Inflammation and Ovarian Cancer

Epithelial ovarian cancer (EOC) is a highly lethal gynecological cancer for which overall prognosis has remained poor over the past few decades. A number of theories have been postulated in an effort to explain the etiology of EOC. Noteworthy, these theories likely are not mutually exclusive, as they all converge more or less on the role of inflammation in promoting ovarian tumorigenesis and cancer progression. The tumor milieu in which ovarian carcinoma develops has been described as one enriched with a broad spectrum of pro-inflammatory cytokines and chemokines. In particular, several of these cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, produced by tumor itself or/and activated immune cells, besides stimulating cancer cell growth, have been shown to influence clinical disease status and prognosis, by reducing responsiveness to chemotherapy and inducing symptoms such as anorexia, altered energy metabolism, anemia, weight loss, depression and fatigue. Recent data show that cytokine antagonists may have a role to play in the treatment of ovarian cancer. Their action by inhibiting both production and activity of inflammatory cytokines seems to obtain the control of angiogenetic and apoptotic events, the reversal of chemoresistance, the improvement of systemic symptoms and prognosis. In the light of our scientific research and the most recent experimental and clinical advances, our review will discuss the most relevant and recent findings on the role of proinflammatory cytokines in the pathogenesis and prognosis of ovarian cancer and the possible therapeutic implications

Obesity, Inflammation, and Postmenopausal Breast Cancer: Therapeutic Implications

Breast cancer is the female malignant neoplasia with the highest incidence in the industrialized world. Although early diagnosis has contributed to therapeutic success, breast cancer remains a major health issue. In the last few year the hormone therapy for estrogen-dependent breast cancer has evolved achieving significant clinical results; at the same time, it has enabled us to better define the role of estrogens in the etiopathogenesis of this tumour. Weight increase and obesity have been identified as the most important risk and prognostic factors for breast cancer in postmenopausal women. Several hypotheses have been proposed to explain the association of obesity with postmenopausal breast cancer. Specific obesity-associated factors, including leptin, insulin and inflammatory mediators, seem to influence breast cancer growth and prognosis independently of estrogens and at least in part by interacting with estrogen signalling at a cellular level. Therefore, a careful assessment of the nutritional status and body composition is paramount for a proper therapeutic approach for postmenopausal breast carcinoma. The use of antidiabetic and anti-inflammatory drugs associated with conventional hormone therapies and dietary/physical interventions could offer a new therapeutic approach for breast carcinoma that develops in the context of adiposity

COVID-19 and cytokine storm syndrome: can what we know about interleukin-6 in ovarian cancer be applied?

Improving early diagnosis along with timely and effective treatment of COVID-19 are urgently needed. However, at present, the mechanisms underlying disease spread and development, defined prognosis, and immune status of patients with COVID-19 remain to be determined. Patients with severe disease state exhibit a hyperinflammatory response associated with cytokine storm syndrome, hypercoagulability, and depressed cell-mediated immunity. These clinical manifestations, sharing similar pathogenesis, have been well-studied in patients with advanced ovarian cancer. The present review suggests treatment approaches for COVID-19 based on strategies used against ovarian cancer, which shares similar immunopathology and associated coagulation disorders. The chronicization of the hyperinflammatory cytokine storm in patients with severe COVID-19 highlights a defective resistance phase that leads to aspecific chronic inflammation, associated with oxidative stress, which impairs specific T-cell response, induces tissue and endothelial damage, and thrombosis associated with systemic effects that lead to severe multi-organ failure and death. These events are similar to those observed in advanced ovarian cancer which share similar pathogenesis mediated primarily by Interleukin-6, which is, as well demonstrated in ovarian cancer, the key cytokine driving the immunopathology, related systemic symptoms, and patient prognosis. Consistent with findings in other disease models with similar immunopathology, such as advanced ovarian cancer, treatment of severe COVID-19 infection should target inflammation, oxidative stress, coagulation disorders, and immunodepression to improve patient outcome. Correctly identifying disease stages, based on available laboratory data, and developing a specific protocol for each phase is essential for effective treatment

EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment

Lung cancer is a leading cause of cancer-related deaths worldwide. About 10-30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. EGFR-Tyrosine Kinase Inhibitors (TKIs) strengthen MHC class I and II antigen presentation in response to IFN-gamma, boost CD8+ T-cells levels and DCs, eliminate FOXP3+ Tregs, inhibit macrophage polarization into the M2 phenotype, and decrease PD-L1 expression in cancer cells. Thus, targeted therapy blocks specific signaling pathways, whereas immunotherapy stimulates the immune system to attack tumor cells evading immune surveillance. A combination of TKIs and immunotherapy may have suboptimal synergistic effects. However, data are controversial because activated EGFR signaling allows NSCLC cells to use multiple strategies to create an immunosuppressive TME, including recruitment of Tumor-Associated Macrophages and Tregs and the production of inhibitory cytokines and metabolites. Therefore, these mechanisms should be characterized and targeted by a combined pharmacological approach that also concerns disease stage, cancer-related inflammation with related systemic symptoms, and the general status of the patients to overcome the single-drug resistance development

Laparoscopic splenectomy both for primary cytoreductive surgery for advanced ovarian cancer and for secondary surgery for isolated spleen recurrence: feasibility and technique

This study investigated the feasibility and safety of laparoscopic splenectomy conducted in the contexts of both laparoscopic secondary surgery for isolated recurrence in the spleen and primary laparoscopic cytoreductive surgery for advanced ovarian cancer

Laparoscopic management of isolated nodal recurrence in gynecological malignancies is safe and feasible even for large metastatic nodes up to 8 cm: A prospective case series

The surgical treatment of isolated lymph node recurrence (ILNR) of gynecological malignancies is still debated. The feasibility and effectiveness of minimally invasive lymphadenectomy have been reported by few studies; however, it remains unclear what the upper tumor size limit is for a minimally invasive approach. We prospectively analyzed cases of ILNR treated by laparoscopy in our unit while focusing on the safety and feasibility of resecting large tumors suspected of recurrence using a minimally invasive approach

Decrease in neutrophil-to-lymphocyte ratio during neoadjuvant chemotherapy as a predictive and prognostic marker in advanced ovarian cancer

Since chronic inflammation is associated with ovarian cancer growth and progression, some clinical studies have assessed the association between the pre-treatment neutrophil-to-lymphocyte ratio (NLR) and the prognosis of ovarian cancer. The purpose of this study was to assess the dynamic behavior of the NLR during the course of neoadjuvant chemotherapy (NACT) in patients with high grade serous (HGS) advanced epithelial ovarian cancer and assess its correlation with clinical response, progression free survival (PFS) and changes in other inflammatory indexes. We performed a prospective observational study on 161 patients who underwent NACT at the Department of Gynecologic Oncology, ARNAS G. Brotzu, Cagliari, between 2009 and 2019. NLR was evaluated before starting and after three cycles of NACT. Based on response after three cycles of NACT, patients were divided into two groups: responsive and non-responsive. The primary endpoint was to assess the predictive role of NLR by comparing the responsive and non-responsive patients at baseline and after three cycles of NACT. Secondary endpoints were (a) to correlate NLR with other inflammation markers (CRP, fibrinogen, ferritin, IL-6), albumin, and modified Glasgow Prognostic Score (mGPS) with NLR at baseline and after NACT; (b) to assess the association between NLR and PFS. We found that the NLR value at baseline was not associated with response to NACT, while a decrease in NLR after three cycles was correlated with a better response to NACT. Also, values of CRP, IL-6, ferritin, and mGPS after three cycles of NACT (but not at baseline) were significantly associated with clinical response. Moreover, we found that patients with a low NLR value after 3 cycles of NACT, but not at baseline, had a significantly higher PFS than patients with high NLR after 3 cycles of NACT. In conclusion, NLR change during treatment could serve as a predictive marker of response to NACT in patients with HGS advanced ovarian cancer. This allows for the early identification of non-responsive patients who will need treatment remodeling

Biological mechanism-based and patient-centered management of cancer-related symptoms and syndromes

In recent years, full recovery rates for cancer patients significantly increased and mean survival improved. Moreover, chronicization of cancer disease and concerns about aggressive care close to the end-of-life raised the awareness of better risk-benefit balancing. [...