Immunotherapy and Cancer: The Multi-Omics Perspective.

Immunotherapies have revolutionized cancer treatment approaches. Because not all patients respond positively to immune therapeutic agents, it represents a challenge for scientists who strive to understand the mechanisms behind such resistance. In-depth exploration of tumor biology, using novel technologies such as omics science, can help decode the role of the tumor immune microenvironment (TIME) in producing a response to the immune blockade strategies. It can also help to identify biomarkers for patient stratification and personalized treatment. This review aims to explore these new models and highlight their possible pivotal role in changing clinical practice.

Molecular Basis and Advances in Targeted Immunotherapy for Cancer.

Researchers have long attempted to stimulate the immune system of cancer patients as a therapeutic strategy [...].

Alcohol Consumption Is a Modifiable Risk Factor for Breast Cancer: Are Women Aware of This Relationship?

AIMS: Despite alcohol consumption being a dose-dependent risk factor for breast cancer, a recent study conducted in the UK found <20% of women attending breast screening programmes were aware of this relationship and proposed proper information campaigns need to be conducted. We aimed to investigate the awareness of this relationship among a related sample of Italian women to evaluate whether similar information campaigns should also be conducted in Italy. METHODS: The questionnaire used by the UK study was translated into Italian, slightly modified for the Italian context, validated and submitted to a sample of Italian women. RESULTS: Overall 507 women were interviewed. Among them, 160 were classified as breast cancer screening attenders (SG), 44 as symptomatic breast clinic attenders (CAG) and 303 as non-screening group (NSG). Alcohol was correctly identified as a risk factor for breast cancer by 16.9, 11.4 and 14.9% of participants of SG, CAG and NSG, respectively without differences between the three groups. Despite the methodological differences, the rates of participants who correctly identified alcohol as a risk factor among women attending breast screening programmes were surprisingly similar between the study conducted in UK (15.7%) and the present study (16.9%). CONCLUSION: The results of the present study confirm the limited awareness of the relationship between alcohol consumption and risk of developing breast cancer among women and suggest the urgent need to conduct proper awareness-raising campaigns to counter this in the Italian female population.

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-γ, 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.

Feasibility and safety of total laparoscopic hysterectomy for uteri weighing from 1.5 kg to 11.000 kg.

PURPOSE: To assess the feasibility and safety of total laparoscopic hysterectomy (TLH) for uteri ≥ 1.5 kg. METHODS: We prospectively evaluated all elective TLHs (with or without adnexectomy) performed for fibromatous uteri between August 2009 and August 2019 in the Department of Obstetrics and Gynecology, Sirai Hospital, Carbonia, and the Department of Gynecologic Oncology, Businco Hospital, Azienda Ospedaliera Brotzu, Cagliari. Patients with large myomatous uteri (uterine weight ≥ 1.5 kg on pathology reports) were included in the analysis. We examined all procedures and collected data about intra- and post-operative short-term and long-term complications, intraoperative blood loss, operative time, hospital stay, and time to achieve well-being. RESULTS: Seventy-eight patients were included. The median weight was 2,000 g (range 1,500-11,000 g), estimated blood loss was 100 mL (range 10-700 mL), operating time was 135 min (range 60-300 min), and hospital stay was 2 days (range 2-5 days). Conversion to laparotomy occurred in 4 patients (5.1%) with uterine weight ranging from 3 to 5.5 kg, due to severe adherence syndrome or inadequate visualization. As for intraoperative complications, 1 patient (who had the largest removed uterus weighing 11,000 g) experienced an intraoperative ureteral injury (grade III). No major postoperative complications occurred. CONCLUSIONS: This study provides the largest case series of TLH for fibromatous uteri > 1.5 kg and includes some of the largest uteri reported to date in the literature (weighing 5,320, 5,720, and 11,000 g, respectively). The study reaffirms the feasibility and safety of a minimally invasive hysterectomy even in the case of abnormally large uteri.

