Common Chemotherapy Research Articles

Real‐World Outcomes of Patients Treated With Gemcitabine Using Standardized Dose and Rate and Docetaxel for Advanced Soft Tissue Sarcoma in an Australian Sarcoma Center

ABSTRACTBackgroundGemcitabine and docetaxel (GD) is a common chemotherapy regimen for metastatic soft tissue sarcoma (STS). The GeDDiS trial compared GD with doxorubicin in the first‐line setting, using gemcitabine 675 mg/m2 over a prolonged rate of 90 min—reporting a 20% response rate and 5.4‐month median progression‐free survival (PFS). We aimed to examine the real‐world efficacy and toxicity of GD in our center, using a standardized dose of gemcitabine 900 mg/m2 over 30 min on Days 1 and 8 and intravenous docetaxel 75 mg/m2 over 60 min on Day 8 every 21 days.MethodsA retrospective analysis was conducted of patients with unresectable or metastatic STS receiving GD between July 2018 and October 2022. Data collected included patient and tumor characteristics, dose intensity, toxicity, response, PFS, and overall survival (OS).ResultsThirty‐eight patients were included. Median follow‐up was 19 months (range 3–30). Line of treatment (n) was first line (10), second line (13), ≥ third line (15). The median number of cycles was 6. Response rate was 42%, including 5% with a complete response. At the time of data collection, 33 patients had disease progression and 24 patients had died. PFS (median, 6‐month rate) was 4.5 months and 44%. OS (median, 12‐month rate) was 15 months and 65%. Grade 3/4 toxicity included anemia (21%), neutropenia (5%), thrombocytopenia (5%), and febrile neutropenia (3%).ConclusionThese data demonstrate the activity of gemcitabine using a standardized dose and rate with docetaxel comparable to other published data and favorable toxicity in a real‐life patient population despite altered gemcitabine dosing and a heavily pretreated patient population.

EPID-36. CLINICAL FEATURES OF 614 PRIMARY INTRACRANIAL GERM CELL TUMORS: AN 15-YEAR EXPERIENCE OF A SINGLE CENTER IN CHINA

Abstract Incidence of primary intracranial germ cell tumors (ICGCT) in Asian countries is higher than Western countries. This study aims to describe the characteristics of ICGCT patients in China. Data on all patients with ICGCT who were seen at the Department of Neuro-oncology, Sanbo Brain Hospital, Capital Medical University from 2007 to 2022 were collected retrospectively. Patient demographics, disease characteristics and treatment outcomes were analyzed. A total of 614 patients were identified, with 309 germinomas and 305 non-germinomatous germ cell tumors (NGGCT). The median age at diagnosis was 12.8 years. The male-female ratio is 2.4 to 1. The primary disease sites were mainly pineal gland and suprasellar region. Adults (age≥23) were more likely to develop germinomas (65.3%). 78% patients received radiotherapy after initial diagnosis. In M0 patients, whole brain radiotherapy was the most common approach, while in M+ was craniospinal radiotherapy. Whole ventricle radiotherapy was uncommon (4%). The most common chemotherapy regimen for germinoma was a combination of bleomycin, cisplatin and etoposide/tenipside; while for the NGGCT was ifosfamide combined with carboplatin/cisplatin and etoposide. For germinoma, the median recurrence-free survival (RFS) and overall survival (OS) were 150.3 months and 222 months; the 10 year RFS and OS were 58.2% and 85.1%, respectively. For NGGCT, the median RFS and OS were 80.4 months and 166.7 months; the 10 year RFS and OS were 46.9% and 60.5%. At relapse, four (0.65%) developed secondary malignancies. Seven (1.14%) developed extracranial dissemination. Chemotherapy and radiotherapy could improve the RFS and OS. Higher radiation dose was associated with better prognosis. The prognosis of focal radiotherapy alone was poor. M0 germinoma treated with focal radiotherapy alone were more likely relapse. This study suggested that treatment outcomes of our ICGCT patients are comparable with those in Western centers. Adjuvant chemotherapy and whole brain/craniospinal radiotherapy are pivotal treatment.

Construction of lysosome-related prognostic signature to predict the survival outcomes and selecting suitable drugs for patients with HNSCC.

