Combination Chemotherapy Optimization with Discrete Dosing.

Chemotherapy drug administration is a complex problem that often requires expensive clinical trials to evaluate potential regimens; one way to alleviate this burden and better inform future trials is to build reliable models for drug administration. This paper presents a mixed-integer program for combination chemotherapy (utilization of multiple drugs) optimization that incorporates various important operational constraints and, besides dose and concentration limits, controls treatment toxicity based on its effect on the count of white blood cells. To address the uncertainty of tumor heterogeneity, we also propose chance constraints that guarantee reaching an operable tumor size with a high probability in a neoadjuvant setting. We present analytical results pertinent to the accuracy of the model in representing biological processes of chemotherapy and establish its potential for clinical applications through a numerical study of breast cancer.

Immunotherapy plus chemotherapy in patients with advanced endometrial cancer: a cost-effectiveness analysis.

OBJECTIVE: Pembrolizumab and dostarlimab are immune checkpoint inhibitors that target programmed death receptor 1 (PD-1). Combination anti-PD-1 regimens have been shown to exhibit favorable survival benefits when treating advanced endometrial cancer (EC). Which treatment was preferable will need to be confirmed by a cost-effectiveness comparison between them. METHODS: Based on patient and clinical parameters from RUBY and NRG-GY018 phase III randomized controlled trials, the Markov model with a 20-year time horizon was established to evaluate the cost-effectiveness of dostarlimab plus chemotherapy (DC), pembrolizumab plus chemotherapy (PC), and chemotherapy alone (C) treatment for patients with mismatch repair-proficient microsatellite-stable (pMMR-MSS) and mismatch repair-deficient microsatellite instability-high (dMMR-MSI-H) advanced EC from the American payers' perspective. The main results include total cost, life-years (LYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) at a $150,000/QALY of willingness-to-pay. RESULTS: In the pMMR-MSS population, DC, PC, and C produced costs (QALYs) of $99,205 (3.02), $322,530 (3.25), and $421,923 (4.40), resulting in corresponding ICERs of $974,177/QALY (PC vs. C), $234,527/QALY (DC vs. C), $86,671/QALY (DC vs. PC), respectively; In the dMMR-MSI-H population, DC, PC, and C obtained costs (QALYs) of $120,177 (5.73), $691,399 (8.43), and $708,787 (11.26), yielding ICERs of $266,423/QALY (PC vs. C), $135,165/QALY (DC vs. C), $7,866/QALY (DC vs. PC), respectively. CONCLUSION: In the US, DC was a more cost-effective treatment than PC for patients with advanced EC irrespective of MMR status. However, compared to C, DC was associated with more cost-effectiveness in the dMMR-MSI-H population.

Conversion surgery for gastric remnant cancer with liver metastasis after nivolumab combination chemotherapy achieving pathological complete response: a case report and literature review.

BACKGROUND: Nivolumab combination chemotherapy has recently emerged as a potential first-line treatment for patients with unresectable or metastatic gastric cancer (GC). Further research has indicated that R0 resection by conversion surgery could be an effective treatment strategy to improve overall survival. However, there have been limited reports on the successful application of conversion surgery following combination chemotherapy achieving pathological complete response (pCR) in cases of advanced gastric remnant cancer with liver metastasis. Here, we present a case of long-term survival in a patient who underwent this treatment. CASE PRESENTATION: A 54-year-old man was initially referred to our department for treatment of stage III (cT3N1M0) gastric cancer where he underwent laparoscopic distal gastrectomy and D2 lymph node dissection. After a year of uneventful follow-up, the patient was diagnosed with a tumor in the gastric remnant combined with liver metastasis, resulting in a diagnosis of stage IV (cT3N0M1) gastric remnant cancer. Subsequently, the patient was treated with four cycles of TS-1, Oxaliplatin, and Nivolumab as the first-line regimen. Remarkably, both the remnant tumor and liver metastasis exhibited significant shrinkage, and no new lesions were found. Given this response, conversion surgery was performed to achieve complete resection of the remnant gastric cancer and liver metastasis, followed by laparoscopic remnant gastrectomy and partial hepatectomy. Pathological examination revealed the absence of residual carcinoma cells and lymph node metastases. Postoperatively, the patient was treated with adjuvant chemotherapy with S-1 for 1 year, and survived without recurrence for 18 months after conversion surgery. CONCLUSIONS: Nivolumab combination chemotherapy shows promise as a clinically beneficial treatment approach for gastric remnant cancer with liver metastasis, particularly when pCR can be achieved following conversion surgery.

