Priming with oncolytic adenovirus followed by anti-PD-1 and paclitaxel treatment leads to improved anti-cancer efficacy in the 3D TNBC model.

Triple-negative breast cancer (TNBC) is considered one of the most incurable malignancies due to its clinical characteristics, including high invasiveness, high metastatic potential, proneness to relapse, and poor prognosis. Therefore, it remains a critical unmet medical need. On the other hand, poor delivery efficiency continues to reduce the efficacy of anti-cancer therapeutics developed against solid tumours using various strategies, such as genetically engineered oncolytic vectors used as nanocarriers. The study was designed to evaluate the anti-tumour efficacy of a novel combinatorial therapy based on oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with an anti-PD-1 (pembrolizumab) and paclitaxel (PTX). Here, we first tested the antineoplastic effect in two-dimensional (2D) and three-dimensional (3D) breast cancer models in MDA-MB-231, MDA-MB-468 and MCF-7 cells. Then, to further evaluate the efficacy of combinatorial therapy, including immunological aspects, we established a three-dimensional (3D) co-culture model based on MDA-MB-231 cells with peripheral blood mononuclear cells (PBMCs) to create an integrated system that more closely mimics the complexity of the tumour microenvironment and interacts with the immune system. Treatment with OV as a priming agent, followed by pembrolizumab and then paclitaxel, was the most effective in reducing the tumour volume in TNBC co-cultured spheroids. Further, T-cell phenotyping analyses revealed significantly increased infiltration of CD8+, CD4+ T and Tregs cells. Moreover, the observed anti-tumour effects positively correlated with the level of CD4+ T cell infiltrates, suggesting the development of anti-cancer immunity. Our study demonstrated that combining different immunotherapeutic agents (virus, pembrolizumab) with PTX reduced the tumour volume of the TNBC co-cultured spheroids compared to relevant controls. Importantly, sequential administration of the investigational agents (priming with the vector) further enhanced the anti-cancer efficacy in 3D culture over other groups tested. Taken together, these results support further evaluation of the virus in combination with anti-PD-1 and PTX for the treatment of triple-negative breast cancer patients. Importantly, further studies with in vivo models should be conducted to better understand the translational aspects of tested therapy.

Trackable Liposomes for In Vivo Delivery Tracing toward Personalized Medicine Care under NIR Light on Skin Tumor.

We report an near-infrared (NIR)-trackable and therapeutic liposome with skin tumor specificity. Liposomes with a hydrodynamic diameter of ∼20 nm are tracked under the vein visualization imaging system in the presence of loaded paclitaxel and NIR-active agents. The ability to track liposome nanocarriers is recorded on the tissue-mimicking phantom model and in vivo mouse veins after intravenous administration. The trackable liposome delivery provides in vitro and in vivo photothermal heat (∼40 °C) for NIR-light-triggered area-specific chemotherapeutic release. This approach can be linked with a real-time vein-imaging system to track and apply area-specific local heat, which hitchhikes liposomes from the vein and finally releases them at the tumor site. We conducted studies on mice skin tumors that indicated the disappearance of tumors visibly and histologically (H&E stains). The ability of nanocarriers to monitor after administration is crucial for improving the effectiveness and specificity of cancer therapy, which could be achieved in the trackable delivery system.

Evaluating the clinical efficacy and safety of concurrent chemoradiotherapy with cisplatin and nab-paclitaxel in postoperative early-stage cervical cancer.