Lysosomes are digestive organelles responsible for endocytosis and autophagy. Recently, the malignancy and invasiveness head and neck squamous cell carcinoma (HNSCC) has been increasingly studied with the role of lysosomes. A list of lysosome-related genes were obtained from MSigDB. A Spearman correlation and univariate Cox regression analyses combined with differential expression analysis were conducted to detect differentially expressed lysosome-related genes related to prognosis. The prediction of prognostic signature was evaluated by plotting survival curve, ROC, and by developing a nomogram. Immune subtypes, infiltration of immune cells, GSVA, TIDE, IC50 of common chemotherapy and targeted therapy, GO, and KEGG function enrichment analyses were carried out to explore the immune microenvironment of the signature. We constructed a lysosome-related prognostic signature that could function as an independent prognostic indicator for patients with HNSCC. High-risk patients were better suited to receive Doxorubicin, Mitomycin C, Pyrimethamine, anti-PD-L1 and anti-CTLA-4 immunotherapy, whereas low-risk patients had sensitivity to Lapatinib. GO functional enrichment analysis showed that prognostic features were strongly associated with epidermis-related functions (e.g., epidermal cell differentiation, epidermal development, and keratinization). In addition, a KEGG function enrichment analysis revealed a potential relationship between the risk assessment model and cardiomyopathy. We constructed a prognostic signature based on lysosome-related genes and successfully predicted the survival outcome of HNSCC patients, which not only provides potential guidance for personalized treatment but also provides a new idea for precision treatment of HNSCC.

A natural protopanaxatriol from Panax notoginseng enhances osteosarcoma sensitivity to ferroptosis via ASCL4 upregulation

Current treatments for osteosarcoma, the most common primary bone cancer, including surgery, radiotherapy, and chemotherapy, are largely ineffective against metastatic and chemo-resistant cases, emphasizing the need for novel therapies. In this study, we investigated (20S)-Protopanaxatriol [(20S)-PPT], a natural product from Panax notoginseng, an herb used both as food and medicine, for its ability to enhance osteosarcoma sensitivity to ferroptosis induced by inducers such as RSL3, ML210, and IKE. Specifically, (20S)-PPT increased lipid peroxidation in osteosarcoma cells exposed to RSL3. This effect was mediated by ACSL4 upregulation, as ACSL4 knockdown reversed (20S)-PPT-sensitized ferroptosis. Importantly, (20S)-PPT significantly reduced tumor growth in xenograft models when combined with IKE. Collectively, our study confirms that combining (20S)-PPT with ferroptosis inducers offers a promising novel strategy for treating osteosarcoma.

The integrated molecular and histological analysis defines subtypes of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is highly heterogeneous. Our understanding of full molecular and immune landscape of ESCC remains limited, hindering the development of personalised therapeutic strategies. To address this, we perform genomic-transcriptomic characterizations and AI-aided histopathological image analysis of 120 Chinese ESCC patients. Here we show that ESCC can be categorized into differentiated, metabolic, immunogenic and stemness subtypes based on bulk and single-cell RNA-seq, each exhibiting specific molecular and histopathological features based on an amalgamated deep-learning model. The stemness subgroup with signature genes, such as WFDC2, SFRP1, LGR6 and VWA2, has the poorest prognosis and is associated with downregulated immune activities, a high frequency of EP300 mutation/activation, functional mutation enrichment in Wnt signalling and the highest level of intratumoural heterogeneity. The immune profiling by transcriptomics and immunohistochemistry reveals ESCC cells overexpress natural killer cell markers XCL1 and CD160 as immune evasion. Strikingly, XCL1 expression also affects the sensitivity of ESCC cells to common chemotherapy drugs. This study opens avenues for ESCC treatment and provides a valuable public resource to better understand ESCC.

