Search Results (2,967)

Background: This randomized clinical trial compared the effects of topical irrigation with a desiccant agent (HybenX Oral Tissue Decontaminant, HBX) combined with full-mouth ultrasonic debridement as well as scaling and root planing (FMUD-SRP) versus conventional non-surgical periodontal therapy (US-SRP). Methods: Three quadrants per patient with probing pocket depth (PPD) ≥ 5 mm were randomly assigned to (i) the control group (US-SRP only), (ii) test group 1 (HBX + US-SRP at baseline, HBX 1T (one time)), or (ii) test group 2 (HBX + US-SRP across three sessions, HBX 3T (three times)). Clinical parameters included probing pocket depth (PPD), bleeding on probing (BOP), plaque index (PI), gingival recession (REC), and Clinical Attachment Level (CAL), recorded at baseline (Tbase), 45 days (T45d), and 90 days (T90d). Microbiological sampling was conducted for all sites at Tbase, T45d, and T90d to assess periodontal pathogens. HBX-treated sites received gel application for 60 s, followed by a saline rinse and US-SRP. Results: Significant differences were found between groups in PPD (p = 0.04) and CAL (p = 0.02) at T45d versus Tbase, while BOP, PI, and REC showed no significant inter-group differences at T45d. The HBX 3T group demonstrated greater pathogen reduction compared to the control and HBX 1T groups, except for one bacterial species. Conclusions: All treatments improved clinical and microbiological parameters. Even if single and triple applications of HBX showed similar clinical results, the repeated application achieved greater bacterial reduction. Full article

Background/Objectives: Alcohol consumption is a major public health concern, particularly among individuals with type 2 diabetes (T2D), due to its impact on morbidity and mortality. However, alcohol use disorder (AUD) among hospitalized T2D patients in Spain remains understudied. This study analyzed trends in AUD prevalence in adults hospitalized with T2D (2016–2023), identified associated factors, and assessed predictors of in-hospital mortality (IHM). Methods: We conducted a retrospective observational study using the Spanish National Hospital Discharge Database. Adults (≥18 years) with T2D were included. Joinpoint regression and multivariable logistic regression were applied. Results: Among 5,192,189 hospital admissions with T2D, 326,433 (6.29%) had AUD. Prevalence increased from 5.05% in 2016 to 7.52% in 2023 (annual percent change 5.95%; p < 0.05). AUD was more frequent in men (9.99%) than women (1.12%). Rising trends were observed for smoking (67.9% to 70.6%), cocaine use (2.0% to 3.15%), and cannabinoid use (1.08% to 1.78%) (all p < 0.001). Factors strongly associated with AUD included male sex (aOR 5.67; 95% CI 5.60–5.75), age 50–64 years, smoking (aOR 3.68 in men; 5.61 in women), cocaine use (aOR 4.55 in men; 7.68 in women), and mental disorders. IHM was 7.0% in T2D with AUD, peaking at 7.85% in 2020. Higher IHM was associated with age ≥ 80 years, hypoglycemia, and COVID-19, while obesity and mental disorders were linked to lower IHM. Conclusions: AUD prevalence in hospital admission with T2D in Spain is high and rising, particularly among women, with concomitant substance use also increasing. Comprehensive, sex-sensitive strategies are urgently needed in both hospital and outpatient care. Full article

In the current study, we focus on analyzing the relationship between changes in micro- and macrocirculation and different stages of metabolic memory. We hypothesized that early poor glycemic control induces lasting endothelial changes detectable in pediatric type 1 diabetes (T1D) microcirculation. We assessed microcirculation structure and function using capillaroscopy, transcutaneous oxygen pressure (TcPO₂), and optical coherence tomography (OCT). We evaluated macrovascular circulation using pulsatility index (PI), ankle-brachial index (ABI) and pulse pressure (PP). We also examined the relationship between circulation parameters, the age at onset, and diabetes duration. The study included 67 patients with uncomplicated type 1. We divided all patients into four groups based on their HbA_1c levels at T1D onset and their average HbA_1c after one and two years. We assessed the concentrations of TNF-α, IL-35, IL-4, IL-10, IL-18, IL-12, serum angiogenin, VEGF, sVCAM-1, ICAM-1, sP-Selectin, AGEs, and sRAGE. We compared subgroups with different levels of metabolic memory but comparable T1D duration and age at diagnosis. Micro- and macrovascular parameters were similar between the groups. Our comparison of subgroups with identical metabolic memory but different durations and ages at diagnosis revealed clear differences. The subgroup with a shorter T1D duration showed higher capillary density and a smaller inter-capillary distance compared to those with a longer diabetes duration. This subgroup with shorter duration had significantly lower AGE levels and a reduced TNF-α/IL-35 ratio, along with higher levels of IL-35, IL-4, and IL-12, compared to the longer-duration group. Our findings indicate that in youths with uncomplicated T1D, disease duration—not metabolic memory—plays a dominant role in early microvascular alterations. Full article