OBJECTIVE: A preclinical study showed that nab-paclitaxel acted as a radiosensitizer and improved tumor radiotherapy in a supra-additive manner. In this study, we aimed to evaluate the clinical efficacy and safety of concurrent chemoradiotherapy (CCRT) with cisplatin and nab-paclitaxel in postoperative early-stage cervical cancer with an unfavorable prognosis. METHODS: Eligible patients with stage IB1-IIA2 (FIGO 2009) cervical carcinoma were recruited retrospectively between August 2018 to May 2021. Patients in both the cisplatin and nab-paclitaxel groups received postoperative radiotherapy and weekly intravenous cisplatin 40 mg/m2 or nab-paclitaxel 100 mg concurrently. An analysis of overall survival, progression-free survival, and adverse reactions was conducted. RESULTS: A total of 105 early-stage cervical cancer patients were included into our study. The median follow-up time was 38.7 months. The 3-year overall survival and progression-free survival in both group was similar. The cycles of chemotherapy in the cisplatin group were less than those in the nab-paclitaxel group (4.5 vs. 5.0; p = 0.001). Patients in the cisplatin group had a significantly higher frequency of hematological adverse events than patients in the nab-paclitaxel group (P < 0.05). Patients in the cisplatin group had a significantly higher frequency of grade 3-4 leukopenia (46.1% vs. 18.9%; P = 0.03), grade 1-2 thrombocytopenia (32.7% vs. 9.5%; P = 0.014) than patients in the nab-paclitaxel group. Gastrointestinal reactions, such as vomiting, nausea, and anorexia were significantly reduced in the nab-paclitaxel group compared with those in the cisplatin group. Regarding the effects on alopecia, the incidence rate of the nab-paclitaxel group was higher than that of the cisplatin group (P = 0.001). There were no differences between the groups in terms of other adverse reactions. CONCLUSION: The results of this study indicate that nab-paclitaxel-based concurrent radiotherapy is tolerable and effective, and can be considered an alternative to cisplatin chemotherapy.

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin: a systematic review and meta-analysis.

BACKGROUND: Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy. METHODS: Embase, MEDLINE, Web of Science and Cochrane were searched for articles studying the use of repeated administration of palliative intraperitoneal chemotherapy in patients with gastric cancer and peritoneal metastases, published up to January 2024. The primary outcome was overall survival. RESULTS: Twenty-three studies were included, representing a total of 999 patients. The pooled median overall survival was 14.5 months. The pooled hazard ratio of the two RCTs using intraperitoneal paclitaxel and docetaxel favoured the intraperitoneal chemotherapy arm. The median overall survival of intraperitoneal paclitaxel, intraperitoneal docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.4 months, 13.2 months and 9.0 months. All treatment methods had a relatively safe toxicity profile. Conversion surgery after completion of intraperitoneal therapy was performed in 16% of the patients. CONCLUSIONS: Repeated intraperitoneal chemotherapy, regardless of method of administration, is safe for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a subset of patients.

[Safety of patients undergoing radical resection combined with paclitaxel-based hyperthermic intraperitoneal chemotherapy for locally advanced gastric cancer].

Objective: To analyze the safety of paclitaxel-based, hyperthermic, intraperitoneal perfusion chemotherapy (HIPEC) after radical resection of locally advanced gastric cancer. Methods: This was a retrospective cohort study of clinicopathological data of 467 patients with locally advanced gastric adenocarcinoma who had been admitted to the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University between July 2019 and April 2021. Among these patients, 151 had undergone radical resection combined with post-operative paclitaxel-based HIPEC (surgery+HIPEC group) and 316 radical resection alone (surgery group). The adverse perioperative events in study patients were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) published by the U.S. Department of Health and Human Services. Subgroup analysis was performed on patients in the surgery+HIPEC group according to the number of times HIPEC was administered and the incidence of adverse events was compared between subgroups using the χ2 test. Independent risk factors for paclitaxel-based HIPEC-associated adverse events were identified by applying a logistic model. Results: In the surgery+HIPEC group, there were 113 (74.8%) male and 38 (25.2%) female patients of median age 64 (55, 68) years, 18 (11.9%), 79 (52.3%), and 54 (35.8%) of whom had undergone one, two, and three paclitaxel-based HIPEC treatments, respectively, after surgery. The median maximum tumor diameter was 5.0 (3.6, 6.5) cm. In the surgery group, there were 244 (77.2%) male and 72 (22.8%) female patients of median age 63 (54, 68) and the median maximum tumor diameter was 4.0 (3.0, 5.5) cm. In the surgery+HIPEC group, 112 patients (74.2%) had 198 Grade 2 or higher adverse perioperative events, postoperative hypoalbuminemia being the commonest (85 cases, 56.3%), followed by postoperative anemia (50 cases, 33.1%). Compared with the surgery group, the incidences of postoperative hypoalbuminemia (56.3% [85/151] vs. 37.7% [119/316], χ2=14.420, P<0.001), anemia (33.1% [50/151] vs. 22.5% [71/316], χ2=6.030, P=0.014), abdominal pain [7.3% [11/151] vs. 1.6% [5/316], χ2=10.042, P=0.002) and abdominal distension (5.3% [8/151] vs. 1.3% [4/316], χ2=5.123, P=0.024) were all significantly higher in the surgery+HIPEC group. Analysis of the three HIPEC subgroups revealed significant differences in the incidences of postoperative hypoalbuminemia (13/18 vs. 67.1% [53/79] vs. 35.2% [19/54], χ2=12.955, P<0.001) and pulmonary infection (6/18 vs. 6.3% [5/79] vs. 1.9% [1/54], χ2=13.232, P<0.001) between them. Univariate analysis identified body mass index, Borrmann's type and number of HIPEC treatments as associated with perioperative adverse events in the surgery+HIPEC group (P<0.05). However, according to multifactorial logistic analysis, the above factors were not independent risk factors for perioperative adverse events in the surgery+HIPEC group (P>0.05). Conclusions: Paclitaxel-based HIPEC after radical resection significantly increases the risk of postoperative hypoalbuminemia, anemia, abdominal pain, and abdominal distension in patients who have undergone excision of locally advanced gastric cancer. However, increasing the frequency of HIPEC treatments did not significantly increase the risk of paclitaxel-based HIPEC-related adverse events. Moreover, univariate and multivariate analysis did not identify any independent risk factors for paclitaxel HIPEC-related adverse events.