Sinonasal Plasmablastic Lymphoma: A Systematic Review

Abstract Objective Plasmablastic lymphoma (PBL) is a type of non-Hodgkin's B-cell lymphoma associated with human immunodeficiency virus and Epstein–Barr virus, commonly located in the oral cavity or gastrointestinal tract. Sinonasal involvement is rare, and there is no consensus on treatment. Data Sources Peer-reviewed published articles served as data sources. Review Methods A systematic review was conducted of the PubMed database for all cases of sinonasal PBL between 1978 and 2023 with the phrase “plasmablastic lymphoma.” Studies not written in English and that did not separate individual cases of sinonasal PBL from aggregated data were excluded. Age, sex, immune status, treatment, and outcomes were collected. Conclusion PBL is a rare malignancy in the sinonasal region usually treated with chemotherapy. It most commonly occurs in immunocompromised adults but has also been diagnosed in immunocompromised children and in immunocompetent adults. It is aggressive and has a poor prognosis. Implications for Practice PBL is a recently described entity with few cases of the sinonasal anatomic variant in the literature. Sinonasal PBL was most frequently treated with chemotherapy alone, closely followed by chemoradiation. The most common chemotherapy regimen utilized in the literature is cyclophosphamide, doxorubicin, oncovin/vincristine, and prednisone, which is also the most common chemotherapy regimen in nonsinonasal PBL. A second commonly used regimen is cyclophosphamide, vincristine/oncovin, doxorubicin/adriamycin, and dexamethasone. However, no treatment has emerged as superior to others with regard to survival. Further data are needed to better understand this rare disease.

The role of SEC14L4 in esophageal squamous cell cancer: insights into clinical relevance and molecular pathways.

Esophageal squamous cell cancer (ESCC) is the most common type of esophageal cancer. This study aimed to elucidate the role of Saccharomyces cerevisiae-like 4 (SEC14L4) in ESCC. To elucidate the role of SEC14L4 in ESCC, this study analyzed the clinical data, gene sequencing data, and other relevant data retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) of the National Center for Biotechnology Information. The methodology involved several analytical approaches, including nomogram model analysis, co-expression analysis, gene set enrichment and variation analysis, weighted correlation network analysis, drug susceptibility analysis, and single-cell analysis. These methods were employed to evaluate the significance of SEC14L4 in ESCC. The expression of SEC14L4 was evaluated via quantitative real-time polymerase chain reaction (qRT-PCR). SEC14L4 expression (P<0.001) was significantly elevated in those with ESCC, especially in patients with locally advanced disease (P=0.005), and indicated a poor prognosis (P=0.045). Findings from the nomogram model analysis identified the contribution of clinical indicators to survival prediction with good efficacy. Subsequently, the single-nucleotide polymorphisms and co-expressed genes of SEC14L4 were identified. Furthermore, pathways associated with SEC14L4, including DNA metabolic process, transcription factor binding, apoptosis, and others, were examined. Notably, SEC14L4 expression was predominantly observed in monocytes. Drug sensitivity analysis indicated the association of SEC14L4 expression with sensitivity of ESCC to the common chemotherapy drugs AICAR, BMS.708163, GNF.2, Nutlin.3a, PD.0325901, and RDEA119. Verification of the high expression of SEC14L4 in KYSE520 and KYSE150 was conducted, thereby confirming the study's findings. High expression of SEC14L4 is associated with poorer clinical outcomes, highlighting its potential as a therapeutic target and suggesting its involvement in the molecular mechanisms underlying ESCC.

TongGuanWan Alleviates Doxorubicin- and Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis by Modulating Apoptotic and Fibrotic Pathways.

Heart failure, a major public health issue, often stems from prolonged stress or damage to the heart muscle, leading to cardiac hypertrophy. This can progress to heart failure and other cardiovascular problems. Doxorubicin (DOX), a common chemotherapy drug, and isoproterenol (ISO), a β-adrenergic agonist, both induce cardiac hypertrophy through different mechanisms. This study investigates TongGuanWan (TGW,), a traditional herbal remedy, for its effects on cardiac hypertrophy and fibrosis in DOX-induced H9c2 cells and ISO-induced mouse models. TGW was found to counteract DOX-induced increases in H9c2 cell surface area (n = 8, p < 0.01) and improve biomarkers like ANP (n = 3, p < 0.01)) and BNP (n = 3, p < 0.01). It inhibited the MAPK pathway (n = 4, p < 0.01) and GATA-4/calcineurin/NFAT-3 signaling, reduced inflammation by decreasing NF-κB p65 translocation, and enhanced apoptosis-related factors such as caspase-3 (n = 3, p < 0.01), caspase-9 (n = 3, p < 0.01), Bax (n = 3, p < 0.01), and Bcl-2 (n = 3, p < 0.01). Flow cytometry showed TGW reduced apoptotic cell populations. In vivo, TGW reduced heart (n = 8~10, p < 0.01), and left ventricle weights (n = 6~7), cardiac hypertrophy markers (n = 3, p < 0.01), and perivascular fibrosis in ISO-induced mice, with Western blot analysis confirming decreased levels of fibrosis-related factors like fibronectin, α-SMA (n = 3, p < 0.05), and collagen type I (n = 3, p < 0.05). These findings suggest TGW has potential as a therapeutic option for cardiac hypertrophy and fibrosis.

