AIRO Breast Cancer Group Best Clinical Practice 2022 Update

Introduction: Breast cancer is the most common tumor in women and represents the leading cause of cancer death. Radiation therapy plays a key-role in the treatment of all breast cancer stages. Therefore, the adoption of evidence-based treatments is warranted, to ensure equity of access and standardization of care in clinical practice.Method: This national document on the highest evidence-based available data was developed and endorsed by the Italian Association of Radiation and Clinical Oncology (AIRO) Breast Cancer Group.We analyzed literature data regarding breast radiation therapy, using the SIGN (Scottish Intercollegiate Guidelines Network) methodology (www.sign.ac.uk). Updated findings from the literature were examined, including the highest levels of evidence (meta-analyses, randomized trials, and international guidelines) with a significant impact on clinical practice. The document deals with the role of radiation therapy in the treatment of primary breast cancer, local relapse, and metastatic disease, with focus on diagnosis, staging, local and systemic therapies, and follow up. Information is given on indications, techniques, total doses, and fractionations.Results: An extensive literature review from 2013 to 2021 was performed. The work was organized according to a general index of different topics and most chapters included individual questions and, when possible, synoptic and summary tables. Indications for radiation therapy in breast cancer were examined and integrated with other oncological treatments. A total of 50 questions were analyzed and answered.Four large areas of interest were investigated: (1) general strategy (multidisciplinary approach, contraindications, preliminary assessments, staging and management of patients with electronic devices); (2) systemic therapy (primary, adjuvant, in metastatic setting); (3) clinical aspects (invasive, non-invasive and micro-invasive carcinoma; particular situations such as young and elderly patients, breast cancer in males and cancer during pregnancy; follow up with possible acute and late toxicities; loco-regional relapse and metastatic disease); (4) technical aspects (radiation after conservative surgery or mastectomy, indications for boost, lymph node radiotherapy and partial breast irradiation).Appendixes about tumor bed boost and breast and lymph nodes contouring were implemented, including a dedicated web application. The scientific work was reviewed and validated by an expert group of breast cancer key-opinion leaders.Conclusions: Optimal breast cancer management requires a multidisciplinary approach sharing therapeutic strategies with the other involved specialists and the patient, within a coordinated and dedicated clinical path. In recent years, the high-level quality radiation therapy has shown a significant impact on local control and survival of breast cancer patients. Therefore, it is necessary to offer and guarantee accurate treatments according to the best standards of evidence-based medicine

Adult-onset autoimmune diabetes in 2020: An update

An increasing number of new cases of autoimmune diabetes occur during adulthood. Most are cases of latent autoimmune diabetes in adults (LADA), a form of autoimmune diabetes with older mean age at onset, slower rate of beta-cell loss and longer period of insulin independence after onset when compared with type 1 diabetes. Unfortunately, patients with LADA are often misdiagnosed as having type 2 diabetes, the most frequent form of adult-onset diabetes, and show a sustained poor glycemic control over time. Recent evidence shows that this translates into a significantly increased risk of complications. Therefore, an enhanced awareness of LADA is essential. In this narrative review we aim to provide an update on knowledge about LADA pathophysiology and clinical implications by critically reporting the most recent evidence

Chitotriosidase Activity Is Inversely Associated with Diastolic Blood Pressure and HbA1c but Not with Arterial Stiffness in Patients with Type 2 Diabetes without Complications

Abstract Background and Aim: Chitotriosidase (Chit), a mammalian chitinases secreted by monocytes and epithelial cells, is increased in both cardiovascular disease (CVD) and type 2 diabetes (T2D). Arterial stiness rises early in T2D and increases the risk of CVD. Aim of the study was to evaluate Chit activity as a precocious biomarker of arterial stiness in T2D patients without overt vascular complications. Methods: Arterial stiness was measured by Cardio-Ankle Vascular Index (CAVI) in 174 T2D patients (mean±SD age=55±4 years, 103 men) without established diabetic complications. For this cross-sectional study, we measured Chit activity by electrochemiluminescent assay in the sera from the 41 patients with the lowest (L_CAVI) and the 42 patients with the highest (H_CAVI) CAVI values. Results: Compared with L_CAVI, H_CAVI patients were older (57±4years vs. 52±4years, p<0.01), had longer T2D duration (6±3years vs. 4±3years, p=0.02), higher diastolic blood pressure (DBP) (90±9 vs. 86±9mmHg, p=0.03), HbA1c (6,5±0,9% vs. 6,01±0,6%, p<0.01) and fasting blood glucose (130±29 vs. 117±27 mg/dL, p=0,024) values, lower BMI (28,5±4,2 vs. 32,3±7,2 kg/m , p=0.01) and glomerular ltration rate (91,3±11,2 vs. 96,1±10,0mL/min/1.73m , p=0.04). Chit activity was similar in L_CAVI and H_CAVI groups (11,6±5,6 vs. 14,0±8,3 nmol/mL/h respectively). Although, Chit was inversely related to DBP (r=-0.22; p <0.041) and HbA1c (r=-0.21; p=0.048) and directly related to albuminuria (r=0.22; p=0.04). No signicant dierences were found in systolic blood pressure, gender, lipid prole, calcium, urate, inammatory markers between the two groups. Conclusion: Arterial stiness raises with age, metabolic control, DBP and impaired kidney function. Chit is also associated with DBP, metabolic control and kidney damage but did not result as a direct marker of arterial stiness in T2D patients without established complications

