Sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity.

Background: Anthracycline-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in patients with cancer. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert multiple cardiometabolic benefits in patients with/without type 2 diabetes, chronic kidney disease, and heart failure with reduced and preserved ejection fraction. We hypothesized that the SGLT2i dapagliflozin administered before and during doxorubicin (DOXO) therapy could prevent cardiac dysfunction and reduce pro-inflammatory pathways in preclinical models. Methods: Cardiomyocytes were exposed to DOXO alone or combined with dapagliflozin (DAPA) at 10 and 100 nM for 24 h; cell viability, iATP, and Ca++ were quantified; lipid peroxidation products (malondialdehyde and 4-hydroxy 2-hexenal), NLRP3, MyD88, and cytokines were also analyzed through selective colorimetric and enzyme-linked immunosorbent assay (ELISA) methods. Female C57Bl/6 mice were treated for 10 days with a saline solution or DOXO (2.17 mg/kg), DAPA (10 mg/kg), or DOXO combined with DAPA. Systemic levels of ferroptosis-related biomarkers, galectin-3, high-sensitivity C-reactive protein (hs-CRP), and pro-inflammatory chemokines (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified. After treatments, immunohistochemical staining of myocardial and renal p65/NF-kB was performed. Results: DAPA exerts cytoprotective, antioxidant, and anti-inflammatory properties in human cardiomyocytes exposed to DOXO by reducing iATP and iCa++ levels, lipid peroxidation, NLRP-3, and MyD88 expression. Pro-inflammatory intracellular cytokines were also reduced. In preclinical models, DAPA prevented the reduction of radial and longitudinal strain and ejection fraction after 10 days of treatment with DOXO. A reduced myocardial expression of NLRP-3 and MyD-88 was seen in the DOXO-DAPA group compared to DOXO mice. Systemic levels of IL-1ß, IL-6, TNF-α, G-CSF, and GM-CSF were significantly reduced after treatment with DAPA. Serum levels of galectine-3 and hs-CRP were strongly enhanced in the DOXO group; on the other hand, their expression was reduced in the DAPA-DOXO group. Troponin-T, B-type natriuretic peptide (BNP), and N-Terminal Pro-BNP (NT-pro-BNP) were strongly reduced in the DOXO-DAPA group, revealing cardioprotective properties of SGLT2i. Mice treated with DOXO and DAPA exhibited reduced myocardial and renal NF-kB expression. Conclusion: The overall picture of the study encourages the use of DAPA in the primary prevention of cardiomyopathies induced by anthracyclines in patients with cancer.

Proposal of model for personalized early adapted cancer screening in people living with HIV: experience of "Gaetano Martino" Hospital University of Messina.

Human immunodeficiency virus (HIV) infection has historically been related to the development of specific cancers, some of which are so closely linked to the infection, such as Kaposi's Sarcoma (KS), that they have earned the name Acquired Immuno-Deficiency Syndrome (AIDS)-defining cancers (ADCs). While the development of antiretroviral therapy (ART) has decreased the incidence of AIDS-defining cancers, the resulting aging of people living with HIV (PLWH) highlighted an increased occurrence of other forms of cancer. At the "Gaetano Martino" hospital in Messina, we developed a multidisciplinary approach by creating a bridge between the Oncology Unit and the Infectious Diseases Unit to carry out screening and a more rapid diagnostic and therapeutic journey for cancers in PLWH. The goal is to improve the diagnosis of various types of cancer by involving other professionals, such as gastroenterologists and gynecologists, to ensure faster access to treatment and, therefore, a greater chance of survival. In addition, our multidisciplinary approach has also included vaccine screening, offered by the "Gaetano Martino" hospital and useful for preventing the development of specific forms of cancer in the entire population and particularly in PLWH.

Application and internal validation of lung ultrasound score in COVID-19 setting: The ECOVITA observational study.

