Pre-treatment levels of inflammatory markers and chemotherapy completion rates in patients with early-stage breast cancer.

BACKGROUND: Chemotherapy efficacy is largely dependent on treatment adherence, defined by the relative dose intensity (RDI). Identification of new modifiable risk factors associated with low RDI might improve chemotherapy delivery. Here, we evaluated the association between low RDI and pre-chemotherapy factors, including patient- and treatment-related characteristics and markers of inflammation. METHODS: This exploratory analysis assessed data from 267 patients with early-stage breast cancer scheduled to undergo (neo-)adjuvant chemotherapy included in the Physical training and Cancer (Phys-Can) trial. The association between low RDI, defined as < 85%, patient-related (age, body mass index, co-morbid condition, body surface area) and treatment-related factors (cancer stage, receptor status, chemotherapy duration, chemotherapy dose, granulocyte colony-stimulating factor) was investigated. Analyses further included the association between RDI and pre-chemotherapy levels of interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP) and Tumor Necrosis Factor-alpha (TNF-α) in 172 patients with available blood samples. RESULTS: An RDI of < 85% occurred in 31 patients (12%). Univariable analysis revealed a significant association with a chemotherapy duration above 20 weeks (p < 0.001), chemotherapy dose (p = 0.006), pre-chemotherapy IL-8 (OR 1.61; 95% CI (1.01; 2.58); p = 0.040) and TNF-α (OR 2.2 (1.17; 4.53); p = 0.019). In multivariable analyses, inflammatory cytokines were significant association with low RDI for IL-8 (OR: 1.65 [0.99; 2.69]; p = 0.044) and TNF-α (OR 2.95 [1.41; 7.19]; p = 0.007). CONCLUSIONS: This exploratory analysis highlights the association of pre-chemotherapy IL-8 and TNF-α with low RDI of chemotherapy for breast cancer. IL-8 and TNF-α may therefore potentially help to identify patients at risk for experiencing dose reductions. Clinical trial number NCT02473003 (registration: June 16, 2015).

Human immune cell mobilization during exercise: effect of IL-6 receptor blockade.

NEW FINDINGS: What is the central question of this study? Does blockade of the IL-6 receptor by tocilizumab inhibit immune cell mobilization to the blood stream in humans during an acute bout of exercise? What is the main finding and its importance? Blockade of IL-6 receptor signalling by tocilizumab attenuates mobilization of NK cells and dendritic cells to the blood stream during exercise. This implies an inhibitory effect of tocilizumab on the innate immune response to physical stress, which could be considered in clinical settings. ABSTRACT: Immune cells are recruited from their storage organs and the endothelial walls to the blood stream in response to physiological stress. This is essential for the recognition and clearing of infected, transformed or damaged cells. One of the most potent stimuli to recruit immune cells to the circulation is exercise. Accordingly, exercise has proven beneficial in disease settings, such as cancer and diabetes. Interleukin-6 (IL-6) is released from contracting skeletal muscle in response to exercise, and rodent studies have established a link between exercise-induced IL-6 and recruitment of natural killer (NK) cells. Whether exercise-induced IL-6 is involved in regulating NK cell mobilization in humans is unclear. This study explored the effect of IL-6 receptor blockade on immune cell mobilization during an acute bout of exercise in humans. In a randomized, placebo-controlled clinical study, abdominally obese humans receiving placebo infusions or tocilizumab infusions performed an acute bout of exercise before and after the intervention. Immune cell recruitment was measured by flow cytometry. IL-6 receptor blockade attenuated the increase of NK cells by 53% (mean difference -0.49 (95% CI: -0.89 to -0.08) × 109 cells L-1 , P < 0.001) and dendritic cells by 66% (mean difference -0.14 (95% CI: -0.28 to 0.010) × 109 cells L-1 , P < 0.001) induced by an acute bout of exercises. No changes were observed for T cells, monocytes and neutrophils. Treatments which interact with the exercise-mediated immune surveillance provide relevant clinical information in pursuing the 'exercise as medicine' concept.

Voluntary wheel running can lead to modulation of immune checkpoint molecule expression.