Unveiling the potential of ursolic acid modified hyaluronate nanoparticles for combination drug therapy in triple negative breast cancer.

Triple negative breast cancer (TNBC) represents the most aggressive and heterogenous disease, and combination therapy holds promising potential. Here, an enzyme-responsive polymeric prodrug with self-assembly properties was synthesized for targeted co-delivery of paclitaxel (PTX) and ursolic acid (UA). Hyaluronic acid (HA) was conjugated with UA, yielding an amphiphilic prodrug with 13.85 mol% UA and a CMC of 32.3 µg/mL. The HA-UA conjugate exhibited ∼14 % and 47 % hydrolysis at pH 7.4 and in tumor cell lysate. HA-UA/PTX NPs exhibited a spherical structure with 173 nm particle size, and 0.15 PDI. The nanoparticles showed high drug loading (11.58 %) and entrapment efficiency (76.87 %) of PTX. Release experiments revealed accelerated drug release (∼78 %) in the presence of hyaluronidase enzyme. Cellular uptake in MDA-MB-231 cells showed enhanced uptake of HA-UA/PTX NPs through CD44 receptor-mediated endocytosis. In vitro, HA-UA/PTX NPs exhibited higher cytotoxicity, apoptosis, and mitochondrial depolarization compared to PTX alone. In vivo, HA-UA/PTX NPs demonstrated improved pharmacokinetic properties, with 2.18, 2.40, and 2.35-fold higher AUC, t1/2, and MRT compared to free PTX. Notably, HA-UA/PTX NPs exhibited superior antitumor efficacy with a 90 % tumor inhibition rate in 4T1 tumor model and low systemic toxicity, showcasing their significant potential as carriers for TNBC combination therapy.

Randomized Trial Comparing a Stent-Avoiding With a Stent-Preferred Strategy in Complex Femoropopliteal Lesions.

