New Strategies for Endometrial Cancer Detection and Management.

With 400,000 new cases and over 80,000 deaths a year worldwide, endometrial cancer (EC) holds a rather unfortunate record, namely, that of the tumour with the highest increase in incidence, a unique trend among gynaecological cancers [...].

Taste and Smell Disorders in Cancer Treatment: Results from an Integrative Rapid Systematic Review.

Taste and smell disorders (TSDs) are common side effects in patients undergoing cancer treatments. Knowing which treatments specifically cause them is crucial to improve patients' quality of life. This review looked at the oncological treatments that cause taste and smell alterations and their time of onset. We performed an integrative rapid review. The PubMed, PROSPERO, and Web of Science databases were searched in November 2022. The article screening and study selection were conducted independently by two reviewers. Data were analyzed narratively. Fourteen studies met the inclusion criteria and were included. A high heterogeneity was detected. Taste disorders ranged between 17 and 86%, while dysosmia ranged between 8 and 45%. Docetaxel, paclitaxel, nab-paclitaxel, capecitabine, cyclophosphamide, epirubicin, anthracyclines, and oral 5-FU analogues were found to be the drugs most frequently associated with TSDs. This review identifies the cancer treatments that mainly lead to taste and smell changes and provides evidence for wider studies, including those focusing on prevention. Further studies are warranted to make conclusive indication possible.

Cancer Prevention with Molecular Targeted Therapies.

Today, the oncologist is like a detective of the human body who, instead of a magnifying glass, uses the new tools of molecular pathology to search not only for genes or molecular targets, to be targeted with innovative anticancer therapies, but also molecular alterations that allow the identification of population groups at risk of developing tumors for preventive purposes [...].

A Presurgical Study of Curcumin Combined with Anthocyanin Supplements in Patients with Colorectal Adenomatous Polyps.

Adenomatous polyps are precancerous lesions associated with a higher risk of colorectal cancer (CRC). Curcumin and anthocyanins have shown promising CRC-preventive activity in preclinical and epidemiological studies. The objective of this window-of-opportunity, proof-of principle trial was to evaluate the effect of curcumin combined with anthocyanin supplements on tissue biomarkers of colorectal adenomatous polyps. Eligible patients received either anthocyanin and curcumin supplementation or related matching placebo for 4-6 weeks before polyp removal. Adenomatous polyps and adjacent tissue biopsies were collected at baseline and after supplementation for immunohistochemical assessment of ß-catenin, NF-kappa B (NF-κB), Ki-67, P53, and dysplasia. No differences were observed in baseline biomarker expression between normal and dysplastic tissues. The combination of anthocyanins and curcumin resulted in a significant borderline reduction of NF-κB immunohistochemistry (IHC) expression in adenoma tissue (geometric mean ratio (GMR): 0.72; 95% confidence interval (CI): 0.51-1.00; p-value: 0.05) and a trend to a reduction of Ki-67 (GMR: 0.73; 95% CI: 0.50-1.08; p-value: 0.11). No significant modulation of biomarkers in normal adjacent mucosa was observed. We concluded that the combined supplementation of anthocyanins and curcumin seems to lead to a potentially favorable modulation of tissue biomarkers of inflammation and proliferation in colon adenomas.

Aromatase Inhibitors as Adjuvant Treatment for ER/PgR Positive Stage I Endometrial Carcinoma: A Retrospective Cohort Study.

OBJECTIVE: Although endometrial cancer (EC) is a hormone dependent neoplasm, there are no recommendations for the determination of steroid hormone receptors in the tumor tissue and no hormone therapy has ever been assessed in the adjuvant setting. The purpose of this study was to explore the effect of adjuvant aromatase inhibitors (AIs) on progression-free survival (PFS) and overall survival (OS) in patients with early stage and steroid receptors-positive EC. METHODS: We retrospectively analyzed clinical and pathological factors in 73 patients with high-risk (49.3%) or low-risk (50.7%) stage I (n = 71) or II (n = 2) endometrial cancer who received by their preference after counseling either no treatment (reference group) or AI. Prognostic factors were well balanced between groups. Expression of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 index was correlated with clinical outcomes. RESULTS: Univariate and multivariate Cox proportional regression analyses, adjusted for age, grade, stage, depth of myometrial invasion, lymphovascular space invasion, BMI, ER, PgR and Ki-67 labeling index levels, showed that PFS and OS had a trend to be longer in patients receiving AI than in the reference group HR= 0.23 (95% CI; 0.04-1.27) for PFS and HR= 0.11 (95% CI; 0.01-1.36) for OS. CONCLUSION: Compared with no treatment, AI exhibited a trend toward a benefit on PFS and OS in patients with early stage hormone receptor-positive EC. Given the exploratory nature of our study, randomized clinical trials for ER/PgR positive EC patients are warranted to assess the clinical benefit of AI and the potential predictive role of steroid receptors and Ki-67.