BACKGROUND: Exercise and physical activity (PA) are associated with reduced tumor growth and enhanced intra-tumoral immune cell infiltration in mice. We aimed to investigate the role of PA achieved by voluntary wheel running in promoting the immunogenic profile across several murine tumor models, and to explore the potential of checkpoint blockade and PA in the form of voluntary wheel running as combination therapy. MATERIAL AND METHODS: The experiments were performed with C57BL/6 mice bearing subcutaneous tumors while having access to running wheels in their cages, where key immunoregulatory molecules expressed in the tumor tissue were measured by qPCR. Furthermore, we tested the hypothesis that wheel running combined with PD-L1 -or PD-1 inhibitor treatment could lead to an additive effect on tumor growth in mice bearing B16 melanoma tumors. RESULTS: Wheel running increased immune checkpoint expression (PD-1, PD-L1, PD-L2, CD28, B7.1 and B7.2) in B16 tumor-bearing mice, while induction of only PD-L2 was found in E0771 breast cancer and Lewis Lung Cancer. In studies combining voluntary wheel running with PD-1 -and PD-L1 inhibitors we found significant effects of wheel running on attenuating B16 melanoma tumor growth, in line with previous studies. We did, however, not find an additive effect of combining either of the two immunotherapeutic treatments with access to running wheels. CONCLUSION: B16 tumors displayed upregulated expression of immune regulatory molecules and decreased tumor growth in response to PA. However, combining PA with PD-1 or PD-L1 blockade did not lead to a further augmented inhibition of tumor growth.

Exercise training as prophylactic strategy in the management of neutropenia during chemotherapy.

Chemotherapy-induced immune-suppression is a common, but potential detrimental, adverse reaction in patients undergoing treatment for cancer and strategies with capacity to boost the immune cell populations are needed. Physical exercise training is a potent regulator of immune cell viability and function and may serve as a viable, non-pharmacological prophylactic strategy in addition to the current pharmacological management by, for example, granulocyte-colony stimulating factor (G-CSF). Here, we review the mechanistic evidence linking exercise training to haematopoietic function and subsequent possible amelioration of chemotherapy-related neutropenia. First, we briefly describe neutrophil regulation and management of neutropenia in cancer patients. Second, we summarize the effect of acute and chronic exercise training on neutrophils and their progenitors, and finally, we outline the current clinical evidence of exercise interventions in ongoing anti-cancer treatment in regard to neutropenia incidence, treatment tolerance and related outcomes. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.

The effects of acute exercise and inflammation on immune function in early-stage prostate cancer.

Background: The immune system plays a vital role in cancer development and progression. Strategies mobilizing cytotoxic cells of the immune system to combat immunosuppression in cancer may help to improve the treatment response of patients. To this end, we aimed to characterize the anti-cancer effect of acute exercise, including the involvement of inflammatory signals. Patients and methods: Twenty patients with early-stage prostate cancer (PCa) scheduled to undergo prostatectomy performed one bout of acute exercise consisting of a watt-max test and four high-intensity intervals. Natural Killer (NK), NKT-like and T cell phenotype, NK cell cytotoxic activity (NKCA), and NKCA per-cell against cell lines of leukemia (K562) and prostate cancer origin (LNCaP and PC-3) were assessed. Inflammatory markers (TNF-α, IL-6, and CRP) were measured in plasma. Results: Exercise increased NK, NKT-like, and CD8 T cell concentration in the circulation. Furthermore, exercise shifted immune cells towards a mature and cytotoxic phenotype e.g., NK cells exhibited higher CD57 as well as lower NKG2A expression. NKT-like and CD8 cells exhibited elevated CD57, TIGIT and Granzyme-B expression. Exercise significantly improved NKCA against K562 (+16% [5%; 27%]; p = 0.002) and LNCaP (+24% [14%; 34%]; p < 0.001) but not PC-3. NKCA per NK cell decreased during exercise and increased 1-h post exercise compared to baseline in K562, LNCap, and PC-3 cell lines. Baseline IL-6 correlated with lymphocyte, monocyte and T cell concentration pre-exercise and inversely correlated with the fold-change of mobilized lymphocytes and CD8 T cells during exercise. Furthermore, baseline IL-6 and TNF-α inversely correlated with NKCA against PC-3 cells during exercise. Conclusions: Acute exercise mobilized cytotoxic immune cells and improved NKCA in patients with PCa whereas low-grade inflammation might impair the response. Whether the observed improvements impact long-term outcomes warrant further investigation. Clinical trial number: NCT03675529.

A randomized double-blind single center study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention).

INTRODUCTION: Elevated luteinizing hormone (LH) in combination with low-normal testosterone (mild Leydig cell insufficiency) is common in testicular cancer (TC) survivors and is associated with impaired insulin sensitivity and metabolic syndrome. The aim was to evaluate if testosterone replacement therapy (TRT) improves metabolic health in this subgroup of TC survivors. PATIENTS AND METHODS: This was a single-center, double-blind, randomized, controlled trial. The main eligibility criterion was LH above the age-adjusted upper limit of normal in combination with free testosterone in the lower half of the age-adjusted normal range (mild Leydig cell insufficiency) >1 year after TC treatment. Eligible patients were randomly assigned (1:1) to 12 months transdermal TRT (Tostran, gel, 2%) or placebo with a maximum daily dose of 40 mg. The primary outcome was difference in Δ2 hour glucose measured with oral glucose tolerance test between groups assessed at 12 months. Outcomes were assessed after 6-, 12- and 3 months post-treatment. The study was registered at www. CLINICALTRIAL: gov (NCT02991209) and ended June 2019. RESULTS: Between October 2016 and February 2018, 140 patients were screened for eligibility and 69 were randomized to testosterone (n = 35, 51%) or placebo (n = 34, 49%). TRT was not associated with a statistically significant difference in Δ2 hour glucose compared to placebo after 12 months of treatment (0.04 mmol/L (95% CI: -0.53, 0.60)). There was no statistically significant difference in Δ2 hour insulin between the groups after 12 months of treatment (28.23 pmol/L (95% CI: -34.40, 90.86)). Similarly, TRT was not associated with significant improvement in components of metabolic syndrome. TRT was associated with a decrease in fat mass after 12 months compared to placebo (-1.35 kg, (95% CI: -2.53, -0.18)). CONCLUSION: In TC survivors with mild Leydig cell insufficiency, TRT was not associated with improvement of metabolic health. These findings do no not support routine use of TRT in these patients.

