Side Effects In Cancer Patients Research Articles

Immune Modulation Effects of Lactobacillus casei Variety rhamnosus on Enterocytes and Intestinal Stem Cells in a 5-FU-Induced Mucositis Mouse Model.

Background Intestinal mucositis remains one of the most deleterious side effects in cancer patients undergoing chemotherapy. We hypothesize that the probiotics could preserve gut ecology, ameliorate inflammation, and protect epithelia via immune modulations of enterocytes and intestinal stem cells. Our aim is to characterize these changes and the safety of probiotics via a 5-fluorouracil- (5-FU-) induced intestinal mucositis mouse model. Methods 5-FU-injected BALB/c mice were either orally administrated with saline or probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35). Diarrhea scores, serum proinflammatory cytokines, and T-cell subtypes were assessed. Immunostaining analyses for the proliferation of intestinal stem cells CD44 and Ki67 were processed. Samples of blood and internal organs were investigated for bacterial translocation. Results Diarrhea was attenuated after oral Lcr35 administration. Serum proinflammatory cytokines were significantly increased in the 5-FU group and were reversed by Lcr35. A tremendous rise of the CD3+/CD8+ count and a significant decrease of CD3+CD4+/CD3+CD8+ ratios were found in the 5-FU group and were both reversed by Lcr35. 5-FU significantly stimulated the expression of CD44 stem cells, and the expression was restored by Lcr35. 5-FU could increase the number of Ki67 proliferative cells. No bacterial translocation was found in this study. Conclusions Our results showed that 5-FU caused intestinal inflammation mainly via Th1 and Th17 responses. 5-FU could stimulate stem cells and proliferation cells in a mouse model. We demonstrate chemotherapy could decrease immune competence. Probiotics were shown to modulate the immune response. This is the first study to analyze the immune modulation effects and safety of Lactobacillus strain on enterocytes and intestinal stem cells in a mouse model.

Effectiveness of nursing interventions in preventing and treating radiotherapy side effects in cancer patients: a systematic review.

To synthesize the best available evidence on the effectiveness of nursing interventions in radiotherapy patient care and to summarize the evidence on the experience and acceptability of interventions reported by health professionals involved in the prevention and treatment of side effects. A mixed-method systematic review. Quantitative and qualitative studies are presented. Twelve studies published between 2013 and 2017 were included. Most interventions found focused on skin care, oral care, nausea and vomiting and nursing consultation. In accordance with high level of evidence and recommendation grade of the studies, the use of Calendula officinalis and thyme honey were considered effective for preventing and treating radiodermatitis and mucositis, respectively. The quality of evidence of nursing interventions is weak. Although there are studies with a strong design and a high level of evidence, publication of nursing interventions is not enough and does not present a high quality to support practice to plan an effective patient-centered care.

Successive treatment with naltrexone induces epithelial-mesenchymal transition and facilitates the malignant biological behaviors of bladder cancer cells.

Naltrexone is widely used for alleviating opioid-related side effects in cancer patients. However, the effects of naltrexone on cancer progression are controversial in the literature. The present study was carried out to investigate the effects of successive treatment with clinically relevant doses of naltrexone on the malignant biological behaviors of bladder cancer cells. The human bladder cancer T24 cells and mouse bladder cancer MB49 cells were treated with naltrexone. Cell proliferation, migration, and invasion abilities were analyzed. Morphological changes of the cells were confirmed by F-actin immunofluorescence staining. Epithelial-mesenchymal transition (EMT)-related markers and transcriptional factors, as well as activation of the phosphatidylinositol 3 kinase (PI3K)/AKT signaling pathway, were analyzed. Results showed that, compared with the control group, successive treatment with naltrexone significantly promoted the proliferation and decreased the apoptosis of bladder cancer cells, together with increase in cell migration and invasion ability. Continuous treatment with naltrexone also significantly reduced the expression of epithelial markers (E-cadherin and cytokeratin 19), increased the expression of mesenchymal markers (N-cadherin and vimentin) and EMT-inducing transcription factors (Snail and Slug), and further shifted the morphological phenotype of bladder cancer cells to a mesenchymal phenotype. The PI3K/AKT signaling pathway was activated by successive treatment with naltrexone. Notably, incubation with the specific PI3K inhibitor LY294002 together with naltrexone reversed the naltrexone-induced EMT progression. In conclusion, successive treatment with naltrexone may be favorable for the progression of bladder tumors by activating the PI3K/AKT signaling pathway and inducing EMT. Long-term exposure to naltrexone should be used cautiously in patients with bladder cancer.

