Paclitaxel Injection Research Articles

Regional lymph node changes on breast MRI in patients with early-stage breast cancer receiving neoadjuvant chemo-immunotherapy

Abstract Purpose Establishing breast MRI imaging patterns associated with neoadjuvant immunotherapy is needed to monitor response. We analyzed serial breast MRIs in patients receiving neoadjuvant chemo-immunotherapy on the I-SPY2 clinical trial. Methods Patients with stage 2–3 HER2-negative breast cancer were randomized to weekly paclitaxel (control), weekly paclitaxel and pembrolizumab, or weekly paclitaxel, pembrolizumab and intra-tumoral injection of SD-101, a TLR9 agonist. All patients received AC. Regional lymph nodes were retrospectively evaluated on breast MRI at baseline, 3, 12 and 20 weeks by a single blinded radiologist. MRIs were assessed for development of new regional lymphadenopathy, or increase in the longest diameter or cortical thickness of the largest abnormal regional lymph node. Results Between 12/2015 and 4/2021, a total of 43 patients enrolled in the control (n = 16) and paclitaxel + pembrolizumab ± SD-101 (n = 27) arms. 12 of 27 patients (44.4%) receiving chemo-immunotherapy experienced increased lymphadenopathy within the first 12 weeks compared to 1 of 16 patients (6.3%) in the control group (p = 0.014). Most patients with increased lymphadenopathy were in the SD101/pembro arm (n = 10, p = 0.002). Increased lymphadenopathy was observed despite concomitant decrease in breast tumor size at all time points. 11 of 12 patients with increased lymphadenopathy had pathologically negative nodes at surgery. There was no association between lymphadenopathy and lower residual cancer burden or immune-related toxicity. Conclusions The combination of neoadjuvant paclitaxel and pembrolizumab ± SD101 intratumoral injection was associated with early increases in regional lymphadenopathy on MRI despite decreased breast tumor size. Increased lymphadenopathy was not associated with node positive disease at surgery.

Unusual Scenario: Ipsilateral Pelvic Lymph Node Metastasis in High- Grade Serous Ovarian Carcinoma without Peritoneal Extension - A Case Report

Introduction:: Ovarian cancers are the third most common gynecological cancers worldwide with serous carcinomas being the most common subtype with 90% of them as high-grade carcinomas. Case Presentation:: In the present case report a 60 years postmenopausal, nulliparous woman presented with complaints of bleeding per vaginum for 1-2 months with a left-sided solid-cystic ovarian mass of size 4x5 cm and ipsilateral enlarged external iliac and obturator lymph nodes which were diagnosed on histopathological examination as high-grade serous ovarian carcinoma (HGSOCs) with ipsilateral pelvic lymph node metastasis in presence of intact ovarian capsule and no metastatic deposits over the uterus, contralateral ovary and fallopian tubes, omentum, or any other gross peritoneal deposits. There was coexisting non-atypical endometrial hyperplasia. The patient was managed successfully with staging laparotomy with modified radical hysterectomy, and bilateral pelvic lymphadenectomy followed by six cycles of adjuvant chemotherapy with Paclitaxel and Carboplatin injections. Conclusion:: Patients with HGSOCs can have varied presentations with unusual involvement of lymph nodes in the absence of peritoneal spread. Hence, the clinician must be aware of these unusual presentations for the successful management of such cases.

KLS-13019, a Novel Structural Analogue of Cannabidiol and GPR55 Receptor Antagonist, Prevents and Reverses Chemotherapy-Induced Peripheral Neuropathy in Rats.

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7-10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain. SIGNIFICANCE STATEMENT: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect of cancer treatment with no known cure. The GPR55 antagonist KLS-13019 represents a novel class of drug for this condition that is a potent, durable inhibitor of allodynia associated with CIPN in rats in both prevention and reversal-dosing paradigms. This novel therapeutic approach addresses a critical area of unmet medical need.

Development of a Two-Dimensional Liquid Chromatography Online Deproteinization Method for Determining Paclitaxel-Related Substances in a Paclitaxel Injection (Albumin-Bound)

To determine the paclitaxel-related substances in a paclitaxel injection (albumin-bound), it is necessary to remove human blood albumin from the sample via solid-phase extraction and subsequently perform high-performance liquid chromatography analysis. The pre-processing operation is complicated, the duration of analysis is long, and much human power and material resources are needed in the sample testing process. Thus, the purpose of this study was to develop a quick two-dimensional liquid chromatography method that requires less consumables and possesses high sensitivity. Samples were directly injected into one-dimensional solid-phase extraction columns to remove human blood albumin. Paclitaxel and its related substances in the solid-phase extraction columns were then eluted into two-dimensional analytical columns through valve switching technology. The sample pretreatment step can be omitted in this method, which allows for the analysis of paclitaxel and its related substances to be completed more quickly, within only 15 min, under the developed two-dimensional elution conditions. The established method had good linearity (R2 = 0.9994), limit of detection (0.25 μg·mL−1), limit of quantification (0.5 μg·mL−1), precision (RSD = 0.5%), and accuracy (102.53–107.97%).

