction mechanisms remained unclear. We employed a reliable, sensitive, comprehensive, quantitative, high-throughput IonStar proteomic workflow to investigate the time course of gemcitabine and trabectedin effects, alone and combined, upon pancreatic cancer cells. MiaPaCa-2 cells were incubated with vehicle (controls), gemcitabine, trabectedin, and their combinations over 72 hours. Samples were collected at intervals and analyzed using the label-free IonStar liquid chromatography-mass spectrometry (LC-MS/MS) workflow to provide temporal quantification of protein expression for 4,829 proteins in four experimental groups. To characterize diverse signal transduction pathways, a comprehensive systems pharmacodynamic (SPD) model was developed. The analysis is presented in two parts. Here, Part I describes drug responses in cancer cell growth and migration pathways included in the full model: receptor tyrosine kinase- (RTK), integrin-, G-protein coupled receptor- (GPCR), and calcium-signaling pathways. The developed model revealed multiple underlying mechanisms of drug actions, provides insight into the basis of drug interaction synergism, and offers a scientific rationale for potential drug combination strategies.

Cost-efficiency and budget-neutral expanded access modeling of the novel PD-1 inhibitor toripalimab versus pembrolizumab in recurrent or metastatic nasopharyngeal carcinoma.

AIMS: To estimate, in the setting of recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) for an assumed 1,207 incident US cases in 2024, (1) the cost-efficiency of a toripalimab-gemcitabine-cisplatin regimen compared to a similar pembrolizumab regimen; and (2) the budget-neutral expanded access to additional toripalimab cycles and regimens afforded by the accrued savings. METHODS: Simulation modeling utilized two cost inputs (wholesale acquisition cost (WAC) at market entry and an ex ante toripalimab price point of 80% of pembrolizumab average sales price (ASP)) and drug administration costs over 1 and 2 years of treatment with treatment rates ranging from 45% to 90%. In the absence of trial data for pembrolizumab-gemcitabine-cisplatin in R/M NPC, it is assumed that such a regimen would be comparable to toripalimab-gemcitabine-cisplatin in efficacy and safety. RESULTS: In the models utilizing the WAC, toripalimab saves $2,223 per patient per cycle and $40,014 over 1 year of treatment ($77,805 over 2 years). Extrapolated to the 1,207-patient panel, estimated 1-year savings range from $21,733,702 (45% treatment rate) to $43,467,404 (90% rate). Reallocating these savings permits budget-neutral expanded access to an additional 2,359 (45% rate) to 4,717 (90% rate) toripalimab maintenance cycles or to an additional 126 (45% rate) to 252 (90%) full 1-year toripalimab regimens with all agents. Two-year savings range from $42,259,976 (45% rate) to $84,519,952 (90% rate). Reallocating these efficiencies provides expanded access, ranging from an additional 4,586 (45% rate) to 9,172 (90% rate) toripalimab cycles or to an additional 128-257 full 2-year toripalimab regimens. The ex ante ASP model showed similar results. CONCLUSION: This simulation demonstrates that treatment with toripalimab generates savings that enable budget-neutral funding for up to an additional 252 regimens with toripalimab-gemcitabine-cisplatin for one full year, the equivalent of approximately 21% of the 2024 incident cases of R/M NPC in the US.

An estimated 1,207 patients will be diagnosed with late-stage nasopharyngeal cancer in the US in 2024. Toripalimab is a novel PD-1 inhibitor drug approved by the US Food and Drug Administration on October 27, 2023 as first-line treatment for patients with recurrent or metastatic nasopharyngeal cancer when used in combination with gemcitabine and cisplatin. We conducted economic evaluations of the costs of this toripalimab regimen versus the costs of a similar regimen with the PD-1 inhibitor pembrolizumab. Our simulation models used two pricing scenarios: the wholesale acquisition cost (WAC) or "list price" at market entry and, as no average sales price (ASP) will be available for toripalimab for several quarters, an estimated toripalimab price point of 80% of the pembrolizumab ASP. We compared the savings in each scenario when between 45% and 90% of the 1,207 patients are treated with the toripalimab regimen. We then evaluated how these savings could be re-allocated, on a budget-neutral basis and without requiring extra cash outlays, to provide more patients with access to toripalimab treatment; specifically, how many toripalimab doses and how many full toripalimab regimens could be purchased to provide more patients with treatment. We found that, if 90% of new cases of recurrent or metastatic nasopharyngeal cancer were treated with toripalimab over 1 year, these savings are enough to purchase up to 4,717 additional doses on a budget-neutral basis, which could provide up to an additional 252 newly diagnosed patients with 1 year of treatment with toripalimab. In combination with gemcitabine and cisplatin, toripalimab can markedly improve access to care for patients with recurrent or metastatic nasopharyngeal cancer in a cost-responsible way.