Molecular Logic Gate for Sensing pH/Peroxynitrite with Potential Applications in Cisplatin Treatment.

Cisplatin is a common chemotherapy drug for multiple solid tumors; however, due to the nitrification of peroxynitrite (ONOO-), a series of side effects seriously affect its dose and efficacy. Considering that the reactivity of ONOO- is significantly affected by pH in vitro, revealing their roles in living cells contributes to understanding the side-effect process induced by cisplatin. Herein, we present a near-infrared fluorescent logic gate for sensing pH/ONOO-, which can accurately discriminate four scenarios (no analyte, analyte H+ alone, analyte ONOO- alone, and H+ + ONOO-) and which one comes first. With this probe, the significant roles of pH and ONOO- in cisplatin treatment are disclosed, in which the cell account shows a dramatic reduction accompanied by decreased pH and upregulated ONOO- levels. By artificially recovering the pH, the ONOO- content and cell account can maintain a stable state, possibly due to the protection from acidification and nitration. This work provides an ideal pH/ONOO- logical sensor for revealing their potential roles under cisplatin, which is expected to proffer new insights into more related diseases and drug research.

The Endocannabinoid System of the Nervous and Gastrointestinal Systems Changes after a Subnoxious Cisplatin Dose in Male Rats

Background/Objectives: Cisplatin, a common chemotherapy agent, is well known to cause severe side effects in the gastrointestinal and nervous systems due to its toxic and pro-inflammatory effects. Although pharmacological manipulation of the endocannabinoid system (ECS) can alleviate these side effects, how chemotherapy affects the ECS components in these systems remains poorly understood. Our aim was to evaluate these changes. Methods: Male Wistar rats received cisplatin (5 mg/kg, i.p.) or saline on day 0 (D0). Immediately after, serial X-rays were taken for 24 h (D0). Body weight was recorded (D0, D1, D2 and D7) and behavioural tests were performed on D4. On D7, animals were euthanized, and gastrointestinal tissue, dorsal root ganglia (DRGs) and brain areas were collected. Expression of genes related to the ECS was assessed via Rt-PCR, while LC-MS/MS was used to analyse endocannabinoid and related N-acylethanolamine levels in tissue and plasma. Results: Animals treated with cisplatin showed a reduction in body weight. Cisplatin reduced gastric emptying during D0 and decreased MAGL gene expression in the antrum at D7. Despite cisplatin not causing mechanical or heat sensitivity, we observed ECS alterations in the prefrontal cortex (PFC) and DRGs similar to those seen in other chronic pain conditions, including an increased CB1 gene expression in L4/L5 DRGs and a decreased MAGL expression in PFC. Conclusions: A single dose of cisplatin (5 mg/kg, i.p.), subnoxious, but capable of inducing acute gastrointestinal effects, caused ECS changes in both gastrointestinal and nervous systems. Modulating the ECS could alleviate or potentially prevent chemotherapy-induced toxicity.

Metaplastic breast cancer: Experience with ifosfamide based chemotherapy

BackgroundMetaplastic breast cancer (MPBC) is a rare variant of breast cancer and most treatment protocols are based on the guidelines for triple negative breast cancer. However, response to standard anthracycline and taxane based chemotherapy is poor. Published literature on use of ifosfamide based chemotherapy in the first line setting for MPBC is scarce. Patients and methodsWe carried out this record based analysis on MPBC patients treated at our institute with the combination of ifosfamide and Adriamycin (IA) as first line therapy. Patients were analysed for the clinical and demographic profile; pathology and treatment details; and treatment outcomes. ResultsFour patients who received IA chemotherapy were evaluated. Three of the four patients were postmenopausal. The median size of the tumor was 7.5 cm, only one patient had a heavy nodal burden and lung was the most common site of metastases seen in all three patients with metastatic disease. Pathology showed heterogenous, mixed histology with high grade tumors. All patients had triple negative tumors. All four patients underwent mastectomy and received IA chemotherapy as per standard doses. One patient had complete response, one had partial response and one patient progressed after 4 cycles of chemotherapy. The patient with localized disease continues to be disease free till date. Grade 3,4 neutropenia and grade 2 anemia was the most common chemotherapy related toxicity. ConclusionThe response rates in MPBC with IA regimen appear to be similar to the currently used anthracycline-taxane combinations, with slightly more haematological toxicity. Ifosfamide and adriamycin regimen may be considered in MPBC patients as primary or salvage systemic therapy.