Duloxetine to prevent neuropathy in breast cancer patients under paclitaxel chemotherapy (a double-blind randomized trial).

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the major side effects and main reasons for affecting quality of life and dose reduction or even discontinuation of treatment in breast cancer patients. One of the most widely prescribed chemotherapies is the "taxanes." Considering that duloxetine has been used in treating neuropathies in recent years, this study aimed to investigate its effectiveness in preventing taxane-related neuropathy. This is a randomized controlled trial on 47 patients: 24 received a placebo and 23 received duloxetine at 30mg daily in the first week following the injection of paclitaxel and 60mg during the second week in each chemotherapy cycle. Patients objective (nerve conduction velocity (NCV) values) and subjective symptoms (visual analog scale including; neuropathy, paresthesia, pain, cold sensitivity, and numbness), the grades of the patients' neuropathy (calculated according to Common Terminology Criteria for Adverse Events (CTCAE) v.5), and the presence of complications, before and after each chemotherapy cycle, were recorded. The placebo group experienced significantly higher occurrences of new neuropathy (8/23 in duloxetine vs 16/24 in placebo, P = 0.029) in NCV by tibial nerve latency (- 0.28% vs 19.87%, P = 0.006), tibial amplitude (4.40% vs - 10.88%, P = 0.049), and median nerve latency (8.72% vs 31.16%, P = 0.039); administration of duloxetine significantly reduced the scores of neuropathies (P < 0.001), pain (P = 0.027), during chemotherapy, and 6weeks later; however, no significant effect was observed on paresthesia, numbness, cold sensitivity, and other NCV measurements. Paclitaxel can cause neuropathy, lasting for a long time. Our study showed duloxetine is potentially an effective medication that can prevent subjective and objective neuropathy.

Clinical Efficacy of Ultrasonic Medicinal Penetration in the Removal of Blood Stasis and Alleviation of Zhuyu Juanbi Formula in the Treatment of Peripheral Neuropathy Induced by Paclitaxel

Objective: To observe the clinical efficacy and differences of the Zhuyu Juanbi formula delivered through ultrasound at Zusanli on patients with chemotherapy-induced peripheral neuropathy (CIPN) due to paclitaxel injection. Methods: A total of 72 breast cancer patients with CIPN were randomly divided into two groups. The treatment group (36 cases) was treated with oral methylcobalamin plus ultrasonic medicine permeating Zhuyu Juanbi formulae, while the control group (36 cases) was treated with oral methylcobalamin alone. Following two 2 cycles of continuous treatment, the efficacy of peripheral neurotoxicity, TCM syndrome score, FACT/GOG-Ntx score, total neuropathy score, and safety indicators of gynecological cancer patients were observed in the two groups. Result: In the treatment of CIPN, the addition of ultrasonic medicine permeating Zhuyu Juanbi formulae was more effective than oral methylcobalamin alone in reducing peripheral neurotoxicity and improving the quality of life of patients. The difference between the two groups was statistically significant (P &lt; 0.05), and ultrasound drug penetration Zhuyu Juanbi formulae significantly reduced the FACT/GOG-Ntx score and TNS score in the treatment group. In terms of drug safety, it rarely caused adverse reactions such as grade 3 and 4 leukopenia, and the safety profile was therefore good. Conclusion: The combination of ultrasonic medicine permeating Zhuyu Juanbi formulae and methylcobalamin has been demonstrated to be an effective treatment for peripheral neurotoxicity in patients with PIPN. It has been shown to significantly improve the clinical symptoms of PIPN patients, improve the quality of life of patients, and have a good safety profile.

Paclitaxel oral solution versus paclitaxel injection as second-line therapy in advanced gastric cancer: A randomized, open-label, non-inferiority phase 3 trial.

