Dose Of Paclitaxel Research Articles

Safety and efficacy of low-dose versus high-dose paclitaxel-coated balloons in patients with femoropopliteal lesions: an updated and meta-analysis

Abstract Introduction Drug-coated balloons (DCBs) have reduced restenosis and reintervention of femoropopliteal lesions compared to uncoated percutaneous transluminal angioplasty (PTA). However, limited data are available on different dosages of the DCBs. Purpose We aimed to give a comprehensive analysis in this regard and update the current evidence. Methods We searched Scopus, Cochrane, PubMed, and WOS from inception till February 2024 to include all randomized controlled trials (RCTs) that addressed different dosages of DCBs in femoropopliteal lesions. The primary endpoint was all-cause death, primary patency, and amputation at six months, while the secondary outcomes were all-cause death, primary patency, and amputation at 12 months. Dichotomous data were pooled using Odds Ratio (OR) and 95% Confidence Interval (CI) in a random-effect model. Results A total of 21 studies, including 4081 patients in the analysis. Low-dose DCB was associated with high rates of primary patency compared to the standard dose at both 6 and 12 months of follow-up with the following values (OR: 2.46, 95% CI: 1.48 to 4.08, and 1.93, 95% CI: 1.5 to 2.49, receptively). Also, low-dose DCB reduced the incidence of clinically driven target lesion revascularization (CD-TLR) compared to the standard dose at 12 months (OR: 0.45, 95% CI: 0.31 to 0.65). Regarding high-dose DCB, higher primary patency rates were observed when compared to standard doses at 6 and 12 months (OR: 1.89, 95% CI: 1.19 to 2.99, and 5.47, 95% CI: 4.31 to 6.95, respectively). Moreover, high-dose DCB reduced the incidence of CD-TLR at 6 and 12 months of follow-up (OR: 0.33, 95% CI: 0.18 to 0.63, and 0.63, 95% CI: 0.48 to 0.84, respectively). Conclusion Low-dose DCBs were associated with higher primary patency without significant differences in all-cause mortality or amputation. On the other hand, high-dose DCBs were associated with a higher incidence of amputation without significant differences in other studied outcomes.Low dose Paclitaxel coated balloon vs CoHigh dose Paclitaxel coated balloon vs C

A Mem-dELISA platform for dual color and ultrasensitive digital detection of colocalized proteins on extracellular vesicles

Accurate, multiplex, and ultrasensitive measurement of different colocalized protein markers on individual tumor-derived extracellular vesicles (EVs) and dimerized proteins with multiple epitopes could provide insights into cancer heterogeneity, therapy management and early diagnostics that cannot be extracted from bulk methods. However, current digital protein assays lack certain features to enable robust colocalization, including multi-color detection capability, large dynamic range, and selectivity against background proteins. Here, we report a lithography-free, inexpensive (< $0.1) and ultrasensitive dual-color Membrane Digital ELISA (Mem-dELISA) platform by using track-etched polycarbonate (PCTE) membranes to overcome these shortcomings. Their through-pores remove air bubbles through wicking before they are sealed on one side by adhesion to form microwells. Immunomagnetic bead-analyte complexes and substrate solution are then loaded into the microwells from the opposite side, with >80% loading efficiency, before sealing with oil. This enables duplex digital protein colorimetric assay with beta galactosidase and alkaline phosphatase enzymes. The platform achieves 5 logs of dynamic range with a limit of detection of 10 aM for both Biotinylated β-galactosidase (B-βG) and Biotin Alkaline Phosphatase Conjugated (B-ALP) proteins. We demonstrate its potential by showing that a higher dosage of paclitaxel suppresses EpCAM-positive EVs but not GPC-1 positive EVs from breast cancer cells, a decline in chemo-resistance that cannot be detected with Western blot analysis of cell lysate. The Mem-dELISA is poised to empower researchers to conduct ultrasensitive, high throughput protein colocalization studies for disease diagnostics, treatment monitoring and biomarker discovery.

Development and Validation of a Clinical Prediction Model for Paclitaxel Hypersensitivity Reaction on the Basis of Real-World Data: Pac-HSR Score.

