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Purpose: To predict deep myometrial infiltration (DMI), clinical risk category, histological type, and lymphovascular space invasion (LVSI) in women with endometrial cancer using machine learning classification methods based on clinical and image signatures from T2-weighted MR images., Methods: A training dataset containing 413 patients and an independent testing dataset consisting of 82 cases were employed in this retrospective study. Manual segmentation of the whole tumor volume on sagittal T2-weighted MRI was performed. Clinical and radiomic features were extracted to predict: (i) DMI of endometrial cancer patients, (ii) endometrial cancer clinical high-risk level, (iii) histological subtype of tumor, and (iv) presence of LVSI. A classification model with different automatically selected hyperparameter values was created. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve, F1 score, average recall, and average precision were calculated to evaluate different models., Results: Based on the independent external testing dataset, the AUCs for DMI, high-risk endometrial cancer, endometrial histological type, and LVSI classification were 0.79, 0.82, 0.91, and 0.85, respectively. The corresponding 95% confidence intervals (CI) of the AUCs were [0.69, 0.89], [0.75, 0.91], [0.83, 0.97], and [0.77, 0.93], respectively., Conclusion: It is possible to classify endometrial cancer DMI, risk, histology type, and LVSI using different machine learning methods.

Background: Immune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues., Patients and Methods: The aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes., Results: Sixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs = -0.351; P = .049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs = 0.50; two-sided P < 0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P = .002), even when adjusted for the IMDC prognostic group and type of therapy (HR = 8.70; 95%CI, 2.52-30.05; P = .001)., Conclusion: Extension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort., Competing Interests: Disclosure The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. RI served as consultant for Astellas, BMS, Ipsen; Janssen, Merk, MSD, Novartis; Pfizer; Sanofi and received research grant from Pfizer. SS served as consultant for Astellas, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, Sanofi-Genzyme. EV served as consultant for Ipsen, Janssen, Merck, MSD, Pfizer. Astellas, Novartis. CC served as consultant for Pfizer, BMS, MSD, Janssen. SB served as consultant for Pfizer, BMS, MSD, Roche, Astellas, Janssen, Ipsen, Bayer, Sanofi-Genzyme, Merck, AstraZeneca. Travel accommodation from Pfizer, BMS, Roche, Astellas, Janssen, Ipsen, AstraZeneca. UDG served as consultant for Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer and Sanofi; has received travel support from BMS, Ipsen, Janssen and Pfizer; and has received research funding from AstraZeneca, Roche and Sanofi (Inst). UB served as consultant for Advisory board BMS, MSD, Janssen. He received speaker's fees BMS, Ipsen, Janssen, Astellas. GT served as consultant for BMS and MSD. GP served as consultant for Astellas, Astra-Zeneca, Bayer, BMS, Ipsen, Janssen, Merck, MSD, Pfizer, Novartis, Sanofi. CC, MM. AF, LG, FM, AC, MGM, DB, FMD, MD, FP, FR declared not conflict of interests., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: To define the prevalence and determinants of peripheral microvascular endothelial dysfunction (ED) in a large series of rheumatoid arthritis (RA) patients free of previous cardiovascular events., Materials and Methods: Data from 874 RA patients enrolled in the EDRA study (Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis-ClinicalTrials.gov: NCT02341066) were analyzed. Log-transformed reactive hyperemia index (Ln-RHI) was evaluated by peripheral arterial tonometry (PAT) using the EndoPAT2000 device: values of Ln-RHI < 0.51 were considered indicative of peripheral ED., Results: Peripheral microvascular ED was documented in one-third of RA patients (33.5%); in multiple logistic regression analysis, ACPA negativity and higher triglycerides concentrations were independently associated with the presence of peripheral ED [OR (95% CI) = 1.708 (1.218-2.396), p < 0.01 and OR (95% CI) = 1.005 (1.002-1.009), p < 0.01, respectively]. Multiple regression analysis showed a positive correlation between Ln-RHI values and systolic blood pressure and HDL cholesterol levels; furthermore, higher values of Ln-RHI were associated with ACPA positivity, while smoking habit was associated with lower Ln-RHI values., Conclusions: This study demonstrates for the first time a high prevalence of peripheral microvascular ED in patients with RA free of previous cardiovascular events that appear to be only partially driven by traditional cardiovascular risk factors. The association between ACPA negativity and ED warrants further exploration.

