Targeting RAC1 reactivates pyroptosis to reverse paclitaxel resistance in ovarian cancer by suppressing P21-activated kinase 4.

Pyroptosis may play an important role in the resistance of ovarian cancer (OC) to chemotherapy. However, the mechanism by which pyroptosis modulation can attenuate chemotherapy resistance has not been comprehensively studied in OC. Here, we demonstrated that RAS-associated C3 botulinum toxin substrate 1 (RAC1) is highly expressed in OC and is negatively correlated with patient outcomes. Through cell function tests and in vivo tumor formation tests, we found that RAC1 can promote tumor growth by mediating paclitaxel (PTX) resistance. RAC1 can mediate OC progression by inhibiting pyroptosis, as evidenced by high-throughput automated confocal imaging, the release of lactate dehydrogenase (LDH), the expression of the inflammatory cytokines IL-1ß/IL-18 and the nucleotide oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Mechanically, RNA-seq, gene set enrichment analysis (GSEA), coimmunoprecipitation (Co-IP), mass spectrometry (MS), and ubiquitination tests further confirmed that RAC1 inhibits caspase-1/gasdermin D (GSDMD)-mediated canonical pyroptosis through the P21-activated kinase 4 (PAK4)/mitogen-activated protein kinase (MAPK) pathway, thereby promoting PTX resistance in OC cells. Finally, the whole molecular pathway was verified by the results of in vivo drug combination tests, clinical specimen detection and the prognosis. In summary, our results suggest that the combination of RAC1 inhibitors with PTX can reverse PTX resistance by inducing pyroptosis through the PAK4/MAPK pathway.

Outcomes After Multimodality Treatment of Pancreatic Cancer in an Unselected Single-Center Cohort.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal and rarely resectable malignancy. Here we explore the outcomes of surgery, as compared to definitive radiotherapy (dRT) or systemic therapy only in PDAC. Methods: Pancreatic surgery and radiotherapy in Southwest Finland have been centralized to Turku University Hospital. Previously validated population-based electronic health records database was searched for all unselected PDAC patients from the years 2009-2019. Main outcome was median overall survival (mOS). Demographics, pathology, surgery, and oncological treatment data were collected. Results: We identified 1006 patients with PDAC, 49% male, median age 71 years and 77% presenting with metastatic disease. In total, 405 patients were treated; 92 resected, 26 dRT without resection and 287 systemic therapy only. mOS was 34.6 months for resected, 26.7 months for dRT, and 7.5 months for systemic therapy patients. Among the 88 patients with locally advanced inoperable PDAC, dRT was independently associated with longer mOS (26.7 months) as compared to systemic therapy only (mOS 10.6 months). Among the 287 patients treated with systemic therapy only, combination chemotherapy was independently associated with longer mOS (11.6 months) as compared to gemcitabine-monotherapy (6.8 months). In patients progressing to second-line systemic treatment after gemcitabine failure, mOS was the same (5.0 months) with single or combination regimens. Conclusion: Surgery remains the only curative approach for PDAC. In locally advanced PDAC, dRT was associated with longer survival as compared to systemic therapy only. Concerning first-line systemic therapy, our results support the use of combination chemotherapy over single-agent therapy.

Paclitaxel-Coated Balloon Versus Uncoated Balloon Angioplasty For Coronary In-Stent Restenosis: A Systematic Review And Meta-Analysis Of Randomized Controlled Trials.