4051 Background: Paclitaxel injection (paclitaxel IV) is category 1 preferred regimen in the second-line therapy of gastric cancer. Safer and more convenient paclitaxel oral solution (Liporaxel), the world’s first oral formulation, has been initially approved in Korea for treatment of gastric cancer. This study aimed to determine non-inferiority in efficacy and safety profile of paclitaxel oral solution versus paclitaxel IV, as monotherapy in larger population with unresectable locally advanced, recurrent or metastatic gastric cancer in China. Methods: This is a randomized, open-label, non-inferiority phase 3 trial conducted at 53 centers in China. Patients with unresectable or recurrent or metastatic gastric cancer progressed after fluoropyrimidine- or fluoropyrimidine plus platinum-based first-line therapy were randomly assigned 1:1 (stratified by gastrectomy, ECOG PS and prior chemotherapy) to receive oral paclitaxel (200mg/m2 twice daily on days 1, 8, 15 every 4 weeks) or paclitaxel IV (175mg/m2 on day 1 every 3 weeks). The co-primary endpoints were blind independent review committee (BIRC)-assessed progression-free survival (PFS) and overall survival (OS), with non-inferiority margin of hazard ratio (HR) of 1.18 and 1.16 in statistical comparison, respectively. Results: From April 22, 2019, to January 31, 2022 (data cut-off), 536 patients were randomized to oral paclitaxel (n=268) or paclitaxel IV (n=268), with median follow-up of 13.4 vs. 12.6 months, respectively. The PFS showed non-inferiority of oral paclitaxel to paclitaxel IV with median BIRC-assessed PFS 3.02 months (95% confidence interval [CI]: 2.69, 3.71) in oral paclitaxel vs. 2.89 months (95% CI: 2.53, 3.48) in paclitaxel IV (HR 0.894, 95% CI: 0.719, 1.112, p=0.311). The OS (cutoff on February 15, 2023) showed superiority of oral paclitaxel over paclitaxel IV with median OS 9.13 months (95% CI: 7.72, 10.97) in oral paclitaxel vs. 6.54 months (95% CI: 5.75, 7.26) in paclitaxel IV (HR 0.770, 95.5% CI: 0.635, 0.934, p=0.006). For the treatment-related adverse events (TRAEs), oral paclitaxel decreased neuropathy incidence (22.3% vs. 38.7% all grade) and no hypersensitivity occurred in oral paclitaxel without premedication. The most common ≥Grade 3 TRAEs were neutrophil count decreased (47.9% in oral paclitaxel vs. 54.5% in paclitaxel IV), white blood cell count decreased (41.5% vs. 35.3%) and anemia (16.6% vs. 10.9%). Grade 5 TRAEs were at low with comparable incidences (four [1.5%] vs. three [1.1%]). Conclusions: The study showed statistical non-inferiority of paclitaxel oral solution in PFS and statistically significant and clinically meaningful improvement in OS as compared to paclitaxel IV, with clinically manageable safety profile, supporting paclitaxel oral solution as second-line treatment option for patients with gastric cancer. Clinical trial information: CTR20190050.

Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice.

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H1 receptor antagonist, but also acted as a selective antagonist of 5HTR2A. In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model wasestablished. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A. We conclude that spinal 5HTR2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR2A-specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR2A/c-FOS pathway. Our findings have supported that spinal 5HTR2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.

Efficacy and safety of the combination of paclitaxel, cisplatin and bevacizumab for the treatment of non-small cell lung cancer

Purpose: To investigate the efficacy and safety of the combined use of paclitaxel, cisplatin, and bevacizumab for the treatment of non-small cell lung cancer (NSCLC). Methods: 98 NSCLC patients who received therapy at Hainan Hospital of Traditional Chinese Medicine, Changsha, China from January 2018 to December 2022 were retrospectively analyzed. The 45 patients who received paclitaxel and cisplatin injections were enrolled in a control group while 53 patients who received additional chemotherapy with bevacizumab injection were enrolled in a study group. Levels of vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) were compared before and after treatment. Furthermore, the efficacy and incidence of adverse reactions were evaluated and compared between the two groups. Results: There was no significant inter-group difference in VEGF and bFGF levels (p &gt; 0.05) before treatment. There was a significant reduction in VEGF and bFGF levels in the study group compared to control group (p &lt; 0.05). The study group showed a significantly higher total remission rate compared to control group (p &lt; 0.05). Furthermore, there was no significant difference in the incidence of adverse reactions between the two groups (p &gt; 0.05). Also, age, tumor, node, metastasis (TNM) stage, metastasis, and smoking history are risk factors that influence patient prognosis. Conclusion: Combination of paclitaxel, cisplatin and bevacizumab demonstrates significant efficacy in the treatment of NSCLC. The combination lowers VEGF and bFGF levels without worsening adverse reactions. Future large population studies would be required to obtain a more detailed and comprehensive outcome on this combination in NSCLC.