Paclitaxel is effective chemotherapy against various cancers but can cause hypersensitivity reaction (HSR). This study aimed to identify predictors associated with paclitaxel HSR and develop a clinical prediction model to guide clinical decisions. Data were collected from the medical records database of Rajavithi Hospital. Patients with cancer treated with paclitaxel from 2015 to 2022 were included, and a multivariable logistic regression analysis identified predictors associated with paclitaxel HSR. The scoring system was transformed and calibrated on the basis of diagnostic parameters. Discrimination and calibration performances were assessed. Internal validation was conducted using bootstrap resampling with 1,000 replications. This study involved 3,708 patients with cancer, with an incidence of paclitaxel HSR of 10.11%. An 11-predictor-based Pac-HSR scoring system was developed, involving the following factors: younger age; poor Eastern Cooperative Oncology Group performance status; previous history of paclitaxel HSR; medication allergy history; chronic obstructive airway disease; lung and cervical cancers; high actual dose of paclitaxel; no diphenhydramine premedication; low hemoglobin level; high WBC count; and high absolute lymphocyte count. The C-statistics was 0.73 (95% CI, 0.70 to 0.76), indicating acceptable discrimination. The P value of the Hosmer-Lemeshow goodness-of-fit test was 0.751. The ratio of observed and expected values was 1.00, indicating good calibration. At a cutoff point of 8, specificity was 75.28% and sensitivity was 57.07%. Internal validation indicated good performance with minimal bias, and decision curve analysis demonstrated improved prediction with the use of this scoring system in clinical decision making. This study developed the 11-predictor-based Pac-HSR scoring system for predicting paclitaxel HSR in patients with cancer. High-risk patients identified by this score should be prioritized for close monitoring and early treatment prophylaxis.

Early taxane exposure and neurotoxicity in breast cancer patients

IntroductionBreast cancer is the most diagnosed tumor and a leading cause of cancer death in women worldwide. Taxanes are the most used chemotherapeutic agents and are strictly connected to neurotoxicity. Taxane-induced neuropathy (TIN) significantly impacts patients’ quality of life (QOL). Early identification and management of TIN could improve preventive strategies to preserve patients’ QOL during and after breast cancer treatment.ObjectiveThis prospective, observational study aimed to evaluate the taxane-induced neuropathy (TIN) in early breast cancer patients treated with weekly paclitaxel at an earlier stage and identify any correlation between TIN and QOL.MethodsData from stage I-III breast cancer patients treated with taxane-based therapy between 2018 and 2022 were collected at the Medical Oncology Unit of the University Hospital of Cagliari. Peripheral neuropathy was evaluated using the NCI-CTCAE scale (National Cancer Institute, Common Terminology Criteria for Adverse Events) at every drug administration. In contrast, QOL was assessed using EORTC QLC-CIPN20 and FACT-Taxane questionnaire at baseline (T0), after 4 weeks (T1) and 12 (T2) weeks of treatment. Statistical analysis was performed to evaluate the correlation between neurotoxicity and QOL.ResultsNeurotoxicity incidence peaked at the third, fourth, and sixth week of treatment, with patients reporting grade 1 and 2 neurotoxicity. Simultaneously with increasing doses of paclitaxel, significant differences in QOL were observed in early treatment cycles relating to TIN presentation. Patients with higher neurotoxicity grades reported lower QOL scores.ConclusionsDespite the absence of effective treatments to prevent paclitaxel-induced neurotoxicity, symptoms are managed through dosage reduction, delay, or treatment interruption. Future research should focus on identifying neuroprotective measures to avoid an irreversible decline in the quality of life for breast cancer survivors.

Phase 1 trial of intraperitoneal paclitaxel in patients with gastric adenocarcinoma and carcinomatosis or positive cytology.

The purpose of this phase 1 trial was to evaluate the safety and toxicity of repeated normothermic intraperitoneal paclitaxel (PTX) for patients with gastric cancer metastatic to the peritoneum. A Bayesian optimal interval design was used to prospectively identify the safety and tolerability of escalating doses of intraperitoneal paclitaxel at weekly treatments for 3 weeks, followed by a 1-week break, and then three additional treatments. The primary objective was to define the maximum tolerated dose. Secondary end points included safety, tolerability, and antitumor activity. A total of 25 patients were treated between January 2020 and April 2023. Five dose-limiting toxicities were observed at 100 mg/m2. Treatment-related grade 3-4 toxicity included leukopenia (32%) and neutropenia (32%). Seven patients required a schedule change to every other week treatments. The maximum tolerated dose for intraperitoneal PTX was 100 mg/m2. The peritoneum post-intraperitoneal PTX demonstrated progression in five (20%), stable disease in five (20%), improvement in 10 (40%), and not evaluable in five (20%). Eight patients (32%) had resolution of their peritoneal disease and seven (28%) underwent attempted resection. The median overall survival (OS) from the diagnosis of metastatic disease was 18.8 months and from the date of treatment initiation was 10.8 months. One-, 2-, and 3-year OS rates from the diagnosis of metastatic disease were 84%, 38%, and 25%, respectively. Paclitaxel may be safely used at intraperitoneal doses of 100 mg/m2. Neutropenia associated with weekly treatments was common. Peritoneal complete clinical response rates with multimodality therapy including PTX were promising.