Effects of acute exercise training on tumor outcomes in men with localized prostate cancer: A randomized controlled trial.

Postdiagnosis physical activity is associated with improved cancer outcomes, but biological mechanisms mediating anticancer effects remain unclear. Recent findings suggest that physiological adaptations to acute exercise comprise potential anticancer effects, but these remain poorly explored in clinical settings. The objective of this study was to explore the effects of a single exercise bout on tumor oxygenation and immune cell infiltration in patients with prostate cancer. Thirty patients with localized prostate cancer were randomized (2:1) to either one high-intensity interval training bout or no exercise on the day before radical prostatectomy. Immunohistochemical analyses were performed on prostatic tissue from surgery and assessed for tumor hypoxia, natural killer (NK) cell infiltration, and microvessel density (MVD). Acute systemic response in blood lymphocytes, epinephrine, norepinephrine, IL-6, tumor necrosis factor, cortisol, lactate, and glucose was also evaluated. We did not find between-group differences in tumor hypoxia (Mann-Whitney U test, U = 83.5, p = 0.604) or NK cell infiltration (U = 77.0, p = 0.328). Also, no significant correlation was found between MVD and tumor hypoxia or NK cell infiltration. One exercise bout is likely insufficient to modulate tumor hypoxia or NK cell infiltration. Future studies may elucidate if an accumulation of several exercise bouts can impact these outcomes (NCT03675529, www.clinicaltrials.gov).

Exercise intensity and markers of inflammation during and after (neo-) adjuvant cancer treatment.

Exercise training has been hypothesized to lower the inflammatory burden for patients with cancer, but the role of exercise intensity is unknown. To this end, we compared the effects of high-intensity (HI) and low-to-moderate intensity (LMI) exercise on markers of inflammation in patients with curable breast, prostate and colorectal cancer undergoing primary adjuvant cancer treatment in a secondary analysis of the Phys-Can randomized trial (NCT02473003). Sub-group analyses focused on patients with breast cancer undergoing chemotherapy. Patients performed 6 months of combined aerobic and resistance exercise on either HI or LMI during and after primary adjuvant cancer treatment. Plasma taken at baseline, immediately post-treatment and post-intervention was analyzed for levels of interleukin 1 beta (IL1B), IL6, IL8, IL10, tumor-necrosis factor alpha (TNFA) and C-reactive protein (CRP). Intention-to-treat analyses of 394 participants revealed no significant between-group differences. Regardless of exercise intensity, significant increases of IL6, IL8, IL10 and TNFA post-treatment followed by significant declines, except for IL8, until post-intervention were observed with no difference for CRP or IL1B. Subgroup analyses of 154 patients with breast cancer undergoing chemotherapy revealed that CRP (estimated mean difference (95% CI): 0.59 (0.33; 1.06); P = 0.101) and TNFA (EMD (95% CI): 0.88 (0.77; 1); P = 0.053) increased less with HI exercise post-treatment compared to LMI. Exploratory cytokine co-regulation analysis revealed no difference between the groups. In patients with breast cancer undergoing chemotherapy, HI exercise resulted in a lesser increase of CRP and TNFA immediately post-treatment compared to LMI, potentially protecting against chemotherapy-related inflammation.

Effects of heavy-load resistance training during (neo-)adjuvant chemotherapy on muscle cellular outcomes in women with breast cancer.