Synchronized Codelivery of Combination Chemotherapies Intratumorally Using a Lipidic Lyotropic Liquid Crystal System.

In this work, an injectable in situ depot-forming lipidic lyotropic liquid crystal (L3C) system is developed to codeliver a precisely synchronized combination of chemotherapeutics intratumorally. The developed L3C system is composed of amphiphilic lipids and surfactants, including monoolein, phosphatidylcholine, tocopherol acetate, and d-α-tocopherol polyethylene glycol 1000 succinate. Owing to its amphiphilic nature, the developed formulation can coaccommodate both hydrophobic and hydrophilic chemotherapeutic moieties simultaneously. The study presents a proof of concept by designing a combination chemotherapy regimen in vitro and demonstrating its in vivo translation using doxorubicin and paclitaxel as model hydrophilic and hydrophobic drug moieties, respectively. The synchronized combination of the two chemotherapeutics with maximum synergistic activity was identified, coloaded in the developed L3C system at predefined stoichiometric ratios, and evaluated for antitumor efficacy in the 4T1 breast tumor model in BALB/c mice. The drug-loaded L3C formulation is a low-viscosity injectable fluid with a lamellar phase that transforms into a hexagonal mesophase depot system upon intratumoral injection. The drug-loaded depot system locally provides sustained intratumoral delivery of the chemotherapeutics combination at their precisely synchronized ratio for over a period of one month. Results demonstrate that the exposure of the tumor to the precisely synchronized intratumoral chemotherapeutics combination via the developed L3C system resulted in significantly higher antitumor activity and reduced cardiotoxicity compared to the unsynchronized combination chemotherapy or the synchronized but uncoordinated drug delivery administered by a conventional intravenous route. These findings demonstrate the potential of the developed L3C system for achieving synchronized codelivery of the chemotherapeutics combination intratumorally and improving the efficacy of combination chemotherapy.

Let-7a-3p overexpression increases chemosensitivity to carmustine and synergistically promotes autophagy and suppresses cell survival in U87MG glioblastoma cancer cells.

In terms of primary brain tumors, glioblastoma is one of the most aggressive and common brain tumors. The high resistance of glioblastoma to chemotherapy has made it vital to find alternative treatments and biological mechanisms to reduce the survival of cancer cells. Given that, the objective of the present research was to explore the potential of let-7a-3p when used in combination with carmustine in human glioblastoma cancer cells. Based on previous studies, the expression of let-7a is downregulated in the U87MG cell line. Let-7a-3p transfected into U87MG glioblastoma cells. Cell viability of the cells was assessed by MTT assay. The apoptotic induction in U87MG cancerous cells was determined through the utilization of DAPI and Annexin V/PI staining techniques. Moreover, the induction of autophagy and cell cycle arrest was evaluated by flow cytometry. Furthermore, cell migration was evaluated by the wound healing assay while colony formation assay was conducted to evaluate colony formation. Also, the expression of the relevant genes was evaluated using qRT-PCR. Transfection of let-7a-3p mimic in U87MG cells increased the expression of the miRNA and also increased the sensitivity of U87MG cells to carmustine. Let-7a-3p and carmustine induced sub-G1 and S phase cell cycle arrest, respectively. Combination treatment of let-7a-3p and carmustine synergistically increased arrested cells and induced apoptosis through regulating involved genes including P53, caspase-3, Bcl-2, and Bax. Combined treatment with let-7a-3p and carmustine also induced autophagy and increased the expression of the ATG5 and Beclin 1 (ATG6). Furthermore, let-7a-3p combined with carmustine inhibited cell migration via decreasing the expression of MMP-2. Moreover, the combination therapy decreased the ability of U87MG to form colonies through downregulating CD-44. In conclusion, our work suggests that combining let-7a-3p replacement therapy with carmustine treatment could be considered a promising strategy in treatment and can increase efficiency of glioblastoma chemotherapy.