Strengthening the AntiTumor NK Cell Function for the Treatment of Ovarian Cancer.

The crosstalk between cancer cells and host cells is a crucial prerequisite for tumor growth and progression. The cells from both the innate and adaptive immune systems enter into a perverse relationship with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment (TME). Epithelial ovarian cancer (EOC), the most lethal of all gynecological malignancies, is characterized by a unique TME that paves the way to the formation of metastasis and mediates therapy resistance through the deregulation of immune surveillance. A characteristic feature of the ovarian cancer TME is the ascites/peritoneal fluid, a malignancy-associated effusion occurring at more advanced stages, which enables the peritoneal dissemination of tumor cells and the formation of metastasis. The standard therapy for EOC involves a combination of debulking surgery and platinum-based chemotherapy. However, most patients experience disease recurrence. New therapeutic strategies are needed to improve the prognosis of patients with advanced EOC. Harnessing the body's natural immune defenses against cancer in the form of immunotherapy is emerging as an innovative treatment strategy. NK cells have attracted attention as a promising cancer immunotherapeutic target due to their ability to kill malignant cells and avoid healthy cells. Here, we will discuss the recent advances in the clinical application of NK cell immunotherapy in EOC.

The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients.

BACKGROUND: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials. METHODS/DESIGN: This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year. DISCUSSION: A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC. TRIAL REGISTRATION: EudraCT Number: 2015-004824-77; ClinicalTrial.gov Identifier: NCT03047837 . Registered on February 1, 2017.

Endocrine therapy in ovarian cancer: where do we stand?

PURPOSE OF REVIEW: Hormonal factors play a pivotal role in epithelial ovarian tumorigenesis and steroid receptor expression has been associated with epithelial ovarian cancer (EOC) response and survival in recent studies. However, the degree of activity of endocrine therapy overall and by specific agents remains unclear. The purpose of this work is to summarize the evidence provided by the recent literature on the effectiveness of endocrine treatment for advanced EOC. RECENT FINDINGS: The results of 53 trials of different endocrine therapies in EOC indicate a clinical benefit of 41% [95% confidence interval (CI), 0.34-0.48], with a trend for a higher benefit in those with estrogen receptor (ER) + and/or progesteron receptor (PgR) + tumors. Moreover, the odd ratio for death showed a reduced mortality with endocrine regimens (0.69, 95% CI, 0.50-0.97), with a propensity for a better outcome in first-line and low-grade tumors. SUMMARY: We suggest that ER and PgR have a predictive role and their inhibition by endocrine therapy may be a treatment option for EOC. Randomized clinical trials in the first-line treatment of advanced hormone receptor positive EOC are warranted given the potential cost effectiveness of this approach.

Clinical benefit and risk of death with endocrine therapy in ovarian cancer: A comprehensive review and meta-analysis.

BACKGROUND: Steroid hormones promote epithelial ovarian cancer (EOC) growth and their receptor expression is associated with disease outcome. Hormone therapy is frequently used in pretreated EOC, but the magnitude of activity overall and by specific agents or tumor characteristics is unknown. METHODS: Clinical Benefit Rates (CBR) and deaths from clinical trials of endocrine agents were meta-analyzed. Summary estimates of CBR (SCBR) and Odd Ratio for death (SOR) were calculated according with type of drug, ER and PgR status, platinum resistance, line of therapy, tumor grade and tamoxifen dose. RESULTS: Fifty-three trials in 2490 patients were analyzed. Overall, SCBR was 41% (95%CI, 0.34-0.48) for any endocrine treatment, 43% (95%CI, 0.30-0.56) for tamoxifen, 39% (95%CI, 0.29-0.50) for aromatase inhibitors and 37% (95%CI, 0.26-0.48) for progestins. The SCBR for ER+ and/or PgR+ tumors was 46% (95%CI, 0.34-0.57) versus 37% (95%CI, 0.27-0.48) in tumors with unknown receptors and 55% in platinum sensitive (95%CI, 0.28-0.80) versus 40% (95%CI, 0.29-0.51) in platinum resistant tumors The SOR for death calculated from 6 out of 9 randomized clinical trials (RCTs) showed a reduced mortality with endocrine therapy (SOR=0.69, 95%CI, 0.50-0.97), with a possible tendency for a greater effect in first line and low grade tumors. The overall quality of the RCTs was low. CONCLUSIONS: The activity of endocrine therapy in advanced EOC is worth considering and seems to support large properly designed randomized trials in the first treatment of hormone sensitive EOC.