High- Versus Low-Dose Paclitaxel-Coated Balloons for Femoropopliteal Disease: A systematic review and meta-analysis.

To evaluate the comparative effectiveness of high- and low doses of paclitaxel in endovascular revascularization procedures for patients with femoropopliteal disease. The databases (Embase, PubMed, Scopus, and Web of Science) were searched for studies that had compared outcomes of high-dose and low-dose paclitaxel-coated balloons (PCBs) in the treatment of patients with femoropopliteal disease. Randomized controlled trials and nonrandomized comparative studies (eg, cohort studies and case-control studies) were eligible for inclusion. The primary outcomes of interest were patency rates, risk of restenosis, and clinically-driven target lesion revascularization (CD-TLR). Pooled effect sizes were reported as relative risk (RR) with 95% confidence intervals (CI). The analysis included 7 studies. High-dose PCB use was associated with higher patency (RR, 1.10; 95% CI, 1.00-1.21), reduced risk of restenosis (RR, 0.60; 95% CI, 0.46-0.79), and reduced need for CT-TLR (RR, 0.57; 95% CI, 0.41-0.79) compared to low-dose PCB. Rates of limb salvage (RR, 1.01; 95% CI, 0.99-1.04), freedom from major adverse limb events (RR, 1.39; 95% CI, 0.79-2.42), and overall survival (RR, 1.02; 95% CI, 0.99-1.05) were comparable in the 2 groups. There was no evidence of publication bias. High-dose PCB correlates with superior outcomes in patients with femoropopliteal disease, particularly in terms of better vascular patency, reduced restenosis risk, and lower need for target lesion revascularization, compared to low-dose PCB.

N6-methyladenosine modification of linc-OIP5 confers paclitaxel resistance in breast cancer through a DDX5-dependent mechanism

Chemoresistance is a significant obstacle in the treatment of breast cancer (BC). Due to its diverse composition, the causes of chemoresistance in BC are complex and have not been completely understood. In this article, we explored the mechanism of N6-methyladenosine (m6A)-modified long intervening noncoding RNA (linc)-OIP5 in BC chemoresistance. We successfully constructed drug-resistant cell lines MCF-7/P and MDA-MB-231/P by exposing parental MDA-MB-231 and MCF-7 cells to escalating doses of paclitaxel (PTX) and revealed multiple m6A methylation modification sites on linc-OIP5 according to the predictive analysis of the SRAMP database. Linc-OIP5 expression and m6A modification were up-regulated in PTX-resistant BC cells. Inhibition of m6A modification or linc-OIP5 knockdown facilitated PTX-resistant and parental BC cell apoptosis and repressed proliferation and migration. Mechanistically, linc-OIP5 bound to TRIM5 and reduced the ubiquitination of DDX5, thus stabilizing the DDX5 protein. Additionally, DDX5 overexpression partly abrogated the suppressing effects of inhibited m6A modification or si-linc-OIP5 on cell proliferation, migration and PTX resistance. These findings indicate that m6A-modified linc-OIP5 reduced DDX5 ubiquitination and enhanced DDX5 stability by binding to TRIM5, thereby promoting BC cell proliferation, migration and PTX resistance, and inhibiting apoptosis.

Chaos-Assisted Production of Micro-Architected Spheres (CAPAS).

Hydrogel droplets with inner compartments are valuable in various fields, including tissue engineering. A droplet-based biofabrication method is presented for the chaos-assisted production of architected spheres (CAPAS) for the rapid generation of multilayered hydrogel spheres (ranging from 0.6 to 3.5mm in diameter) at high-throughput rates (up to 2000 spheres per min). This method is based on the use of chaotic advection generated by a Kenics static mixer (KSM) nozzle. The configuration of the KSM (i.e., the number of mixing elements) determines the number of compartments within the sphere. Sphere size is adjusted by flow rate, printhead outlet diameter, polymer concentration (sodium alginate or gelatin-methacryloyl (GelMA)), and crosslinking bath composition. This versatile system operates in dripping and jetting modes, preserving multilayered architecture in both modes. Proof-of-concept experiments with breast cancer (MDA-MB-231), human dermal fibroblast (HDF), and murine myoblast (C2C12) lines show over 80% cell viability immediately post-fabrication, maintained over extended culture (14 or 30 days). CAPAS is used to create a breast cancer model with cancer-tissue-like and healthy-tissue-like micro-niches to test paclitaxel doses. It is envisioned that CAPAS will enable high-throughput fabrication of hydrogel spheres for tissue engineering, chemical engineering, and material sciences applications.