Development of an aptamer capable of multidrug resistance reversal for tumor combination chemotherapy.

Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments.

Dendritic polymer prodrug-based unimolecular micelles for pH-responsive co-delivery of doxorubicin and camptothecin with synergistic controlled drug release effect.

Combination chemotherapy has been recognized as a more powerful strategy for tumor treatment rather than the single chemotherapy. However, the interactive mechanism of the two hydrophobic chemotherapeutic drugs has not been explored by now. Aiming for a better synergistic effect, such interactive mechanism was investigated in the present work, by designing CPT@DOX-DPUTEA-PEG nanomedicine with encapsulated camptothecin (CPT) and conjugated doxorubicin (DOX). The synergistic controlled drug release effect was found for the two drugs loaded on the different sites of the dendritic polyurethane core. Synergism was achieved on the HepG2 cells with a combination index (CI) of 0.58 in the in vitro cellular experiments. The results demonstrated the promising application of the unimolecular micelles-based nanomedicine with independently loading of two hydrophobic chemotherapeutic drugs.

Securinine inhibits the tumor growth of human bladder cancer cells by suppressing Wnt/ß-catenin signaling pathway and activating p38 and JNK signaling pathways.

Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/ß-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, ß-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/ß-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC.

Phase I trial of apatinib and paclitaxel+oxaliplatin+5-FU/levoleucovorin for treatment-naïve advanced gastric cancer.

Chinese guidelines recommend POF (paclitaxel, oxaliplatin, and 5-FU/levoleucovorin) as first-line treatment for advanced gastric cancer (AGC). Apatinib can augment the antitumor effect of paclitaxel, oxaliplatin, or fluorouracil in preclinical studies of AGC. A phase I clinical trial was conducted to evaluate the anticancer activity and maximum tolerated dose (MTD) of apatinib plus POF in treatment-naïve patients with AGC and to establish a recommended phase II dose. Participants received escalating doses of daily oral apatinib (250, 375, 500, 625, 750, and 850 mg) plus POF every 2 weeks using a conventional "3 + 3" study design. Among 21 treated patients, one experienced a dose-limiting toxicity (grade 3 skin ulceration at 850 mg). No MTD was reached. Apatinib 750 mg plus POF was recommended for phase II study. The most common grade 3-4 adverse events (AEs) were neutropenia (33.3%), mucositis (14.3%), and hand-foot syndrome (14.3%). Median progression-free and overall survival were 10.4 months (95% CI: 6.3, 14.6) and 18.4 months (95% CI: 9.8, 28.2), respectively. Apatinib up to 850 mg coadministered with POF was well tolerated with manageable AEs. The safety and anticancer activity of this regimen warrants its further investigation as first-line treatment for AGC in a larger study.

A Polymeric Nanoparticle to Co-Deliver Mitochondria-Targeting Peptides and Pt(IV) Prodrug: Toward High Loading Efficiency and Combination Efficacy.

Developing combination chemotherapy systems with high drug loading efficiency at predetermined drug ratios to achieve a synergistic effect is important for cancer therapy. Herein, a polymeric dual-drug nanoparticle composed of a Pt(IV) prodrug derived from oxaliplatin and a mitochondria-targeting cytotoxic peptide is constructed through emulsion interfacial polymerization, which processes high drug loading efficiency and high biocompatibility. The depolymerization of polymeric dual-drug nanoparticle and the activation of Pt prodrug can be effectively triggered by the acidic tumor environment extracellularly and the high levels of glutathione intracellularly in cancer cells, respectively. The utilization of mitochondria-targeting peptide can inhibit ATP-dependent processes including drug efflux and DNA damage repair. This leads to increased accumulation of Pt-drugs within cancer cells. Eventually, the polymeric dual-drug nanoparticle demonstrates appreciable antitumor effects on both cell line derived and patient derived xenograft lung cancer model. It is highly anticipated that the polymeric dual-or multi-drug systems can be applied for combination chemotherapy to achieve enhanced anticancer activity and reduced side effects.