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

BACKGROUND: 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. METHODS: We performed a perspective observational study including all consecutive patients with ovarian cancer who underwent laparoscopic splenectomy as part of primary cytoreductive procedures for advanced stage ovarian cancer or secondary surgery for isolated splenic recurrence between January 2016 and May 2020. RESULTS: We enrolled 13 consecutive patients, candidate to laparoscopic splenectomy as part of primary cytoreductive procedures for advanced stage ovarian cancer (6 patients) or secondary surgery for isolated splenic recurrence of platinum-sensitive ovarian cancer (7 patients). Median operative time (509 min [range, 200-845]) for primary cytoreductive surgery varied according to surgical complexity depending on the extensiveness of the disease. Median operative time for secondary surgery for isolated splenic metastasis was 253 min (90-380). Only 1 patient with isolated splenic recurrence required conversion to an open approach. No intraoperative complication occurred, and no intraoperative blood transfusions were required. Median hospital stay was 3 days (range, 2-5) for isolated recurrence and 9 days (7-18) for primary cytoreductive surgery. Complete tumor resection was achieved in all patients. Median time from surgery to adjuvant chemotherapy was 16 days (7-24). All six patients who underwent laparoscopic splenectomy during primary cytoreductive surgery remain alive, four of whom exhibit no evidence of disease (median follow-up 25 months [4-36]). Among patients who underwent laparoscopic splenectomy during secondary surgery for isolated splenic relapse, all patients are alive and only one had a central diaphragmatic relapse 2 years after surgery (median follow-up 17 months ([5-48 months]). CONCLUSIONS: The laparoscopic approach to splenectomy is feasible and safe both in patients undergoing primary cytoreductive surgery for advanced stage disease and those with isolated recurrence of ovarian cancer, without compromising survival and allowing early initiation of postoperative systemic chemotherapy.

Cachexia as Evidence of the Mechanisms of Resistance and Tolerance during the Evolution of Cancer Disease.

During its evolution, cancer induces changes in patients' energy metabolism that strongly affect the overall clinical state and are responsible for cancer-related cachexia syndrome. To better understand the mechanisms underlying cachexia and its metabolic derangements, research efforts should focus on the events that are driven by the immune system activation during the evolution of neoplastic disease and on the phenomena of "resistance" and "tolerance" typically involved in the human body response against stress, pathogens, or cancer. Indeed, in the case where resistance is not able to eliminate the cancer, tolerance mechanisms can utilize the symptoms of cachexia (anemia, anorexia, and fatigue) to counteract unregulated cancer growth. These notions are also sustained by the evidence that cancer cachexia may be reversible if the resistance and tolerance phases are supported by appropriate antineoplastic treatments. Accordingly, there is no doubt that anticachectic therapies have an irreplaceable role in cases of reversible cancer cachexia where, if harmoniously associated with effective antineoplastic therapies, they can contribute to preserve the quality of life and improve prognosis. Such anticachectic treatments should be based on targeting the complex immunological, inflammatory, and metabolic pathways involved in the complex pathogenesis of cachexia. Meanwhile, the role of the anticachectic therapies is very different in the stage of irreversible cachexia when the available antineoplastic treatments are not able to control the disease and the resistance mechanisms fail with the prevalence of the tolerance phenomena. At this stage, they can be useful only to improve the quality of life, allowing the patient and their family to get a better awareness of the final phases of life, thereby opening to the best spiritual remodulation of the final event, death.

The Difficult Task of Diagnosing Depression in Elderly People with Cancer: A Systematic Review.

Background: Depression is a common psychiatric problem in the elderly and oncology patients. In elderly people with cancer, depression has a peculiar phenomenology. It has a significant impact on the quality of life. Moreover, it is associated with poor adherence to treatments, increased risk of suicide, and mortality. Nevertheless, the topic of depression in elderly people with cancer remains unexplored. Objective: The main goal of this article is to review the literature from the past 20 years on the relationships between depression, cancer, and aging. Methods: The methods followed the Prisma model for eligibility of studies. The articles in which the keywords "depression", "cancer", " elderly, aging, or geriatric" were present, either in the text or in the abstract, were selected. 8.056 articles, by matching the keywords "depression and elderly and cancer," were identified. Only 532 papers met the eligibility criteria of search limits and selection process. Out of 532 papers, 467 were considered irrelevant, leaving 65 relevant studies. Out of 65 suitable studies, 39 (60.0%) met our quality criteria and were included. Results: The risk factors associated with depression in elderly people with cancer can be divided into 4 groups: 1) tumor-related; 2) anticancer treatment-related; 3) patients-related; 4) number and type of comorbidity. The main obstacles in diagnosing depression in elderly patients with cancer are the overlap of the symptoms of cancer and side effects of treatment with the symptoms of depression but also the different ways of reporting depressive symptoms of elderly people and the different clinical types of depression. There is a lack of data regarding validated scales to assess depression in geriatric patients with cancer. Any mental illness, specifically co-occurring anxiety and depression, increases the risk of diagnosis delay and anticancer treatment adherence. Cancer and the diagnosis of mental disorders prior to cancer diagnosis correlate with an increased risk for suicide. A non-pharmacological therapeutic approach, pharmacological treatment and/or a combination of both can be used to treat elderly patients with cancer, but a detailed analysis of comorbidities and the assessment of polypharmacy is mandatory in order to avoid potential side-effects and interactions between antidepressants and the other drugs taken by the patients. Conclusion: Future research should be conducted with the aim of developing a modified and adapted assessment method for the diagnosis and treatment of depression in elderly people with cancer in order to improve their clinical outcomes and quality of life.