The effect of amplitude of heat flux on the adsorption of doxorubicin by MOF11 bio-carrier using molecular dynamics simulation

A common chemotherapy drug, doxorubicin's effectiveness is restricted by its quick excretion from the body and poor solubility. Because of their large surface area and adjustable pore size, bio MOF11 carriers demonstrated promise as drug delivery systems. Examining how external heat flux amplitude (EHFA) affects bio MOF11's ability to adsorb doxorubicin can reveal ways to improve drug loading and release, which will improve drug delivery. Moreover, by shortening the time needed for adsorption (Ads) and desorption, using EHFA in drug Ads processes can increase energy efficiency. Through comprehending the effect of EHFA on the Ads procedure, researchers can ascertain the ideal circumstances for optimizing drug loading while reducing energy usage. The current work examined the effect of EHFA amplitude on doxorubicin Ads via a bio MOF11 carrier using molecular dynamics (MD) modeling. According to MD data, EHFA was expected to have a significant effect on the atomistic evolution of the proposed drug-MOF11 system. The system's interaction energy (IE) and diffusion coefficient rose from −937.27 kcal/mol and 61.40 nm2/ns to −984.08 kcal/mol and 75.16 nm2/ns when EHFA changed from 0.01 to 0.05 W/m2. Increasing EHFA to 0.05 W/m2 resulted in a mean square displacement (MSD) parameter of 69.16 Å2. Therefore, based on the numerical results from this study, it can be said that the doxorubicin drug-MOF11 system changed and atomically evolved when the applied EHFA changes in magnitude.

Mu-Opioid Receptor (MOR) Dependence of Pain in Chemotherapy-Induced Peripheral Neuropathy.

We recently demonstrated that transient attenuation of Toll-like receptor 4 (TLR4) in dorsal root ganglion (DRG) neurons, can both prevent and reverse pain associated with chemotherapy-induced peripheral neuropathy (CIPN), a severe side effect of cancer chemotherapy, for which treatment options are limited. Given the reduced efficacy of opioid analgesics to treat neuropathic, compared with inflammatory pain, the cross talk between nociceptor TLR4 and mu-opioid receptors (MORs), and that MOR and TLR4 agonists induce hyperalgesic priming (priming), which also occurs in CIPN, we determined, using male rats, whether (1) antisense knockdown of nociceptor MOR attenuates CIPN, (2) and attenuates the priming associated with CIPN, and (3) CIPN also produces opioid-induced hyperalgesia (OIH). We found that intrathecal MOR antisense prevents and reverses hyperalgesia induced by oxaliplatin and paclitaxel, two common clinical chemotherapy agents. Oxaliplatin-induced priming was also markedly attenuated by MOR antisense. Additionally, intradermal morphine, at a dose that does not affect nociceptive threshold in controls, exacerbates mechanical hyperalgesia (OIH) in rats with CIPN, suggesting the presence of OIH. This OIH associated with CIPN is inhibited by interventions that reverse Type II priming [the combination of an inhibitor of Src and mitogen-activated protein kinase (MAPK)], an MOR antagonist, as well as a TLR4 antagonist. Our findings support a role of nociceptor MOR in oxaliplatin-induced pain and priming. We propose that priming and OIH are central to the symptom burden in CIPN, contributing to its chronicity and the limited efficacy of opioid analgesics to treat neuropathic pain.