Mitomycin C in the treatment of early triple-negative locally advanced BRCA-associated breast cancer

Rationale. BRCA1 associated triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. At the same time, carcinomas that develop in carriers of BRCA1 mutations are characterized by extremely high sensitivity to DNA-damaging chemotherapy. Mitomycin C alone or in combination with platinum agents has already demonstrated promising results in the treatment of BRCA-associated ovarian cancer (OC) and metastatic breast cancer. In this article, we present the results of a retrospective study aimed at comparing standard neoadjuvant chemotherapy regimens (NACT) with mitomycin-based regimens for primary locally advanced BRCA1-associated TNBC.The aim of the study is to determine the effectiveness of the combination of mitomycin and platinum compounds during neoadjuvant therapy in patients with primary locally advanced BRCA1 – associated TNBC.Materials and methods. The study included 89 patients diagnosed with primary locally advanced BRCA1-associated TNBC. Patients were divided into three groups depending on the therapy: 1) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel (n = 48) (AC + T), 2) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel and carboplatin (n = 27) (AC + TCbP), 3) mitomycin C plus platinum followed by 12 weekly injections of paclitaxel (n = 14) (MR + T). Pathological complete response (pCR) rates were compared.Results. The pCR rate in the MP+T group was 10/14 (71%). In patients with BRCA1-associated breast cancer who received AC + T and AC + TCbP regimens as NACT, the pCR rate was 17/48 (35%) and 19/27 (70%), respectively. The difference in pCR rate between mitomycin-containing therapy and the standard AC + T regimen was statistically significant (p = 0.03); the frequency of regressions was comparable to the frequency in the AC + TCbP group. During the 20-month follow-up period, no relapses were observed in the MR + T group. Relapses were more frequent in the AC + T group compared with the AC + TCbP group (16/48 (33%) vs 1/27 (4%), p = 0.003, Fisher’s exact test). The toxicity profile of the mitomycin-containing regimen included hematologic adverse events, the most common of which were anemia and leukopenia. Compared to standard regimens, nausea was significantly less pronounced. No patients reported alopecia with this regimen.Conclusions. The addition of mitomycin C to neoadjuvant therapy for BRCA1-associated TNBC may be a promising treatment option for this category of patients and merits further study.

Abstract PO4-13-06: Effect of neoadjuvant dose-dense dose-intense chemotherapy timing infusion on complete histological response rate among patients with triple negative breast cancer (SIMCLOCK)

Abstract Background: Triple-negative breast cancers (TNBC) exhibit major responses to dose-dense, dose-intense (DD-DI) neoadjuvant chemotherapy (NAC) (1). Although chronomodulated chemotherapy has shown efficacy and reducing toxicity in other cancers, there are no data in breast cancers (2). We report here a series of patients with TNBC treated with DD-DI NAC and analyzed the association between chemotherapy time infusion and pathological complete response rate (pCR) and residual tumor burden (RCB). Patients and Methods: Patients with non-metastatic TNBC treated at breast cancer disease center, St Louis hospital (Paris, France), with neoadjuvant DD-DI cyclophosphamide (1200 mg/m2 d1) – epirubicin (75 mg/m2 d1) q2w (SIM regimen) followed by 12 injections of paclitaxel (80 mg/m2) qw were included. Starting time of each chemotherapy infusion were systematically recorded. Primary endpoint was pCR defined as no residual invasive tumor in breast and in lymph nodes. Patients were dichotomized into “morning” and “afternoon” infusion groups, independently for “SIM” and “paclitaxel” regimens. Two timing cut-offs were defined according to: 1) median time of all infusions 2) cut-off maximizing morning/afternoon differences of RCB. Statistical differences between the two patient groups were assessed for metabolic response at 2 courses at Pet scan (breast delta SUVmax), RCB class (0-1 vs 2-3), pCR, dose reduction rate and 24-months event-free survival (24-months EFS). Results: Between January 2018 and January 2022, 93 patients were included. Median age was 51 (28-74). Majority of SIM administrations occurred between 12:00 and 15:00 and Paclitaxel administrations between 11:20 and 14:30. Median follow-up was 32.4 months. Main characteristics between “morning group” or “afternoon” groups in the SIM or paclitaxel were similar. pCR was obtained in 48.9% of the whole population. Regardless of cut-offs defined, no difference in pCR rate was observed. Similarly, no differences were observed between morning and afternoon groups in terms of either metabolic response, dose reduction rate or 24-months EFS (table 1). Conclusion: Time of DD-DI NAC infusion is not associated with differences in pCR rate nor in RCB, toxicity and EFS in patients with early TNBC. As immunotherapy combined with NAC is a new standard in TNBC, the impact of immunotherapy infusion time combined with NAC is under evaluation.

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.