In-stent restenosis (ISR) accounts for 10% of percutaneous coronary intervention (PCI) in the Unites States. Paclitaxel coated balloons (PCBs) have been evaluated as a therapy for coronary ISR in multiple randomized controlled trials (RCTs). We searched PubMed/MEDLINE, Cochrane library, and ClinicalTrials.gov (from inception to April 1, 2024) for RCTs evaluating PCBs versus uncoated balloon angioplasty (BA) in patients with coronary ISR. The outcomes of interest were target lesion revascularization (TLR), major adverse cardiovascular events (MACE), all-cause mortality, cardiovascular mortality, myocardial infarction (MI), and stent thrombosis. We pooled the estimates using inverse variance random-effects model. The effect sizes were reported as risk ratio (RR) with 95% confidence interval (CI). A total of 6 RCTs with 1,343 patients were included. At a follow-up ranging from 6-12 months from randomization, use of PCBs was associated with a statistically significant decrease in TLR (RR 0.28; 95% CI 0.11 to 0.68), and MACE (RR 0.35; 95% CI 0.20 to 0.64) when compared with BA for coronary ISR. However, there was no significant difference in risk between PCBs and BA in terms of all-cause mortality (RR 0.56; 95% CI 0.14 to 2.31), cardiovascular mortality (RR 0.61; 95% CI 0.02 to 16.85), MI (RR 0.60; 95% CI 0.27 to 1.31), and stent thrombosis (RR 0.13; 95% CI 0.00 to 5.06). In conclusion, this meta-analysis suggests that PCBs compared with uncoated BA for treatment of coronary ISR at intermediate term follow-up of one-year was associated with significant decrease in TLR, and MACE without any difference in mortality, MI, or stent thrombosis.

Nab-paclitaxel plus S-1 followed by gemcitabine-oxaliplatin as first-line alternating sequential treatment of pancreatic ductal adenocarcinoma.

BACKGROUND: Alternating sequential administration of drugs may be a promising approach to overcome chemotherapy resistance in advanced pancreatic ductal adenocarcinoma (PDAC). METHODS: This study was an open-label, single-arm, and prospective trial included patients with untreated advanced PDAC. They received 2 cycles of NS regimen (nab-paclitaxel:125 mg/m2, intravenously injected on days 1 and 8, plus S-1:40-60 mg, orally twice per day for 1-14 days) followed by 2 cycles of GemOx regimen (gemcitabine, intravenously injected on days 1 and 8, and oxaliplatin: 130 mg/m2, intravenously injected on day 1). The primary efficacy endpoint was a progression-free survival rate at 6 months (PFSR-6m). The secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Specific mRNA transcripts were used to explore survival associated genes. RESULTS: Forty-two patients received a minimum of one treatment cycle, and of these, 30 patients completed one alternating treatment consisting of 4 cycles. The PFSR-6m was 71% (95% CI = 58%-87%). The median PFS and OS were 6.53 months (95% CI = 6.03-8.43) and 11.4 months (95% CI = 9.8-14.4), respectively. Common grades 3-4 hematological AEs included neutropenia 30.9%, leukopenia 26.2%, anemia 2.4%, and thrombocytopenia in 11.9%. Patients with OS > 10 months showed high expression of HLA-DQA2 while melanoma-associated antigen genes (MAGE) were notably upregulated in patients with OS < 10 months. CONCLUSION: The alternating sequential administration of the NS and GemOx regimens may be a novel approach for first-line chemotherapy in patients with advanced PDAC requiring further study (ClinicalTrials.gov Identifier: ChiCTR1900024867).

Efficacy of initial and repeat DCB angioplasty of restenotic arteriovenous fistulas compared with plain angioplasty.

PURPOSE: To evaluate the effect of drug-coated balloon (DCB) with high-dose paclitaxel for the treatment of restenotic dysfunctional arteriovenous fistulas (AVFs). MATERIALS AND METHODS: In this single-arm, multicenter, prospective, observational study, 334 patients using IN.PACT AV DCB (Medtronic Inc., Plymouth, MN) for the first time in the restenotic lesion of dysfunctional AVF between April 2021 and March 2022 were registered. RESULTS: Procedural success, defined as <30% residual stenosis, was achieved in 96.7% of cases. During a median follow-up of 7.4 months, 179 target lesion reinterventions (TLRs) were observed, and the 6-month freedom from TLR was 73.2% (68.2%-78.2%). When compared with the previous plain percutaneous transluminal angioplasty, the median time to reintervention was significantly longer with DCB (9.1 [8.0-10.6] versus 3.2 [3.0-3.4] months; P<.001). Baseline characteristics that were independently associated with TLR were: months from the last intervention (adjusted hazard ratio, 0.50 [95% confidence interval, 0.40-0.62] per doubling; P<.001), partial lesion coverage by DCB (2.13 [1.10-4.12]; P=.024), and residual stenosis after DCB (2.19 [1.53-3.12] per 15% increase; P<.001) with its time interaction (0.91 [0.86-0.97] per month; P=.003). Of the 179 TLRs, 84 used DCB once again. The median time to reintervention was significantly longer for TLR using DCB (7.1 [6.2-9.7] versus 3.3 [3.1-4.0] months; P<.001). CONCLUSIONS: DCB with high-dose paclitaxel is effective at both the initial treatment in the restenotic lesion of dysfunctional AVF and during TLR after DCB use. However, partial lesion coverage by DCB and residual stenosis should be avoided.