Comparison of Weekly Paclitaxel Regimens in Recurrent Platinum-Resistant Ovarian Cancer: A Single Institution Retrospective Study.

Weekly paclitaxel (WP) is a chemotherapeutic cornerstone in the management of patients with platinum-resistant ovarian carcinoma. Multiple WP dosing regimens have been used clinically and studied individually. However, no formal comparison of these regimens is available to provide objective guidance in clinical decision making. The primary objective of this study was to compare the cumulative dose of paclitaxel delivered using 80 mg/m2/week, administered using either a 3 weeks out of 4 (WP3) or a 4 weeks out of 4 (WP4) regimen. The secondary objective was to evaluate the clinical outcomes associated with both regimens, including efficacy and toxicity parameters. Our retrospective cohort comprised 149 patients harboring platinum-resistant ovarian cancer treated at the CHU de Québec from January 2012 to January 2023. WP3 and WP4 reached a similar cumulative dose (1353.7 vs. 1404.2 mg/m2; p = 0.29). No significant differences in the clinical outcomes were observed. The frequency of dose reduction was significantly higher for WP4 than WP3 (44.7% vs. 4.9%; p < 0.01), mainly due to treatment intolerance from toxicity (34.0% vs. 3.9%; p < 0.01). Our data suggest that a WP3 regimen delivers a similar cumulative dose to WP4, hence offering a better tolerability profile without compromising efficacy.

Blood biomarkers for neuroaxonal injury and astrocytic activation in chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome side effect in patients exposed to taxanes in the treatment of cancer and may affect quality of life dramatically. Here we assessed whether serum levels of neurofilament light (NfL) and tau (two neuroaxonal injury biomarkers) and glial fibrillary acidic protein (GFAP, a biomarker for astrocytic activation) correlate with the development of CIPN in the adjuvant setting of early breast cancer. Using ultrasensitive single molecule array technology, serum levels of NfL, GFAP, and tau were measured before and every 3 weeks in 10 women receiving adjuvant EC (epirubicin 90 mg/m² and cyclophosphamide 600 mg/m²) every 3 weeks × 3, followed by weekly paclitaxel 80 mg/m² × 9-12 weeks after surgery due to early breast cancer. CIPN was graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) and the questionnaire EORTC QLQ CIPN-20. Serum levels of GFAP increased successively during cycles of EC. NfL increased instead in response to the treatment of paclitaxel. NfL and GFAP continued to rise throughout exposure of cumulatively higher doses of paclitaxel and were reduced 3 months after the end of chemotherapy. Serums levels of tau were marginally affected by exposure to chemotherapy. Women with worse symptoms of CIPN had higher concentrations of NfL than women with mild symptoms of CIPN. NfL and GFAP are promising biomarkers to identify women at risk of developing CIPN. Larger prospective studies are now needed.

Induction chemotherapy backbone in frail patients with advanced NSCLC treated with chemotherapy plus pembrolizumab: a single institution retrospective audit of dose intensities from modified regimens.