Background and Objectives: Diabetic complications represent a major healthcare challenge globally. The Kingdom of Saudi Arabia has one of the highest prevalence rates, yet comprehensive data on complication profiles from southern regions remain limited. This study characterizes the spectrum of diabetic complications and identifies associated risk factors in the Najran region of southern Saudi Arabia. Materials and Methods: A hospital-based retrospective analysis of 500 diabetic patients from two major public hospitals in the Najran region was conducted using electronic medical records from January 2022 to December 2023. A systematic sampling approach was adopted. Type 1 diabetes (T1D), Type 2 diabetes (T2D), and their complications were defined using standardized criteria. Data extraction utilized a validated proforma, and analysis employed SPSS version 20. Separate analyses were conducted for T1D and T2D, with multivariable logistic regression identifying independent predictors of complications (p < 0.05). Results: The study included 200 T1D (median age 14.0 years, IQR 3.0) and 300 T2D patients (median age 23.0 years, IQR 7.0). The high proportion of T1D patients (40%) reflects the hospital’s role as a specialized pediatric and young adult diabetes referral center. Among T1D patients, 63.5% (127/200) developed complications, predominantly microvascular, whereas 50.0% (150/300) developed complications in T2D. Poor glycemic control was the strongest predictor of complications in both groups (p = 0.01). Rural residence significantly increased complication risk in T2D patients (p = 0.02). Disease duration showed differential effects; complications appeared earlier in T1D (median 6.5 years) versus T2D (median 8.2 years). Conclusions: This study gives the first comprehensive analysis of diabetic complications from southern Saudi Arabia, revealing distinct patterns and associated risk factors. The findings provide regional perspective on diabetic complications in Najran, highlighting the importance of early glycemic control and equitable healthcare access. The results are not intended for nationwide generalization, rather, they point to the need for region-specific diabetes management strategies. Full article

Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder in which inflammation plays a central role in its onset, progression, and complications. Identifying reliable biomarkers is essential to improve risk prediction, disease monitoring, and early intervention. Methods: A total of 169 Ecuadorian participants were stratified into four clinical groups: non-diabetic controls (NDC), controlled T2D (C-T2D), uncontrolled T2D (NC-T2D), and diabetic kidney disease (DKD). Circulating levels of cytokines (IL-6, IL-8, TNF-α), adipokines (leptin, adiponectin), and PBMC-derived microRNAs (miR-146a, miR-155) were quantified. Associations with disease stage were evaluated using ROC curve analysis and logistic regression. Results: Leptin showed the strongest association with T2D (OR = 13.76, 95% CI: 6.47–29.26), followed by IL-8 (OR = 6.73, 95% CI: 3.30–13.70) and IL-6 (OR = 4.43, 95% CI: 2.26–8.97). Adiponectin distinguished NC-T2D from DKD (OR = 4.15, 95% CI: 1.77–9.71), underscoring its potential as an indicator of renal complications. Interestingly, TNF-α levels declined across disease stages, possibly reflecting subclinical inflammation in Ecuadorian NDC with high rates of obesity and dyslipidemia. PBMC-derived miR-146a was upregulated in T2D patients, contrasting with prior serum-based studies and emphasizing the importance of compartment-specific analysis. miR-155 was elevated in C-T2D, suggesting a compensatory immune-regulatory mechanism that diminishes with poor glycemic control and advanced disease. Conclusions: Inflammatory cytokines, adipokines, and microRNAs act in distinct yet complementary ways in T2D. Leptin, IL-6, and IL-8 emerge as strong predictors of disease, while miR-146a and miR-155 provide additional insight into immune-inflammatory regulation. Integrated biomarker panels may enhance patient stratification and support personalized monitoring of T2D progression. Full article