A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer.

Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.

Comparative analysis of adverse event risks in breast cancer patients receiving pembrolizumab combined with paclitaxel versus paclitaxel monotherapy: insights from the FAERS database.

Objective: This study aimed to evaluate the risk of adverse events (AEs) in breast cancer patients treated with pembrolizumab combined with paclitaxel versus those receiving pembrolizumab or paclitaxel monotherapy, using the FDA Adverse Event Reporting System (FAERS) database. Methods: Data were extracted from the FAERS database for breast cancer patients treated with pembrolizumab combined with paclitaxel or with pembrolizumab or paclitaxel monotherapy from Q1 2016 to Q2 2023. Disproportionation analysis was performed by calculating the reporting odds ratio (ROR) with corresponding 95% confidence interval (95% CI), the information component (IC), and the lower bound of the information component 95% confidence interval (IC025) to identify potential safety signals. Results: No significant difference in AEs was observed between the combined treatment group and the pembrolizumab monotherapy group. However, the combined treatment group exhibited a substantial increase in AE risk compared to the paclitaxel monotherapy group. The most significant increases in AE risk were adrenal insufficiency (ROR = 189.94, 95% CI 25.41-1419.7, IC = 3.37, IC025 = 1.59), hypophysitis (ROR = 99.46, 95% CI 12.72-777.4, IC = 3.31, IC025 = 1.44), and myocarditis (ROR = 69.5, 95% CI 8.55-565.23, IC = 3.25, IC025 = 1.33). The time-to-event for combined treatment was 35 (34-70) days, for pembrolizumab was 43 (35-90) days, and for paclitaxel was 42 (37-76) days. The combination therapy group demonstrated significantly shorter intervals to the onset of adrenal insufficiency (p = 0.008), myocarditis (p < 0.001), and immune-related enterocolitis (p = 0.009). Conclusion: Analysis of the FAERS database indicates that combination therapy significantly elevates the risk of adrenal insufficiency, myocarditis, hypophysitis, and immune-related enterocolitis compared to paclitaxel monotherapy. These findings provide critical insights for clinicians in predicting and managing potential AEs associated with this treatment regimen.

A multicenter retrospective study to assess feasibility, safety and efficacy of first-line carboplatin-paclitaxel versus carboplatin monotherapy in a frail, elderly epithelial ovarian cancer population.

OBJECTIVE: Underrepresentation of elderly ovarian cancer patients in clinical trials has led to lack of clarity regarding optimal first-line chemotherapy in this cohort. The Elderly Women with Ovarian Cancer (EWOC)-1 trial demonstrated that 3-weekly carboplatin (3wC) resulted in worse survival and feasibility compared with standard 3-weekly carboplatin-paclitaxel (3wCP) in frail, elderly ovarian cancer patients. Our retrospective study compares feasibility, safety, and efficacy of first-line 3wCP and 3wC in a frail ovarian cancer cohort. METHODS: Clinical data were retrospectively analyzed for newly-diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV, ≥70-year-old epithelial ovarian cancer patients, treated by clinician choice with 3wC or 3wCP at two London cancer centers over a 2 year period. Charlson Comorbidity Index (CCI) and Eastern Cooperative Oncology Group (ECOG) performance status provided surrogate markers of frailty. Common Terminology Criteria for Adverse Events v5.0 graded toxicity. RESULTS: A total of 107 patients were treated with 3wC (n=30) and 3wCP (n=77). Age, performance status, and CCI were significantly different between cohorts, with 3wC patients older (84 vs 75 years, p<0.001), with more comorbidities (median CCI 4 vs 3, p<0.001) and worse performance status (47% vs 17% PS ≥2, p=0.015). Surgical outcomes differed significantly between cohorts, with 20 (67%) 3wC patients not undergoing surgery, compared with 22 (29%) 3wCP patients (p<0.001). Median follow-up was 45.8 months (IQR 38.7-56.3 months). While we observed improved progression-free (HR 0.55, 95% CI 0.33 to 0.90, p=0.017) and overall survival (HR 0.44, 95% CI 0.27 to 0.73, p=0.001, log-rank test) in a univariate cox proportional hazards comparison between 3wCP and 3wC, this was not significant on multivariate analysis. Completion of six planned chemotherapy cycles was achieved by the majority, with similar discontinuation rates between groups (13% 3wC vs 8% 3wCP, p>0.05). Overall grade ≥3 hematological toxicity rates were similar between regimens (33% 3wC vs 44% 3wCP, p=0.37) with grade ≥3 neutropenia (p=0.019) and grade ≥3 thrombocytopenia (p=0.006) more common with 3wCP and 3wC, respectively. No treatment-related deaths occurred. CONCLUSION: Our data demonstrates that standard 3wCP is a well-tolerated, feasible first-line treatment for frail, elderly ovarian cancer patients. Improved survival with 3wCP was not significant when corrected for established clinical prognostic factors.