The Multiple Sclerosis (MS) diagnosis is based on dissemination of focal lesions in time and space. The free light chains (FLCs) determination might be a sensitive alternative to oligoclonal bands assay. The study aim was to redefine sensitivity, specificity of the kFLC Index cut-off. We analyzed serum and cerebrospinal fluid of 176 patients, with different neurological disorders. We obtained a cut off of 12,3 for kFLC Index with a sensitivity and specificity of 93% and 100% respectively. Our data confirm that the kFLC Index is a valid tool in the diagnosis of MS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Glycated hemoglobin (HbA1c) provides a useful estimate of mean glycemia in patients with diabetes and is directly related to risks for diabetes complications. The aim of this study is to compare a capillary electrophoresis method and two high-performance liquid chromatography (HPLC) cation-exchange analyzers (Variant II (Bio-Rad Laboratories, Inc., Hercules, CA) and G8 (Tosoh Biosciences, San Francisco, CA)) to identify the most reliable method in Hb variants' presence., Methods: Measurements of HbA1c were carried out in blood samples from 200 Tor Vergata Hospital patients, using G8 Tosoh, and from 107 San Filippo Neri Hospital patients, using Variant II Bio-Rad methods. All samples were analyzed by Capillarys 2 Flex Piercing (FP; Sebia, Lisses, France)., Results: There was a good concordance between the results of capillary electrophoresis and HPLC methods (R(2) = 0.99, P < 0.0001 for G8 HPLC; R(2) = 0.99, P < 0.0001 for Variant II HPLC). During the study, we observed that some Hb variants, HbS and HbD-Iran, can alter the HbA1c level., Conclusions: Since the HbA1c test is now recommended for diagnosing diabetes, and minimal variation of the concentration affects the clinical therapy, it is very important that the results are reliable and interference-free. Capillarys 2-FP analyzer is suitable for this purpose and sometimes it showed some advantages with respect to the HPLC analyzers tested, especially when Hb variants are present., (© 2014 Wiley Periodicals, Inc.)

Background: Immediate two-stage prosthetic breast reconstruction in the setting of postmastectomy radiotherapy (PMRT) currently is hardly achieved with the fast-track expander exchange proposed by Cordeiro and colleagues or the delayed-immediate breast reconstruction proposed by Kronowitz and Robb. Each of these techniques has important drawbacks and complications. To overcome these problems, the authors in 2011 described lipofilling on irradiated expanders in patients undergoing unplanned PMRT (Cagliari University Hospital [CUH] protocol) for early breast cancers with specific risk factors. The authors report their experience after expanding the use of such a protocol for any immediate expander/implant reconstruction in a patient undergoing PMRT., Methods: The timing for advanced breast cancer involves immediate reconstruction with a tissue expander, complete tissue expansion, radiotherapy (RT) after neoadjuvant chemotherapy starting 2-3 months after mastectomy, one or two fresh fat-grafting sessions at least 6 weeks after RT, and an expander-implant exchange with anterior capsulectomy at least 3 months after the completion of fat grafting. The timing for early breast cancers with specific risk factors involves immediate reconstruction with a tissue expander, complete tissue expansion during postoperative chemotherapy, RT 6 months after mastectomy, one or two fat-grafting sessions 6 weeks after RT, and an expander-implant exchange with anterior capsulectomy at least 3 months after the completion of fat grafting. From 2008 to 2012, 16 patients undergoing total mastectomy and immediate expander-implant breast reconstruction with subsequent PMRT were treated according to the CUH protocol., Results: The results have been extremely encouraging, with rates of ulceration and implant exposure in the radiotreated area dropping to 0 %. These results were retrospectively compared with those for a control group of 16 patients who underwent immediate implantation of an expander. In this latter group, the extrusion rate of the implant in the end was 31.25 %, and this was statistically significant (p < 0.03). The shape and symmetry also were significantly better in the lipofilled patients., Conclusion: Protective lipofilling on irradiated expanders appears to be a valid technique for avoiding ulceration and implant exposure after PMRT while allowing a complete expansion., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Intrathecal immunoglobulin synthesis is observed in several disorders of the central nervous system, but its detection by current laboratory tests is relatively insensitive and operator depending. We assessed the diagnostic accuracy of a nephelometric assay for k free light chain determination in cerebrospinal fluid and serum. The patients were grouped according to clinical and laboratory criteria. ROC curves for all methods were performed to find the best cut-off value. kFLC Index seems to be more accurate than other parameters. Our data indicate that nephelometric assay for kFLCs in CSF reliably detect intrathecal immunoglobulin synthesis and discriminate multiple sclerosis patients., (© 2013.)