Connexin 26 (Cx26), a gap junction protein, is poorly understood in the context of cardiac milieu, including extracellular vesicles (EVs). Here, we report for the first time the presence of Cx26 on EVs obtained from human induced pluripotent stem cell-derived cardiomyocytes and human plasma. Using an in vitro model of oxidative stress and apoptosis in dH9c2 cardiomyocytes, we observed a significant decrease in Cx26 levels in EVs released by injured cells, accompanied by changes in EV concentration, particularly in exosomes. Our findings revealed that Cx26 modulates the selective loading of specific microRNAs, namely miR-1 and miR-30a, into EVs, suggesting a novel non-canonical, gap junction-independent role of Cx26 in EV-mediated cardiac signaling. Analysis of plasma EVs from healthy donors confirmed the presence of Cx26-positive EVs of cardiomyocyte origin, indicated by co-staining with cardiac troponin T. These findings suggest that further studies on the measurement of Cx26 on circulating EVs from patients with ischemic heart disease and heart failure are warranted to clarify its potential as a biomarker for cardiomyocyte injury in cardiomyopathies with oxidative stress and apoptosis. Full article

(1) Background: diabetic ketoacidosis (DKA) remains one of the most serious acute complications of type 1 diabetes, especially among young adults. At the same time the ketogenic diet, characterized by high fat and very low carbohydrate intake, is becoming increasingly popular, raising concerns about its appropriateness and safety for individuals with type 1 diabetes, (2) Methods: a literature review was conducted using MEDLINE and SCOPUS databases, complemented by additional searches in Embase, Cochrane Library, and Web of Science to ensure broad coverage of both international and European studies with the focus on keywords including “diabetic ketoacidosis”, “type 1 diabetes”, and “ketogenic diet”. The most relevant and up-to-date studies were selected to evaluate both risks and potential clinical applications of this diet in T1D in young adults, (3) Results and Conclusions: While nutritional ketosis under controlled conditions is typically safe, individuals with T1D, especially young adults, may be more vulnerable to DKA due to factors such as inconsistent insulin administration, lack of ketone monitoring, and lifestyle changes. Reports of euglycemic DKA further highlight the importance of regular ketone tracking, even when blood glucose appears within target ranges. Although low-carbohydrate diets may offer improved glycemic profiles, their use in young adults with T1D must be carefully evaluated, emphasizing individualized care plans, close metabolic monitoring, and comprehensive patient education. Ongoing research is essential to clarify whether ketogenic diet can be safely integrated into diabetes management in this population. Full article

Background: Variceal upper gastrointestinal bleeding (VUGIB) remains a major cause of short-term mortality in cirrhosis despite advances in endoscopic and pharmacological therapy. Prognostic factors and outcomes were evaluated in a historical cohort, and a guideline-aligned management algorithm is proposed. Methods: We conducted a retrospective study of 98 consecutive adults admitted with VUGIB to a tertiary surgical center in Romania (2009–2014). Demographics, etiology, admission hemoglobin (Hb), timing of presentation, endoscopic and surgical management, and outcomes were recorded. Survival was analyzed using Kaplan–Meier with log-rank tests; associations were tested with chi-square and t-tests; predictors of mortality were assessed with logistic regression. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory ability of hemoglobin for in-hospital mortality. Results: Mean age was 57.8 ± 11.7 years; 60.2% were male. Cirrhosis etiology was alcoholic in 73%, viral in 18%, and metabolic in 9%. Endoscopy occurred within 48 h in 62% of patients, but only 4% underwent the procedure within 8 h. Overall mortality was 17.3%. Kaplan–Meier analysis showed no survival difference between alcoholic and viral cirrhosis (log-rank p = 0.39), but survival was markedly lower with Hb < 8 g/dL (p < 0.001). Admission delay was prognostic: >24 h was associated with worse survival (p < 0.05). On multivariable analysis (reference 1–2 days), admission at 3–4 days (OR 35.3, 95% CI 1.6–786, p = 0.024), >4 days (OR 71.0, 95% CI 2.16–2337, p = 0.017), and <6 h (OR 22.4, 95% CI 1.25–399.7, p = 0.035) independently predicted death. Admission Hb predicted mortality with an AUC of 0.79; the optimal cut-off was 4.3 g/dL (sensitivity 57%, specificity 95%). Limited use of pre-emptive TIPS likely contributed to outcomes. Conclusions: In this historical cohort, mortality from VUGIB was driven mainly by bleeding severity and admission delay, rather than by cirrhosis etiology. The study provides a historical benchmark for Eastern Europe, highlights gaps in adherence to contemporary standards, and supports restrictive transfusion, early vasoactive therapy, antibiotics, urgent endoscopy, and pre-emptive TIPS. The retrospective single-center design and limited therapies available during the study period remain important limitations. Full article