Ionic co-aggregates based intravenous drug delivery: Evaluation on kinetics and distribution of the drug payloads and nanocarriers.

Surfactants are crucial in formulating poorly soluble drugs but lead to serious side effects due to PEG chains. Novel supra-amphiphiles consisting of fatty acids and choline are developed, which spontaneously form ionic co-aggregates (ICAs) in water and exhibit strong solubilizing capacity. Paclitaxel (PTX) is adopted as a model drug here to evaluate the feasibility of choline oleate-based ICAs in the intravenous delivery of poorly soluble drugs by comparing the kinetics and distribution of payloads and nanocarriers. Choline oleate presents a maximum 10-fold enhancement in solubilizing capacity to PTX than Cremophor EL (CreEL), enabling a one-tenth use level in the formulation. Aggregation-caused quenching probes are utilized to evaluate the kinetics and biodistribution of ICAs or CreEL-based micelles (MCs). A huge gap is found between the pharmacokinetic and particokinetic curves of either nanocarrier, indicating fast leakage. ICAs lead to faster PTX leakage in blood circulation but higher PTX distribution to organs than MCs. MCs present a longer circulation in blood but a slower distribution to organs than ICAs. ICAs do not arise adverse reactions in rats following repeated injections, while MCs cause pathological changes in varying degrees. In conclusion, choline oleate-based ICAs provide an alternative to surfactants in formulating poorly soluble drugs.

Telotristat ethyl, a tryptophan hydroxylase inhibitor, enhances antitumor efficacy of standard chemotherapy in preclinical cholangiocarcinoma models.

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.

Pathological response and safety of albumin-bound paclitaxel as a neoadjuvant treatment for HER2-positive breast cancer compared to docetaxel combined with anti-HER2 therapy: a real-world study.

Background: This study aimed to retrospectively analyse the pathological response and safety of combining albumin-bound paclitaxel (nab-paclitaxel) or docetaxel with anti-HER2 therapy as a neoadjuvant treatment for HER2-positive breast cancer. Methods: From June 2020 to August 2023, 225 HER2-positive breast cancer patients who underwent radical surgery following neoadjuvant treatment were enrolled in this study. The patients were divided into two groups based on the drugs they received: the nab-paclitaxel group (n=166, receiving nab-paclitaxel + platinum along with trastuzumab and pertuzumab) and the docetaxel group (n=59, receiving docetaxel + platinum along with trastuzumab and pertuzumab). The pathological response and adverse events related to the drugs were collected and evaluated in both groups. Results: In the nab-paclitaxel group, the rates of breast and total pathological complete response (bpCR and tpCR) were significantly greater than those in the docetaxel group (69.27% vs. 47.45%, P=0.003; 68.67% vs. 45.76%, P=0.002). For patients who did not achieve pCR after chemotherapy, the pathological response of chemotherapy was analysed using MP grading and RCB grading. The results showed that there was a statistically significant difference between the two groups (P<0.05). Multivariate analysis revealed that therapeutic drugs, clinical stage, ER status, and Ki-67 level were independent predictors of pCR. The nab-paclitaxel group had a significantly greater proportion of patients with peripheral sensory neuropathy than did the docetaxel group (58.43% vs. 38.98%, P=0.035), while the docetaxel group had a greater proportion of patients with allergies and elevated ALT (31.93% vs. 69.49%, P=0.000; 23.49% vs. 40.68%, P=0.021). Conclusions: Our real-world study revealed that nab-paclitaxel combined with anti-HER2 therapy was an effective neoadjuvant therapy for HER2-positive breast cancer. The multivariate analysis revealed that chemotherapy drugs, clinical stage, ER status, and Ki-67 level was the significant factor influencing treatment outcome. These findings offer a valuable reference for the neoadjuvant treatment of patients with HER2-positive breast cancer.