Breast cancer incidence after hormonal treatments for infertility: systematic review and meta-analysis of population-based studies.

The increasing practice of hormonal infertility treatments (HITs) raised concerns about their effects on breast cancer (BC) risk. Available evidence reported conflicting results. The aim of this study was to assess the potential association between HITs and BC risk. The literature was searched through November 2014. Eligible studies included cohort studies reporting BC incidence in women undergone HITs. Data were analyzed with standard meta-analytic techniques. Subgroup analyses were performed by type of intervention (IVF vs. NO IVF), follow-up duration (<10 vs. >10 years), and type of control (population vs. infertile). 20 eligible studies (207.914 women, 2347 BC) were retrieved: no increased risk was detected (SRR = 1.05, 95 % CI 0.96-1.14), with a significant heterogeneity (I (2) = 59 %, p = 0.001) among studies. In the seven studies with the in vitro fertilization (IVF) procedure, no increase in BC risk was observed (SRR = 0.96, 95 % CI 0.80-1.14); in the three NO IVF studies, an increased BC risk was identified (SRR = 1.26, 95 %CI 1.06-1.50). A borderline interaction between type of intervention (IVF vs. NO IVF) and BC risk was observed (p = 0.06). An increased risk with longer follow-up (≥10 vs. <10 years) was detected (SRR = 1.13, 95 % CI 1.02-1.26 vs. SRR = 0.95, 95 % CI 0.85-1.06). Overall, HITs are not associated with an increased BC risk. In particular, no increased risk was observed in women undergoing IVF. Conversely, an increased in BC risk cannot be ruled out with older treatment protocols based on clomiphene. The long-term administration of clomiphene outside the current indications should be discouraged because of a possible increase in BC risk.

APS8, a polymeric alkylpyridinium salt blocks α7 nAChR and induces apoptosis in non-small cell lung carcinoma.

Naturally occurring 3-alkylpyridinium polymers (poly-APS) from the marine sponge Reniera sarai, consisting of monomers containing polar pyridinium and nonpolar alkyl chain moieties, have been demonstrated to exert a wide range of biological activities, including a selective cytotoxicity against non-small cell lung cancer (NSCLC) cells. APS8, an analog of poly-APS with defined alkyl chain length and molecular size, non-competitively inhibits α7 nicotinic acetylcholine receptors (nAChRs) at nanomolar concentrations that are too low to be acetylcholinesterase (AChE) inhibitory or generally cytotoxic. In the present study we show that APS8 inhibits NSCLC tumor cell growth and activates apoptotic pathways. APS8 was not toxic for normal lung fibroblasts. Furthermore, in NSCLC cells, APS8 reduced the adverse anti-apoptotic, proliferative effects of nicotine. Our results suggest that APS8 or similar compounds might be considered as lead compounds to develop antitumor therapeutic agents for at least certain types of lung cancer.

EU-Funded Telemedicine Projects - Assessment of, and Lessons Learned From, in the Light of the SARS-CoV-2 Pandemic.

The SARS-CoV-2 health emergency has demonstrated the need for developing structured telemedicine systems to protect citizens from the spread of the virus. Thereby, their importance and the necessity to tailor their diffusion at large scale for providing services both at a distance and in time has been shown. For these reasons, the European Union advocates the digital transition of health systems for the next 5 years. The main aim of this work is to revisit the telemedicine research projects financed by European Community during the period 2000-2020 with particular respect to the results derived from their application. The analysis showed that some integration of tele-care and tele-health could be obtained with tele-monitoring systems and the implementation of Electronic Personal Record (EPR). Furthermore, telemedicine allows enhancing health care in critical environments, to protect health and life of the most vulnerable patients, and to encourage cross-border dialogue. The criteria of "from distance" and "timely delivered" are granted, but the effectiveness of the overall offered services highly depends on the availability and the quality of the input data. Unfortunately, this remains a relevant problem in the SARS-CoV-2 pandemic.

The Impact of the Introduction of the Breast Unit Model in a Northwestern Italian Region.