Deciphering drug resistance in gastric cancer: Potential mechanisms and future perspectives.

Gastric cancer (GC) is a malignant tumor that originates from the epithelium of the gastric mucosa. The latest global cancer statistics show that GC ranks fifth in incidence and fourth in mortality among all cancers, posing a serious threat to public health. While early-stage GC is primarily treated through surgery, chemotherapy is the frontline option for advanced cases. Currently, commonly used chemotherapy regimens include FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine). However, with the widespread use of chemotherapy, an increasing number of cases of drug resistance have emerged. This article primarily explores the potential mechanisms of chemotherapy resistance in GC patients from five perspectives: cell death, tumor microenvironment, non-coding RNA, epigenetics, and epithelial-mesenchymal transition. Additionally, it proposes feasibility strategies to overcome drug resistance from four angles: cancer stem cells, tumor microenvironment, natural products, and combined therapy. The hope is that this article will provide guidance for researchers in the field and bring hope to more GC patients.

Different Genomic Clusters Impact on Responses in Advanced Biliary Tract Cancer Treated with Cisplatin Plus Gemcitabine Plus Durvalumab.

BACKGROUND: The results reported in the TOPAZ-1 phase III trial led to the approval of the combination of cisplatin and gemcitabine with durvalumab as the new first-line standard of care for patients with locally advanced or metastatic cholangiocarcinoma. OBJECTIVE: We performed a clustering analysis to classify patients into different groups based on their mutation profile, correlating the results of the analysis with clinical outcomes. METHODS: We selected 51 patients with cholangiocarcinoma who were treated with the combination of chemotherapy and durvalumab and who were screened using the next-generation sequencing-based FoundationOne gene panel. We conducted mutation-based clustering of tumors and a survival analysis. RESULTS: Three main clusters were identified. Cluster 1 is mostly characterized by mutations in genes belonging to the chromatin modification pathway, altered in 100% of patients. Cluster 2 is characterized by the alteration of several pathways, among which DNA damage control, chromatin modification, RTK/RAS, cell-cycle apoptosis, TP53, and PI3K were the most affected. Finally, most altered pathways in cluster 3 were RTK/RAS and cell-cycle apoptosis. Overall response rate was 4/13 (31%), 12/24 (50%), and 0/10 (0%) in cluster 1, cluster 2, and cluster 3, respectively, and the difference between the three clusters was statistically significant (p = 0.0188). CONCLUSIONS: By grouping patients into three clusters with distinct molecular and genomic alterations, our analysis showed that patients included in cluster 2 had higher overall response rates, whereas patients included in cluster 3 had no objective response. Further investigations on larger and external cohorts are needed in order to validate our results.

Suppression of hypoxia-induced CAV1 autophagic degradation enhances nanoalbumin-paclitaxel transcytosis and improves therapeutic activity in pancreatic cancer.

Nanoalbumin-paclitaxel (nab-paclitaxel) is a standard chemotherapy for pancreatic cancer but has shown limited efficacy. However, the mechanism through which circulating nab-paclitaxel passes through the tumour vascular endothelium has not been determined. In our study, a new nonradioactive and highly sensitive method for analysing nab-paclitaxel transcytosis was established. Based on these methods, we found that hypoxia significantly enhanced the autophagic degradation of CAV1 and therefore attenuated caveolae-mediated nab-paclitaxel transcytosis across endothelial cells (ECs). In a proof-of-concept experiment, higher levels of CAV1, accompanied by lower levels of LC3B, were observed in the vascular endothelium of pancreatic cancer tissues collected from patients who showed a good response to nab-paclitaxel compared with those from patients who showed a poor response to nab-paclitaxel. Furthermore, both in vivo and in vitro studies confirmed that suppressing the autophagic degradation of CAV1 via EC-specific ATG5 knockdown or hydroxychloroquine sulfate (HCQ) treatment significantly enhanced nab-paclitaxel translocation across the endothelial barrier into pancreatic cancer cells and amplified the inhibitory effect of nab-paclitaxel on pancreatic tumour growth. The stimulation of CAV1 expression by EC-specific overexpression of exogenous CAV1 or administration of gemcitabine hydrochloride (GE) had the same effect. These results demonstrated that suppressing CAV1 autophagic degradation is a novel translatable strategy for enhancing nab-paclitaxel chemotherapeutic activity in the treatment of pancreatic cancer.