BACKGROUND: Limited comparative data exist on different interventional strategies for endovascular revascularization of complex femoropopliteal interventions. OBJECTIVES: In this study, the authors aimed to compare a stent-avoiding (SA) vs a stent-preferred (SP) strategy, promoting optimal lesion preparation and the use of drug-eluting technologies in both arms. METHODS: Within a prospective, multicenter, pilot study, 120 patients with symptomatic complex femoropopliteal lesions (Rutherford classification 2-4, mean lesion length 187.7 ± 78.3 mm, 79.2% total occlusions) were randomly assigned in a 1:1 fashion to endovascular treatment with either paclitaxel-coated balloons or polymer-coated, paclitaxel-eluting stents. Lesion preparation including the use of devices for plaque modification and/or removal was at the operators' discretion in both treatment arms. RESULTS: In the SA group, lesion preparation was more frequently performed (71.7% SA [43/60] vs 51.7% [31/60] SP; P = 0.038) with a high provisional stenting rate (48.3% [29/60]). At the 12-month follow-up, primary patency was 78.2% (43/55) in the SA group and 78.6% (44/56) in the SP group (P = 1.0; relative risk: 0.995; 95% CI: 0.818-1.210). Freedom from major adverse events was determined in 93.1% (54/58) in the SA group and in 94.9% (56/59) in the SP group (P = 0.717; relative risk: 0.981; 95% CI: 0.895-1.075), with all adverse events attributable to clinically driven target lesion revascularization. CONCLUSIONS: Both endovascular strategies promoting lesion preparation before the use of drug-eluting devices suggest promising efficacy and safety results in complex femoropopliteal procedures with a high proportion of total occlusions through 12 months. Ongoing follow-up will show whether different results emerge over time. (Best Endovascular Strategy for Complex Lesions of the Superficial Femoral Artery [BEST-SFA]; NCT03776799).

Efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in the treatment of locally advanced cervical cancer.

BACKGROUND: Evaluate the efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in treating locally advanced cervical cancer (LACC). METHODS: Retrospective data was collected from LACC patients who were treated at our institution. These patients were categorized into three groups: the single-agent cisplatin (DDP) chemoradiotherapy group, the paclitaxel plus cisplatin (TP) chemoradiotherapy group, and the nanoparticle albumin-bound (nab-) paclitaxel combined with cisplatin (nPP) chemoradiotherapy group. The primary endpoints were overall survival (OS) and progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR) and incidence of adverse events (AEs). RESULTS: A total of 124 patients were enrolled (32 in the DDP group, 41 in the TP group, and 51 in the nPP group). There were differences in OS (P = 0.041, HR 0.527, 95% CI 0.314-0.884) and PFS (P = 0.003, HR 0.517, 95% CI 0.343-0.779) between the three groups. Notably, the 2-year OS rate was significantly higher in the nPP group compared to the DDP group (92.2% vs. 85.4%, P = 0.012). The 2-year PFS rates showed a marked increase in the TP group (78.0% vs. 59.4%, P = 0.048) and the nPP group (88.2% vs. 59.4%, P = 0.001) relative to the DPP group, with multiple comparisons indicating that the 2-year PFS rate was significantly superior in the nPP group versus the DDP group (88.2% vs. 59.4%, P = 0.001). Moreover, the ORR was also significantly higher in the nPP group than in the DDP group (P = 0.013); and no statistically significant differences were found in the incidence of AEs among the groups (P > 0.05). CONCLUSIONS: In LACC treatment, the two cisplatin-based doublet chemotherapy regimens are associated with better outcomes, with the nab-paclitaxel plus cisplatin regimen showing better efficacy than the paclitaxel plus cisplatin regimen. Furthermore, the AEs associated with these regimens were deemed tolerable. These findings could provide a reference for the clinical treatment of LACC. However, further prospective studies are needed to verify it.

Predictors of late lumen enlargement after drug-coated balloon angioplasty for de novo coronary lesions.