Guidelines historically recommended mono-chemotherapy for the 1st line treatment of elderly patients with non-small cell lung cancer (NSCLC) and poor performance status (PS). Nowadays, there is no clear indication whether chemo-immunotherapy (chemo-IO) combinations can be effectively delivered in this population. We collected induction chemotherapy data in consecutive patients with advanced NSCLC treated with carboplatin-based chemotherapy regimens plus pembrolizumab, to compute the received dose intensity (RDI) from standard regimens or patient-tailored regimens modified due to age, comorbidities and PS. Comorbidities were stratified according to the comorbidity-polypharmacy score (CPS). The established cut-off of ≥85% for RDI was used to define adequate delivery. 116 pts were treated from Feb-20 to July-23, of whom 96 and 20 with non-squamous and squamous NSCLC, treated with carboplatin-pemetrexed or carboplatin-paclitaxel doublets plus pembrolizumab, respectively. The majority of patients were aged ≥ 70 years (52.6%), the median CPS was 5, with 58.6% having a CPS ≥5, whilst 47.4%, 44.8% and 7.8% had an Eastern Cooperative Oncology Group (ECOG) - PS of 0, 1 and 2, respectively. PD-L1 TPS were <1% in 31.9% and 1-49% in 65.4%. Overall, 47.4% received a priori modified regimens due to poor PS, age, or comorbidities. Among patients with non-squamous NSCLC, median received doses of carboplatin and pemetrexed were 1.37 AUC/week and 138.8 mg/m2/week, with RDIs of 86% and 75% (p < 0.01) for patients treated with standard or modified regimens, respectively. Of note, the RDI was 57.9% among patients with ECOG-PS 2. However, patients treated with modified regimens experienced similar toxicities as those treated with standard regimens, despite being older (p < 0.01), with higher PS (p < 0.01) and more comorbid (p = 0.03). Patients treated with modified regimens achieved a shorter survival (7.1 vs 13.9 months), which is comparable to IO-free historical controls. Among patients with squamous NSCLC, 90% received modified regimens upfront, with median received doses of carboplatin and paclitaxel of 1.19 AUC/week and 40 mg/m2/week, and an overall RDI of 73.5%. Although regimen modifications ensure a safe administration of chemotherapy plus pembrolizumab in frail patients, the RDI seems to be subtherapeutic, especially in those with squamous histology. Dedicated trials are needed to implement combination strategies in this population.

Phase III randomized trial comparing palliative systemic therapy to best supportive care in advanced esophageal/GEJ cancer.

No study has unequivocally proven that chemotherapy prolongs overall survival (OS) in advanced esophageal cancer. We conducted a Phase III randomized study in first-line advanced unresectable/metastatic esophageal/GEJ cancer. Patients aged 18-70 years, with performance status 0-2, were randomized to best supportive care (BSC) alone, or BSC with weekly paclitaxel 80 mg/m2. BSC comprised, as indicated, education, counselling, radiation, stenting, feeding tube placement, nutritional supplementation, medications like analgesics, and referral to a support group and palliative care. The primary endpoint was OS; secondary endpoints included progression free survival (PFS), response, toxicity, and QoL. Between May 2016-December 2020, we recruited 281 patients: 143 to chemotherapy and 138 to BSC. Histopathology was squamous in 269 (95.7%) patients. Median number of paclitaxel doses was 12 (IQR, 7-23). Median OS was 4.2 months (95% CI, 3.42-5.32) in BSC, and 9.2 months (95% CI, 8.02-10.48) in chemotherapy; HR, 0.49 (95% CI, 0.39-0.64); p < .001. As compared to BSC, chemotherapy increased response (2.9% to 39%), median PFS (2.1 to 4.2 months), 1-year OS (11% to 32%), 2-year OS (0 to 9%), median dysphagia-free survival (2.9 to 14.8 months), and global and esophagus-specific QoL, without significantly increasing all-grade or grade ≥3 toxicities. Using ESMO clinical benefit scale and ASCO Value Framework, palliative chemotherapy scored as having "substantial value." Our study provides the first level 1 evidence that chemotherapy prolongs survival in advanced esophageal/GEJ carcinoma. BSC alone is no longer appropriate. Weekly paclitaxel is an attractive option, especially in LMICs with limited access to immunotherapy.

Re-positioning of low dose paclitaxel against depressive-like behavior and neuroinflammation induced by lipopolysaccharide in rats: Crosstalk between NLRP3/caspase-1/IL-1β and Sphk1/S1P/ NF-κB signaling pathways