Silk Nanofiber Carriers for Both Hydrophilic and Hydrophobic Drugs to Achieve Improved Combination Chemotherapy.

Combination chemotherapy is considered an effective strategy to inhibit tumor growth. Here, beta-sheet-rich silk nanofibers are co-loaded with hydrophilic doxorubicin (DOX) and hydrophobic paclitaxel (PTX) through a sequential physical blending-centrifugation-blending process. The ratio and amount of DOX and PTX on the nanofibers are regulated independently to optimize cooperative interaction. Both PTX and DOX are immobilized on the same nanofibers to avoid burst release problems. Besides the water-insoluble PTX, more than half of the DOX remained fixed on the nanofibers for more than 28 days, which facilitated the co-internalization of both DOX and PTX by tumor cells in vitro. Changing the ratio of co-loaded DOX and PTX achieved optimal combination therapy in vitro. The DOX-PTX co-loaded nanofibers are assembled into injectable hydrogels to facilitate in situ injection around tumor tissues in vivo. Long-term inhibition is achieved for tumors treated with DOX-PTX co-loaded hydrogels, superior to those treated with free DOX and PTX, and hydrogels loaded with only DOX or PTX. Considering the mild and controllable physical loading process and superior loading capacity for both hydrophilic and hydrophobic ingredients, these injectable silk nanofiber hydrogels are promising carriers to deliver multiple drug types simultaneously in situ, enhancing combination chemotherapies towards clinical applications.

Combination chemotherapy in rodents: a model for chemotherapy-induced neuropathic pain and pharmacological screening.

Chemotherapy-induced neuropathic pain (CINP) remains a therapeutic challenge, with no US-FDA approved drugs or effective treatments available. Despite significant progress in unravelling the pathophysiology of CINP, the clinical translation of this knowledge into tangible outcome remains elusive. Here, we employed behavioural and pharmacological approaches to establish and validate a novel combination-based chemotherapeutic model of peripheral neuropathy. Male Sprague Dawley rats were subjected to chemotherapy administration followed by assessment of pain behaviour at different time-points post-chemotherapy. Paclitaxel-treated animals displayed an enhanced thermal and mechanical hypersensitivity from day four onwards which continued till day thirty-five post last paclitaxel injection. Notably, rats subjected to combination chemotherapy, displayed prolonged hypersensitivity that emerged on day four and persisted until day fifty-six. RT-PCR analysis revealed significant upregulation in DRG and spinal mRNA expressions of TRP channels (TRPA1, TRPV1, & TRPM8), pro-inflammatory cytokines (TNF-α & IL-1ß) and neuropeptides, Substance P and CGRP in both the pain models. Interestingly, the combination chemotherapy model demonstrated a significant increase in DRG and spinal NR2B expressions compared to rats solely treated with paclitaxel. Pharmacological investigations revealed that gabapentin treatment substantially mitigates pain hypersensitivity in both the combined chemotherapy and paclitaxel-administered groups, with the simultaneous reversal of cellular and molecular changes observed in the lumbar DRG and spinal cord of rats. The findings from this study suggests that combination chemotherapy model exhibits heightened and prolonged hypersensitivity in comparison to the conventional paclitaxel-induced neuropathic pain model. This model not only recapitulates clinical biomarkers of neuropathy but also presents a potential alternative platform for screening analgesic drugs targeted at CINP.

Dose-dependent bidirectional pharmacological effects of vinorelbine-based metronomic combination chemotherapy on tumor growth and metastasis and mechanisms in melanoma mouse model.

