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Uncovering the Links between Inflammation and Recurrence in Cancer Patients

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 28273

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Dr. Elda Tagliabue

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Head of Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy
Interests: HER2-positive breast cancer; triple-negative breast cancer; tumor microenvironment
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Dr. Francesca Bianchi

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Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy
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Dear Colleagues,

A relationship between inflammation and prognosis has been reported in several types of cancer. At the local side, strong evidence has highlighted the good prognosis and good response to chemotherapy and immunotherapy of so-called “hot” tumors, with inflamed features resulting in a high density of tumor-infiltrating lymphocytes (TILs). However, the therapeutic effect of immunomodulatory agents can be counteracted by inflammatory mediators reprogramming immune cells towards an immunosuppressive phenotype.

In addition to directly sustaining cancer cell proliferation, migration, and invasion, cytokines, chemokines, and growth factors at the tumor site can mold the tumor microenvironment, affecting the composition and phenotype of the surrounding stromal cells and promote angiogenesis and vasculogenesis processes. At the systemic level, elevated inflammation is consistently associated with poor outcome in many solid tumors. Markers obtained from complete blood count (CBC) such as C-reactive protein (CRP), neutrophil, lymphocyte, and platelet counts and their ratio (i.e., neutrophil:lymphocyte ratio (NLR), platelet:lymphocyte ratio (PLR)) are effective predictors of poor survival outcome in cancer patients. Furthermore, circulating growth factors can enhance cancer stem cells that are highly resistant to current treatments and are responsible for repopulating the tumor after treatment, causing local and systemic recurrence. Therefore, the elucidation of bidirectional cross-talk between local and systemic inflammatory responses in cancer patients still represents an important challenge for clinical oncologists to optimize treatment allocation.

Several co-morbidities such as diabetes, obesity, and metabolic disorders can contribute to sustain a low-grade systemic inflammatory status in cancer patients as well as the wrong well-known habits of smoking and alcohol consumption. In addition to chronic inflammatory conditions, surgery and perioperative treatments can also deeply affect cancer patient inflammation. Surgical tissue damage boosts the release of proinflammatory mediators, and the choice of perioperative anesthesia and analgesia has been found to affect patient outcome likely based on their impact on systemic inflammation.

The aim of this Special Issue is to provide recent findings in understanding how host inflammatory status affects tumor aggressiveness to improve therapeutic options and to develop new criteria to evaluate cancer patient prognosis. We invite authors to submit original research or review articles addressing these issues. Potential topics include but are not limited to the following: · Mechanisms underlying how host features sustain inflammation · Immune and/or microenvironment components involved in inflammatory processes, at tumor site, and/or at systemic level · Insights in the relationship between inflammation at systemic level and at tumor site · Tissue- and blood-based inflammation-related biomarkers predictive of immunotherapy and chemotherapy response · Novel surgery and/or perioperative approaches and tumor-removal-driven inflammation.

Dr. Elda Tagliabue
Dr. Francesca Bianchi
Guest Editors

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Keywords

cancer
inflammation
cytokines
circulating markers
surgery
obesity
diabetes
smoke

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Published Papers (8 papers)

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Research

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16 pages, 769 KiB

Open AccessArticle

Effects of a Home-Based Lifestyle Intervention Program on Cardiometabolic Health in Breast Cancer Survivors during the COVID-19 Lockdown

by Valentina Natalucci, Carlo Ferri Marini, Marco Flori, Francesca Pietropaolo, Francesco Lucertini, Giosuè Annibalini, Luciana Vallorani, Davide Sisti, Roberta Saltarelli, Anna Villarini, Silvia Monaldi, Simone Barocci, Vincenzo Catalano, Marco Bruno Luigi Rocchi, Piero Benelli, Vilberto Stocchi, Elena Barbieri and Rita Emili