Reduced early response to SARS-CoV2 vaccination in people with type 1 and type 2 diabetes, a six months follow-up study. The CoVaDiab study I

Introduction: Diabetes mellitus worsens the prognosis of SARS-CoV-2 infection, and vaccination has been the major tool for reducing the risk of hospitalisation, and mortality. The primary aim of this study was to evaluate the response to the SARS-CoV-2 vaccine in subjects with diabetes and controls. Differences between type 1 (T1D) and type 2 (T2D) diabetes and clinical determinants of vaccination response were also evaluated. Methods: 128 subjects with diabetes (60 with T1D and 62 with T2D) and 202 subjects acting as controls who completed a full vaccination cycle with two doses of mRNA vaccine were enroled. People with previous SARS-CoV-2 infection were excluded. Antibodies (Ab) directed against the spike protein of the SARS-CoV-2 were evaluated at one and 6 months after vaccination. Results: In the whole cohort, the Ab level was higher among women than in men (p = 0.011) and negatively correlated with age (rho = -0.155, p = 0.005). Subjects with diabetes showed decreased levels of Ab after one month compared to controls (1217[747-1887]BAU/mL vs. 1477[942-2556]BAU/mL, p = 0.002), even after correction for age and gender (p = 0.002). No difference was found between subjects with T1D and T2D. After 6 months, antibody levels significantly decreased in people with and without diabetes, with no differences between groups, although some subjects were lost at follow-up. In subjects with diabetes, only a significant correlation was found between Ab level and renal function (rho 0.190, p = 0.042). Conclusions: Both T1D and T2D are associated with a reduced early response to vaccination. The serum concentration of Ab significantly reduced over time in both groups, highlighting the relevance of vaccination boosters independently of the presence of diabetes

Diastolic Pressure And Acr Are Modifiable Risk Factors Of Arterial Stiffness In T2DM Without Cardiovascular Disease

Aim: To evaluate early, before the onset of cardiovascular events and of chronic renal insufficiency, the association between CKD-mineral bone disorder biomarkers and vascular stiffness (Cardio Ankle Vascular Index, CAVI) in the course of type 2 diabetes (T2DM). Method: we evaluated 174 T2DM patients (median age 56 y; M/F = 100/74) with diabetes duration less than 10 years and without decreased glomerular filtration rate (eGFR ≥60 ml/min/1.73 m 2) or macrovascular complications. Thirty-four age matched healthy subjects (M/F: 13/21; age: 53.5[50.0-57.7] y.o; eGFR 107.5[97.0-119.7]) ml/ml/min1.73m2) served as local reference control for CAVI (pathological: ≥8) and the novel CKD-MBD biomarkers. Results: albumin-to-creatinine ratio (ACR) averaged 8.5 mg/g [5.6-17.2] with 12.6% of the patients showing pathologic values, indicative of incipient diabetic nephropathy (DN). Serum parathyroid hormone, Fibroblast Growth Factor 23 and Sclerostin were higher while 1,25-dihydroxyvitamin D and Klotho were lower than a control group. CAVI was normal (<8) in only 54% and correlated positively with age (p<.001), Hb1A1c (p=.036), systolic (p=.021) and diastolic blood pressure (DBP) (p=.001) and negatively with 25D (p=.046). In multivariate analysis, age, DBP, ACR, and s-Klotho were independent positive predictors of CAVI. Conclusion: in the absence of overt cardiovascular disease and of chronic renal insufficiency, CAVI is frequently pathologic in T2DM. DBP, and ACR are modifiable risk factors of vascular stiffness in T2DM thus warranting optimal assessment