BACKGROUND: There is evidence that the empirical setting of doses and schedules of antineoplastic agents in metronomic chemotherapy (MC) might lead to undesirable outcomes, such as promoting tumor growth or metastasis at certain low doses. However, details about the dose effect of antineoplastic agents in MC have not been fully known yet. OBJECTIVES: Vinorelbine combined with cisplatin or fluorouracil (VNR/CDDP or VNR/FU) was selected to investigate its effects on tumor growth or metastasis as well as mechanisms. METHODS: Experimental techniques, including immunohistochemistry, western blot, immunofluorescence, and flow cytometry, were used to explore the mechanisms, along with cell proliferation, apoptosis, migration, and invasion. RESULTS: The results showed that VNR/CDDP or VNR/FU promoted tumor growth and metastasis at low doses and inhibited them at high ones. Except that expressions of apoptotic proteins were elevated at both low and high doses, low-dose treatments enhanced angiogenesis and promoted the mobilization and recruitment of myeloid-derived suppressor cells (MDSCs), while high-dose treatments reversed these effects. Additionally, low concentrations of VNR/CDDP or VNR/FU stimulated tumor cell functions such as anti-apoptosis, migration, and invasion, but high concentrations only suppressed cell proliferation and increased apoptosis. CONCLUSION: This study elucidated a bidirectional action mode regulated by multiple mechanisms at different doses in MC and also highlighted the risks of low-dose metronomic administration of antineoplastic agents in the clinic. More preclinical and clinical studies focusing on the dose-effect of metronomic regimens are urgently needed because an effective therapeutic regimen should be an optimal setting of drugs, doses, schedules, or combinations.

Selecting Optimal First-Line Treatment for Microsatellite Stable and Non-Mutated RAS/BRAF Metastatic Colorectal Cancer.

OPINION STATEMENT: Standard frontline treatment of metastatic colorectal cancer (CRC) is cytotoxic chemotherapy plus a biologic agent such as an anti-EGFR monoclonal antibody (cetuximab or panitumumab) or anti-VEGF antibody (bevacizumab). Predictive biomarkers include mismatch repair (MMR) status, and RAS and BRAF mutation status; and important factors in treatment selection include primary tumor location, intent of therapy, and potential toxicity, as well as patient age, comorbidities, and patient preference. To date, single-, double-, or triple-agent cytotoxic chemotherapy all have important roles in appropriately selected patients, with the addition of anti-VEGF or anti-EGFR antibody therapy based on the relevant predictive biomarker. Data indicate that patients with proficient MMR, RAS/BRAF wt mCRC are candidates for an anti-EGFR antibody plus doublet chemotherapy if they have a left-sided primary tumor, or for anti-VEGF (bevacizumab) plus doublet or triplet chemotherapy if they have a right-sided primary tumor. Future studies may provide more predictive biomarkers to further personalize therapy for this heterogeneous disease.

Are We Ready For "Triplet" Therapy in Higher-Risk MDS?

Higher-risk Myelodysplastic Syndromes/Neoplasms (MDS) represent an ongoing therapeutic challenge, with few effective therapies, many of which may have limited use in this older patient population often with considerations around comorbidities. Outside of transplant, azacitidine and decitabine remain the only disease-modifying therapies, and are palliative in nature. Recent interest has grown in extending combination chemotherapies used to treat acute myeloid leukemia (AML) to patients with MDS, including novel combination chemotherapy "doublets" and "triplets." In this review, we discuss considerations around combination chemotherapy in MDS, specifically as relates to study design, appropriate endpoints, supportive considerations, and how to integrate these into the current treatment paradigm. New therapies in MDS are desperately needed but also require considerations particular to this unique patient population.

Proteasome inhibitors in the treatment of nonsmall cell lung cancer: A systematic review of clinical evidence.