AimsDepression is a potentially fatal illness affecting millions of individuals worldwide, across all age groups. Neuroinflammation is a key factor in depression development. Paclitaxel (PXL), a well-known chemotherapeutic agent has been used as therapy for several types of cancer. This study aims to evaluate the ameliorative effect of low-dose PXL against lipopolysaccharide (LPS)-induced depression in rats. Materials and methodsAdult male Sprague-Dawley rats were administrated a single dose of LPS (5 mg/kg, i.p.); 2 h later, rats received PXL (0.3 mg/kg, i.p. three times/week) for one week. Key findingsLow-dose PXL alleviated LPS-induced depressive-like behavior in rats as evidenced by significantly improving behavioral changes in both forced swim test (FST) and open field test (OFT), successfully mitigated depletion of monoamines (serotonin, norepinephrine, and dopamine), in addition to markedly decreasing lipid peroxidation with antioxidant levels elevation in brain tissues. Low-dose PXL substantially decreased inflammation triggered by LPS in brain tissue via repressing the expression of NLRP3 and its downstream markers level, caspase-1 and IL-1β jointly with a corresponding decrease in proinflammatory cytokine levels (TNF-α). Furthermore, low-dose PXL remarkably down-regulated Sphk1/S1P signaling pathway. Concurrent with these biochemical findings, there was a noticeable improvement in the brain tissue's histological changes. SignificanceThese findings prove the role of low-dose PXL in treatment of LPS-induced neuroinflammation and depressive-like behavior through their anti-depressant, antioxidant and anti-inflammatory actions. The suggested molecular mechanism may entail focusing the interconnection among Sphk1/S1P, and NLRP3/caspase-1/IL-1β signaling pathways. Hence PXL could be used as a novel treatment against LPS-induced depression.

Definitive chemoradiotherapy with paclitaxel for locally advanced esophageal squamous cell carcinoma in older patients (PARADISE-1): a phase I trial

BackgroundIn older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients.MethodsEnrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m2 or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT).ResultsWe enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m2 groups, respectively. All adverse events, except death in the 60 mg/m2 group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores.ConclusionsThe recommended PTX dose with concomitant radiation was determined to be 50 mg/m2 weekly. Phase II trials at this dose are underway.

Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.

Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC. In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo. Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses. RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.

TNBC response to paclitaxel phenocopies interferon response which reveals cell cycle-associated resistance mechanisms.

Paclitaxel is a standard of care neoadjuvant therapy for patients with triple negative breast cancer (TNBC); however, it shows limited benefit for locally advanced or metastatic disease. Here we used a coordinated experimental-computational approach to explore the influence of paclitaxel on the cellular and molecular responses of TNBC cells. We found that escalating doses of paclitaxel resulted in multinucleation, promotion of senescence, and initiation of DNA damage induced apoptosis. Single-cell RNA sequencing (scRNA-seq) of TNBC cells after paclitaxel treatment revealed upregulation of innate immune programs canonically associated with interferon response and downregulation of cell cycle progression programs. Systematic exploration of transcriptional responses to paclitaxel and cancer-associated microenvironmental factors revealed common gene programs induced by paclitaxel, IFNB, and IFNG. Transcription factor (TF) enrichment analysis identified 13 TFs that were both enriched based on activity of downstream targets and also significantly upregulated after paclitaxel treatment. Functional assessment with siRNA knockdown confirmed that the TFs FOSL1, NFE2L2 and ELF3 mediate cellular proliferation and also regulate nuclear structure. We further explored the influence of these TFs on paclitaxel-induced cell cycle behavior via live cell imaging, which revealed altered progression rates through G1, S/G2 and M phases. We found that ELF3 knockdown synergized with paclitaxel treatment to lock cells in a G1 state and prevent cell cycle progression. Analysis of publicly available breast cancer patient data showed that high ELF3 expression was associated with poor prognosis and enrichment programs associated with cell cycle progression. Together these analyses disentangle the diverse aspects of paclitaxel response and identify ELF3 upregulation as a putative biomarker of paclitaxel resistance in TNBC.

Natural products to enhance anti-tumor effects of trastuzumab and paclitaxel on the SKBR3, which is human breast cancer cell line.