Distinctive phenogroup to differentiate diagnosis of cardiac myxoma vs cardiovascular disease examining blood-based circulating cell biomarkers

Abstract Cardiac myxoma (CM) is a potentially life-threatening disease because frequently asymptomatic or debuts with aspecific manifestations. Definitive diagnosis is established by histopathological assessment including tumor and endothelial cell markers. To derive a specific panel of circulating cells antigenically detectable, pre-surgery peripheral blood samples of CM patients were analyzed. Pre-surgery peripheral blood samples from patients with CM were simultaneously analyzed for Circulating tumor cells (CTCs) and circulating endothelial cells (CECs) that were matched with tumor tissue profiles and with patient-derived xenografts (PDXs) distinguishing tumor regions. Moreover, CECs values in CM patients were further matched with CEC’s levels in cardiovascular disease and control subjects. The blood-derived cytological specimens detected at least 1–3 CTCs/ml in 10 tested CM samples (p = 0.0001) showing specific CM features preserved in the central zones of the tumor. The central zone of the primary tumor, supported by a vessel density rate (55 ± 7%), with a proliferative profile of 32 ± 3% and a percentage of Calretininpos cells (p = 0.03), is the principal site of CTCs (r = 00) dissemination. The subsets of endothelial cells recognized in the blood were indifferent to their topological distribution within the tumor and corresponding PDXs. With further refinement and validation in large cohorts, multiparametric liquid biopsies can optimally integrate clinically informative datasets and maximize their utility in pre-surgery evaluation of CM patients. Blood-derived culture’s protocol provides a versatile method capable of viable analysis of CTCs of non-hematological rare tumors which conventional antibody-mediated analytical platform is unable to perform. Distinctive blood- based cell phenotype contributes to differentiate CM from other differentials assuring its prompt surgical resection by combining blood-based cell biomarkers integrated with clinically informative datasets

Saxagliptin/dapagliflozin is non‐inferior to insulin glargine in terms of β‐cell function in subjects with latent autoimmune diabetes in adults: A 12‐month, randomized, comparator‐controlled pilot study

Aim: To compare the efficacy and safety of saxagliptin/dapagliflozin and insulin glargine in people with latent autoimmune diabetes in adults (LADA). Methods: In this phase 2b multicentre, open-label, comparator-controlled, parallel-group, non-inferiority study, we randomly assigned 33 people with LADA who had a fasting C-peptide concentration >= 0.2 nmol/L (0.6 ng/mL) to receive 1-year daily treatment with either the combination of saxagliptin (5 mg) plus dapagliflozin (10 mg) or insulin glargine (starting dose: 10 IU), both on top of metformin. The primary outcome was the 2-h mixed meal-stimulated C-peptide area under the curve (AUC), measured 12 months after randomization. Secondary outcomes were glycated haemoglobin (HbA1c) levels, change in body mass index (BMI), and hypoglycaemic events. Results: In the modified intention-to-treat analysis, the primary outcome was similar in participants assigned to saxagliptin/dapagliflozin or to insulin glargine (median C-peptide AUC: 152.0 ng*min/mL [95% confidence interval {CI} 68.2; 357.4] vs. 122.2 ng*min/mL [95% CI 84.3; 255.8]; p for noninferiority = 0.0087). Participants randomized to saxagliptin/dapagliflozin lost more weight than those randomized to insulin glargine (median BMI change at the end of the study: -0.4 kg/m(2) [95% CI -1.6; -0.3] vs. +0.4 kg/m(2) [95% CI -0.3; +1.1]; p = 0.0076). No differences in HbA1c or in the number of participants experiencing hypoglycaemic events were found. Conclusions: Saxagliptin/dapagliflozin was non-inferior to glargine in terms of beta-cell function in this 12-month, small, phase 2b study, enrolling people with LADA with still viable endogenous insulin production. Weight loss was greater with saxagliptin/dapagliflozin, with no differences in glycaemic control or hypoglycaemic risk

MASLD, hepatic steatosis and fibrosis are associated with the prevalence of chronic kidney disease and retinopathy in adults with type 1 diabetes mellitus