Aim: To evaluate feasibility, tolerability and cosmetic outcome of intra-operative radiation therapy (IORT) as an exclusive post-surgery treatment of early stage breast cancer., Patients and Methods: From October 2008 to October 2009 30 patients underwent wide breast cancer excision or quadrantectomy followed by IORT on tumor bed with accelerated electrons at the dose of 21Gy. The characteristics of the patients were: ductal breast cancer or invasive lobular cT1, cT2 ≤ 2,5 cm, cN0, G1-2, age over 35 years, M0., Results: The average age was 51.7 (range 38 - 75) with an average follow up of 11.7 months (range 6 - 18). The pathologic stage of the lesions resulted pT1 in 29 cases (96,6%), in particular: one case pT1a (3,3%), 21 cases pT1b (70,0%) and 7 cases pT1c (23,3%). One case (3,3%) was pT2 with a diameter of 2.5 cm. The grading was G2 in 20 cases (66,6%) and G1 in 10 cases (33,3%). The toxicity, evaluated according to the EORTC-RTOG criteria, was G0 (33.3%) in 10 cases, G1 (63,3%) in 19 cases, G2 in one case (3,4%); there was no G3 toxicity. The time needed for a complete healing of the wound was less than 10 days in 96,7% of the cases, with one case of limphocele (3,3%). There were no infections of the surgical wound nor any mastitis, neither in the treated quadrant nor in the other ones. We observed a light fibrosis in 5 cases (16,6%), moderate in 2 cases (6,6%) but never severe. Cosmetics, evaluated in four levels, according to Danoff et al., was excellent in 3 cases (43,3%), good in 15 cases (50%), sufficient in 2 cases (6,7%), never insufficient. As regards local control, there was no local relapse. The global survival was 100%., Conclusions: The IORT in early breast cancer, at the doses used in this study, proved itself as a secure technique, repeatable, with limited complications. The advantages of its use are the possibility of a direct control, by the surgeon and the radiotherapist, of the structures to treat and those to protect; the absence of time needed for cellular repopulation between surgery and radiotherapy; a good cosmetic outcome; and logistic advantages. It is necessary to have a long term follow up to evaluate the efficacy in terms of long term cosmetic and local control.

Background and Aim: In the present paper, the toxicity of prolamines derived from three cereals with a different genome was investigated in human colon cancer Caco-2/TC7 and human myelogenous leukemia K562(S) cells. The purpose of this study was to investigate if species from ancient wheat could be considered as healthy food crops devoid or poor in cytotoxic prolamines for celiac disease., Methods: Cytotoxicity was measured in terms of inhibition of cell growth, activation of apoptosis, release of nitric oxide (NO), detection of tissue transglutaminase (TG II) and alteration of transepithelial electrical resistance (TEER) on Caco-2/Tc7 and K562 (S) cell agglutination. Peptic-tryptic (PT) digest from bread wheat (T. aestivum S. Pastore) was used as a positive control., Results: PT digests of prolamins from spelt wheat (T. aestivum ssp. spelta) were found to exert toxic effects on Caco-2/TC7 cells and to agglutinate K562(S) cells. Increased amounts of NO and TG II expression were observed in Caco-2/TC7 cells exposed to 1 mg/mL of spelt prolamins, suggesting that spelt wheat can induce cellular mechanisms implicated in the pathogenesis of celiac disease. By contrast, the PT digests from monoccum wheat (Triticum monococcum) and farro wheat (T. turgidum ssp. dicoccum) did not exhibit any negative effects on Caco-2/TC7 and K562(S) cells., Conclusions: The results have shown a constant and significant toxic effect of spelt wheat which is not shared by the two other ancient cereals. Future studies on celiac intestinal organ cultures are needed to increase the prospects of breeding programs aimed at developing wheat cultivars potentially tolerated by most celiac patients.