J. Clin. Med. 2021, 10(12), 2678; https://doi.org/10.3390/jcm10122678 - 17 Jun 2021

Cited by 30 | Viewed by 4166

Abstract

This study aimed to evaluate the cardiometabolic effects of a home-based lifestyle intervention (LI) in breast cancer survivors (BCSs) during the COVID-19 lockdown. In total, 30 BCSs (women; stages 0–II; non-metastatic; aged 53.5 ± 7.6 years; non-physically active; normal left ventricular systolic function) with a risk factor for recurrence underwent a 3-month LI based on nutrition and exercise. Anthropometrics, Mediterranean diet adherence, physical activity level (PAL), cardiorespiratory fitness (VO_2max), echocardiographic parameters, heart rate variability (average standard deviation of NN intervals (ASDNN/5 min) and 24 h very- (24 hVLF) and low-frequency (24 hLF)), and metabolic, endocrine, and inflammatory serum biomarkers (glycemia, insulin resistance, progesterone, testosterone, and high-sensitivity C-reactive protein (hs-CRP)) were evaluated before (T0) and after (T1) the LI. After the LI, there were improvements in: body mass index (kg/m²: T0 = 26.0 ± 5.0, T1 = 25.5 ± 4.7; p = 0.035); diet (Mediet score: T0 = 6.9 ± 2.3, T1 = 8.8 ± 2.2; p < 0.001); PAL (MET-min/week: T0 = 647 ± 547, T1 = 1043 ± 564; p < 0.001); VO_2max (mL·min⁻¹·kg⁻¹: T0 = 30.5 ± 5.8, T1 = 33.4 ± 6.8; p < 0.001); signs of diastolic dysfunction (participants: T0 = 15, T1 = 10; p = 0.007); AS-DNN/5 min (ms: T0 = 50.6 ± 14.4, T1 = 55.3 ± 16.7; p = 0.032); 24 hLF (ms²: T0 = 589 ± 391, T1 = 732 ± 542; p = 0.014); glycemia (mg/dL: T0 = 100.8 ± 11.4, T1 = 91.7 ± 11.0; p < 0.001); insulin resistance (HOMA-IR score: T0 = 2.07 ± 1.54, T1 = 1.53 ± 1.11; p = 0.005); testosterone (ng/mL: T0 = 0.34 ± 0.27, T1 = 0.24 ± 0.20; p = 0.003); hs-CRP (mg/L: T0 = 2.18 ± 2.14, T1 = 1.75 ± 1.74; p = 0.027). The other parameters did not change. Despite the home-confinement, LI based on exercise and nutrition improved cardiometabolic health in BCSs. Full article

(This article belongs to the Special Issue Uncovering the Links between Inflammation and Recurrence in Cancer Patients)

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10 pages, 1719 KiB

Open AccessArticle

Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

by Giovanni Centonze, Vincenzo Lagano, Giovanna Sabella, Alessandro Mangogna, Giovanna Garzone, Martina Filugelli, Beatrice Belmonte, Laura Cattaneo, Valentina Crisafulli, Alessio Pellegrinelli, Michele Simbolo, Aldo Scarpa, Paola Spaggiari, Tatiana Brambilla, Sara Pusceddu, Natalie Prinzi, Andrea Anichini, Claudio Tripodo and Massimo Milione

J. Clin. Med. 2021, 10(8), 1741; https://doi.org/10.3390/jcm10081741 - 17 Apr 2021

Cited by 6 | Viewed by 2324

Abstract

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman’s correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61–28.33, p < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20–0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies. Full article

(This article belongs to the Special Issue Uncovering the Links between Inflammation and Recurrence in Cancer Patients)

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7 pages, 1141 KiB

Open AccessArticle

Does Physical Activity Have an Impact on Recurrence Dynamics in Early Breast Cancer Patients?

by Elia Biganzoli, Christine Desmedt and Romano Demicheli

J. Clin. Med. 2021, 10(4), 831; https://doi.org/10.3390/jcm10040831 - 18 Feb 2021

Cited by 7 | Viewed by 2452

Abstract

Several studies have suggested that pre and/or postdiagnosis physical activity can reduce the risk of recurrence in breast cancer patients, however its effect according to follow-up time has not yet been investigated. We analyzed recurrence and mortality dynamics in randomized clinical trials (RCTs) from Australia and Canada. The combined Australian RCTs evaluated, at a median follow-up of 8.3 years, an 8-month pragmatic exercise intervention in 337 women with newly diagnosed breast cancer, while the Canadian RCT evaluated, at a median follow-up of 7.4 years, supervised aerobic or resistance exercise during chemotherapy in 242 patients. For each RCT, the control arm consisted of patients undergoing usual care. We estimated the event dynamics by the discrete hazard function, through flexible regression of yearly conditional event probabilities with generalized additive models. In the considered RCTs, the recurrence and mortality risk of patients enrolled in the physical activity arm were stably decreased at medium/long term after five year of follow-up. In the Australian RCTs where patients were recruited by urban versus rural area, the latter group did not display benefit from physical activity. Estimated odds ratios (95% confidence intervals) for disease-free survival (DFS) in urban women were 0.63 (0.22–1.85); 0.27 (0.079–0.90); 0.11 (0.013–0.96) at the 3rd, 5th and 7th year of follow-up, respectively. For rural women, DFS patterns were overlapping with odds ratios (ORs), approximating 1 at the different years of follow-up. Although not reaching statistical evidence, the estimates in the Canadian trial were in line with the results from the Australian urban women with ORs (95% CI) for DFS of 0.70 (0.33–1.50); 0.47 (0.19–1.18); 0.32 (0.077–1.29) at 3rd, 5th, 7th follow-up year, respectively. While we acknowledge that the analyzed RCTs were not designed for investigating disease recurrence over time, these results support the evidence that physical activity reduces the risk of developing medium-/long-term metastases. Additional translational research is needed to clarify the mechanisms underlying these observations. Full article