FAM109B plays a tumorigenic role in low-grade gliomas and is associated with tumor-associated macrophages (TAMs)

BackgroundFamily with sequence similarity 109, member B (FAM109B) is involved in endocytic transport and affects genetic variation in brain methylation. It is one of the important genes related to immune cell-associated diseases. In the tumor immune system, methylation can regulate tumor immunity and influence the maturation and functional response of immune cells. Whether FAM109B is involved in tumor progression and its correlation with the tumor immune microenvironment has not yet been disclosed.MethodsA comprehensive pan-cancer analysis of FAM109B expression, prognosis, immunity, and TMB was conducted. The expression, clinical features, and prognostic value of FAM109B in low-grade gliomas (LGG) were evaluated using TCGA, CGGA, and Gravendeel databases. The expression of FAM109B was validated by qRT-PCR, immunohistochemistry (IHC), and Western blotting (WB). The relationship between FAM109B and methylation, Copy Number Variation (CNV), prognosis, immune checkpoints (ICs), and common chemotherapy drug sensitivity in LGG was explored through Cox regression, Kaplan–Meier curves, and Spearman correlation analysis. FAM109B levels and their distribution were studied using the TIMER database and single-cell analysis. The potential role of FAM109B in gliomas was further investigated through in vitro and in vivo experiments.ResultsFAM109B was significantly elevated in various tumor types and was associated with poor prognosis. Its expression was related to aggressive progression and poor prognosis in low-grade glioma patients, serving as an independent prognostic marker for LGG. Glioma grade was negatively correlated with FAM109B DNA promoter methylation. Immune infiltration and single-cell analysis showed significant expression of FAM109B in tumor-associated macrophages (TAMs). The expression of FAM109B was closely related to gene mutations, immune checkpoints (ICs), and chemotherapy drugs in LGG. In vitro studies showed increased FAM109B expression in LGG, closely related to cell proliferation. In vivo studies showed that mice in the sh-FAM109B group had slower tumor growth, slower weight loss, and longer survival times.ConclusionsFAM109B, as a novel prognostic biomarker for low-grade gliomas, exhibits specific overexpression in TAMs and may be a potential therapeutic target for LGG patients.

Impact of 10% Dose Reductions and Duration of Treatment Delays in the Management of Chemotherapy-Induced Neutropenia in Dogs Treated With Common Chemotherapy Protocols: A Single-Centre Experience.

Neutropenia is a common chemotherapy-associated adverse event (AE) in dogs and a significant cause of decreased relative dose intensity. Dose reductions (DRs) and treatment delays (TDs) are frequently applied to decrease the risk of further neutropenic events (NEs) and AEs, but there is no standardised approach. The two main objectives of this retrospective study were to determine: (1) the failure rate of a 10% DR to prevent a subsequent inadequate absolute neutrophil count (ANC), defined as a nadir ANC <0.75 × 109/L or pretreatment ANC <1.5 × 109/L; and (2) if the duration of TDs due to pretreatment neutropenia affects the occurrence of subsequent NEs. A total of 1056 chemotherapy treatments were recorded for 128 dogs that developed at least one NE. In 75 of 124 (60.5%, 95% CI: 51.2%-69%) evaluable NEs, a nadir ANC of ≥0.75 × 109/L and pretreatment ANC of ≥1.5 × 109/L were achieved after a single 10% chemotherapy DR, while a 10% DR failed to prevent a subsequent inadequate ANC in the remaining 49/124 (39.5%, 95% CI: 30.1%-48.3%). The only variable associated with failure was the drug prescribed. DR failure occurred in 22/39 (56.4%, 95% CI: 40.9%-70.6%) lomustine DRs, 14/27 (51.9%, 95% CI: 33.9%-69.2%) cyclophosphamide DRs, but only 2/22 (9.1%, 95% CI: 2.5%-27.8%) doxorubicin DRs and 2/24 (8.3%, 95% CI: 2.3%-25.8%) vincristine DRs. Seventy-three evaluable TDs (mean: 5 days, SD ± 2.2 days) were prescribed. There was no association between TD duration and subsequent NEs (p = 0.11).

The dynamic changes of circulating myeloid-derived suppressor cells (MDSCs) subsets in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy.