Improved survival without increased toxicity with influenza vaccination in cancer patients treated with checkpoint inhibitors

ABSTRACT In international guidelines, influenza vaccination is recommended to cancer patients receiving antitumor treatment. Whether this recommendation should include patients treated with the recently introduced and now widely used checkpoint inhibitors (CPIs) is unclear. The immune hyperactivation after vaccination in a patient on CPI treatment may strengthen the antitumor immunity and improve patients´ prognosis. On the other hand, the hyperactivation might increase the risk for immune-related adverse events (IRAEs). Furthermore, there is a risk for decreased antitumor effect by the phenomenon of antigenic competition. Only results from few studies addressing survival have been reported and the results from studies on IRAEs are contradictory. We performed a multi-center retrospective cohort study at three Swedish centers in patients with metastatic cancer. All patients previously not treated with CPIs and who received monotherapy with a PD-1 or PD-L1 blocker between January 1st, 2016 until May 31st, 2019 were included. The most common type of malignancy was melanoma (47.8%) followed by non-small cell lung cancer (31.0%). Statistically significant longer PFS and OS were observed in multivariate analyses at 6-month landmark time in the vaccinated compared to the non-vaccinated group after adjustment for age, gender, comorbidity, performance status, CNS metastasis and line of treatment (p = .041 and 0.028, respectively). Furthermore, the incidence of any IRAE grade was comparable between vaccinated and non-vaccinated group (p = .85). In conclusion, the current study indicates that survival improves with influenza vaccination while not increasing the risk for side effects in cancer patients treated with checkpoint inhibitors. Hence, our results strongly support influenza vaccination in cancer patients receiving checkpoint inhibitors.

Effect of Traditional Chinese Medicine Injection on Cancer-Related Fatigue: A Meta-Analysis Based on Existing Evidence.

Methods We systematically searched randomized controlled studies reported through March 2020 in PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, China Biomedical Literature Database (CBM), the China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases. Two investigators independently screened the studies according to the predetermined criteria, extracted data, and evaluated the bias risk of the included studies, using RevMan5.3 software. Results Twelve studies enrolling 1005 participants were included in this systematic review. We found that TCMJ could improve the clinical efficacy of CRF patients (RR = 1.24, 95% CI: 1.05–1.46, P=0.01), ameliorate fatigue status (RR = 1.44, 95% CI: 1.27–1.65, P < 0.00001), and improve quality of life (MD = 8.34, 95% CI: 3.31–13.37, P=0.001), but there was no statistical significance in the fatigue score (MD = −1.10, 95% CI: −2.23–0.04, P=0.06). Referring to the number of adverse events, the safety of TCMJ was good. Subgroup analysis showed that TCMJ could improve clinical efficacy, fatigue, and quality of life in a short time (≤4 weeks). Among them, tonic TCMJ could improve the clinical efficacy. TCMJ had advantages in improving fatigue of lung cancer and gastric cancer. In addition, life quality of lung cancer patients improved significantly. Conclusion Current research evidence showed that TCMJ could improve the clinical efficacy, fatigue status, and life quality of patients with CRF. In addition, we found that TCMJ could improve the clinical efficacy of CRF patients in a short period of time. Tonic TCMJ could improve the clinical efficacy, but heat-clearing TCMJ could not. Life quality and fatigue status of lung cancer patients improved significantly. However, due to the sample size and quality of the included studies, the results of this analysis should be treated with caution. The above conclusions still need to be verified by more large-sample and high-quality randomized controlled trials.