(This article belongs to the Special Issue Uncovering the Links between Inflammation and Recurrence in Cancer Patients)

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14 pages, 470 KiB

Open AccessArticle

A Psychosocial Genomics Pilot Study in Oncology for Verifying Clinical, Inflammatory and Psychological Effects of Mind-Body Transformations-Therapy (MBT-T) in Breast Cancer Patients: Preliminary Results

by Mauro Cozzolino, Stefania Cocco, Michela Piezzo, Giovanna Celia, Susan Costantini, Valentina Abate, Francesca Capone, Daniela Barberio, Laura Girelli, Elisa Cavicchiolo, Paolo Antonio Ascierto, Gabriele Madonna, Alfredo Budillon and Michelino De Laurentiis

J. Clin. Med. 2021, 10(1), 136; https://doi.org/10.3390/jcm10010136 - 3 Jan 2021

Cited by 13 | Viewed by 3443

Abstract

Several studies have highlighted the key role of chronic inflammation in breast cancer development, progression, metastasis, and therapeutic outcome. These processes are mediated through a variety of cytokines and hormones that exert their biological actions either locally or distantly via systemic circulation. Recent findings suggest that positive psychosocial experiences, including psychotherapeutic interventions and therapeutic mind-body protocols, can modulate the inflammatory response by reducing the expression of genes/proteins associated with inflammation and stress-related pathways. Our preliminary results indicate that a specific mind-body therapy (MBT-T) could induce a significant reduction of the release of different cytokines and chemokines, such as SCGFβ, SDF-1α, MCP3, GROα, LIF, and IL-18, in the sera of breast cancer patients compared to a control group, suggesting that MBT-T could represent a promising approach to improve the wellness and outcome of breast cancer patients. Full article

(This article belongs to the Special Issue Uncovering the Links between Inflammation and Recurrence in Cancer Patients)

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14 pages, 1067 KiB

Open AccessArticle

The Inflammatory Cytokine Profile of Patients with Malignant Pleural Effusion Treated with Pleurodesis

by Li-Han Hsu, Thomas C. Soong, Nei-Min Chu, Chung-Yu Huang, Shu-Huei Kao and Yung-Feng Lin

J. Clin. Med. 2020, 9(12), 4010; https://doi.org/10.3390/jcm9124010 - 11 Dec 2020

Cited by 6 | Viewed by 2206

Abstract

Patients with malignant pleural effusion (MPE) who underwent successful pleurodesis survive longer than those for whom it fails. We hypothesize that the therapy-induced inflammatory responses inhibit the cancer progression, and thereby lead to a longer survival. Thirty-three consecutive patients with MPE that were eligible for bleomycin pleurodesis between September 2015 and December 2017 were recruited prospectively. Nineteen patients (57.6%) achieved fully or partially successful pleurodesis, while 14 patients either failed or survived less than 30 days after pleurodesis. Two patients without successful pleurodesis were excluded because of missing data. Interleukin (IL)-1 beta, IL-6, IL-10, transforming growth factor beta, tumor necrosis factor alpha (TNF-α), and vascular endothelial growth factor in the pleural fluid were measured before, and after 3 and 24 h of pleurodesis. Their pleurodesis outcome and survival were monitored and analyzed. Patients who underwent successful pleurodesis had a longer survival rate. Patients without successful pleurodesis had significantly higher TNF-α and IL-10 levels in their pleural fluid than in the successful patients before pleurodesis. Following pleurodesis, there was a significant increment of IL-10 in the first three hours in the successful patients. In contrast, significant increments of TNF-α and IL-10 were found in the unsuccessful patients between 3 and 24 h after pleurodesis. The ability to produce specific cytokines in the pleural space following pleurodesis may be decisive for the patient’s outcome and survival. Serial measurement of cytokines can help allocate the patients to adequate treatment strategies. Further study of the underlying mechanism may shed light on cytokine therapies as novel approaches. Full article

(This article belongs to the Special Issue Uncovering the Links between Inflammation and Recurrence in Cancer Patients)

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26 pages, 6502 KiB

Open AccessArticle

Alterations in the Gut Microbiome and Suppression of Histone Deacetylases by Resveratrol Are Associated with Attenuation of Colonic Inflammation and Protection Against Colorectal Cancer

by Haider Rasheed Alrafas, Philip Brandon Busbee, Kumaraswamy Naidu Chitrala, Mitzi Nagarkatti and Prakash Nagarkatti