BACKGROUND: The severe acute respiratory syndrome Coronarovirus-2 associated still causes a significant number of deaths and hospitalizations mainly by the development of respiratory failure. We aim to validate lung ultrasound score in order to predict mortality and the severity of the clinical course related to the need of respiratory support. METHODS: In this prospective multicenter hospital-based cohort study, all adult patients with diagnosis of SARS-CoV-2 infection, performed by real-time reverse transcription polymerase chain reaction were included. Upon admission, all patients underwent blood gas analysis and lung ultrasound by expert operators. The acquisition of ultrasound scan was performed on 12 peculiar anatomic landmarks of the chest. Lung ultrasound findings were classified according to a scoring method, ranging 0 to 3: Score 0: normal A-lines. Score 1: multiple separated B-lines. Score 2: coalescent B-lines, alteration of pleural line. Score 3: consolidation area. RESULTS: One thousand and seven patients were included in statistical analysis (male 62.4 %, mean age 66.3). Oxygen support was needed in 811 (80.5 %) patients. The median ultrasound score was 24 and the risk of having more invasive respiratory support increased in relation to higher values score computed. Lung ultrasound score showed negative strong correlation (rho: -0.71) with the P/F ratio and a significant association with in-hospital mortality (OR 1.11, 95 %CI 1.07-1.14; p < 0.001), even after adjustment with the following variables (age, sex, P/F ratio, SpO2, lactate, hypertension, chronic renal failure, diabetes, and obesity). CONCLUSIONS: The novelty of this research corroborates and validates the 12-field lung ultrasound score as tool for predicting mortality and severity clinical course in COVID-19 patients. Baseline lung ultrasound score was associated with in-hospital mortality and requirement of intensive respiratory support and predict the risk of IOT among COVID-19 patients.

Cancer-related fatigue in the elderly.

PURPOSE: Cancer is a disease of the elderly: 60 % of tumours occur in patients aged 65 years or older. Cancer-related fatigue is a common symptom experienced by cancer patients and cancer survivors that profoundly affects all aspects of the quality of life. Although it has been estimated that up to 70 % of elderly with cancer experience fatigue, this symptom is still largely ignored in ageing population. METHODS: We performed a systematic review of the literature identified by MEDLINE. RESULTS: The relationship between ageing process and pathogenesis of cancer-related fatigue is still not fully understood. CONCLUSIONS: Ageing is associated with an increased prevalence of chronic diseases, decreased functional reserve in multiple organ systems and enhanced susceptibility to stress. Ageing and the concomitant presence of a condition of frailty may predispose to the presence of fatigue. Nevertheless, only few studies have to date specifically assessed the impact of fatigue in the geriatric population. Since cancer-related fatigue is a peculiarly debilitating condition characteristic of elderly cancer patient population, we suggest the early recognition and thorough evaluation of the symptom fatigue, its co-existing causes (i.e. anaemia, mood disorders and sleep disturbances) and co-morbidities (i.e., endocrine disorders, metabolic, cardiovascular and liver diseases).

Treatment of 741 Italian patients with chronic fatigue syndrome.

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a distinctive syndrome characterized by specific symptoms cluster. CFS mostly affects women and often results in severe functional limitation. Its prevalence varies from 0.4 to 2.5% in the general population. In our prior studies on the clinical features of 205 CFS patients we founded immunological and brain abnormalities. In this paper we illustrate our caseload on CFS treatment. PATIENTS AND METHODS: From January 2000 to December 2005, we evaluated all the patients admitted at the CFS Unit of the Aviano National Cancer Institute, for staging procedures and treatments. Patients not meeting the Fukuda diagnostic criteria were excluded. RESULTS: 250 male and 491 female (median age 35.5 and 39.3 years, respectively) were enrolled and treated for CFS. As expected, CFS resulted from previous infectious disease in all patients. Female patients showed to be more affected by symptoms than male patients. The treatment schedules followed by the patients included nutritional supplements alone, corticosteroids, antidepressant/sedative drugs, and antiviral/immunoglobulin drugs. Antiviral/ immunoglobulin drugs achieved the best response (15.3% positive responses vs. 8.3% negative responses; OR 0.44, CI 0.26-0.74, p = 0.002). The carrying out of 4 or more treatments showed a protective effect (OR 0.46, CI 0.28-0.77, p = 0.003). This finding was confirmed in the multivariate analysis, adjusted by type of drugs (OR 0.49, CI 0.28-0.84, p = 0.009) and number of treatments carried out (OR 0.51, CI 0.30-0.86, p = 0.01); these two variables were independent. CONCLUSIONS: These findings show that the antiviral/immunoglobulin approach has a longer positive disease free survival in comparison with other approaches. However, CSF still remains a difficult disease to be effectively treated.