Preventive effect and safety of Chinese herbal medicine mouthwash in chemotherapy-induced oral mucositis: A protocol for systematic review and meta analysis.

Background:Oral mucositis (OM), one of the most common side effects for cancer patients who have undergone chemotherapy, can cause severe impairment to patients’ functional ability and impact their quality of life, resulting in delayed and/or incomplete treatment. Traditional Chinese medicine offers empirical herbal decoctions to gargle for the prevention of chemotherapy-induced OM; however, evidence for its clinical efficacy and safety is lacking. Therefore, we provide a protocol to evaluate the preventive effect and safety of Chinese herbal medicine mouthwash in chemotherapy-induced OM.Methods:We will comprehensively retrieve relevant articles published till August 15, 2020, in the following electronic databases: the Cochrane Library, PubMed, EMBASE, Chinese National Knowledge Infrastructure Database, Chinese Biomedical Literature Database, Chinese Science and Technique Journals Database, and the Wan-fang Database. Only randomized controlled trials will be included. We will use the criteria provided by the Cochrane Handbook for quality assessment and risk assessment of the included studies and use the RevMan 5.3 software for meta-analysis of the preventive effect and safety.Results:This study will assess the preventive effect and safety of Chinese herbal medicine mouthwash in chemotherapy-induced OM.Conclusion:This systematic review will provide evidence-based medical corroboration for the clinical application of the Chinese herbal medicine mouthwash in chemotherapy-induced OM.PROSPERO registration number:CRD42020206614.

Polysaccharides extracted from Rheum tanguticum ameliorate radiation-induced enteritis via activation of Nrf2/HO-1.

ABSTRACTRadiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. The Nrf2/HO-1 pathway is a critical endogenous antioxidant stress pathway, but its precise role in radiation-induced enteritis remains to be clarified. Polysaccharides extracted from Rheum tanguticum (RTP) can protect the intestinal cells from radiation-induced damage, but the underlying mechanism is unknown. SD rats and IEC-6 cells were exposed to 12 or 10 Gy X-ray radiation. Rat survival, and histopathological and immunohistochemical profiles were analyzed at different time points. Indicators of oxidative stress and inflammatory response were also assessed. Cell viability, apoptosis and Nrf2/HO-1 expression were evaluated at multiple time points. Significant changes were observed in the physiological and biochemical indexes of rats after radiation, accompanied by significant oxidative stress response. The mRNA and protein expression of Nrf2 peaked at 12 h after irradiation, and HO-1 expression peaked at 48 h after irradiation. RTP administration reduced radiation-induced intestinal damage, upregulated Nrf2/HO-1, improved physiological indexes, significantly decreased apoptosis and inflammatory factors, and upregulated HO-1, particularly at 48 h after irradiation. In conclusion, Nrf2 is activated in the early stage of radiation-induced intestinal injury and plays a protective role. RTP significantly ameliorates radiation-induced intestinal injury via the regulation of Nrf2 and its downstream protein HO-1.

Use of Text Messaging (SMS) for the Management of Side Effects in Cancer Patients Undergoing Chemotherapy Treatment: a Randomized Controlled Trial.

Cancer patients are often not sufficiently oriented to manage side effects at home. Sending text messages with self-care guidelines aimed managing side effects is the main objective of this randomized controlled trial. Patients who started outpatient chemotherapy treatment between March and December 2017 at a hospital in southern Brazil were invited to participate in this study and were allocated to the intervention or control group (ratio 1: 1). Each patient in the intervention group received a daily SMS (short message service) with some guidance on management or prevention of side effects. All text messages were sent to the intervention group patients in an automated and tailored way by our app called cHEmotHErApp. Side effects experienced by patients were verified using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30). Results showed intervention group patients experienced fewer side effects compared to the control group in cycle 1 (p < 0.05), in general. In addition, intervention group experienced less nausea in relation to the control group, in the cycle 1 and cycle 2 (p < 0.05). This study indicate text messaging may be a tool for supporting side effect management in patients receiving chemotherapy. This study was enrolled in ClinicalTrials.gov with the identification number NCT03087422. This research was performed in accordance with the Declaration of Helsinki.Electronic supplementary materialThe online version of this article (10.1007/s10916-020-01663-x) contains supplementary material, which is available to authorized users.