Paclitaxel-Associated Mechanical Sensitivity and Neuroinflammation Are Sex-, Time-, and Site-Specific and Prevented through Cannabigerol Administration in C57Bl/6 Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients. One identified mechanism underlying CIPN is neuroinflammation. Most of this research has been conducted in only male or female rodent models, making direct comparisons regarding the role of sex differences in the neuroimmune underpinnings of CIPN limited. Moreover, most measurements have focused on the dorsal root ganglia (DRG) and/or spinal cord, while relatively few studies have been aimed at characterizing neuroinflammation in the brain, for example the periaqueductal grey (PAG). The overall goals of the present study were to determine (1) paclitaxel-associated changes in markers of inflammation in the PAG and DRG in male and female C57Bl6 mice and (2) determine the effect of prophylactic administration of an anti-inflammatory cannabinoid, cannabigerol (CBG). In Experiment 1, male and female mice were treated with paclitaxel (8-32 mg/kg/injection, Days 1, 3, 5, and 7) and mechanical sensitivity was measured using Von Frey filaments on Day 7 (Cohort 1) and Day 14 (Cohort 2). Cohorts were euthanized on Day 8 or 15, respectively, and DRG and PAG were harvested for qPCR analysis of the gene expression of markers of pain and inflammation Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. In Experiment 2, male and female mice were treated with vehicle or 10 mg/kg CBG i.p. 30 min prior to each paclitaxel injection. Mechanical sensitivity was measured on Day 14. Mice were euthanized on Day 15, and PAG were harvested for qPCR analysis of the gene expression of Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. Paclitaxel produced a transient increase in potency to produce mechanical sensitivity in male versus female mice. Regarding neuroinflammation, more gene expression changes were apparent earlier in the DRG and at a later time point in the PAG. Also, more changes were observed in females in the PAG than males. Overall, sex differences were observed for most markers at both time points and regions. Importantly, in both the DRG and PAG, most increases in markers of neuroinflammation and pain occurred at paclitaxel doses higher than those associated with significant changes in the mechanical threshold. Two analytes that demonstrated the most compelling sexual dimorphism and that changed more in males were Cxcl9 and Ccl2, and Tlr4 in females. Lastly, prophylactic administration of CBG protected the male and female mice from increased mechanical sensitivity and female mice from neuroinflammation in the PAG. Future studies are warranted to explore how these sex differences may shed light on the mechanisms of CIPN and how non-psychoactive cannabinoids such as CBG may engage these targets to prevent or attenuate the effects of paclitaxel and other chemotherapeutic agents on the nervous system.

Abstract LB023: A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics

Abstract The therapeutic efficacy of a novel oral Paclitaxel formulation was evaluated and compared in Balb/c nude mice bearing PDX NSCLC, gastric cancer, liver cancer, breast cancer, and ovarian cancer treated with Abraxane, Taxol, Lenvatinib and Sorafenib. Therapeutic parameters including tumor volume, tumor growth inhibition (TGI), and treatment-to-control ratio (T/C) were compared among different treatment groups. The drug tolerance, cytotoxicity and safety profile of the oral Paclitaxel formulations were evaluated in Balb/c nude mice and beagle dogs. The tumor distribution of Paclitaxel in NCI-N87 gastric cancer-bearing mice after administration of oral Paclitaxel formulation and Paclitaxel Injection was investigated. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Albumin-bound Paclitaxel for Injectable Suspension at 30 mg/Kg and Paclitaxel Injection at 15 mg/Kg for NCI-N87 gastric cancer-bearing mice, while the same 100 mg/Kg dose demonstrated noninferior therapeutic efficacy to Abraxane and significant better therapeutic efficacy than Taxol in Hs467T gastric cancer-bearing mice. The oral Paclitaxel formulation administrated at 180 mg/Kg demonstrated noninferior therapeutic efficacy compared with Lenvatinib at 40 mg/Kg, and significant better therapeutic efficacy than Sorafenib at 30 mg/Kg for Hep G2 liver cancer-bearing mice, while the oral paclitaxel at 180 mg/Kg showed inferior therapeutic efficacy than Lenvatinib at 30 mg/Kg but noninferior therapeutic efficacy to Sorafenib at 30 mg/Kg for Huh-7 liver cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Abraxane for Injectable Suspension at 30 mg/Kg and Taxol at 15 mg/Kg for NCI-H358 NSCLC-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane for Injectable Suspension at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for MDA-MB-231 breast cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for SK-OV-3 ovarian cancer-bearing mice. The gastric tumor distribution of Paclitaxel between 6-24 hour was similar after oral and intravenous administration. The Maximum Tolerated Dose (MTD) of the oral Paclitaxel was determined to be ≥ 200 mg/Kg in mice and ≥ 8.0 mg/Kg in beagle dogs when dosing at Q3DX3Weeks, there were no significant body weight losses, tissue damages and animal death observed during the long-term safety assessment study. The oral Paclitaxel formulation demonstrated better or noninferior therapeutic efficacy in five different PDX tumor-bearing mice compared with standard treatment drugs, good safety and low cytotoxicity at high doses in long-term safety and toxicity studies were observed in both mice and beagle dogs. The oral Paclitaxel formulation showed promising therapeutic potential for various cancer treatment and conducting “chemotherapy at home” with lower medical costs. Citation Format: Hui Yu Huang, Richard Jun Huang. A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB023.