Kaposi' s sarcoma in HIV-positive patients: the state of art in the HAART-era.

Kaposi's sarcoma (KS) is a multicentric angioproliferative cancer of endothelial origin typically occurring in the context of immunodeficiency, i.e. coinfection with Human Immonodeficiency Virus (HIV) or transplantation. The incidence of KS has dramatically decreased in both US and Europe in the Highly Active Antiretroviral Therapy (HAART) era. However, KS remains the second most frequent tumor in HIV-infected patients worldwide and it has become the most common cancer in Sub-Saharan Africa. In 1994, Yuan Chang et al discovered a novel γ-herpesvirus in biopsy specimens of human KS. Epidemiologic studies showed that KS-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) was the etiological agent associated with all subtypes of KS. KS has a variable clinical course ranging from very indolent forms to a rapidly progressive disease. HAART represents the first treatment step for slowly progressive disease. Chemotherapy (CT) plus HAART is indicated for visceral and/or rapidly progressive disease. The current understanding of KS as a convergence of immune evasion, oncogenesis, inflammation and angiogenesis has prompted investigators to develop target therapy, based on anti-angiogenic agents as well as metalloproteinase and cytokine signaling pathway inhibitors. These drugs may represent effective strategies for patients with AIDS-associated KS, which progress despite chemotherapy and/or HAART. In this review, we focus on the current state of knowledge on KSHV epidemiology, pathogenesis and therapeutic options.

Intravesical chemo-immunotherapy in non muscle invasive bladder cancer.

Non-Muscle-Invasive-Bladder-Cancer represents 75-85% of the new bladder cancer cases per year. Trans-uretral vesical resection is the milestone for diagnosis and therapy. After primary treatment, recurrence is frequent depending on the presence of several established risk factors: multiplicity, T dimension, prior recurrence. In some patients disease progress to an advanced stage. Adjuvant chemo-immunotherapy has been widely used depending on the risk category assigned on the basis of the risk factors for recurrence. In low risk categories a one shot treatment with chemotherapy is considered the standard treatment without any maintenance therapy. In intermediate risk patients, adjuvant induction therapy and maintenance chemotherapy or immunotherapy for at least one year is recommended. In high risk patients adjuvant induction and maintenance immunotherapy until 3 years is considered the best strategy. In this review data on the different drugs used in this setting will be discussed.

Lung cancer and COVID-19: problems and perspectives.

COVID-19 pandemic generated concerns about the healthcare of patients with cancer, not simply because of the formidable impact of COVID-19 patients in the public healthcare system, but also due to the overlapping pathognomonic signs of many forms of lung cancer with lung injuries associated with COVID-19. This report tries to shed light on the issue. We evaluated the great concern of people suffering from lung cancer and also infected with SARS-CoV-2 by discussing evidence and data from current literature. Lung cancer in Italy has represented more than 1 case/4 (27%) in the latest ten years and nevertheless, even due to the concurrence of many complex interplays between COVID-19 and cancer even at the immune level, a consensus protocol and expert guidelines to diagnose and treat lung cancer upon SARS-CoV-2 infection are yet lacking. New insights and consensus panels should be therefore proposed, even at the simplistic level about if priority must be either given to COVID-19 or to cancer therapy.