Anticancer Efficacy of Oral Docetaxel Nanoformulation for Metronomic Chemotherapy in Metastatic Lung Cancer.

Metronomic chemotherapy, giving low doses of chemotherapeutics (e.g., docetaxel) on a frequent schedule over a long time, may improve outcomes and reduce side effects for cancer patients. Oral medications are vital for applying metronomic chemotherapy. However, low solubility, low absorption, low drug availability in the targeted tissue, and side effects limit the development of oral chemotherapeutics. Many chemotherapeutics are intravenously delivered. In this work, we developed a new docetaxel granule that produces docetaxel-loaded in situ self-assembled nanoparticle (180 nm) upon contact with water. The process of manufacturing docetaxel granules is scalable in industrial settings. The lung selectivity of docetaxel granule was observed in animals. The mechanistic studies demonstrated the nanoparticle bound with red blood cells, which selectively delivers docetaxel to the lungs. Finally, docetaxel granule (5 mg/kg twice per week) can profoundly inhibit the tumor growth of lung-metastatic cancer xenograft model over 24 days. The material-based lungselective oral nanoformulation provides an opportunity for conventionally intravenous chemotherapy drugs to be easily applied in oral administration for metronomic chemotherapy for cancer patients with lung cancers.

A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo.

Naphthalimides, such as amonafide and mitonafide in clinical trials, have been developed as antitumor agents for orthotopic tumor. However, the serious side effects in cancer patients limit their applications. Herein, a new class of polyamine-based naphthalimide conjugates 5a-5c, 7a-7b, and 11a-11b with and without the alkylation of the distant nitrogen in the polyamine chain were synthesized and the mechanism was determined. Compared with amonafide, dinitro-naphthalimide conjugate 5c with a 4,3-cyclopropyl motif preferentially accumulates in cancer cells and minimizes side effects in vitro and in vivo. More importantly, 5c at the dosage of as low as 3 mg/kg (57.97%) displays better antitumor effects than the positive control amonafide (53.27%) at 5 mg/kg in vivo. And a remarkably elevated antitumor activity and a reduced toxicity are also observed for 5c at 5 mg/kg (65.90%). The upregulated p53 and the apoptotic cells (73.50%) indicate that the mechanism of 5c to induce apoptosis may result from its enhanced DNA damage. Further investigation indicates that in addition to target DNA, 5c can modulate the polyamine homeostasis by upregulating polyamine oxidase (PAO) in a different way from that of amonafide. And also by targeting PTs overexpressed in most of cancer cells, 5c downregulates the contents of Put, Spd, and Spm, which are in favor of suppressing fast-growing tumor cells. Our study implies a promising strategy for naphthalimide conjugates to treat hepatic carcinoma with notable activities and reduced toxicities at a low dosage.

Expert Consensus on Effective Management of Chemotherapy-Induced Nausea and Vomiting: An Indian Perspective.

Chemotherapy-induced nausea and vomiting (CINV) is one of the most common and feared side effects in cancer patients undergoing chemotherapy. Scientific evidence proves its detrimental impact on a patient's quality of life (QoL), treatment compliance, and overall healthcare cost. Despite the CINV-management landscape witnessing a radical shift with the introduction of novel, receptor-targeting antiemetic agents, this side effect remains a chink in the armor of a treating oncologist. Though global guidelines acknowledge patient-specific risk factors and chemotherapeutic agent emetogenic potential in CINV control, a “one-fit-for-all” approach cannot be followed across all geographies. Hence, in a pioneering attempt, India-based oncologists conveyed easily implementable, region-specific, consensus-based statements on CINV prevention and management. These statements resulted from integrating the analysis of scientific evidence and guidelines on CINV by the experts, with their clinical experience. The statements will strengthen decision-making abilities of Indian oncologists/clinicians and help in achieving consistency in CINV prevention and management in the country. Furthermore, this document shall lay the foundation for developing robust Indian guidelines for CINV prevention and control.