Sonic hedgehog restrains the ubiquitin-dependent degradation of SP1 to inhibit neuronal/glial senescence associated phenotypes in chemotherapy-induced peripheral neuropathy via the TRIM25-CXCL13 axis

IntroductionChemotherapy-induced peripheral neuropathy (CIPN) is a common complication that affects an increasing number of cancer survivors. However, the current treatment options for CIPN are limited. Paclitaxel (PTX) is a widely used chemotherapeutic drug that induces senescence in cancer cells. While previous studies have demonstrated that Sonic hedgehog (Shh) can counteract cellular dysfunction during aging, its role in CIPN remains unknown. ObjectivesHerein, the aim of this study was to investigate whether Shh activation could inhibits neuronal/glial senescence and alleviates CIPN. MethodsWe treated ND7/23 neuronal cells and RSC96 Schwann cells with two selective Shh activators (purmorphamine [PUR] and smoothened agonist [SAG]) in the presence of PTX. Additionally, we utilized a CIPN mouse model induced by PTX injection. To assess cellular senescence, we performed a senescence-associated β-galactosidase (SA-β-gal) assay, measured reactive oxygen species (ROS) levels, and examined the expression of P16, P21, and γH2AX. To understand the underlying mechanisms, we conducted ubiquitin assays, LC-MS/MS, H&E staining, and assessed protein expression through Western blotting and immunofluorescence staining. ResultsIn vitro, we observed that Shh activation significantly alleviated the senescence-related decline in multiple functions included SA-β-gal activity, expression of P16 and P21, cell viability, and ROS accumulation in DRG sensory neurons and Schwann cells after PTX exposure. Furthermore, our in vivo experiments demonstrated that Shh activation significantly reduced axonal degeneration, demyelination, and improved nerve conduction. Mechanistically, we discovered that PTX reduced the protein level of SP1, which was ubiquitinated by the E3 ligase TRIM25 at the lysine 694 (K694), leading to increased CXCL13 expression, and we found that Shh activation inhibited PTX-induced neuronal/glial senescence and CIPN through the TRIM25-SP1-CXCL13 axis. ConclusionThese findings provide evidence for the role of PTX-induced senescence in DRG sensory neurons and Schwann cells, suggesting that Shh could be a potential therapeutic target for CIPN.

Abstract A048: Enhancing the immune response in locally advanced pancreatic cancer (LAPC) with intratumoral endoscopic ultrasound-guided fine needle injection of large surface area microparticle paclitaxel (LSAM-PTX)

Abstract Background: The complex tumor microenvironment (TME) of locally advanced pancreatic cancer (LAPC) is resistant to immune effector cell infiltration and drug bioavailability, limiting the effectiveness of current systemic therapies. Large Surface Area Microparticle Paclitaxel (LSAM-PTX) was developed for intratumoral (IT) injection to solid tumors to provide a paclitaxel depot at therapeutic levels with a prolonged residence time. We previously reported enhanced tumor kill in LAPC subjects receiving two monthly IT LSAM-PTX injections and demonstrated immunomodulation in the TME. Multiplex immunofluorescence (mIF) performed on pre-treatment biopsy tissue and post-LSAM-PTX resection showed increases in densities of effector T cells and NK cells and decreases in myeloid derived suppressor cells (MDSC). To further evaluate immunomodulation following IT LSAM-PTX therapy, blood samples were obtained for immunophenotyping using flow cytometry (NCT03077685). Methods: Pretreatment samples were obtained from subjects administered four injections (n=14) and at visits throughout the treatment period and up to six months post first LSAM-PTX injection. Flow cytometric analysis was performed using three panels to evaluate absolute counts and percentages of up to 45 immunophenotypes. Results: Treatment with four IT injections of LSAM-PTX (ongoing median overall survival = 12.6 months; follow-up = 12.2 months) was associated with increases in peripheral lymphocytes during the treatment period. An enhancement of immune subsets associated with anti-tumor effector functions was found, including significant increases in circulating CD3+ and CD4+ cells (p=0.0012 and 0.002 respectively) which is consistent with the 4-fold increase in CD4+helper T cells detected in the TME of resected tissue. A significant increase in LAG3+CD8+ T cells was seen following treatment initiation (p=0.048) marking early T cell activation. Increases in circulating CD8+ T cells, B cells, and NK cells were seen during the treatment period corresponding with effector T cells and NK cells increases (4.8-fold increase in density) within the TME. Six months following treatment initiation there was a significant decrease in circulating Treg cells (p=0.0183) and a decrease in peripheral immunosuppressive G-MDSC, consistent with the reduction in MDSC measured in the TME. Notably, systemic taxane toxicities, including immunosuppression, were not reported following IT LSAM-PTX and negligible amounts of paclitaxel were found in blood samples. Conclusion: Immunophenotyping of blood from LAPC subjects treated with IT LSAM-PTX demonstrates immunomodulation to a phenotype associated with anti-tumor immune effects, including favorable immunosurveillance, and is consistent with changes found in the TME in resected tissues. Immunosuppressive cell types typically associated with poor outcomes were reduced at six months. Anti-tumor immunomodulation without immunosuppression suggests that IT LSAM-PTX may be amenable to combination with immunotherapy. Citation Format: Andrew E. Hendifar, Max M. Wattenberg, Holly A. Maulhardt, Alyson M. Marin, Alison E. Wendt, Shelagh J. Verco, Gere S. diZerega. Enhancing the immune response in locally advanced pancreatic cancer (LAPC) with intratumoral endoscopic ultrasound-guided fine needle injection of large surface area microparticle paclitaxel (LSAM-PTX) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A048.