Blocking inflammation to improve immunotherapy of advanced cancer.

The ability to induce functional reprogramming of regulatory T (Treg) cells in the tumor microenvironment is an extremely important therapeutic opportunity. However, when discussing such an approach, the opposing effect that the activation of the Treg cell compartments may have in inducing the immune inflammatory response and its link with the efficacy of immunotherapy should be considered. In fact, Treg reprogramming has a dual effect: immediate, with mechanisms that activate immunosurveillance, and late, mediated by the macrophage activation that yields an inflammatory status that is deleterious for the antineoplastic efficiency of the immune system response. Persistence of the inflammatory response is associated with specific changes of oxidative and glycolytic metabolic pathways that interfere with conventional T-cell activation and function and may be one of the reasons for the failure of immunotherapy in advanced cancer patients. Therefore, in addition to modulating Treg cell action, the combined use of drugs able to block chronic inflammation mediated mainly by macrophages, to counteract the oxidative stress, and to positively regulate the metabolic derangements, could improve the effectiveness of modern immunotherapy. In conclusion, reprogramming of Treg cells may be an appropriate strategy for treating early stages of neoplastic diseases, whereas other immunosuppressive mechanisms should be the target of a combined immunotherapy approach in more advanced phases of cancer.

Laparoscopic removal of a very large uterus weighting 5320 g is feasible and safe: a case report.

BACKGROUND: Total laparoscopic hysterectomy (TLH) has demonstrated to be feasible and safe in the presence of very large uteri. However, it is currently difficult to establish the upper uterine weight limit for successful performance of a laparoscopic hysterectomy. CASE PRESENTATION: Here we report the case of a TLH performed for a very large fibromatous uteri weighing 5320 g in a 40-year-old Caucasian woman. The surgery had no complications with an operating time of approximately 220 min. The patient was discharged from the hospital on postoperative day 3 in very good condition. To our knowledge, the present paper is the only to describe a uterus of this size removed by laparoscopic hysterectomy. CONCLUSIONS: Our case demonstrates that uterine size is not a determinant for a final surgical decision to use laparoscopic hysterectomy. Therefore, if not contraindicated by the patient's comorbidities or peculiar anatomical conditions, we believe that laparoscopic hysterectomy could be performed in the presence of large uteri without hypothetical weight limits.

Long-Term Survival in a Patient With Abdominal Sarcomatosis From Uterine Leiomyosarcoma: Role of Repeated Laparoscopic Surgery in Treatment and Follow-Up.

Uterine leiomyosarcoma (LMS) in some cases may disseminate through the abdominal cavity, without extra-abdominal spreading, determining a condition of abdominal sarcomatosis, which represents a peculiar situation. Only radical surgical removal offers a chance of long-term survival in such cases of LMS. Here we describe a case of diffuse abdominal sarcomatosis from uterine LMS in a 51-year-old perimenopausal woman who underwent laparoscopic radical hysterectomy, bilateral salpingo-oophorectomy, total pelvic peritonectomy, pelvic lymphadenectomy to the mesenteric inferior artery, and omentectomy. Then, given the high probability of disease recurrence, the patient underwent a close follow-up consisting of positron emission tomography (PET)/computed tomography every 3 months and diagnostic (and if necessary operative) laparoscopy every 6 months. To date, the patient had 11 laparoscopies; 5 of them were preceded by a PET indicative of the presence of disease with high metabolic activity, which was confirmed at surgery and each time completely removed laparoscopically with no evidence of residual disease. To date, 5 years from diagnosis the patient is alive and continues her follow-up. Our report brings to light the ability of laparoscopic surgery to obtain disease control in a case of LMS with abdominal dissemination. Moreover, laparoscopic surgery, as demonstrated in our case, may have an important role in the close follow-up of the disease and allow a timely and early radical surgical approach of relapses before they become extremely large and difficult to remove radically.