Cancer Vaccines and Oncolytic Viruses Exert Profoundly Lower Side Effects in Cancer Patients than Other Systemic Therapies: A Comparative Analysis.

This review compares cytotoxic drugs, targeted therapies, and immunotherapies with regard to mechanisms and side effects. Targeted therapies relate to small molecule inhibitors. Immunotherapies include checkpoint inhibitory antibodies, chimeric antigen receptor (CAR) T-cells, cancer vaccines, and oncolytic viruses. All these therapeutic approaches fight systemic disease, be it micro-metastatic or metastatic. The analysis includes only studies with a proven therapeutic effect. A clear-cut difference is observed with regard to major adverse events (WHO grades 3–4). Such severe side effects are not observed with cancer vaccines/oncolytic viruses while they are seen with all the other systemic therapies. Reasons for this difference are discussed.

PD-1 Imposes Qualitative Control of Cellular Transcriptomes in Response to T Cell Activation.

Targeted blockade of programmed cell death 1 (PD-1), an immune-checkpoint receptor that inhibits Tcell activation, provides clinical benefits in various cancers. However, how PD-1 modulates gene expression in Tcells remains enigmatic. Here weinvestigated how PD-1 affects transcriptome changes induced by Tcell receptor (TCR) activation. Intriguingly, we identified a huge variance in PD-1 sensitivity among TCR-inducible genes. When we quantified the half maximal effective concentration (EC50) as the relationship between change in gene expression and TCR signal strength, we found that genes associated with survival and proliferation were efficiently expressed upon TCR activation and resistant to PD-1-mediated inhibition. Conversely, genes encoding cytokines and effector molecules were expressed less efficiently and sensitive to PD-1-mediated inhibition. We further demonstrated that transcription factor binding motifs and CpG frequency in the promoter region affect EC50 and thus the PD-1 sensitivity of genes. Our findings explain how PD-1, dependent on the TCR signal strength, calibrates cellular transcriptomes to shape functional properties of Tcell populations.

Effects of exercise therapy in cancer patients undergoing radiotherapy treatment: a narrative review.

Despite its beneficial effects, radiotherapy still results in a range of side effects that negatively impact quality of life of patients. Exercise has been shown to counteract the side effects induced by cancer treatment. This narrative review aims to provide an up-to-date review of the effects of an exercise intervention in cancer patients during radiotherapy. A literature search was performed on PubMed to identify original articles that evaluated the effects of an exercise programme to alleviate treatment-related side effects in cancer patients undergoing radiotherapy with or without other cancer treatments. Benefits related to exercise training have been shown in breast, prostate, rectal, lung, head and neck cancer patients undergoing radiotherapy. Therefore, exercise should be considered as a concurrent treatment alongside radiotherapy to alleviate treatment-related side effects and facilitate effective recovery. Due to the onset and progress of treatment-related side effects throughout radiotherapy, a regular clinical evaluation seems strongly advisable in order to continuously adapt the exercise programme depending on symptoms and side effects. An exercise professional is needed to personalize exercise training based on the medical condition and tailor it throughout the intervention according to progress and the patient’s medical status. Future studies are needed to confirm the potential benefits of exercises observed on treatment-related side effects. Furthermore, because of the narrative design of this study, a systematic review is required to evaluate the strength of the evidence reported.

Efficacy of Ice Ball Oral Care on Subjective-Objective Oral Health Status in Cancer Patients: A Pilot Study

Background/Objectives: Oral mucositis and oral discomfort are common side effects in cancer patients undergoing chemotherapy. The purpose of this study is to examine the efficacy of ice ball oral care on subjective-objective oral health status induced by chemotherapy in adult cancer patients among Korean Women . Method/Statistical analysis: Participants were randomly assigned either to the experimental group(n=15) that received ice ball oral care during chemotherapy or the control group(n=15) that received normal saline oral care during chemotherapy. Findings: There was a significant difference in oral mucositis, and oral discomfort between the two groups, and there were significant changes over time and the group by time interactions. Improvements/Applications: The findings of the study demonstrated that ice ball oral care was more effective than the normal saline oral care in improving subjective-objective oral health status in adult cancer patientss undergoing chemotherapy.