BACKGROUND: Late lumen enlargement (LLE) - a positive remodelling phenomenon - after drug-coated balloon (DCB) angioplasty for stable coronary disease contributes to a lower restenosis rate. However, lesion characteristics promoting LLE remain unclear. AIMS: This study aimed to investigate predictive lesion characteristics for LLE using serial optical frequency domain imaging (OFDI) following DCB angioplasty for de novo coronary artery lesions. METHODS: This retrospective, single-centre observational study included patients with angina pectoris who underwent paclitaxel-coated balloon angioplasty without stenting under OFDI guidance as well as follow-up OFDI. OFDI endpoints were lumen volume, plaque phenotype, and procedure-associated dissection. LLE was defined as a ≥10% increase in the lumen volume of the treated lesion at follow-up. RESULTS: Between August 2016 and December 2019, among patients with successful DCB angioplasty, 108 lesions (83 patients) had available follow-up imaging after a median of 6.1 months. LLE was detected in 44 (40.7%) lesions. Fibrous/fibrocalcific and layered plaques had significantly larger lumen volumes at follow-up than immediately after the index procedure, whereas lipid plaques exhibited no significant difference. Medial dissection with an arc >90° revealed an increased lumen volume. Multivariate analysis showed that layered plaques (odds ratio [OR] 8.73, 95% confidence interval [CI]: 1.92-39.7; p=0.005) and medial dissection with an arc >90° (OR 4.65, 95% CI: 1.63-13.3; p=0.004) were independent LLE predictors. CONCLUSIONS: Layered plaques and extensive medial dissection after DCB angioplasty were associated with higher LLE occurrence in de novo coronary lesions. These findings may be clinically applicable to DCB therapeutic strategies based on plaque features.

Exosomal miR-493 suppresses MAD2L1 and induces chemoresistance to intraperitoneal paclitaxel therapy in gastric cancer patients with peritoneal metastasis.

Intraperitoneal (IP) chemotherapy with paclitaxel (PTX) for gastric cancer (GC) with peritoneal metastasis (PM) is considered a promising treatment approach, however, there are no useful biomarkers to predict the efficacy of IP therapy. We examined the association between intra-peritoneal exosomes, particularly exosomal micro-RNAs (exo-miRNAs), and IP-chemo sensitivity. MKN45 cells that were cultured with intra-peritoneal exosomes from patients who did not respond to IP therapy with PTX (IPnon-respond group) exhibited resistance to PTX compared with exosomes from responding patients (IPrespond group) (p = 0.002). A comprehensive search for exo-miRNAs indicated that miR-493 was significantly up-regulated in exosomes from the IPnon-respond group compared with those collected from the IPrespond group. The expression of miR-493 in PTX-resistant MKN45 cells (MKN45PTX-res) was higher compared with that in MKN45. In addition, MKN45PTX-res cells exhibited lower MAD2L1 gene and protein expression compared with MKN45. Finally, miR-493 enhancement by transfection of miR-493 mimics significantly down-regulated MAD2L1 expression in MKN45 cells and reduced PTX sensitivity. Our results suggest that intra-peritoneal exo-miR-493 is involved in chemoresistance to PTX by downregulating MAD2L1 in GC with PM. Exo-miR-493 may be a biomarker for chemoresistance and prognosis of GC patients with PM and may also be a promising therapeutic target.

Fabrication of PEGylated SPIONs-Loaded Niosome for Codelivery of Paclitaxel and Trastuzumab for Breast Cancer Treatment: In Vivo Study.

There is a growing appeal for engineering drug delivery systems for controlled and local drug delivery. Conjugation of antibodies on the nanocarriers for targeted chemotherapeutic drugs has always been one of the main techniques. This work aims to develop a polycaprolactone/chitosan electrospun mat incorporated with paclitaxel/Fe3O4-loaded niosomes (SPNs) decorated with trastuzumab (TbNs) for cancer therapy. SPNs and TbNs were analyzed by DLS, zeta potential, scanning electron microscopy, transmission electron microscopy, and Fourier transform infrared spectroscopy. Fabricated mats with distinct concentrations of TbNs were classified into four groups (G0 (0), G1 (1), G2 (2.5), and G3 (5%)) and were studied physicochemically, mechanically, and biologically. Paclitaxel release was also studied for 7 days under an alternative magnetic field (AMF). The optimized mat was nominated for an in vivo study to evaluate its tumor growth inhibition. Based on the results, the TbNs had a spherical core and shell morphology with a smooth surface. The zeta potential and the mean size of TbNs were equal to -14.7 mV and 221 nm. TbNs did not affect the morphology and quality of nanofibers, but in general, the presence of TbNs increased the elastic modulus, water uptake, and degradation. Regarding the release study, AMF showed a significant increase in accelerating paclitaxel release from mats, and most releases belonged to the mat with 5% of TbNs. Results from the in vivo study showed the effective and synergistic effects of AMF on drug release and significant tumor growth inhibition. To summarize, the proposed nanocarrier under AMF can be a good candidate for cancer therapy.