e13051 Background: Neoadjuvant chemotherapy (ChT) with targeted therapy is the standard treatment for human epidermal growth factor 2 (HER2)- positive breast cancer (BC). In this context, Trastuzumab (Tz) and ChT significantly improved the pathological complete response (pCR) rate. Tz and Paclitaxel (PTX) combination therapy is also one of the neoadjuvant treatments used in HER2+BC, and despite the effectiveness of this treatment, there is a critical need for innovative approaches and further research that will improve the neoadjuvant response rate. Addressing this, the NaturaProDB tool presents a novel avenue for predicting in silico natural non-toxic compounds with potential anti-cancer properties. Our study aims to investigate synergistic effect of natural products proposed by this database on theurapeutic action of Tz and PTX on BC. Methods: The NaturaProDB database was searched using the ‘Target Cancer’ option in order to identify those natural products with anti-BC potential and the corresponding experimentally verified target genes. Using this database, Biochanin A (BCA) and Delphinidin (Dp) were selected as natural compounds because they both commonly inhibit the MAPK signaling pathway. We used the HER2+ SKBR3 cell line to determine IC20, IC30 and IC50 doses for BCA, Dp, Tz, and PTX through MTT assay. Notably, all experiments were done after 72 hrs treatment of all compounds. Further, various combinations within different concentrations of natural products and Tz and PTX were tested to define additive anti-proliferative effects on SKBR3 cell line. Results: We first defined two natural products with drug-like properties, BCA and Dp, which have anti-proliferative effect on BC. Treatment of SKBR3 with increasing concentrations of BCA and Dp caused dose-dependent proliferation inhibition and IC50 dose of compounds were defined as 42,70uM and 40,70uM, respectively. In addition, IC20 dose of Tz was 2,8µM, while IC30 dose of PTX was 2,3nM.Then, we showed that combinations of increasing doses of Dp (from 30µM to 90 µM) with IC20 Tz caused significant dose-dependent cell death compared to the control group (p&lt;0.0001). And the combinations of increasing doses of BCA (from 45µM to 360 µM) with IC20 Tz led similar significant results (p&lt;0.0001). Conclusions: Herein, it is shown that combining natural compounds (Dp, BCA) with conventional treatments (PTX,Tz) predicted for the SKBR3 cell line can enhance the inhibitory effect on cell proliferation. This study is one of the rare first cell line studies in which the synergistic effect of BCA and Dp, which are natural compounds selected using the NaturaProDB database, were combined with ChT and Tz to show their synergistic effect, and these findings indicate that synergistic combination treatments acting through different pathways (MAPK signaling pathway) can be used in the treatment of HER2+ and TN BC. It opens avenues for further research.

A phase I/II study of intraperitoneal (IP) paclitaxel (PTX) in patients with metastatic appendiceal adenocarcinoma.

TPS4215 Background: Appendiceal cancer is a rare, orphan disease, that is unfortunately becoming more common. There is growing data from our lab and others that particular subtypes of AA do not respond to CRC chemotherapy. The use of CRC chemotherapy to treat patients with AA tragically results in many patients enduring side effects from chemotherapy that is ineffective; however, this practice will likely continue unless AA-specific treatments are developed. The Shen lab has recently tested IP paclitaxel (PTX) in orthotopic PDX models of AA. After allowing implanted tumors to grow for four weeks to simulate diffuse peritoneal metastases, baseline MRI was performed and mice were randomly assigned to treatment groups of four mice and intraperitoneally (IP) administered increasing doses of PTX. Marked response was seen in all three models at dose of 25 mg/kg IP weekly, with a near complete response in model AAPDX-10. This dose given IP was well tolerated by the mice, notably this dose exceeds the know lethal IV PTX dose. Methods: The Phase I component of this study will be a prospective single-arm intervention trial giving IP PTX every 2 weeks for a total of 5 doses with primary endpoint of safety and tolerability (MTD determination). Each patient will have an initial diagnostic laparoscopy where PCI score will be calculated and IP catheter placed, dx lap is repeated at the end of study after 5 biweekly doses. For the Phase 1 portion of the trial a Bayesian Optimal Interval (BOIN) approach will be used to determine recommended phase 2 dose (RP2D). All patients treated at that dose or higher will be included in Phase 2 component of the study where the primary objective is response, determined by change in PCI score. With 15 patients Based on historical data, we estimate that the proportion of patients who will demonstrate an objective response without going on trial is 0.05, i.e., the null hypothesis is a 0.05 ORR. Treatment is expected to raise this proportion to 30%. Using an exact binomial test with one-sided type I error of 0.05, we will reject the null if at least 3 patients achieve response. This test has power of 87%. Secondary end points include pathologic, biochemical and radiographic response, PFS, OS, and the influence of KRAS/GNAS/TP53 mutation on response. PK measurements will also be performed during the Phase 1 portion of the trial to determine the degree to which the IP injected PTX enters the blood stream. Patients will be followed for up to 1 year. Adverse events (AEs) will be captured and graded using the National Cancer Institute’s (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) v. 5.0 (or latest version) and will include the event term, grading, duration and attribution. Attribution to the study agent or intervention will be determined by the PI, Co-PI or treating physician. Clinical trial information: NCT06207305 . [Table: see text]

Paclitaxel hypersensitivity reaction (HSR) rate: Titrated versus non-titrated infusions among gynecologic oncology patients.