Background and Aims: Nonsmall cell lung cancer accounts for over 85% of lung cancer incidences worldwide, and often has a poor prognosis. Proteasome inhibitors, such as bortezomib, have previously demonstrated evidence in preclinical and clinical models in the treatment of NSCLC both alone and as part of chemotherapeutic regimens. Methods: Five databases were searched from inception to February 2023 to identify published clinical trial data and ongoing clinical trials on the use of proteasome inhibitors in treatment of NSCLC with a comprehensive search strategy. Results: This review examines the clinical evidence from 21 completed and published phase I and II trials studying the use of bortezomib monotherapy and combination therapy in the treatment of NSCLC. Bortezomib/docetaxel combination resulted in longer median time-to-progression (TTP), median duration of response, median duration of disease control and median progression-free survival (PFS) than bortezomib monotherapy, with concurrent administration having greater 6-month PFS and median overall survival (OS) than sequential administration. Bortezomib/vorinostat with chemotherapy was well tolerated and effective. Bortezomib/gemcitabine/carboplatin, bortezomib/bevacizumab/carboplatin and bortezomib/paclitaxel/carboplatin combinations showed promising results and were of further investigational value. Conclusion: Bortezomib showed some clinical promise in combination therapy but not monotherapy. It also demonstrated a manageable side effect profile. Combination regimens are of further investigation value in Phase II trials.

Combination chemotherapy against colorectal cancer cells: Co-delivery of capecitabine and pioglitazone hydrochloride by polycaprolactone-polyethylene glycol carriers.

BACKGROUND: Colorectal cancer causes numerous deaths despite many treatment options. Capecitabine (CAP) is the standard chemotherapy regimen for colorectal cancer, and pioglitazone hydrochloride (PGZ) for diabetic disease treatment. However, free drugs do not induce effective apoptosis. This work aims to co-encapsulate CAP and PGZ and evaluate cytotoxic and apoptotic effects on HCT-119, HT-29 colorectal cancer cells, and human umbilical vein endothelial cells (HUVECs). METHOD: CAP, PGZ, and combination treatment nano-formulations were prepared by triblock (TB) (PCL-PEG-PCL) biodegradable copolymers to enhance drugs' bioavailability as anti-cancer agents. The Ultrasonic homogenization method was used for preparing nanoparticles. The physicochemical characteristics of nanoparticles were studied using 1H NMR, FTIR, DLS, and FESEM techniques. The zeta potential, entrapment efficiency, drug release, and storage stability were studied. Also, cell viability and apoptosis were examined by using MTT, acridine orange (AO), and propidium iodide (PI), respectively. RESULT: The smaller hydrodynamic size (236.1 nm), polydispersity index (0.159), and zeta potential (-20.8 mV) were observed in nanoparticles. Nanoparticles revealed a proper formulation and storage stability at 25 °C than 4 °C in 90 days. The synergistic effect was observed in (CAP-PGZ)-loaded TB nanoparticles in HUVEC, HCT-116, and HT-29 cells. In (AO/PI) staining, the high percentage of apoptotic cells in the (CAP-PGZ)-loaded TB nanoparticles in HUVEC, HCT-116, and HT-29 were calculated as 78 %, 71.66 %, and 69.31 %, respectively. CONCLUSION: The (CAP-PGZ)-loaded TB nanoparticles in this research offer an effective strategy for targeted combinational colorectal cancer therapy.

Identifying synergistic combinations of Doxorubicin-Loaded polyquercetin nanoparticles and natural Products: Implications for breast cancer therapy.