Bazedoxifene Inhibits Cell Viability, Colony-Forming Activity, and Cell Migration in Human Non-Small Cell Lung Cancer Cells and Improves the Treatment Efficacy of Paclitaxel and Gemcitabine.

BACKGROUND: Bazedoxifene is a third-generation selective estrogen receptor modulator that inhibits the IL6/IL6R/GP130 signaling pathway by inhibiting IL6-induced homodimerization of GP130. Considering that the IL6/IL6R/GP130 signaling pathway is important in tumorigenesis and metastasis, bazedoxifene is thought to have an antitumor effect, which has been proven preliminarily in breast cancer and pancreatic cancer but has not yet been studied in non-small cell lung cancer (NSCLC). This study is aimed at evaluating the antitumor effect of bazedoxifene in NSCLC. METHODS: A549 and H1299 NSCLC cell lines were employed and exposed to various concentrations of bazedoxifene, paclitaxel, gemcitabine, and their combinations for cell viability, colony formation, and wound healing assays to demonstrate the antitumor effect of bazedoxifene with or without paclitaxel or gemcitabine. RESULTS: MTT cell viability, colony formation, and wound healing assays showed that bazedoxifene was capable of inhibiting cell viability, colony formation, and cell migration in a dose-dependent manner. In addition, bazedoxifene was capable of working with paclitaxel or gemcitabine synergistically to inhibit cell viability, colony formation, and cell migration. CONCLUSION: This study demonstrated the potential antitumor effect of bazedoxifene and its ability to improve the treatment efficacy of paclitaxel and gemcitabine.

Optimization of a human induced pluripotent stem cell-derived sensory neuron model for the in vitro evaluation of taxane-induced neurotoxicity.

Human induced pluripotent stem cell-derived sensory neuron (iPSC-dSN) models are a valuable resource for the study of neurotoxicity but are affected by poor replicability and reproducibility, often due to a lack of optimization. Here, we identify experimental factors related to culture conditions that substantially impact cellular drug response in vitro and determine optimal conditions for improved replicability and reproducibility. Treatment duration and cell seeding density were both found to be significant factors, while cell line differences also contributed to variation. A replicable dose-response in viability was demonstrated after 48-h exposure to docetaxel or paclitaxel. Additionally, a replicable dose-dependent reduction in neurite outgrowth was demonstrated, demonstrating the applicability of the model for the examination of additional phenotypes. Overall, we have established an optimized iPSC-dSN model for the study of taxane-induced neurotoxicity.

Polycaprolactone-Vitamin E TPGS Micellar Formulation for Oral Delivery of Paclitaxel.