Background: Severe asthma is a chronic, difficult-to-treat disorder that significantly affects quality of life, and oral glucocorticosteroids are usually required. Many patients suffering from severe asthma exhibit T2 inflammation and may benefit from biological treatment. This study aims to evaluate changes in cytokine concentrations during therapy with benralizumab, dupilumab, and mepolizumab in severe eosinophilic asthma. Materials and Methods: In this prospective, single-center study, 39 patients with severe eosinophilic asthma received treatment with one of the above-mentioned biologics. Parameters, such as the cytokine profile (Human Th9/Th17/Th22 Luminex, Performance Assay 18-plex Fixed Panel, R&D Systems, Minneapolis, MN, USA) and additionally the Asthma Control Questionnaire (ACQ), mini-Asthma Quality of Life Questionnaire (mini-AQLQ), spirometry (FEV1, FEV/FVC), FeNO, and functional status, were assessed at baseline and after 3–4 months of therapy. Results: The biologic therapies demonstrated diverse effects on inflammatory biomarkers. Dupilumab showed the most pronounced decreases in CD40L, IL-6, and FeNO in comparison to other drugs. In turn, the greatest decrease in TNF-α concentration was observed in the group treated with mepolizumab. Conclusion: Changes in cytokine concentrations highlight the heterogenous immunomodulatory mechanisms of biologics and support personalized strategies based on inflammatory profiles. However, the results should be interpreted with prudence, as the concentrations of cytokines in blood serum fluctuate and the study sample size is small. Full article

Background and Objectives: Dyslipidemia and hyperuricemia frequently co-exist in uncontrolled type 2 diabetes mellitus (T2DM), amplifying renal and cardiovascular risk. This study aimed to develop and evaluate an optimized Renal–Metabolic Risk Score (RMRS) integrating renal and lipid parameters to identify patients with both conditions. Materials and Methods: We conducted a retrospective observational study including 304 patients with uncontrolled T2DM hospitalized at the Emergency County Hospital Oradea, Romania (2022–2023). Hyperuricemia was defined as uric acid > 6 mg/dL in females and >7 mg/dL in males; dyslipidemia was diagnosed according to standard lipid thresholds. RMRS was calculated from standardized values of urea, TG/HDL ratio, and eGFR, with variable weights derived from logistic regression coefficients. The score was normalized to a 0–100 scale. Receiver operating characteristic (ROC) analysis assessed discriminative performance; quartile analysis explored stratification ability. Results: The prevalence of dyslipidemia and hyperuricemia co-occurrence was 81.6%. RMRS was significantly higher in the co-occurrence group compared to others (median 16.9 vs. 10.0; p < 0.001). ROC analysis showed an AUC of 0.78, indicating good discrimination. Quartile analysis demonstrated a monotonic gradient in co-occurrence prevalence from 64.5% in Q1 to 96.1% in Q4. Conclusions: The Renal–metabolic Risk Score (RMRS) demonstrated moderate discriminative performance in identifying patients with uncontrolled T2DM at risk for combined hyperuricemia and dyslipidemia. Because it relies on inexpensive, routine laboratory parameters, RMRS may be particularly useful in resource-limited settings to support early risk stratification, dietary counseling, and timely referral. Further validation in larger and more diverse cohorts is required before its clinical adoption. Full article