Breast cancer is the most common tumor in middle-aged and older women. In 2003, the European Parliament recommended to Member States that all women with breast cancer should be treated by a multidisciplinary team and that a network of certified breast centers be organized (the centers have been called Breast Units (BUs)). With the present study, we aim to explore the impact of the introduction of the BU organizational model in the Liguria region, Italy, through different outcome indicators. An explorative retrospective analysis was conducted through the period from 2013 to 2019 to assess the impact of the introduction of the BU model in our region. We identified two periods: before (2014-2015) and after (2017-2018) the introduction of this organizational model to assess its value impact through the definition of six measurable outcome indicators. Length of hospitalization, repeated specialist outpatient diagnostic procedures and the rate of subjects who started radiotherapy treatment within 60 days improved after the introduction of BUs. The passive health migration rate only improved significantly for one local health unit (LHU), while reintervention and diagnosis-surgery time did not show any enhancement after the introduction of the BU model. The BU model seems to provide an increase in several aspects of the healthcare offered to breast cancer patients in Liguria, specifically in those areas where a shared guideline could assist healthcare workers. Future research, such as pilot studies, are needed to assess the impact of the introduction of the BU model in our reality.

NK Cell-Based Immunotherapy in Colorectal Cancer.

Human Natural Killer (NK) cells are all round players in immunity thanks to their powerful and immediate response against transformed cells and the ability to modulate the subsequent adaptive immune response. The potential of immunotherapies based on NK cell involvement has been initially revealed in the hematological setting but has inspired the design of different immune tools to also be applied against solid tumors, including colorectal cancer (CRC). Indeed, despite cancer prevention screening plans, surgery, and chemotherapy strategies, CRC is one of the most widespread cancers and with the highest mortality rate. Therefore, further efficient and complementary immune-based therapies are in urgent need. In this review, we gathered the most recent advances in NK cell-based immunotherapies aimed at fighting CRC, in particular, the use of monoclonal antibodies targeting tumor-associated antigens (TAAs), immune checkpoint blockade, and adoptive NK cell therapy, including NK cells modified with chimeric antigen receptor (CAR-NK).

Molecular tests for SARS-CoV-2: data from Liguria Region (Italy).

The current Covid-19 pandemic makes necessary to identify people affected by SARS-CoV-2. To do this, the most reliable method is the use of the molecular test that is the gold standard to detect positive peoples.Here, we provide a comprehensive review on the diagnostic processes through molecular tests for SARS-CoV-2 infection. First, we have obtained information about the testing technologies in the Liguria region's hospitals to find and describe the most common technologies used and to calculate the molecular test's average cost. Second, we have evaluated the sensitivity, the specificity, the safety with respect to the data reported on scientific literature (Real Word Data VS Registrative Studies) and the organizational aspects of the molecular tests.Clinical Relevance- This study aims to provide support to the decision makers on clinical, economic, organizational, social and ethical issues related to the use of molecular test for SARS-CoV-2.

Italian Public Health Expenditure for Vitamin D is still high: New Outlook to Saving From a Consumption Analysis in the Liguria Region.

PURPOSE: Italian expenditure for vitamin D greatly increased in the last few years, reaching €314 million ($376.8 million) in 2019. In Italy, the main cause of the increase in public spending for vitamin D is the marketing of high-cost medicines. At national and regional levels, some interventions have been performed to reduce expenditure, but spending has continued to increase. The aim of this work is to propose a new saving strategy determined by an analysis of a significant sample of the market. METHODS: Data on the use of vitamin D formulations, including data for the different active substances that represent its pharmaceutical analogue and composition of groups of equivalence, were extrapolated from the Italian Medicines Agency transparency lists and from the Farmadati database. Data on pharmaceutical expenditure were obtained from the Data Warehouse of Liguria Region; the composition of this expenditure was analyzed in detail, focusing on the characteristics of the pharmaceutical preparations and their cost (price per defined daily dose). FINDINGS: Vitamin D expenditure paralleled that of cholecalciferol, the most used active ingredient, which in Liguria increased from €643,352 ($772,022.4) in 2010 to €8,006,574 ($9,607,888.8) in 2019 (increase of 1144%). Spending focused on high-cost formulations, exceeding 90% of total cholecalciferol cost in 2019. We simulated a possible optimization of the expense for cholecalciferol by applying a revised price to all the cholecalciferol consumptions in high-cost products because these formulations do not have an added therapeutic value, finding that the saving would be at least 60%. National data on the detailed expenditure composition for vitamin D are not available, but we found a strong resemblance between total cholecalciferol expenditure time series in Italy and the Liguria Region. IMPLICATIONS: The expense of cholecalciferol and consequently the expense of vitamin D could be optimized by modifying the reimbursement of high-cost formulations. At a national level, savings should be proportional to that estimated for the Liguria Region. On the basis of the 2019 data, Italian savings with respect to total cholecalciferol expenditure should be €170.65 million ($204.78 million); per capita cholecalciferol expenditure would shift from €4.66 ($5.59) to €1.84 ($2.21).