This study aimed to investigate the potential of polycaprolactone-vitamin E TPGS (PCL-TPGS) micelles as a delivery system for oral administration of paclitaxel (PTX). The PCL-TPGS copolymer was synthesized using ring opening polymerization, and PTX-loaded PCL-TPGS micelles (PTX micelles) were prepared via a co-solvent evaporation method. Characterization of these micelles included measurements of size, polydispersity, and encapsulation efficiency. The cellular uptake of PTX micelles was evaluated in Caco-2 cells using rhodamine 123 (Rh123) as a fluorescent probe. Moreover, an everted rat sac study was conducted to evaluate the ex vivo permeability of PTX micelles. Additionally, a comparative pharmacokinetic study of PTX micelles versus the marketed formulation, Ebetaxel® (a Taxol generic), was performed after a single oral administration to rats. The results demonstrated that the micellar formulation significantly improved PTX solubility (nearly 1 mg/mL). The in vitro stability and release of PTX micelles in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) demonstrated that PTX micelles remained stable for up to 24 h and significantly slowed the release of PTX in both media compared to Ebetaxel®. The in vitro cellular uptake, ex vivo intestinal permeability, and in vivo pharmacokinetic profile demonstrated that PTX micelles enhanced the permeability and facilitated a rapid absorption of the drug. Conclusively, the PCL7000-TPGS3500 micelles exhibit potential as an effective oral delivery system for PTX.

Corrigendum: Paclitaxel-incorporated nanoparticles improve functional recovery after spinal cord injury.

[This corrects the article DOI: 10.3389/fphar.2022.957433.].

Outcomes of patients with initially unresectable pancreatic cancer who underwent conversion surgery after FOLFIRINOX or gemcitabine plus nab-paclitaxel chemotherapy: A multicenter retrospective cohort study (PC-CURE-1).

BACKGROUND: The efficacy and safety of conversion surgery (CS) after FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP) chemotherapy in patients with initially unresectable pancreatic cancer (PC) remains unclear. METHODS: This multicenter retrospective cohort study enrolled patients, between 2014 and 2018, with initially locally advanced or metastatic PC who were considered candidates for CS following FOLFIRINOX or GnP chemotherapy. They were classified into surgery (207 patients [194 resection and 13 exploratory laparotomy only]) and continued chemotherapy (10 patients, control) groups. The primary endpoint was overall survival (OS) from the day of diagnosis of potentially curative resection on imaging studies, with an expected hazard ratio (HR) of 0.7. RESULTS: OS in the surgery group was longer than that in the control group (HR, 0.47; 95% confidence interval [CI]: 0.24-0.93). The median OS was 34.4 (95% CI: 27.9-43.4) and 19.8 (95% CI: 14.9-31.1) months in the surgery and control groups, respectively. The Clavien-Dindo grade ≥ IIIa postoperative complication and in-hospital mortality rates were 19.6% and 0.5%, respectively. Multivariate analysis revealed that preoperative chemotherapy duration was not associated with OS. CONCLUSIONS: CS, following a favorable response to FOLFIRINOX or GnP chemotherapy, improved initially unresectable PC prognosis (specifically, OS), regardless of the chemotherapy duration.

Construction and Evaluation of BAL-PTX Co-Loaded Lipid Nanosystem for Promoting the Anti-Lung Cancer Efficacy of Paclitaxel and Reducing the Toxicity of Chemotherapeutic Drugs.

Purpose: The present study aimed to develop a lipid nanoplatform, denoted as "BAL-PTX-LN", co-loaded with chiral baicalin derivatives (BAL) and paclitaxel (PTX) to promote the anti-lung cancer efficacy of paclitaxel and reduce the toxicity of chemotherapeutic drugs. Methods: BAL-PTX-LN was optimized through central composite design based on a single-factor experiments. BAL-PTX-LN was evaluated by TEM, particle size, encapsulation efficiency, hemolysis rate, release kinetics and stability. And was evaluated by pharmacokinetics and the antitumor efficacy studied both in vitro and in vivo. The in vivo safety profile of the formulation was assessed using hematoxylin and eosin (HE) staining. Results: BAL-PTX-LN exhibited spherical morphology with a particle size of 134.36 ± 3.18 nm, PDI of 0.24 ± 0.02, and with an encapsulation efficiency exceeding 90%, BAL-PTX-LN remained stable after 180 days storage. In vitro release studies revealed a zero-order kinetic model of PTX from the liposomal formulation. No hemolysis was observed in the preparation group. Pharmacokinetic analysis of PTX in the BAL-PTX-LN group revealed an approximately three-fold higher bioavailability and twice longer t1/2 compared to the bulk drug group. Furthermore, the IC50 of BAL-PTX-LN decreased by 2.35 times (13.48 µg/mL vs 31.722 µg/mL) and the apoptosis rate increased by 1.82 times (29.38% vs 16.13%) at 24 h compared to the PTX group. In tumor-bearing nude mice, the BAL-PTX-LN formulation exhibited a two-fold higher tumor inhibition rate compared to the PTX group (62.83% vs 29.95%), accompanied by a ten-fold decrease in Ki67 expression (4.26% vs 45.88%). Interestingly, HE staining revealed no pathological changes in tissues from the BAL-PTX-LN group, whereas tissues from the PTX group exhibited pathological changes and tumor cell infiltration. Conclusion: BAL-PTX-LN improves the therapeutic effect of poorly soluble chemotherapeutic drugs on lung cancer, which is anticipated to emerge as a viable therapeutic agent for lung cancer in clinical applications.