Since colonic dopamine levels are markedly reduced during inflammatory bowel disease (IBD), we investigated how dopamine affects regulatory T-cells (Treg), which critically limit gut inflammation. Previously, we showed that the stimulation of the high-affinity dopamine receptor D₃ (Drd3) impairs suppressive Treg activity and limits their recruitment into the colon upon gut inflammation. Here we study the role of the low-affinity dopamine receptor Drd2 in Treg. We find that mice harbouring Drd2-deficient T-cells developed more severe colitis induced by dextran sodium sulphate. The stimulation of Drd2 potentiated the suppressive Treg activity and increased their ability to reach the colonic tissue. A transcriptomic analysis of intestinal mucosa from IBD patients revealed an association with increased DRD3 and reduced DRD2 expression. Bioluminescence resonance energy transfer assays revealed that Drd2 and Drd3 form a heteromer. An in situ proximity ligation assay indicated that the Drd2:Drd3 heteromer was expressed on colonic Treg, and its expression was increased upon inflammation. Using peptides analogous to the transmembrane (TM) segments from Drd2 and Drd3 in bimolecular fluorescence complementation assays, we found TM peptides able to disassemble this heteromer. The heteromer disassembly dampened the suppressive Treg activity and impaired the recruitment of Treg into the colon upon inflammation. Our findings indicate that the Drd2:Drd3 heteromer constitutes a dopamine sensor that regulates suppressive Treg activity and their colonic recruitment. Full article

Background and Objectives: This study aimed to compare target volumes and organ-at-risk (OAR) doses using five different volume definitions in radiotherapy (RT) planning of patients with glioblastoma multiforme (GBM). Materials and Methods: Rigid image fusion was performed using simulation computed tomography and postoperative magnetic resonance imaging scans of 20 patients with GBM. Volumetric modulated arc therapy (VMAT) plans were generated according to three two-phase protocols—American Brain Tumor Consortium (ABTC), North Central Cancer Treatment Group/Alliance (NCCTG/Alliance), and Radiation Therapy Oncology Group/NRG (RTOG/NRG)—and two single-phase protocols—European Organisation for Research and Treatment of Cancer (EORTC) and European Society for Radiotherapy and Oncology–European Association of Neuro-Oncology (ESTRO/EANO)—each delivering a total dose of 60 Gy. OARs and dose constraints were evaluated. Statistical analysis was performed using the paired sample t-test. Results: The ESTRO/EANO volume had the smallest median PTV overall (p < 0.001). The lowest brain-PTV Dmean in the initial phase was observed in the ABTC group, followed closely by ESTRO/EANO (p < 0.001). Among boost volumes, the ABTC volume was the smallest, and the median brain-PTV Dmean was lowest in the ESTRO/EANO volume. ESTRO/EANO provided the lowest doses for contralateral and ipsilateral cochlea Dmean, brainstem D1cc, and contralateral lens Dmax. Notably, both EORTC and ESTRO/EANO plans maintained OAR doses within acceptable constraints, with ESTRO/EANO achieving the most consistently minimised exposure. Conclusions: Reduced irradiated brain volume, acceptable OAR preservation and practical applicability, the use of ESTRO-EANO and EORTC target volumes in radiotherapy of glioblastoma multiforme may provide dosimetric advantages that require further validation in clinical outcome studies. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked with type 2 diabetes mellitus (T2D) and obesity. Despite its growing prevalence, effective pharmacological interventions remain limited, with antidiabetic agents such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) showing emerging promise. This study aimed to evaluate the impact of different antidiabetic therapies on hepatic steatosis, fibrosis, and cardiometabolic risk factors in patients with T2D and MASLD from Romania. Materials and Methods: We conducted a prospective observational study involving 256 patients with T2D and MASLD followed up for 6 months. Assessed parameters included anthropometry, glycemic indices, lipid profile, renal function, liver enzymes, and non-invasive evaluation of hepatic steatosis and fibrosis. Patients were 53% women, had a median age of 63 years, a median BMI of 32.2 kg/m², a median baseline CAP of 281 dB/m, a FibroScan of 8.9 kPa, and an HbA1c of 8.0%. Results: CAP decreased significantly from 281 to 245 dB/m, p < 0.0001; FibroScan from 8.9 to 8.0 kPa, p < 0.0001. The largest changes were observed in the GLP-1 RA subgroup (CAP −50 dB/m, FibroScan −1.0 kPa, weight −8.0 kg, HbA1c −0.7%), and in the SGLT2i subgroup (CAP −30.5 dB/m, FibroScan −0.7 kPa, weight −4.0 kg, HbA1c −0.5%). In regression analysis, independent factors associated with CAP improvement included GLP-1 RA therapy (β = 44.5, 95% CI 38.3–50.6, p < 0.0001), SGLT2i therapy (β = 23.4, 95% CI 15.7–31.1, p < 0.0001), and ≥10% weight loss (β = 23.2, 95% CI 12–34.4, p < 0.0001). For FibroScan improvement, GLP-1 RA (β = 1.0, 95% CI 0.8–1.2, p < 0.0001) and SGLT2i (β = 0.5, 95% CI 0.3–0.7, p < 0.0001) therapies were both significant. Conclusions: Antidiabetic therapy, particularly GLP-1 RA, was significantly associated with improvement in hepatic steatosis, fibrosis, and cardiometabolic risk in T2D patients with MASLD beyond the weight reduction effect. However, weight loss and lipid modulation enhance these benefits, supporting the development of integrated therapeutic strategies for this high-risk population. Full article