Nrf2-modulation by seleno-hormetic agents and its potential for radiation protection.

The trace element selenium (Se) is an essential component of selenoproteins and plays a critical role in redox signaling via regulating the activity of selenoenzymes such as thioredoxin reductase-1 and glutathione peroxidases. Se compounds and its metabolites possess a wide range of biological functions including anticancer and cytoprotection effects, modulation of hormetic genes and antioxidant enzyme activities. Radiation-induced injury of normal tissues is a significant side effect for cancer patients who receive radiotherapy in the clinic and the development of new and effective radioprotectors is an important goal of research. Others and we have shown that seleno-compounds have the potential to protect ionizing radiation-induced toxicities in various tissues and cells both in in vitro and in vivo studies. In this review, we discuss the potential utilization of Se compounds with redox-dependent hormetic activity as novel radio-protective agents to alleviate radiation toxicity. The cellular and molecular mechanisms underlying the radioprotection effects of these seleno-hormetic agents are also discussed. These include Nrf2 transcription factor modulation and the consequent upregulation of the adaptive stress response to IR in bone marrow stem cells and hematopoietic precursors.

Effect of Omega-3 Fatty Acid Supplements on Cancer-related Fatigue in an Outpatient Setting: A Randomized Controlled Trial

Background: Fatigue, as one of the most common side effects of cancer and its associated treatments, induces a distressing, persistent, and inward feeling. This study aimed to investigate the synergistic effect of the omega-3 supplement as an unconfirmed effect on conventional ginseng treatment with a possible effect on this side effect in cancer patients. Method: This clinical trial was conducted in 2018 on 70 cancer patients referring to outpatient clinics affiliated to Isfahan University of Medical Sciences. Patients were included in the study by the convenience sampling method and were randomly divided into control and intervention groups. Patients in the treatment group received an omega-3 supplement and usual treatment. For patients in the control group, only the usual intervention was administered. Data were collected using the Multidimensional Fatigue Inventory questionnaire. The duration of intervention was 6 weeks. The primary outcome was the improvement of fatigue scores measured by the questionnaire. Result: There was a significant difference in both groups concerning the mean total fatigue score in three times; i.e., 0, 3, and 6 weeks after the intervention (P <0.001). Mean value of total fatigue score at the beginning of the study was 77.8±6.6 in the intervention group and 76.8±9.7 in the control group. After 3 weeks of the study, it was 49.2±6.8 and 57.5±9.5 and after 6 weeks it was 25.3±7.8 and 37.2±8.4 in the intervention group and in the control group, respectively. Conclusion: This study revealed that omega-3 supplement can reduce cancerrelated fatigue in outpatient cancer patients compared with the control group.

Nonviral Delivery of GRIM-19 Gene Inhibits Tumor Growth with Reduced Local and Systemic Complications.

Chemotherapy causes inflammation, which promotes cancer development and results in complications such as hemorrhages and thrombosis. Development of new therapeutic strategies to limit inflammatory responses will potentially reduce these side effects in cancer patients. Gene therapy is an attractive cancer treatment because of its high specificity and limited side effects. A tumor suppressor gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) was delivered by an amphiphilic copolymer poly(ɛ-caprolactone) and ethanolamine-functionalized poly (glycidyl methacrylate) (PCG). The transfection outcome of PCG/pGRIM-19 complexes was studied both in vitro and in vivo. The antitumor therapeutic effects were evaluated in a well-vascularized Neuro-2a neuroblastoma tumor mouse model in comparison with that of cisplatin. The PCG/pGRIM-19 nanocomplex showed high transfection efficiency and low toxicity. In vitro transfection of PCG/pGRIM-19 in Neuro-2a cells reduced the expression levels of Cyclin D1, BCL-2, and MMPs 2 and 9, and inhibited cell proliferation, migration, and stimulated apoptosis. In vivo experiments indicated that PCG/pGRIM-19 therapy downregulated signal transducer activator of transcription 3, nuclear factor-κB, and MMP9 expression in tumor tissues. Compared with cisplatin treatment, gene therapy with PCG/pGRIM-19 significantly inhibited local complications of intratumor hemorrhages, and systemic complications such as anemia and pulmonary embolism, thereby effectively prolonged mouse survival. Our results highlight the potential of PCG/pGRIM-19 gene therapy in reducing tumor burden and complications, providing novel strategies to enhance clinical cancer therapy.

Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment

ABSTRACTDexamethasone is a synthetic glucocorticoid commonly used for the prevention and management of side effects in cancer patients undergoing chemotherapy. While it is effective as an anti-emetic and in preventing hypersensitivity reactions, dexamethasone depletes peripheral blood lymphocytes and impacts immune responses. The effect of dexamethasone on the number and quality of tumour-infiltrating leukocytes has not been reported. To address this, we calibrated the dose in two different strains of mice to achieve the same extent of peripheral blood lymphocyte depletion observed in patients with cancer. Doses that caused analogous depletion of T and B lymphocytes and NK cells from the peripheral blood, elicited no change in these populations within the tumour. The expression of immune checkpoint molecules PD-1, OX40, GITR and TIM3 on tumour-infiltrating lymphocytes was not altered. We found that dexamethasone had a small but significant deleterious impact on weakly efficacious chemoimmunotherapy but had no effect when the protocol was highly efficacious. Based on these results, we predict that dexamethasone will have a modest negative influence on the overall effectiveness of chemoimmunotherapy treatment.

Macrophage Toll-like Receptor 9 Contributes to Chemotherapy-Induced Neuropathic Pain in Male Mice

Chemotherapy-induced peripheral neuropathy (CIPN) remains a pressing clinical problem; however, our understanding of sexual dimorphism in CIPN remains unclear. Emerging studies indicate a sex-dimorphic role of Toll-like receptor 4 (TLR4) in driving neuropathic pain. In this study, we examined the role of TLR9 in CIPN induced by paclitaxel in WT and Tlr9 mutant mice of both sexes. Baseline pain sensitivity was not affected in either Tlr9 mutant male or female mice. Intraplantar and intrathecal injection of the TLR9 agonist ODN 1826 induced mechanical allodynia in both sexes of WT and Tlr4 KO mice but failed to do so in Tlr9 mutant mice. Moreover, Trpv1 KO or C-fiber blockade by resiniferatoxin failed to affect intraplantar ODN 1826-induced mechanical allodynia. Interestingly, the development of paclitaxel-evoked mechanical allodynia was attenuated by TLR9 antagonism or Tlr9 mutation only in male mice. Paclitaxel-induced CIPN caused macrophage infiltration to DRGs in both sexes, and this infiltration was not affected by Tlr9 mutation. Paclitaxel treatment also upregulated TNF and CXCL1 in macrophage cultures and DRG tissues in both sexes, but these changes were compromised by Tlr9 mutation in male animals. Intraplantar adoptive transfer of paclitaxel-activated macrophages evoked mechanical allodynia in both sexes, which was compromised by Tlr9 mutation or by treatment with TLR9 inhibitor only in male animals. Finally, TLR9 antagonism reduced paclitaxel-induced mechanical allodynia in female nude mice (T-cell and B-cell deficient). Together, these findings reveal sex-dimorphic macrophage TLR9 signaling in chemotherapy-induced neuropathic pain.SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect in cancer patients undergoing clinical chemotherapy treatment regimens. The role of sex dimorphism with regards to the mechanisms of CIPN and analgesia against CIPN remains unclear. Previous studies have found that the infiltration of immune cells, such as macrophages into DRGs and their subsequent activation promote CIPN. Interestingly, the contribution of microglia to CIPN appears to be limited. Here, we show that macrophage TLR9 signaling promotes CIPN in male mice only. This study suggests that pathways in macrophages may be sex-dimorphic in CIPN. Our findings provide new insights into the role of macrophage signaling mechanisms underlying sex dimorphism in CIPN, which may inspire the development of more precise and effective therapies.