J. Clin. Med. 2020, 9(6), 1796; https://doi.org/10.3390/jcm9061796 - 9 Jun 2020

Cited by 55 | Viewed by 5179

Abstract

Inflammatory bowel disease (IBD) is known to significantly increase the risk for development of colorectal cancer (CRC), suggesting inflammation and cancer development are closely intertwined. Thus, agents that suppress inflammation may prevent the onset of cancer. In the current study, we used resveratrol, an anti-inflammatory stilbenoid, to study the role of microbiota in preventing inflammation-driven CRC. Resveratrol treatment in the azoxymethane (AOM) and dextran sodium sulphate (DSS) CRC murine model caused an increase in anti-inflammatory CD4 + FOXP3 + (Tregs) and CD4 + IL10 + cells, a decrease in proinflammatory Th1 and Th17 cells, and attenuated CRC development. Gut microbial profile studies demonstrated that resveratrol altered the gut microbiome and short chain fatty acid (SCFA), with modest increases in n-butyric acid and a potential butyrate precursor isobutyric acid. Fecal transfer from resveratrol-treated CRC mice and butyrate supplementation resulted in attenuation of disease and suppression of the inflammatory T cell response. Data also revealed both resveratrol and sodium butyrate (BUT) were capable of inhibiting histone deacetylases (HDACs), correlating with Treg induction. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed increased expression of Treg-specific transcription factor FoxP3 or anti-inflammatory IL-10 resulted in an increase in 5-year survival of patients with CRC. These data suggest that alterations in the gut microbiome lead to an anti-inflammatory T cell response, leading to attenuation of inflammation-driven CRC. Full article

(This article belongs to the Special Issue Uncovering the Links between Inflammation and Recurrence in Cancer Patients)

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Review

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18 pages, 354 KiB

Open AccessReview

Links between Inflammation and Postoperative Cancer Recurrence

by Tomonari Kinoshita and Taichiro Goto

J. Clin. Med. 2021, 10(2), 228; https://doi.org/10.3390/jcm10020228 - 10 Jan 2021

Cited by 34 | Viewed by 3772

Abstract

Despite complete resection, cancer recurrence frequently occurs in clinical practice. This indicates that cancer cells had already metastasized from their organ of origin at the time of resection or had circulated throughout the body via the lymphatic and vascular systems. To obtain this potential for metastasis, cancer cells must undergo essential and intrinsic processes that are supported by the tumor microenvironment. Cancer-associated inflammation may be engaged in cancer development, progression, and metastasis. Despite numerous reports detailing the interplays between cancer and its microenvironment via the inflammatory network, the status of cancer-associated inflammation remains difficult to recognize in clinical settings. In the current paper, we reviewed clinical reports on the relevance between inflammation and cancer recurrence after surgical resection, focusing on inflammatory indicators and cancer recurrence predictors according to cancer type and clinical indicators. Full article

(This article belongs to the Special Issue Uncovering the Links between Inflammation and Recurrence in Cancer Patients)

11 pages, 941 KiB

Open AccessReview

Surgical Stress Promotes Tumor Progression: A Focus on the Impact of the Immune Response

by Amblessed E. Onuma, Hongji Zhang, Lindsay Gil, Hai Huang and Allan Tsung

J. Clin. Med. 2020, 9(12), 4096; https://doi.org/10.3390/jcm9124096 - 18 Dec 2020

Cited by 42 | Viewed by 3804

Abstract

Despite advances in systemic therapies, surgery is crucial for the management of solid malignancy. There is increasing evidence suggesting that the body’s response to surgical stress resulting from tumor resection has direct effects on tumor cells or can alter the tumor microenvironment. Surgery can lead to the activation of early and key components of the innate and adaptative immune systems. Platelet activation and the subsequent pro-coagulation state can accelerate the growth of micrometastases. Neutrophil extracellular traps (NETs), an extracellular network of DNA released by neutrophils in response to inflammation, promote the adhesion of circulating tumor cells and the growth of existing micrometastatic disease. In addition, the immune response following cancer surgery can modulate the tumor immune microenvironment by promoting an immunosuppressive state leading to impaired recruitment of natural killer (NK) cells and regulatory T cells (Tregs). In this review, we will summarize the current understanding of mechanisms of tumor progression secondary to surgical stress. Furthermore, we will describe emerging and novel peri-operative solutions to decrease pro-tumorigenic effects from surgery. Full article

(This article belongs to the Special Issue Uncovering the Links between Inflammation and Recurrence in Cancer Patients)

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