62 Background: Increased level of circulating myeloid-derived suppressor cells (MDSCs) have been associated with higher tumor stage, poorer survival, and poorer response to therapeutic agents in colorectal cancer (CRC). It has been reported that the common first-line chemotherapy involving combination with oxaliplatin mediated MDSCs depletion via induction of cell death. However, this phenomenon is yet to be further investigated since it only occurred in polymophonuclear MDSC (PMN-MDSC) subset, not in monocytic MDSC (M-MDSC). The present study aims to learn deeper on the dynamic changes of circulating MDSCs in response to oxaliplatin-based treatment in CRC patients. Methods: This was a prospective study that recruited 30 treatment-naïve patients with varying stage of CRC who were scheduled to receive oxaliplatin-based chemotherapy. Blood sampling was conducted prior and at several time points during and after chemotherapy. Multicolor flow cytometry assay was used to analyze the proportion of HLA-DR-, CD33+, and CD15+ (PMN-MDSC) and CD14+ (M-MDSC) cells within peripheral blood mononuclear cells (PBMCs). Other essential tumor biomarkers such as carcinoembryonic antigen (CEA) and tumor infiltrating lymphocytes (TILs) were assessed as well. As control, 14 healthy subjects were recruited. Results: Our result showed that circulating PMN-MDSCs was significantly higher in CRC patients compared to healthy subjects (p=0.003), whilst insignificant result was shown by M-MDSCs (p=0.890). Following chemotherapy, MDSCs level showed dynamic changes. Interestingly, a subgroup of CRC patients with decreased in both PMN- and M-MDSCs levels on D-14 chemotherapy were consistently showed a significant decreased of MDSCs level during and after therapy completion compared to baseline (p=0.0078). Conclusions: Circulating MDSCs level, particularly PMN-MDSCs in CRC patients was significantly higher compared to healthy subjects. Changes in both circulating PMN- and M-MDSCs levels at D-14 chemotherapy might have prognostic value in oxaliplatin-based chemotherapy.

Immediate intratesticular injection of circulating blood serum-derived exosomes may alleviate orchitis caused by cisplatin

Objective: Cisplatin (CIS), as a common chemotherapy drug, induces detrimental effects on the testis. Besides, exosomes represent various beneficial effects, such as anti-inflammation and proliferation. In this experimental study, the authors aimed to evaluate the anti-inflammatory effects of circulating blood serum-derived exosomes on orchitis caused by CIS exposure. Methods: Male mice (n=18) were categorized into three main groups: control (no treatment), CIS (mice with orchitis caused by CIS injection), and CIS+Exosome (orchitis-induced animals followed by exosome treatment). Exosomes were extracted from circulating blood, and orchitis was induced by intraperitoneal injection of CIS (7.5mg/kg/day) for 5 consequence days. A day after the last dose of CIS, the exosome (10IU/20grmice) was injected intratesticularly. After a week, the samples, including blood serum and testis, were gathered. The levels of oxidative stress were assessed using Malondialdehyde (MDA) and nitric oxide (NO) assays. Sperm parameters (morphology, viability, motility, and count), testosterone levels, and inflammatory (TNF-α, IL-6, and IL-10) gene expression were also evaluated. Histopathological and testicular apoptotic index (AI) were evaluated using H&amp;E and TUNEL stainings, respectively. Finally, data analysis was applied by SPSS (v.19) software, and P&lt;0.05 was considered as a significant level. Results: Following CIS administration, the sperm indices and testosterone levels were decreased (P&lt;0.05); besides, NO, MDA, AI, and inflammatory gene expression were increased (P&lt;0.05) in the CIS group compared to control animals. Following the prescription of Exosomes in CIS animals, the sperm indices and testosterone levels were increased (P&lt;0.05), and NO, MDA, AI, and inflammatory genes were decreased (P&lt;0.05). Histopathological assessments also revealed disruption of seminiferous tubules and free from sperms following CIS administration. Also, the histological structure of damaged seminiferous tubules was changed to normal status following Exoxome prescription in CIS-exposure animals. Conclusion: Immediate intratesticular injection of blood-derived exosomes can alleviate orchitis CIS-exposed animals through anti-inflammatory features.