Hydrophilic Coating Microstructure Mediates Acute Drug Transfer in Drug-Coated Balloon Therapy.

Drug-coated balloon (DCB) therapy is a promising endovascular treatment for obstructive arterial disease. The goal of DCB therapy is restoration of lumen patency in a stenotic vessel, whereby balloon deployment both mechanically compresses the offending lesion and locally delivers an antiproliferative drug, most commonly paclitaxel (PTX) or derivative compounds, to the arterial wall. Favorable long-term outcomes of DCB therapy thus require predictable and adequate PTX delivery, a process facilitated by coating excipients that promotes rapid drug transfer during the inflation period. While a variety of excipients have been considered in DCB design, there is a lack of understanding about the coating-specific biophysical determinants of essential device function, namely, acute drug transfer. We consider two hydrophilic excipients for PTX delivery, urea (UR) and poly(ethylene glycol) (PEG), and examine how compositional and preparational variables in the balloon surface spray-coating process impact resultant coating microstructure and in turn acute PTX transfer to the arterial wall. Specifically, we use scanning electron image analyses to quantify how coating microstructure is altered by excipient solid content and balloon-to-nozzle spray distance during the coating procedure and correlate obtained microstructural descriptors of coating aggregation to the efficiency of acute PTX transfer in a one-dimensional ex vivo model of DCB deployment. Experimental results suggest that despite the qualitatively different coating surface microstructures and apparent PTX transfer mechanisms exhibited with these excipients, the drug delivery efficiency is generally enhanced by coating aggregation on the balloon surface. We illustrate this microstructure-function relation with a finite element-based computational model of DCB deployment, which along with our experimental findings suggests a general design principle to increase drug delivery efficiency across a broad range of DCB designs.

Investigation of efficacy of two different chemotherapy protocols used in neoadjuvant chemotherapy in clinical stages II-IV canine malignant mammary tumours.

The first aim of this study is to demonstrate the clinical efficacy and reliability of two different neoadjuvant chemotherapy (NAC) protocols consisting of doxorubicin/cyclophosphamide (AC) and paclitaxel in dogs with clinical stages II-IV canine malignant mammary tumours (CMTs). Secondly, to determine the Luminal A, Luminal B, HER2-positive and triple-negative molecular subtypes and their value in predicting clinical response to NAC in biopsy samples, and thirdly, to reveal the changes in Ki-67, human epidermal growth factor receptor type 2 (HER2), oestrogen receptor (ER), and progesterone receptor (PgR) expression levels induced by NAC. Thirty dogs with clinical stages II-IV CMTs (T1-3N0-1M0) according to the modified TNM system were included in the study. Dogs in group-1 (n = 15) AC combination and dogs in group-2 (n = 15) were administered paclitaxel. Partial response (PR) was the most common clinical response in both treatment groups (66.66% and 86.66%, respectively). There was no difference between the groups regarding clinical response parameters (p = .001). The rate of treatment responders was higher than the rate of non-responders in both groups (p < .001). The adverse effects observed in both groups were mostly limited to grades 1 and 2 and all were easy to manage. The most frequently detected molecular subtype was Luminal A (59.25%). Complete response (CR) was achieved in 33.33% of dogs with triple-negative CMT in the AC group and 14.29% of the Luminal A subtype in the paclitaxel group. Alterations in Ki-67, HER2, ER, and PgR expressions after chemotherapy were not statistically significant (p > .05). As a result, we have shown that these neoadjuvant chemotherapy protocols are effective and safe alternative treatment options for CMTs.

Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505.

BACKGROUND: Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC. METHODS: SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models. RESULTS: Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11-0.93) and the hospital's city size (small: OR, 0.24 [95% CI, 0.07-0.80] and large: OR, 0.28 [95% CI, 0.10-0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3-5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32-0.95). CONCLUSIONS: Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.

mRNA-responsive two-in-one nanodrug for enhanced anti-tumor chemo-gene therapy.