Background/Objectives: Cardiac autonomic neuropathy (CAN) is a common but also underdiagnosed complication of diabetes mellitus (DM), associated with high cardiovascular risk and mortality. Sudomotor dysfunction can serve as an early indicator of autonomic dysfunction. This study evaluated the association between sudomotor dysfunction and the severity of CAN in patients with type 2 diabetes (T2D). Methods: In this cross-sectional study, 109 patients with T2D were evaluated for diabetic peripheral neuropathy, cardiovascular autonomic dysfunction, and sudomotor dysfunction. Additionally, clinical and biochemical data were collected from patients’ medical records. Results: Sudomotor dysfunction (SUDO+) was present in 59.6% of patients. The presence of SUDO+ was associated with a higher age, longer duration of diabetes, lower eGFR (estimated glomerular filtration rate) values, and more severe signs of peripheral neuropathy. SUDO+ patients showed significantly greater orthostatic systolic and diastolic BP (blood pressure) changes, lower RR interval ratios, and lower feet ESC (electrochemical skin conductance) values. ROC (receiver operating characteristic) analysis for feet ESC in identifying pathological RR ratio showed an AUC of 0.689 (95% CI: 0.593–0.774, p = 0.0022), with a sensitivity of 46.7% and a specificity of 94.7% at a cutoff of ≤68 µS. For orthostatic hypotension and QTc prolongation, the ESC values had limited discriminative power. Chi-squared analysis showed a significant association between feet sudomotor impairment and pathological RR ratio (χ² = 6.521, p = 0.0107). Conclusions: Sudomotor dysfunction is associated with indicators of CAN. SUDOSCAN can be used as a complementary tool for early CAN detection in clinical practice. Full article

Background: Feminizing adrenocortical tumors (FATs) are an exceedingly rare subset of adrenal neoplasms, typically affecting adult men and characterized by an excess of estrogen, suppressed gonadotropins, and gynecomastia. Most FATs are malignant, with a poor prognosis and a high risk of recurrence. Case Presentation: We report the case of a 24-year-old male with bilateral gynecomastia, abdominal mass symptoms, and one year of unexplained infertility. A hormonal evaluation revealed elevated estradiol (90.1 pg/mL) and suppressed ACTH (2.6 pg/mL), with inappropriately normal cortisol levels (12.1 µg/dL). Imaging identified a right adrenal mass. The patient underwent open adrenalectomy, and histopathology confirmed stage II adrenocortical carcinoma (T2NxM0) with autonomous estradiol secretion, negative margins, and a Ki-67 index of 10%. Postoperatively, gonadal function normalized, and infertility resolved at two months. The multidisciplinary tumor board considered but did not initiate adjuvant mitotane, given the completely resected low-stage disease. Conclusions: This case illustrates the rare presentation of feminizing adrenocortical carcinoma with reversible infertility and highlights the importance of early recognition and close surveillance. In addition, our literature review of 12 male cases reported between 2015 and 2025 emphasizes gynecomastia as the hallmark presentation and discusses emerging evidence supporting active surveillance as a potential alternative to adjuvant mitotane in selected low-risk patients. Full article