Poly(2-(dimethylamino) ethyl methacrylate)-b-poly (hydroxy propyl methacrylate) nanoparticles for guided delivery of MCL-1 CRISPR-Cas9 plasmid and doxorubicin to non-small cell lung cancer

Combining gene therapy with other therapeutic methods, such as chemotherapy, using nanocarriers can lead to higher therapeutic effects through different mechanisms. In the current study, poly(2-(dimethylamino) ethyl methacrylate)-b-poly (hydroxy propyl methacrylate) (PDMAEMA-b-PHPMA) copolymer was synthesized in order to encapsulate either doxorubicin (DOX) or MCL-1 CRISPR.Cas9 plasmid (NP/DOX and NP/CRISPR.Cas9 plasmid). Then, for site-specific targeting against non-small cell lung cancer (SKMES-1 and A549 cell lines) overexpressing nucleolin receptors, AS1411 aptamer was attached to the surface of the prepared platforms through electrostatic interactions. The developed system was extensively evaluated for its transfection efficiency, cellular toxicity, and effectiveness in treating SKMES-1 tumor-bearing C57BL/6 nude mice. The results indicated that the targeted NP/DOX+NP/CRISPR.Cas9 plasmid complex enhanced cellular uptake into target cells, SKMES-1 and A549, through receptor- mediated endocytosis. Furthermore, comparative in vitro cytotoxicity results showed that the cells were exposed to the combination of NP/DOX and NP/CRISPR.Cas9 plasmid complex caused significantly enhanced cytotoxicity compared to treatment with each of them alone. In vivo study revealed that the AS1411-tagged nanoparticles (Apt-NP/DOX+Apt-NP/CRISPR.Cas9 plasmid) had a more pronounced inhibitory effect on tumor growth compared to non-targeted nanoparticles (NP/DOX+NP/CRISPR.Cas9 plasmid), moreover, co-treatment with MCL-1 sgRNA CRISPR.Cas9 plasmid and DOX increased the drug sensitivity of SKMES-1 cells towards DOX, which enhanced the therapeutic effects in mice receiving treatment with Apt-NP/DOX in combination with Apt-CRISPR.Cas9 plasmid nanocomplex. In conclusion, the findings indicated that the combination of common chemotherapy such as DOX and genome editing for MCL-1 through CRISPR.Cas9 system would provide a potential and safe method for treating non-small cell lung cancer which has excellent capacity for the clinical translation.

The treatment pattern of advanced HR-positive and HER2-negative breast cancer in central southern China: a hospital-based cross-sectional study

AimsThis investigation aims to elucidate the treatment status of advanced HR+/HER2- breast cancer patients in Hunan Province of Central Southern China from November 2021 to December 2022.MethodsData from 301 patients with advanced HR+/HER2- breast cancer were collected from the breast cancer investigation project in Hunan under the guidance of the Chinese Society of Clinical Oncolfogy (CSCO). The data included the clinical characteristics of patients and the status of first-line and second-line rescue treatment.ResultsFirst-line chemotherapy and endocrine therapy for mBC accounted for 40% (121/301) and 60% (180/301) of treatments, respectively. AI (21%), AI plus CDK4/6 inhibitor (28%), and fulvestrant (24%) or fulvestrant plus CDK4/6 inhibitor (18%) were the most common first-line endocrine therapies. Taxane-based chemotherapy was the most common first-line chemotherapy (59%). Second-line chemotherapy and endocrine therapy for mBC accounted for 43% (72/166) and 57% (94/166) of treatments, respectively. Fulvestrant (23%) or fulvestrant plus CDK4/6 inhibitor (29%) were the most common second-line endocrine therapies. The prevalences of AI and AI plus CDK4/6 inhibitor decreased to 19% and 11%, respectively. T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Third-line chemotherapy was more prevalent than endocrine therapy (57% vs. 41%). T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Fulvestrant plus CDK4/6 inhibitor was the most common endocrine therapy (33%). AI, AI plus CDK4/6 inhibitor, and fulvestrant accounted for 21%, 12% and 18% of third-line endocrine therapies, respectively.ConclusionsCompared to chemotherapy, endocrine therapy was a more favorable choice for first-line and second-line treatment for HR+/HER2- advanced breast cancer patients in Hunan Province.

A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention.

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer-secreted protein that becomes overexpressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig-like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical, and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis. NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia-inducible factor-1α (HIF1α) nuclear retention and function. NPTX1 is overexpressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1α hypoxic response in PDAC. Significance: We identified the NPTX1-AMIGO2 axis as a regulatory mechanism upstream of HIF1α-driven hypoxia response that promotes PDAC liver metastasis. Therapeutic NPTX1 targeting outperformed a common chemotherapy regimen in inhibiting liver metastasis and suppressed primary tumor growth in preclinical models, revealing a novel therapeutic strategy targeting hypoxic response in PDAC.