The combination of chemotherapy and gene therapy holds great promise for the treatment and eradication of tumors. However, due to significant differences in physicochemical properties between chemotherapeutic agents and functional nucleic acid drugs, direct integration into a single nano-agent is hindered, impeding the design and construction of an effective co-delivery nano-platform for synergistic anti-tumor treatments. In this study, we have developed an mRNA-responsive two-in-one nano-drug for effective anti-tumor therapy by the direct self-assembly of 2'-fluoro-substituted antisense DNA against P-glycoprotein (2'F-DNA) and chemo drug paclitaxel (PTX). The 2'-fluoro modification of DNA could significantly increase the interaction between the therapeutic nucleic acid and the chemotherapeutic drug, promoting the successful formation of 2'F-DNA/PTX nanospheres (2'F-DNA/PTX NSs). Due to the one-step self-assembly process without additional carrier materials, the prepared 2'F-DNA/PTX NSs exhibited considerable loading efficiency and bioavailability of PTX. In the presence of endogenous P-glycoprotein mRNA, the 2'F-DNA/PTX NSs were disassembled. The released 2'F-DNA could down-regulate the expression of P-glycoprotein, which decreased the multidrug resistance of tumor cells and enhanced the chemotherapy effect caused by PTX. In this way, the 2'F-DNA/PTX NSs could synergistically induce the apoptosis of tumor cells and realize the combined anti-tumor therapy. This strategy might provide a new tool to explore functional intracellular co-delivery nano-systems with high bioavailability and exhibit potential promising in the applications of accurate diagnosis and treatment of tumors.

Is a low dose of dexamethasone sufficient to prevent paclitaxel-related hypersensitivity reactions? A retrospective study in patients with gynecologic malignancy.

BACKGROUND: Paclitaxel hypersensitivity reactions (HSRs) are prevalent, especially in females. The common paclitaxel pretreatment, dexamethasone, may inhibit chemotherapy efficacy and accelerate tumor progression. We aimed to balance paclitaxel HSRs and the lowest dexamethasone dose for gynecologic malignancies. METHODS: We retrospectively examined 1,074 cycles of 3-weekly paclitaxel-containing treatment for 231 gynecologic malignancies at Xiangya Hospital. HSR incidence with different dexamethasone regimens was the primary outcome. Risk factors were examined in all cycles using univariate and multivariate models with generalized estimating equations. A subgroup analysis of initial exposure to paclitaxel was also conducted. RESULTS: HSR occurred in 33 patients (14.29%) and 49 cycles (4.56%), including 69.39% in cycles 1-2. There were no severe HSRs (grade ≥3). Different premedication regimens, including dexamethasone dosage and route, ranitidine presence or absence, didn't affect HSR incidence in univariate and multivariate analyzes (p > 0.05). Premenopausal women exerted fewer HSRs (ORadj 0.22, 95%CI 0.08-0.58; p = 0.002). At the first exposure to paclitaxel, more than 10 mg of dexamethasone didn't diminish HSRs (OR 0.83, 95%CI 0.27-2.59; p = 0.753). CONCLUSIONS: In gynecologic malignancies, 10 mg dexamethasone along with 20 mg diphenhydramine may be adequate to prevent paclitaxel HSRs without ranitidine. It is necessary to reevaluate paclitaxel premedication regimens.

Neoadjuvant Chemotherapy in Patients with HER2-Negative Breast Cancer: A Report from Clinical Breast Cancer Registry of Iran.

BACKGROUND: Neoadjuvant chemotherapy (NCT) has become an increasingly popular approach in management of breast cancer (BC). This study was conducted to evaluate the pathologic response and 36-month recurrence and survival rates of patients with human epidermal growth factor receptor 2 (HER2)-negative BC treated with different NCT regimens. METHODS: A total of 163 female patients with HER2-negative BC who received NCT during 2017-2020 were identified from the Clinical Breast Cancer Registry of Iran and entered the study. The prescribed NCT regimens included 4 cycles of doxorubicin plus cyclophosphamide, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of paclitaxel, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of docetaxel or 6 cycles of doxorubicin plus cyclophosphamide plus docetaxel (TAC). RESULTS: Thirty-two patients (19.6%) experienced pathologic complete response (pCR). TAC regimen, triple negative-BC and ki67>10% were significantly associated with increased pCR. The recurrence, overall survival (OS) and disease-free survival (DFS) rate at 36 months for all patients were 16.6%, 84.7% and 79.8%, respectively. Type of neoadjuvant regimen as well as age, hormone receptor status, Ki67, grade, clinical stage, type of surgery and pathologic response to chemotherapy did not significantly influence the survival and recurrence; however, TAC results in improved recurrence, OS and DFS rates. CONCLUSION: This study provides further evidence that NCT is a viable treatment option for patients with HER2-negative BC. The TAC regimen resulted in a significantly higher pCR rate compared to other regimens, but did not result in a significant improvement in recurrence, OS and DFS and rates.