Intracystic injection of large surface area microparticle paclitaxel for chemoablation of intraductal papillary mucinous neoplasms: Insights from an expanded access protocol

AimsA novel large surface area microparticle paclitaxel (LSAM-PTX) has unique properties of long retention in cystic spaces while maintaining high drug concentration. We prospectively evaluated the safety and response of EUS-guided fine needle injection (EUS-FNI) of LSAM-PTX to chemoablate branch duct (BD)-IPMNs. MethodsSubjects diagnosed with BD-IPMNs exhibiting at least one worrisome criteria and considered non-surgical were enrolled in a multicenter clinical trial (NCT03188991) and subsequently included in an Expanded Access Protocol (EAP) where they received EUS-FNI of LSAM-PTX (15 mg/mL). ResultsSix BD-IPMNs measuring (mean ± SD) 3.18 ± 0.76 cm in diameter among 5 subjects (mean age: 66 years) were treated by EUS-FNI of LSAM-PTX. A mean of 4 doses of LSAM-PTX (mean dose/cyst: 73 ± 31 mg) were administered, and subjects were followed for up to 32 months. The mean volume reduction/cyst ranged from 42 to 89% (9.58 ± 5.1 ml to 2.2 ± 1.1 ml (p = 0.016)). The mean surface area reduction ranged from 31 to 83% (21.9 ± 8.7 cm2 to 5.7 ± 2.5 cm2 (p = 0.009)). Higher dosing-frequency of EUS-FNI of LSAM-PTX significantly correlated with a reduction in cyst volume (R2 = 0.87, p = 0.03) and surface area (R2 = 0.83, p = 0.04). Comparing pre- and post-ablation samples, molecular analysis of the cyst fluid revealed a loss of IPMN-associated mutations in 5 cases (83.3%), while reemergence was observed in 1 case and persistence in 1 case. Intracystic changes (fibrosis/calcification) were observed in 83.3% (n = 5). One subject developed mild acute pancreatitis (1 of 22 EUS-FNIs of LSAM-PTX). ConclusionIn this EAP, EUS-FNI of LSAM-PTX into BD-IPMNs was safe and resulted in volume and surface area reduction, morphological changes, and loss of pathogenic mutations.

DEVELOPMENT OF PATHOLOGICAL CHANGES IN THE ORAL CAVITY ORGANS OF ANIMALS UNDER CONDITIONS OF POLYNEUROPATHIES OF DIFFERENT GENESIS