Integrative multidisciplinary approaches by the Integrative Medicine Research Group (IMRG): a new frontier in cancer setting.

This conference addresses the topic of integrative, multidisciplinary approaches to cancer settings according to evidence-based medicine. The multidisciplinary approach of the researchers involved characterizes this new and complex scenario. The Integrative Medicine Research Group (IMRG) has always been committed to the activities and dissemination of CAM in cancer patients, focusing on the safety and efficacy of these approaches. Thus, one of the main goals of IMRG is to demonstrate that CAM can support cancer patients during treatment and improve their quality of life and survival. In addition, IMRG's multidisciplinary network is ever vigilant in assessing the risks of interactions between cancer drugs and nutraceuticals. We hope that the integrative medicine approach can be transferred to the level of all chronic diseases, including oncology.

New treatment strategies for HIV-positive cancer patients undergoing anticancer medical treatment: update of the literature.

The introduction of highly active antiretroviral therapy (ART) has deeply modified the outcome of HIV patients by improving their overall survival and ameliorating their quality of life (QoL). The prolongation of these patients' survival has led to an increased risk of highly diffused non-infectious diseases, e.g., cardiovascular diseases, endocrine disease, neurological diseases, and cancer. The management of antiretroviral therapy and anticancer agents (AC) can be challenging, due to the possible drug-drug interactions (DDI) between AC and ART. For this reason, a multidisciplinary approach is always preferred as demonstrated by the GICAT (Italian Cooperation Group on AIDS and Tumors). This review aims to analyze the current scientific data regarding the possible effects of ART on the management of HIV-positive cancer patients and to evaluate the possible DDIs that must be taken into consideration when co-administrating ART and AC. A collaboration between all the involved professional figures, particularly infectious disease specialists and oncologists, represents the key to the correct managing of these patients in order to guarantee the best oncological outcome possible.

Detection and kinetic analysis of Epinotia aporema granulovirus in its lepidopteran host by real-time PCR.

Epinotia aporema granulovirus (EpapGV) has attracted interest as a potential biocontrol agent of the soybean pest Epinotia aporema in Argentina. Studies on virus/host interactions conducted so far have lacked an accurate method to assess the progress of virus load during the infection process. The present paper reports the development of a real-time PCR for EpapGV and its application to describe viral kinetics following ingestion of two different virus doses by last-instar E. aporema larvae. Real-time PCR was shown to be a reliable method to detect and quantify the presence of EpapGV in the analyzed samples. The increase in virus titer (log) exhibited a sigmoidal pattern, with an exponential growth phase between 24 and 48 h postinfection for both initial doses tested.

Antiblastic treatment of haematological malignancies during pregnancy: a crucial decision.

Antiblastic treatment of hematological malignancies during pregnancy poses a number of issues related to the curability of the maternal disease, the need of a prompt treatment and the potential toxicity of chemotherapy for the fetus. Here we report the results of a systematic literature search about the management of the most frequent hematological malignancies that may occur during pregnancy, focusing on specific issues related to gestational age at diagnosis, fetal toxicity and efficacy on the maternal side. The standard approach in non-pregnant women is illustrated as reference.

Antiblastic treatment, for solid tumors, during pregnancy: a crucial decision.

Cancer is the second leading cause of death during the reproductive years complicating between 0.02 percent and 0.1 percent of pregnancies. The incidence is expected to rise with the increase in age of childbearing. The most common types of pregnancy-associated cancers are: cervical cancer, breast cancer, malignant melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma and ovarian cancer. The relatively rare occurrence of pregnancy-associated cancer precludes conducting large, prospective studies to examine diagnostic, management and outcome issues. The treatment of pregnancy-associated cancer is complex since it may be associated with adverse fatal effects. In pregnant patients diagnosed with cancer during the first trimester, treatment with multidrug anti-cancer chemotherapy is associated with an increased risk of congenital malformations, spontaneous abortions or fetal death, and therefore, should follow a strong recommendation for pregnancy termination. Second and third trimester exposure is not associated with teratogenic effect but increases the risk of intrauterine growth retardation and low birth weight. There are no sufficient data regarding the teratogenicity of most cytotoxic drugs. Almost all chemotherapeutic agents were found to be teratogenic in animals and for some drugs only experimental data exist. Moreover, no pharmacokinetic studies have been conducted in pregnant women receiving chemotherapy in order to understand whether pregnant women should be treated with different doses of chemotherapy. This article reviews the available data regarding the different aspects of the treatment of cancer during pregnancy.