INTRODUCTION: (Neo-)adjuvant chemotherapy for breast cancer has a deleterious impact on muscle tissue resulting in reduced cardiorespiratory fitness, skeletal muscle mass and function. Physical exercise during treatment may counteract some of these negative effects. However, the effects of resistance training (RT) alone have never been explored. The present study aims to investigate if heavy-load RT during (neo-)adjuvant chemotherapy counteracts deleterious effects on skeletal muscle in women diagnosed with breast cancer. We hypothesize that (neo-)adjuvant treatment with chemotherapy will reduce muscle fiber size, impair mitochondrial function, and increase indicators of cellular stress and that RT during treatment will counteract these negative effects. We also hypothesize that RT during (neo-)adjuvant chemotherapy will increase muscle and blood levels of potential antitumor myokines and reduce treatment-related side effects on muscle strength and cardiorespiratory fitness. METHODS: Fifty women recently diagnosed with breast cancer scheduled to start (neo-)adjuvant chemotherapy will be randomized to either randomized to either intervention group or to control group.The intervention group will perform supervised heavy-load RT twice a week over the course of chemotherapy (approximately 16-weeks) whereas the control group will be encouraged to continue with their usual activities. Muscle biopsies from m. vastus lateralis will be collected before the first cycle of chemotherapy (T0), after chemotherapy (T1), and 6 months later (T2) for assessment of muscle cellular outcomes. The primary outcome for this study is muscle fiber size. Secondary outcomes are: regulators of muscle fiber size and function, indicators of cellular stress and mitochondrial function, myokines with potential antitumor effects, muscle strength, and cardiorespiratory fitness. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Regional Ethical Review Board in Uppsala, Sweden (Dnr:2016/230/2). Results will be disseminated through presentations at scientific meetings, publications in peer-reviewed journals, social media, and patient organizations. TRIAL REGISTRATION NUMBER: NCT04586517.

Interval Walking Improves Glycemic Control and Body Composition After Cancer Treatment: A Randomized Controlled Trial.

CONTEXT: Patients with colorectal cancer have increased risk of metabolic diseases including diabetes. Exercise training may counteract metabolic dysregulation, but the impact of exercise training on glycemic control, including postprandial glycemia, has never been explored in patients with colorectal cancer. OBJECTIVE: To examine the effects of home-based interval walking on aerobic and metabolic fitness and quality of life in patients with colorectal cancer. DESIGN: Randomized controlled trial. SETTING: Clinical research center. PARTICIPANTS: Thirty-nine sedentary (<150 minutes moderate-intensity exercise per week) patients with stage I to III colorectal cancer who had completed primary treatment. INTERVENTION: Home-based interval walking 150 min/wk or usual care for 12 weeks. MAIN OUTCOME MEASURES: Changes from baseline to week 12 in maximum oxygen uptake (VO2peak) by cardiopulmonary exercise test, glycemic control by oral glucose tolerance test (OGTT), body composition by dual-energy x-ray absorptiometry scan, blood biochemistry, and quality of life. RESULTS: Compared with control, interval walking had no effect on VO2peak [mean between-group difference: -0.32 mL O2 · kg-1 · min-1 (-2.09 to 1.45); P = 0.721] but significantly improved postprandial glycemic control with lower glucose OGTT area under the curve [-126 mM · min (-219 to -33); P = 0.009], 2-hour glucose concentration [-1.1 mM (-2.2 to 0.0); P = 0.056], and improved Matsuda index [1.94 (0.34; 3.54); P = 0.01]. Also, interval walking counteracted an increase in fat mass in the control group [-1.47 kg (-2.74 to -0.19); P = 0.025]. CONCLUSION: A home-based interval-walking program led to substantial improvements in postprandial glycemic control and counteracted fat gain in posttreatment patients with colorectal cancer, possibly providing an effective strategy for prevention of secondary metabolic diseases.

Local application of bacteria improves safety of Salmonella -mediated tumor therapy and retains advantages of systemic infection.

Cancer is a devastating disease and a large socio-economic burden. Novel therapeutic solutions are on the rise, although a cure remains elusive. Application of microorganisms represents an ancient therapeutic strategy, lately revoked and refined via simultaneous attenuation and amelioration of pathogenic properties. Salmonella Typhimurium has prevailed in preclinical development. Yet, using virulent strains for systemic treatment might cause severe side effects. In the present study, we highlight a modified strain based on Salmonella Typhimurium UK-1 expressing hexa-acylated Lipid A. We corroborate improved anti-tumor properties of this strain and investigate to which extent an intra-tumoral (i.t.) route of infection could help improve safety and retain advantages of systemic intravenous (i.v.) application. Our results show that i.t. infection exhibits therapeutic efficacy against CT26 and F1.A11 tumors similar to a systemic route of inoculation. Moreover, i.t. application allows extensive dose titration without compromising tumor colonization. Adverse colonization of healthy organs was generally reduced via i.t. infection and accompanied by less body weight loss of the murine host. Despite local application, adjuvanticity remained, and a CT26-specific CD8+ T cell response was effectively stimulated. Most interestingly, also secondary tumors could be targeted with this strategy, thereby extending the unique tumor targeting ability of Salmonella. The i.t. route of inoculation may reap the benefits of systemic infection and aid in safety assurance while directing potency of an oncolytic vector to where it is most needed, namely the primary tumor.