Surgical outcome and complications of total laparoscopic hysterectomy for very large myomatous uteri in relation to uterine weight: a prospective study in a continuous series of 461 procedures.

PURPOSE: To analyze whether a large uterine size was associated with increased rate of intraoperative and postoperative surgical complications in patients who underwent total laparoscopic hysterectomy (TLH) for myomatous uteri. METHODS: We examined prospectively data from 461 consecutive TLHs performed by a single surgeon between August 2004 and August 2014 at the Department of Obstetrics and Gynecology, Sirai Hospital, Carbonia, and at the Department of Gynecologic Oncology, Businco Hospital, Cagliari, Italy. Demographic and surgical data were stratified by uterine weight (range 90-5500 g) into four groups: <300 g; from 300 to 500 g; from 500 to 800 g; and >800 g. Outcomes examined included blood loss, operative time, intraoperative and postoperative complications, and duration of hospital stay. A linear regression analysis was performed to identify whether uterine weight was an independent predictor affecting these outcomes. In addition, BMI, previous surgery with adhesiolysis, and endometriosis were tested as a predictor of surgical complications and outcomes. RESULTS: No significant difference was found in intraoperative and postoperative complications, as well as hospital stay, by uterine weight. Increased uterine size was significantly associated with longer operative time and increased blood loss. Beside uterine weight, prior surgery was predictive of postoperative complications. In contrast, higher BMI was not associated with increased complication rate. Independent predictors of longer operative time included previous surgery, endometriosis, and BMI. CONCLUSIONS: Our results showed that in experienced hands, TLH is feasible and safe also in presence of very large uteri. TLH results in a few complications and short hospital stay regardless of uterine weight.

The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study.

Anemia in oncology patients is often considered a side effect of cancer therapy; however, it may occur before any antineoplastic treatment (cancer-related anemia). This study was aimed to evaluate the prevalence of cancer-related anemia in a large cohort of oncology patients and whether inflammation and malnutrition were predictive of its development and severity. The present study included 888 patients with cancer at different sites between May 2011 and January 2014. Patients were assessed at diagnosis before any cancer treatment. The prevalence of anemia according to the main clinical factors (tumor site, stage and performance status) was analyzed. In each patient markers of inflammation, iron metabolism, malnutrition and oxidative stress as well as the modified Glasgow prognostic score, a combined index of malnutrition and inflammation, were assessed and their role in predicting hemoglobin level was evaluated. The percentage of anemic patients was 63% with the lowest hemoglobin levels being found in the patients with most advanced cancer and compromised performance status. Hemoglobin concentration differed by tumor site and was lowest in patients with ovarian cancer. Hemoglobin concentration was inversely correlated with inflammatory markers, hepcidin, ferritin, erythropoietin and reactive oxygen species, and positively correlated with leptin, albumin, cholesterol and antioxidant enzymes. In multivariate analysis, stage, interleukin-6 and leptin were independent predictors of hemoglobin concentration. Furthermore, hemoglobin was inversely dependent on modified Glasgow Prognostic Score. In conclusion, cancer-related anemia is a multifactorial problem with immune, nutritional and metabolic components that affect its severity. Only a detailed assessment of the pathogenesis of cancer-related anemia may enable clinicians to provide safe and effective individualized treatment.

Muscle wasting as main evidence of energy impairment in cancer cachexia: future therapeutic approaches.