Obstetrical, fetal and postnatal effects of gestational antiblastic chemotherapy: how to counsel cancer patients.

At least one in a thousand pregnancies is complicated by cancer and, as the maternal age at pregnancy increases, numbers are growing. If chemotherapy cannot be postponed, both doctors and patients face complex medical and ethical issues. There is a conflict between optimal maternal therapy and fetal wellbeing. Treatment during the first trimester increases the risk of congenital malformations, spontaneous abortions and fetal death. Second and third trimester exposure is less risky, but it can cause intrauterine growth retardation and low birth weight. Other effects on pregnancy after the first trimester include premature birth, stillbirth, impaired functional development, myocardial toxicity and myelosuppression. Counseling and management of these cases are difficult, because literature is mostly represented by case reports or retrospective series while randomized prospective studies or guidelines are lacking. Moreover, personal experience is often scanty due to the rarity of the condition. This article reviews the available data regarding the different aspects of systemic treatment of cancer during pregnancy to help oncologist and obstetricians in counseling their patients and treat them accordingly.

Acoustic Radial Force Impulse as an effective tool for a prompt and reliable diagnosis of hepatocellular carcinoma - preliminary data.

ARFI (Acoustic Radiation Force Impulse) is a novel method based on the use of shear acoustic waves remotely induced by the radiation force of a focused ultrasonic beam. Recently, ARFI has been investigated as a non-invasive method for the assessment of liver fibrosis. The reproducibility of ARFI technology was proved in determining liver fibrosis: in detail, for cirrhosis Fibroscan had its best cut-off at >/= 11 kPa (AUROC of 0.80) whereas ARFI >/= 2.0 m/s (AUROC of 0.89). By pair-wise comparison of AUROC, ARFI was significantly more accurate than TE for a diagnosis of significant and severe fibrosis. Due to the low amount of collagen deposition within hepatocellular carcinoma (HCC) nodules in a context of "hard" cirrhotic parenchyma, ARFI propose itself also as a novel, specific method for an early identification of primitive neoplastic nodules during the follow up of cirrhotic patients. The diagnostic accuracy can be demonstrated either versus the surrounding liver tissue or versus dysplastic or metastatic nodules. Further studies are required to confirm ARFI as a useful tool for HCC follow-up.

Genetic variants influencing fluoropyrimidine based-therapy and available methods to detect them.

BACKGROUND: Many clinicians acknowledge the importance of genetics in drug response and are favourable about using genetic tests to guide therapy. The 5-Fluorouracil (5-FU) is the backbone of different regimens for the treatment of several solid tumours. Unlikely, some patients develop gastrointestinal and hematologic toxicities when treated by the 5-FU, leading to the suspension of therapy. Current evidences of pharmacogenomics, have reported different polymorphisms associated to genes involved with fluoropyrimidine biotransformation. A multitude of methods has been applied to assess the mutational status of these genes, without defining a golden standard for the daily diagnostic routine, so far. AIMS: Some adverse drug response due to the administration of 5-FU can be predicted through pharmacogenomics testing tools. This report reviews the recent findings on the polymorphism for genes that are involved in the biotransformation of the drug and its association with the toxic effect in patients receiving 5-FU in mono o polychemoterapy. Most common fluoropyrimidines-based regimens are finely described. Also, we will take in considerations the recent methods used to identify these genetic alterations. CONCLUSION: Recent and evolving technological advances for genotyping will result in personalized treatment. In the next future the oncologists will have new means based on the genetic composition of the individual, to make treatment decisions for their patients maximizing benefit and minimizing toxicity. Based on these purpose, clinician and lab manager may join together to evaluate advantages and limitation, in terms of costs and applicability, of the most appropriate methods to set molecular diagnostics of 5-FU pharmacogenomics tests.