Aim: We examined whether metabolic dysfunction-associated steatotic liver disease (MASLD) with or without significant fibrosis (assessed by validated non-invasive biomarkers) was associated with an increased risk of prevalent chronic kidney disease (CKD) or diabetic retinopathy in people with type 1 diabetes mellitus (T1DM). Methods: We performed a retrospective multicenter cross-sectional study involving 1,409 adult outpatients with T1DM, in whom hepatic steatosis index (HSI) and fibrosis (FIB)-4 index were calculated for non-invasively detecting hepatic steatosis (defined by HSI > 36), with or without coexisting significant fibrosis (FIB-4 index ≥ 1.3 or < 1.3). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or urine albumin/creatinine ratio ≥ 3.0 mg/mmol. The presence of diabetic retinopathy was also recorded in all participants. Results: Patients with MASLD and significant fibrosis (n=93) had a remarkably higher prevalence of CKD and diabetic retinopathy than their counterparts with MASLD without fibrosis (n=578) and those without steatosis (n=738). After adjustment for sex, diabetes duration, hemoglobin A1c, hypertension, and use of antihypertensive or lipid-lowering medications, patients with SLD and significant fibrosis had a higher risk of prevalent CKD (adjusted-odds ratio 1.76, 95% confidence interval 1.05-2.96) than those without steatosis. Patients with MASLD without fibrosis had a higher risk of prevalent retinopathy (adjusted-odds ratio 1.49, 95% CI 1.13-1.46) than those without steatosis. Conclusion: This is the largest cross-sectional study showing that MASLD with and without coexisting significant fibrosis was associated, independently of potential confounders, with an increased risk of prevalent CKD and retinopathy in adults with T1DM

Hepatic steatosis with significant fibrosis is associated with an increased 10-year estimated risk of cardiovascular disease in adults with type 1 diabetes mellitus

Abstract Background We assessed whether hepatic steatosis with or without significant fibrosis (determined by validated non-invasive biomarkers) is associated with an increased 10-year estimated risk for cardiovascular disease (CVD) in people with type 1 diabetes mellitus (T1DM). Methods We conducted a retrospective, multicenter, cross-sectional study involving 1,254 adults with established T1DM without pre-existing CVD. We used the hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting hepatic steatosis (defined as HSI > 36), with or without coexisting significant fibrosis (defined as FIB-4 index ≥ 1.3 or < 1.3). We calculated the Steno type 1 risk engine and the atherosclerotic CVD (ASCVD) risk score to estimate the 10-year risk of developing a first fatal or nonfatal CVD event. Results Using the Steno type 1 risk engine, a significantly greater proportion of patients with hepatic steatosis and significant fibrosis (n = 91) had a high 10-year estimated CVD risk compared to those with hepatic steatosis alone (n = 509) or without steatosis (n = 654) (75.8% vs. 23.2% vs. 24.9%, p < 0.001). After adjustment for sex, BMI, diabetes duration, hemoglobin A1c, chronic kidney disease, and lipid-lowering medication use, patients with hepatic steatosis and significant fibrosis had an increased 10-year estimated risk of developing a first fatal or nonfatal CVD event (adjusted-odds ratio 11.4, 95% confidence interval 3.54–36.9) than those without steatosis. We observed almost identical results using the ASCVD risk calculator. Conclusions The 10-year estimated CVD risk is remarkably greater in T1DM adults with hepatic steatosis and significant fibrosis than in their counterparts with hepatic steatosis alone or without steatosis

Sex differences in cardiovascular disease and cardiovascular risk estimation in patients with type 1 diabetes

Context Patients with type 1 diabetes (T1D) have higher cardiovascular disease (CVD) risk than the general population. Objective This observational study aims to evaluate sex-related differences in CVD prevalence and CVD risk estimates in a large cohort of T1D adults. Methods We conducted a multicenter, cross-sectional study involving 2041 patients with T1D (mean age 46 years; 44.9% women). In patients without pre-existing CVD (primary prevention), we used the Steno type 1 risk engine to estimate the 10-year risk of developing CVD events. Results CVD prevalence (n = 116) was higher in men than in women aged &gt;= 55 years (19.2 vs 12.8%, P = .036), but comparable between the 2 sexes in those aged &lt;55 years (P = .91). In patients without pre-existing CVD (n = 1925), mean 10-year estimated CVD risk was 15.4 +/- 0.4% without any significant sex difference. However, stratifying this patient group by age, the 10-year estimated CVD risk was significantly higher in men than in women until age 55 years (P &lt; .001), but this risk equalized after this age. Carotid artery plaque burden was significantly associated with age &gt;= 55 years and with a medium and high 10-year estimated CVD risk, without any significant sex difference. Diabetic retinopathy and sensory-motor neuropathy were also associated with higher 10-year CVD risk and female sex. Conclusion Both men and women with T1D are at high CVD risk. The 10-year estimated CVD risk was higher in men aged &lt;55 years than in women of similar age, but these sex differences disappeared at age &gt;= 55 years, suggesting that female sex was no longer protective