Search

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors + endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer prognosis. Given the recent publication of overall survival (OS) data for the 3 CDK4/6-inhibitors, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups. Methods: We conducted a systematic literature search to select all available phase II or III randomized clinical trials of CDK4/6-inhibitors + ET reporting OS data in first- or second-line therapy of HR+/HER2-negative pre- or postmenopausal metastatic breast cancer. A random effect model was applied for the analyses. Heterogeneity was assessed with I-2 statistic. Subgroup analysis was performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP). Results: Six studies were included in our analyses (3421 patients). A clear OS benefit was observed in patients without (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.54 to 0.85, I-2 = 0.0%) and with visceral involvement (HR = 0.76, 95% CI = 0.65 to 0.89, I-2 = 0.0%), with at least 3 metastatic sites (HR = 0.75, 95% CI = 0.60 to 0.94, I-2 = 11.6%), in an endocrine-resistant (HR = 0.79, 95% CI = 0.67 to 0.93, I-2 = 0.0%) and sensitive subset (HR = 0.73, 95% CI = 0.61 to 0.88, I-2 = 0.0%), for younger than 65 years (HR = 0.80, 95% CI = 0.67 to 0.95, I-2 = 0.0%) and 65 years or older (HR = 0.71, 95% CI = 0.53 to 0.95, I-2 = 44.4%), in postmenopausal (HR = 0.76, 95% CI = 0.67 to 0.86, I-2 = 0.0%) and pre- or perimenopausal setting (HR = 0.76, 95% CI = 0.60 to 0.96, I-2 = 0.0%) as well as in chemotherapy-naive patients (HR = 0.72, 95% CI = 0.55 to 0.93, I-2 = 0.0%). Conclusions: CDK4/6-inhibitors ET combinations compared with ET alone improve OS independent of age, menopausal status, endocrine sensitiveness, and visceral involvement and should be preferred as upfront therapy instead of endocrine monotherapy.

Proceedings Of The 6Th International Bci Meeting: Bci Past, Present, And Future

The main objective of this roadmap is to provide a global perspective on the BCI field now and in the future. For readers not familiar with BCIs, we introduce basic terminology and concepts. We discuss what BCIs are, what BCIs can do, and who can benefit from BCIs. We illustrate our arguments with use cases to support the main messages. After reading this roadmap you will have a clear picture of the potential benefits and challenges of BCIs, the steps necessary to bridge the gap between current and future applications, and the potential impact of BCIs on society in the next decade and beyond.

An account is given of the results observed with I-131 MIBG scintigraphy in four patients (1 bladder pheochromocytoma, 3 neuroblastomas) chosen on account of their particular clinical and diagnostic interest from a series of 41 apudoma patients examined by means of this technique. In the first patient, the unusual site of the tumor in the posterior wall of the bladder meant that its detection by I-131 MIBG was only possible after catheterization of the bladder. In the second patient, uptake in the metastasis was only evident after removal of the primary tumor. In the third patient, the scintiscan revealed several metastases (some in bone) not detected by CT. In the fourth patient (congenital neuroblastoma), enhanced uptake accompanied the appearance of high plasma catecholamine and urinary vanillylhandelic acid values, suggesting a functional switch from a nonsecreting to a secreting form. a supplementary In-111 DTPA-Octreotide (OCT) scintiscan of this patient demonstrated the presence of somatostatin receptors on the neuroblasts. Thus, this examination would seem particularly useful for the differentiation of nonsecreting neuroblastomas. Its employment in assessment of the therapeutic capacity of OCT itself is also suggested.