Comorbidity assessment and radiotherapy in elderly cancer patients.

More than 60% of all cancer patients in Europe and the USA are older than 65 years at the time of diagnosis. Despite this, elderly patients are generally under-represented in clinical trials. There is a lack of clinical trials to drive evidence-based decision making in the elderly cancer patients. In this review, we address the most important issue surrounding the treatment of older cancer patients: comorbidity assessment.

Radiotherapy and hepatocellular carcinoma: update and review of the literature.

Historically radiotherapy has always played a limited role for the treatment of HCC due to the low tolerance of the liver and the subsequent risk of radiation induced liver disease (RILD). Technologist advancements in radiation planning and treatment delivery such as Stereotactic Body Radiotherapy (SBRT) combined with Image Guided Radiotherapy (IGRT) has allowed us to further increase tumor dose while maximally sparing the surrounding not involved liver. Furthermore, together with the growing knowledge of radiobiological models in liver disease, several mono-institutional retrospective and prospective series are reporting very encouraging results. Therefore, radiotherapy might play a significant role for the treatment of unresectable HCC, alone or combined with other locoregional treatment such as transarterial chemoembolisation (TACE). The rationale for studying this technique is really strong and it should be tested in well designed prospective randomized clinical trials.

Knowledge and skills needs for health professions about pharmacogenomics testing field.

BACKGROUND: Promise in the future, a disease could be ranked into genetic categories, allowing bespoke tailoring of medicine to maximize therapeutic effects and to reduce the potential for adverse drug response. This new feature requires for health professionals to have competencies not only for the basic skills of their discipline, but also for the understanding on why, when, and how that knowledge should be applied to improve personalized therapies for their patients. Current opinion on basic competences of health professions includes knowledge and skills on two fundamental features: (1) genetics of disease, to allow the understanding and the identification of diseases associated to genetic variations, and to facilitate the development of new genomic tests; and (2) ethical, social and economical implications that are fundamental to identify those factors that might contribute to a successful integration of pharmacogenomics into international health and public policy. AIM: Briefly, we described (1) current knowledge on genetic variations that interact with therapies and the need to detect them; (2) the most common available methods for detecting mutations; and (3) ethical, social and economic issues related to pharmacogenetic testing and recording of genetic information (e.g., critical evaluation of the development of new tests, privacy, the current absence of public reimbursement, etc). CONCLUSIONS: These could be useful recommendations for academic institutions and educational programs to prepare health professionals with the necessary abilities for their future practice.

Pharmacogenomics panel test for prevention toxicity in patient who receive Fluoropirimidine/Oxaliplatin-based therapy.

AIM: Both Fluoropirimidine and Oxaliplatin (FluOx) are the most common anticancer drugs used to treat lung, colorectal, ovarian, breast, head/neck, and genitourinary cancers. However, the efficacy of FluOx-based therapy is often compromised because of the severe risk of toxicity. Stratification of patients for multidrug response is a promising strategy for cancer treatment and personalized therapy. METHODS: Here, we review the late findings on the most appropriate gene variants related to the toxicity in patients receiving FluOx chemotherapy. Several criteria were used to select a genotyping panel tests, including dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), Glutathione S-transferase (GSTP1), and ATP-binding cassette, subfamily C member 2 (ABCC2). RESULTS: Results of allelic status from 7 validated polymorphism assays, allow the stratification of the patients who are most likely to respond to FluOx treatments. Also, we will take in consideration the usefulness and costs of the methods used to detect these polymorphisms. CONCLUSIONS: With these pharmacogenomics markers, the oncologists will have new means based on the genetic profile of the individual, to make treatment decisions for their patients in order to maximize benefits and minimize toxicity.