Simultaneous estimation of paclitaxel and bortezomib via LC-MS/MS: pharmaceutical and pharmacokinetic applications.

Aim & Objective: This study evaluates the potential of combining paclitaxel (PTX) and bortezomib (BTZ) for breast cancer therapy. Materials & Methods: The nanoformulation was optimized via Box-Behnken Design (BBD), with method validation adhering to US-FDA guidelines. Results: Multiple reaction monitoring transitions for PTX, BTZ and internal standard were m/z 855.80→286.60, 366.80→226.00 and 179.80→110.00, respectively. Elution done on C18 Luna column with 0.1% FA in MeOH:10 mM ammonium acetate. The size of nanoformulation was 133.9 ± 1.97 nm, PDI 0.19 ± 0.01 and zeta potential -19.20 ± 1.36 mV. Pharmacokinetics showed higher Cmax for PTX-BTZ-NE (313.75 ± 10.71 ng/ml PTX, 11.92 ± 0.53 ng/ml BTZ) versus free PTX-BTZ (104 ± 13.06 ng/ml PTX, 1.9 ± 0.08 ng/ml BTZ). Conclusion: Future findings will contribute to the treatment of breast cancer using PTX and BTZ.

[Box: see text].

Comparative Evaluation of Local and Downstream Responses in Two Commercially Available Paclitaxel-Coated Balloons in Healthy Peripheral Arteries of a Swine Model.

OBJECTIVE: To investigate the local, downstream, and systemic effects of two different paclitaxel-coated balloons. DESIGN: Preclinical study in healthy peripheral arteries of a swine model, with randomized allocation of the distribution of the devices: the test paclitaxel-coated balloon (PCB) (Luminor®), a control PCB (IN.PACT®), and a plain angioplasty balloon (Oceanus®), considering single (1×) and overlapping (3×) doses with simple blind histologic analysis. METHODS: Twenty animals underwent balloon angioplasty at 1× or 3× doses in the external and internal branches of both femoral arteries and were followed-up for 28 days. Post-procedural and follow-up angiography were carried out. Comprehensive necropsy and histology were used to evaluate the local, downstream and systemic effects. RESULTS: Angioplasty was successfully carried out in all animals. Significant protocol deviations appeared in three arteries (treated with Oceanus®) without clinical relevance. Those samples were excluded from the analysis. All the animals survived the follow-up period without major clinical issues. Local signs of drug toxicity were less marked with Luminor® than IN.PACT® at 1× dose, including endothelial loss (p=0.0828), intima/media inflammation (p=0.0004), transmural medial smooth muscle cell (SMC) loss (p=0.0016), wall thickness loss (p=0.0141), presence of fibrin in the vascular wall (p=0.0054), and adventitial inflammation (p=0.0080). A similar pattern was observed at the 3× dose for endothelial loss (p=0.0011), intima/media inflammation (p< 0.0001), circumferential SMC loss (p=0.0004), medial SMC replacement with proteoglycans (p=0.0014), fibrin (p=0.0034), and collagen content (p=0.0205). Downstream vascular histologic changes were mild although more prevalent in the IN.PACT® 3× group (p=0.006). No systemic effects of toxicity were detected in any of the samples analyzed. CONCLUSION: Luminor® showed better healing pattern (lower inflammation, and endothelial and muscular loss) than IN.PACT® balloon. The effect was evident at single and triple doses. The prevalence of downstream lesions, albeit low, was higher with the triple dose of IN.PACT® compared with Luminor®.