New Insights into Endometrial Cancer.

EC is the most common cancer in the female genital tract in developed countries, and with its increasing incidence due to risk factors, such as aging and obesity, tends to become a public health issue. Although EC is a hormone-dependent neoplasm, there are no recommendations for the determination of steroid hormone receptors in the tumor tissue and no hormone therapy has ever been assessed in the adjuvant setting. Furthermore, its immune environment has been slightly characterized, but recent evidences point out how EC microenvironment may increase self-tolerance by reducing the recruitment of cytotoxic immune cells to the tumor site and/or modifying their phenotype, making these cells no longer able to suppress tumor growth. Here we highlight insights for EC management from diagnosis to a desirable trend of personalized treatment.

Expert opinion and patients' in-depth interviews on the impact of pulmonary complications in systemic sclerosis.

OBJECTIVE: To qualitatively explore the perceptions and opinions of experts dealing with systemic sclerosis (SSc) and patients with SSc on the impact of the disease and pulmonary complications on economic status, psycho-social wellbeing and the diagnostic and therapeutic journey, and to identify which strategies/interventions may be useful to address patients' and their family's needs. METHODS: An expert meeting was conducted using the NGT to discuss the consequences of pulmonary complications on the Italian SSc community. The direct experience of five patients with SSc and pulmonary complications was described through in-depth interviews conducted by psychologists. RESULTS: The experts' meeting and patients' in-depth interviews underline the complexity of SSc and the consequences of pulmonary involvement on patients' and caregivers' health-related quality of life, working ability, psychological wellbeing and social interactions. Panellists suggest that improved communication between physicians, associations and institutions could help protect the working status of patients with SSc. Granting patients disability benefits, providing access to part-time jobs and productivity-focused training could also help decrease the economic burden of the disease. A multidisciplinary approach is recommended to reduce treatment burden, together with the implementation of standard diagnostic and therapeutic paths and increased use of telemedicine via platforms that ensure secure health data sharing. Both patients and caregivers may benefit from psychological support. CONCLUSION: SSc and pulmonary fibrosis have profound consequences on patients' and caregivers' health-related quality of life, working ability, psychological wellbeing and social interactions. Some activities may help patients and families deal with these aspects of the disease.

Inhibition of nonneuronal alpha7-nicotinic receptor for lung cancer treatment.

RATIONALE: Studies strongly suggest that the nicotinic acetylcholine receptors for nicotine (nAChRs) play a significant role in lung cancer predisposition and natural history. The nAChR alpha7 subunit has been found to be pivotal in the control of nicotine-induced lung cancer development and in growth signal transduction induced by nicotine binding to nAChRs. OBJECTIVES: To investigate the anticancer effects of alpha7-nAChR antagonists. METHODS: (1) To check the correlation between alpha7-nAChR presence and alpha-cobratoxin (alpha-CbT) sensitivity, binding experiments were performed in various normal human cells, lung cancer cell lines, and primary tumoral cells; (2) to demonstrate that alpha-CbT might be an efficient adjuvant therapy for non-small cell lung cancer (NSCLC) we expanded our previous observations to a panel of NSCLCs of various subtypes orthotopically grafted on nonobese diabetic/severe combined immunodeficient mice; (3) to gain insight into the mechanism of alpha-CbT-induced tumor reduction, the cells obtained after enzymatic digestion of tumors were analyzed for procaspase-9, Bax, Bad, and Bcl-X(L) protein; and (4) Snail/E-cadherin expression was evaluated to acquire information about the chemoresistance of cancer cells to alpha-CbT. MEASUREMENTS AND MAIN RESULTS: We report herein the results of an experimental strategy aimed at investigating the antitumor effects of a powerful alpha7-nAChR antagonist, alpha-CbT, in an in vivo setting set to mimic the clinical setting of lung cancer; in addition, a possible explanation for alpha-CbT selectivity toward cancer cells is presented. CONCLUSIONS: We report the prolonged survival of alpha-CbT-treated animals in our mouse model of NSCLC, which is most likely the result of multiple mechanisms, including various antiproliferative and antiangiogenic effects.