Polymeric nanofiber leveraged co-delivery of anti-stromal PAK1 inhibitor and paclitaxel enhances therapeutic effects in stroma-rich 3D spheroid models.

The role of tumor stroma in solid tumors has been widely recognized in cancer progression, metastasis and chemoresistance. Cancer-associated fibroblasts (CAFs) play a crucial role in matrix remodeling and promoting cancer cell stemness and resistance via reciprocal crosstalk. Residual tumor tissue after surgical removal as well as unresectable tumors face therapeutic challenges to achieve curable outcome. In this study, we propose to develop a dual delivery approach by combining p21-activated kinase 1 (PAK1) inhibitor (FRAX597) to inhibit tumor stroma and chemotherapeutic agent paclitaxel (PTX) to kill cancer cells using electrospun nanofibers. First, the role of the PAK1 pathway was established in CAF differentiation, migration and contraction using relevant in vitro models. Second, polycaprolactone polymer-based nanofibers were fabricated using a uniaxial electrospinning technique to incorporate FRAX597 and/or PTX, which showed a uniform texture and a prolonged release of both drugs for 16 days. To test nanofibers, stroma-rich 3D heterospheroid models were set up which showed high resistance to PTX nanofibers compared to stroma-free homospheroids. Interestingly, nanofibers containing PTX and FRAX597 showed strong anti-tumor effects on heterospheroids by reducing the growth and viability by > 90 % compared to either of single drug-loaded nanofibers. These effects were reflected by reduced intra-spheroidal expression levels of collagen 1 and α-smooth muscle actin (α-SMA). Overall, this study provides a new therapeutic strategy to inhibit the tumor stroma using PAK1 inhibitor and thereby enhance the efficacy of chemotherapy using nanofibers as a local delivery system for unresectable or residual tumor. Use of 3D models to evaluate nanofibers highlights these models as advanced in vitro tools to study the effect of controlled release local drug delivery systems before animal studies.

Drug-loaded polymer-coated silver nanoparticles for lung cancer theranostics.

Lung cancer is the leading cause of death in cancer across the globe. To minimize these deaths, the replacement of traditional chemotherapy with novel strategies is significant. We have developed a nanotheranostic approach using silver nanoparticles for imaging and treatment. Silver nanoparticles (AgNPs) are fabricated by chemical reduction method. The formulation of AgNPs was confirmed by different characterization techniques like stability test, UV-Visible spectroscopy, Confocal Raman Spectroscopy, and Energy-Dispersive X-ray analysis. Further, AgNPs are coated with poly lactic-co-glycolic acid (PLGA) and then loaded with paclitaxel (Pac). Then the drug-loaded PLGA-coated AgNPs were characterized for size and zeta potential measurement by zetasizer, surface morphology study by atomic force microscopy, Fourier transform infrared spectroscopy, and release kinetics study. The imaging and anticancer properties of these nanoformulations are investigated using lung cancer cell lines. The results proved that the particles are in the nanometer range with smooth surface morphology. Moreover, the drug-loaded NPs showed a sustained release of the drug for a longer period of time. Further the formulations showed imaging property with greater anticancer efficacy. Thus, the results suggest the effective use of these nanoformulation in both lung cancer imaging and treatment using a simple and efficient approach.

MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study.

BACKGROUND: Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. METHODS: TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. INTERPRETATION: In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. FUNDING: Roche Netherlands.