Cardiac calcifications are a frequent finding in hemodialysis for chronic renal failure. Several factors may play a role in the intimal and medial calcification of coronary arteries such as age and some known atherogenetic factors. In addition, Fetuin-A has been proposed as a protective agent through solubilization of calcium phosphate salt. Fetuin-A is also a marker of inflammatory-nutritional state, and its changes could be an expression of this condition. The aim of this cross-sectional study is to evaluate the relative importance of risk factors of calcifications with special regard to Fetuin-A. The study was conducted with 132 hemodialysis patients. They were subjected to multislice computed tomography for evaluation of calcium deposits in the heart. In addition, the patients were sampled for evaluation of calcium-phosphate parameters, lipid profile, nutritional and inflammatory markers, and also Fetuin-A. There was a wide variability of the extent of calcium deposits expressed as Agatston score, with only 9.3% of patients without calcifications. Age, hemodialysis age, sex, calcium-phosphate parameters, and lipid profile were important risk factors, together with nutritional and inflammatory status of the patients. An inverse correlation between coronary calcium score and Fetuin-A emerged from a multiple regression analysis. However, there was no significant difference in serum Fetuin-A among different grades of calcium score. By dividing the patients in tertiles of serum Fetuin-A, an association between low levels of Fetuin-A and high calcification score was found. Fetuin-A as dependent variable was strictly linked to prealbumin serum levels. In addition, there was a clear link between cardiac calcification scores and inflammatory-nutritional markers. Serum calcium and treatment with calcitriol emerged as predictive variables of coronary score.Fetuin-A could be involved in the process of calcification both in the case of markedly low serum levels, due to decreased prevention of calcium phosphate precipitation, and also as a marker of inflammation, a well-known risk factor of atherogenesis. Treatment with intravenous calcitriol could marginally enhance cardiac calcifications, probably through its hypercalcemic effect.

Background: Treatment with folic acid and vitamin B12 appears to be effective in lowering total plasma homocysteine (tHcy) concentrations, but whether vitamin B12 alone lowers tHcy in patients with normal vitamin B12 status is unknown. The aims of the present study were to explore the effect of individual supplementation with folic acid or vitamin B12 on tHcy concentrations in hemodialysis (HD) patients and to compare changes in tHcy concentrations with MTHFR genotype., Methods: We recruited 200 HD patients (119 men) from the "Umberto I" Hospital (Frosinone, Italy) and the Dialysis Unit of University Hospital "Tor Vergata". These patients were randomized blindly into 2 groups of 100 each. Unfortunately, during the study, 36 patients in the first group and 16 in the second group died. The first group was treated initially with vitamin B12 for 2 months and with folic acid for a following 2 months. The second group was treated initially with folic acid and then with vitamin B12. Samples were drawn before administration of either, after the first and second periods, and again 2 months after treatment., Results: The concentrations of tHcy decreased in both groups after the consecutive vitamin therapies, and the decrease was genotype-dependent. The decrease was greater for the T/T genotype (P <0.05) and was more significant when the treatment was started with folic acid (P <0.01)., Conclusion: The alternating vitamin treatment demonstrated for the first time the importance of folate therapy and the secondary contribution of vitamin B12 in lowering tHcy in HD patients.

Previous studies suggested that the proteins and peptides that are responsible for coeliac small intestinal lesions, are also able to agglutinate K562(S) cells. On the contrary, peptides from whole gliadins from durum (tetraploid) wheat do not agglutinate these cells. Bread wheat alpha-gliadins have been identified as a major toxic fraction in coeliac disease. In the present research, alpha-gliadins were purified from durum and bread wheat cultivars. alpha-gliadin peptides from bread wheat were active in agglutinating K562(S) cells, whereas alpha-gliadin from durum wheat failed to induce any agglutinating activity. These results suggest that the lack of toxicity of gliadin from durum wheat cultivars is not related to a low content of alpha-gliadins but is mainly due to intrinsic structural differences from bread wheat gliadins.