The aim of our research is to study the effect of polyneuropathy of different genesis on the development of pathological changes in the large salivary glands and periodontal tissues of animals. Methods. The study was conducted on 62 laboratory rats of both sexes. Toxic polyneuropathy was induced by paclitaxel injection, experimental type 1 diabetes mellitus was modeled by streptozocin injection, and alcoholic polyneuropathy was induced by chronic administration of increasing concentrations of ethanol. The development of polyneuropathy was confirmed by a change in the the pain sensitivity threshold (PST) using the Randall-Selitto tensoalgometric method. In the homogenate of oral cavity organs, total proteolytic and total antitryptic activity, catalase activity, content of TBARS, average mass molecules, oxidatively modified proteins, fucose and glycosaminoglycans (GAG), and amylase activity were determined. The level of total, protein-bound and non-protein sulfhydryl groups, activity of superoxide dismutase, glutathione peroxidase, glutathione transferase, glutathione reductase; content of reduced and oxidized glutathione, diene conjugates and Schiff bases were determined in blood serum. Results. We established the increasing of PST in animals that were simulated neuropathies of different genesis. All three types of polyneuropathies are accompanied by the development of carbonyl-oxidative stress in the soft tissues of the periodontium and large salivary glands of rats, which is evidenced by a probable increase in the content of oxidatively modified proteins and the content of TBARS, as well as average mass molecules compared to these indicators in intact animals . Under the conditions of modeling all three polyneuropathies, the protein-synthetic activity in the large salivary glands is suppressed, as evidenced by a decrease in the activity of α-amylase. Under conditions of experimental diabetic and toxic neuropathy in the salivary glands of animals, changes in the proteinase-inhibitor balance of the compensatory type are observed. We found that polyneuropathies of different genesis cause increased catabolism of biopolymers of the extracellular matrix of the periodontal connective tissue of rats, which confirms the increase in the content of GAG and fucose compared to these indicators in control animals. Conclusions. Under conditions of diabetic, toxic and alcoholic neuropathy, the amylolytic activity of the large salivary glands of animals is suppressed, the balance of the pro- and antioxidant system changes. When modeling peripheral polyneuropathy in animals by administration of paclitaxel, streptozocin, and ethanol, the development of periodontal syndrome is observed, the leading pathogenetic mechanisms of which are increased catabolism of connective tissue glycoconjugates and the development of oxidative stress and proteinase-inhibitor imbalance.

Metformin inhibits paclitaxel-induced mechanical allodynia by activating opioidergic pathways and reducing cytokines production in the dorsal root ganglia and thalamus

It has been shown that AMP-activated protein kinase (AMPK) is involved in the nociceptive processing. This observation has prompted us to investigate the effects of the AMPK activator metformin on the paclitaxel-induced mechanical allodynia, a well-established model of neuropathic pain. Mechanical allodynia was induced by four intraperitoneal (i.p) injections of paclitaxel (2 mg/kg.day) in mice. Metformin was administered per os (p.o.). Naltrexoneandglibenclamide were used to investigate mechanisms mediating metformin activity. Concentrations of cytokines in the dorsal root ganglia (DRG) and thalamus were determined. After a single p.o. administration, the two highest doses of metformin (500 and 1000 mg/kg) attenuated the mechanical allodynia. This response was attenuated by all doses of metformin (250, 500 and 1000 mg/kg) when two administrations, 2 h apart, were carried out. Naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, p.o.), attenuated metformin activity. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and CXCL-1 in the DRG were increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentrations of TNF-α, IL-1β and CXCL-1 in the DRG. Concentration of IL-6, but not TNF-α, in the thalamus was increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentration of IL-6 in the thalamus. In summary, metformin exhibits activity in the model of neuropathic pain induced by paclitaxel. This activity may be mediated by activation of opioidergic pathways and reduced production of TNF-α, IL-1β and CXCL-1 in the DRG and IL-6 in the thalamus.

Auraptene Alleviates Paclitaxel-induced Neuropathy in Mice

Background Paclitaxel administration causes peripheral neuropathy. Auraptene is a natural bioactive monoterpene with anti-inflammatory and anti-neuropathic effects that is widely used. Objectives We aimed to study auraptene effects on paclitaxel-induced neuropathy. Materials and Methods This study was comprised of two steps of evaluation of the preventive and treatment effects of auraptene in mice. In the first step, mice were randomly allocated into three groups of six animals, including the negative control (NEG CTL): animals injected with paclitaxel (PTX) together with normal saline, PTX (paclitaxel 2 mg/kg given on days 1, 3, 5, and 7), and PREVENTION: PTX + auraptene 100 mg/kg on days 1, 3, 5, and 7. In the second step, animals were allocated into six groups of six: NEG CTL (normal saline), PTX (paclitaxel 10 mg/kg given on days 1, 3, 5, and 7), PTX AUR (PTX + auraptene 50, 75, and 100 mg/kg), and a positive control (PTX-treated animals receiving imipramine 10 mg/kg). Intraperitoneal injection of PTX 2 mg/kg on days 1, 3, 5, and 7 was used in order to induce neuropathy. In both steps of the study, a hot plate test was done on day 7 in order to determine the response to heat. After the scarification of animals, the interleukin-6 (IL-6) level in the sciatic nerve was assessed by western blotting. Results In the preventive group, auraptene could reduce hyperalgesia significantly. In the treatment step, the AUR 100 mg/kg compared to NEG CTL groups had significantly increased heat latency. The expression of IL-6 protein in the sciatic nerve was remarkably decreased in both the preventive and treatment groups compared to NEG CTL. Conclusion Taken together, our results confirmed that AUR could decrease paclitaxel-induced hyperalgesia in mice and IL-6 protein content in sciatic nerve samples.