The present review aimed at discussing the impact, pathogenesis and therapeutic approaches of muscle wasting, which is a major clinical feature of cancer-related cachexia syndrome. The pathogenesis of muscle wasting in cancer cachexia lies in a discrepancy between anabolic and catabolic pathways mediated by chronic inflammation. Effective interventions specifically aimed at hampering muscle loss and enhancing muscle function are still lacking. Promising agents include anti-inflammatory, orexigenic and anabolic drugs, alongside with nutritional supplements that influence the STAT3 and PI3K/Akt/mTOR pathways involved in muscle wasting. Personalized physical activity combined with pharmacological and nutritional support hold promise. A greater understanding of the pathogenetic processes of cancer cachexia-related muscle wasting will enable the development of an early and effective targeted mechanism-based multimodal approach.

Role of inflammation and oxidative stress in post-menopausal oestrogen-dependent breast cancer.

Weight gain and obesity are among the most important risk factors for post-menopausal oestrogen-dependent breast cancer (EDBC). Weight gain is associated with oxidative stress, which in turn promotes breast cancer progression. We carried out a prospective study in 216 consecutive post-menopausal breast cancer patients aiming to examine the correlations between traditional prognostic factors (tumour size, T, nodal, N, grading, G, and metastasis status, M), and body mass index (BMI), leptin, pro-inflammatory cytokines (Interleukin, IL,-6 and tumour necrosis factor-alpha, TNF-α), and oxidative stress (reactive oxygen species, ROS, glutathione peroxidase, GPx, superoxide dismutase, SOD) among patients with oestrogen receptor (ER)+ and ER- breast cancers. Distribution of T, N and M categories did not differ between ER+ and ER- breast cancer patients. ER- patients showed a higher incidence of G3 tumours. Weight, BMI, leptin, IL-6 and ROS were higher in ER+ compared with ER- patients. Among ER+ patients, BMI, leptin, IL-6 and ROS correlated with T and M. Leptin, IL-6 and ROS were positively correlated also with N. Among ER- patients, BMI and leptin did not correlate with any of prognostic parameters, whereas a positive correlation between IL-6, ROS and M was found. Multivariate regression analysis showed that BMI, leptin, IL-6 and ROS were predictive for T, N and M in ER+ patients. Weight gain, inflammation and oxidative stress are involved in EDBC prognosis. Their modulation through antidiabetic, anti-inflammatory and antioxidants drugs combined with endocrine therapy may constitute a targeted approach in post-menopausal EDBC.

Large twisted ovarian fibroma associated with Meigs' syndrome, abdominal pain and severe anemia treated by laparoscopic surgery.

BACKGROUND: The Meigs' syndrome is a rare but well-known syndrome defined as the triad of benign solid ovarian tumor, ascites, and pleural effusion. Meigs' syndrome always requires surgical treatment. However, the optimal approach for its management has not been sufficiently investigated. CASE PRESENTATION: We report a patient with a large twisted ovarian fibroma associated with Meigs' syndrome, abdominal pain and severe hemolytic anemia that was treated by laparoscopic surgery. This case highlights the difficulties that may be encountered in the management of patients with Meigs' syndrome, including potential misdiagnosis of the tumor as a malignant ovarian neoplasm that may influence the medical and surgical approach and the adverse impact that Meigs' syndrome can have on the patient's condition, especially if it is associated with acute pain and severe anemia. Considering the patient's serious clinical condition and assuming that she had Meigs' syndrome with a twisted large ovarian mass and possible hemolytic anemia, we first concentrated on effective medical management of our patient and chose the most appropriate surgical treatment after laparoscopic examination. The main aim of our initial approach was preoperative management of the anemia. Blood transfusions and glucocorticoid therapy resulted in stabilization of the hemoglobin level and normalization of the bilirubin levels, which confirmed the appropriateness of this approach. Laparoscopic surgery 4 days after admission enabled definitive diagnosis of the tumor, confirmed torsion and removed the bulky ovarian fibroma, resulting in timely resolution of symptoms, short hospitalization, relatively low morbidity and a rapid return to her social and professional life. CONCLUSIONS: This case highlights the difficulties that may be encountered in the management of patients with Meigs' syndrome, including potential misdiagnosis of the tumor as a malignant ovarian neoplasm that may influence the medical and surgical approach, and the adverse impact that Meigs' syndrome can have on the patient's condition, especially if it is associated with acute pain and severe anemia. The present case suggests that laparoscopic surgery for potentially large malignant tumors is feasible and safe, but requires an appropriate medical and gynecological oncology expertise.

Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging.

Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.