e23240 Background: Paclitaxel is a common chemotherapeutic agent used for treatment of various cancers, and is associated with hypersensitivity reactions (HSR). An HSR is mostly likely to occur during first or second infusions. Prior studies have suggested that performing Paclitaxel infusions without titration may be safe for the majority of patients, but increase in number of HSRs. At our institution, Paclitaxel infusions without titration was implemented around April 2023. Our aim was to evaluate the rate of HSR in Paclitaxel infusions without titration among gynecologic patients. Methods: This was a retrospective review of hypersensitivity reactions in patients receiving Paclitaxel at the titrated rate versus the full rate from May 2022 through November 2023. Patients had newly diagnosed gynecologic cancers (ovarian, uterine, cervical), who presented for their first or second Paclitaxel infusions. Patients previously treated with Paclitaxel for any reason were excluded. Results: 145 patients were included in this study, each with one (4%) or two (96%) infusions, for a total of 281 infusion visits. There were 176 infusions with Paclitaxel dose titration (62.6%), and 105 infusions at full rate (37.4%). HSRs occurred in 19% of the full rate Paclitaxel infusions and in 11.9% of titrated Paclitaxel infusions (OR 1.74 [95% CI 0.89 – 3.38]; p = 0.10). When stratifying by first or second infusion, the HSR rate increased significantly for full rate second infusion to 22.4%, compared to 8.3% for titrated infusions (OR 3.18 [95% CI 1.14 – 8.86]; p = 0.026). Grade 3 or greater infusion reactions occurred in 45% of full rate infusion and in 14.2% of titrated infusion reactions (OR 4.91 [95% CI 1.08 – 22.14]; p = 0.0038). There was no difference in timing of hypersensitivity reactions in relation to initiation of Paclitaxel infusion. Conclusions: Overall, the HSR rate was higher with full rate first infusions, and significantly increased during the second infusion with full rate Paclitaxel. Additionally, Grade 3 infusion reactions were more likely to be seen with full rate infusions. There is significant variability in Paclitaxel infusion; further studies to determine optimal infusion rates are warranted.

Beta-Adrenergic Signaling Induces Arrhythmias and Cardiac Dysfunction in Paclitaxel-Treated Mice

In the past two decades, chemotherapy-related cardiac dysfunction (CRCD) has emerged as a dangerous complication in cancer survivors. Despite recent advancements, the mechanisms underlying the development and progression of CRCD remain poorly understood. Paclitaxel (PTX), an antimicrotubular agent, is known to produce dysrhythmia in 29% of patients when used as monotherapy. Since cardiac stress via β-adrenergic signaling is known to exacerbate arrhythmias, here we examine the action of a single isoproterenol (ISO) injection in wild-type mice treated with low and high therapeutic doses of PTX (8mg/kg and 12.5mg/kg, respectively). Male mice were treated with 4 intraperitoneal (IP) injections of PTX or vehicle (1:1:4 ratio of ethanol: Kolliphor: saline) per week for 4 weeks and a remote telemetry device was surgically implanted. Following treatment, mice were challenged with one IP injection of 5mg/kg ISO and ambulatory electrocardiography was performed. Over the course of PTX treatment, low- and high-dose PTX-treated mice displayed significant weight loss compared to vehicle-treated mice (-9.65% vs -0.52%, p=0.0018 and -10.99% vs 0.93%, p=0.0016, respectively). While low-dose PTX-treated mice did not show statistically significant differences in heart weight to body weight ratio compared to vehicle-treated mice (5.56mg/g vs 5.16mg/g, p=0.14), high-dose PTX-treated males showed increased cardiac hypertrophy compared to vehicle-treated mice (5.20mg/g vs 4.89mg/g, p=0.081). Prior to ISO challenge, there was no difference in arrhythmia severity between groups (0.0 vs 0.0, p=0.45 and 0.0 vs 1.0, p=0.99). One hour following ISO challenge, all mice treated with either a low or high dose of PTX showed higher arrhythmia severity than vehicle-treated mice (4.0 vs 2.5, p=0.0087 and 4.0 vs 3.0, p=0.0079, respectively). Additionally, low and high-dose PTX-treated mice experienced more atrioventricular block than vehicle-treated mice in the first hour following ISO challenge (9.17 vs 0.67, p=0.01 and 4.0 vs 1.0, p=0.06, respectively). After 24-hours, differences in arrhythmia severity returned to baseline (0.5 vs 1.0, p=0.99 and 1.0 vs 0.0, p=0.4). Our data indicates that chronic treatment of male mice with therapeutic levels of PTX predisposes to cardiac stress-induced atrial arrhythmias. This finding might have important implications for the treatment of CRCD. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.