Combining chemotherapeutic agents with bioactive natural products is an attractive cancer treatment modality to reduce the dose and side effects of chemotherapy. Combination treatments with drugs having different mechanisms of action can also be beneficial in combatting the development of drug resistance by cancer cells. Nanoparticle (NP)-mediated drug delivery can further improve the therapeutic index of cytotoxic agents by enabling passive and/or active targeting to tumor tissues in vivo. Using doxorubicin (DOX) as a model chemotherapeutic agent, we developed three NP formulations based on polyquercetin (pQCT), an emerging nanocarrier platform. The NPs were co-assembled with DOX, pQCT, and either Pluronic P123, methoxy poly(ethylene glycol)-amine, or D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS). Physicochemical characterization of the NPs revealed them to have a spherical morphology with high monodispersity, excellent drug loading capacity, and sustained drug release. Then, the NPs were evaluated in vitro to determine their potential synergism when combined with the bioactive natural products curcumin (CUR), tannic acid (TA), and thymoquinone (TQ) against breast cancer cells (MCF-7 and MDA-MB-231). Surprisingly, most of the combinations were found to be antagonistic. However, combinations containing CUR exhibited greater pro-apoptotic effects compared to the single agents, with polymer-modified pQCT NPs presenting as a promising nanoplatform for enhancing DOX's ability to promote cancer cell apoptosis. Our findings provide insights into the potential application of pQCT in nanomedicine, as well as the use of bioactive natural products in combination with DOX as a free agent and as an NP formulation in the treatment of breast cancer.

Safety and Effectiveness of Chemotherapy in Elderly Biliary Tract Cancer Patients.

The safety and effectiveness of chemotherapy in elderly patients with biliary tract cancer (BTC) remain unclear. Therefore, we retrospectively reviewed patients who underwent chemotherapy for locally advanced, metastatic, or recurrent BTC at our institution from January 2016 to December 2021. Of the 283 included patients, 91 (32.5%) were aged 75 years or older when initiating chemotherapy. Elderly patients were more likely than non-elderly patients to receive monotherapy with gemcitabine or S-1 (58.7% vs. 9.4%, p < 0.001) and were less likely to experience grade 3-4 toxicities (55.4% vs. 70.2%, p = 0.015). The rates of termination due to intolerance (6.5% vs. 5.8%, p = 0.800) and transition to second-line chemotherapy (39.1% vs. 40.3%, p = 0.849) were similar between groups. In the overall cohort, age was not an independent predictor of overall survival (OS). Within the elderly cohort, there were no differences in severe adverse events between patients receiving monotherapy and combination therapy (50.0% vs. 63.2%, p = 0.211). Median OS was longer in the combination therapy group (10.4 vs. 14.1 months; p = 0.010); however, choice of monotherapy was not an independent predictor of overall survival. Monotherapy appears to be a viable alternative in selected elderly BTC patients.

Thrombotic risk of platinum combination chemotherapy with and without immune checkpoint inhibitors for advanced non-small cell lung cancer: a nationwide inpatient database study.

OBJECTIVES: To determine the associated thromboembolism risk with adding immune checkpoint inhibitors (ICI) to platinum combination chemotherapy compared with platinum combination chemotherapy alone in patients with advanced non-small cell lung cancer. MATERIALS AND METHODS: This study identified 75,807 patients with advanced non-small cell lung cancer from the Japanese Diagnosis Procedure Combination database who started platinum combination chemotherapy between July 2010 and March 2021. The incidence of venous thromboembolism (VTE), arterial thromboembolism (ATE), and all-cause mortality within 6 months after commencing platinum combination chemotherapy was compared between patients receiving chemotherapy with ICI (ICI group, n = 7,177) and without ICI (non-ICI group, n = 37,903). Survival time analysis was performed using the overlap weighting method with propensity scores to adjust for background factors. The subdistribution hazard ratio for developing thromboembolism was calculated using the Fine-Gray model with death as a competing risk. The hazard ratio for all-cause mortality was also calculated using the Cox proportional hazards model. RESULTS: Overall, VTE and ATE occurred in 761 (1.0%) and 389 (0.51%) patients, respectively; mortality was 11.7%. Propensity score overlap weighting demonstrated that the subdistribution hazard ratio (95% confidence interval) for VTE and ATE in the ICI group was 1.27 (1.01-1.60) and 0.96 (0.67-1.36), respectively, compared with the non-ICI group. The mortality hazard ratio in the ICI group was 0.68 (0.62-0.74). CONCLUSION: The addition of ICI to platinum combination therapy was associated with a higher risk of VTE compared with platinum combination therapy alone, while the risk of ATE might be comparable.