486 children born to HIV-positive mothers, 57 children infected by blood products, and 1 child for whom the personal history was not available were studied. Perinatal infection had a more varied clinical picture and a worse outcome compared with infection acquired later in childhood. Severe secondary infections, neurological disorders, and hepatitis (but not lymphoid interstitial pneumonia) were linked to a high mortality rate in perinatally infected children, in whom an early onset of symptoms was also a bad prognostic factor. Perinatal HIV infection occurred in 32·6% of children born to seropositive mothers, with a higher transmission rate in children born by vaginal delivery and then breast-fed. Preterm delivery and low birthweight seemed to be related to drug abuse during pregnancy, not to intrauterine HIV infection. Girls had a higher rate of perinatal infection and, of those infected, had an increased mortality.

Thyroid function was investigated in eleven β-thalassaemia major prepubertal children, 3–15 years old. Basal serum levels and the levels during a TRH-test of TSH, T4, T3, and rT3 were determined. The data were correlated with age and with serum ferritin levels. Although the patients were euthyroid clinically, the mean serum T3 and rT3 levels were significantly lower than the values in normal control children. Basal serum T4 and TSH values were similar to those of normal controls. In thalassaemic children, during the TRH-test, the increases in serum TSH at 20, 30, and 45 min, the peak and the maximum ΔTSH were higher than those normally found. Basal T3 and the 60 min value during the TRH-test were lower than normal, and the peak was delayed to 120 min. No statistically significant correlation was found between the hormonal parameters studied, and either chronological age or serum ferritin levels. That there is a slight impairment of thyroid secretion in thalassaemia major children is suggested only by the differences in response during the TRH-test (peak and maximum ΔTSH is increased, T3 increase delayed, the negative linear correlation between basal TSH values and per cent increase in T3 and maximum ΔT3, and the positive linear correlation between per cent increase in TSH and in T3). The low basal T3 and rT3 values might be explained by a decrease in the monodeiodinating enzymatic systems for T4, although other interpretations, e.g., increased clearance of T3 and rT3, cannot be excluded. The absence of clinical signs of hypothyroidism in thalassaemia major children might be due to the normal circulating levels of T4 if we accept that T4 has hormonal activity at least when T3 is low.

It is well known that thalassemic patients exhibit an increased frequency of thrombotic events. Most individuals with resistance to activated protein C (APCR) are the result of a point mutation replacing Arg 506 with Gln in the factor V aminoacidic sequence (factor V Leiden). Recently APCR has been shown to account for up to 50% of cases of thrombophilia. In this report, we describe a 10 year old thalassemic intermedia patient heterozygous for Factor V R506Q who developed a stroke following transfusion. Coagulation laboratory values were all within the normal range and there was no evidence of a lupus anticoagulant. Computerized brain tomography showed an ischemic area in the left temporo-parietal region. At follow-up, plasma from the patient demonstrated APCR and molecular diagnostic testing revealed heterozygosity for factor V R506Q. We suggest that the heterozygosity for factor V Leiden could increase the thrombotic risk in thalassemia intermedia. We believe it may be beneficial to screen all intermedia thalassemic patients for APCR especially before starting a transfusional regimen.

X-chromosome inactivation in mammals is regarded as an essentially random process, but the resulting somatic-cell mosaicism creates the opportunity for cell selection. In most people with red-blood-cell glucose-6-phosphate dehydrogenase (G6PD) deficiency, the enzyme-deficient phenotype is only moderately expressed in nucleated cells. However, in a small subset of hemizygous males who suffer from chronic nonspherocytic hemolytic anemia, the underlying mutations (designated class I) cause more-severe G6PD deficiency, and this might provide an opportunity for selection in heterozygous females during development. In order to test this possibility we have analyzed four heterozygotes for class I G6PD mutations: two with G6PD Portici (1178G-->A) and two with G6PD Bari (1187C-->T). We found that in fractionated blood cell types (including erythroid, myeloid, and lymphoid cell lineages) there was a significant excess of G6PD-normal cells. The significant concordance that we have observed in the degree of imbalance in the different blood-cell lineages indicates that a selective mechanism is likely to operate at the level of pluripotent blood stem cells. Thus, it appears that severe G6PD deficiency affects adversely the proliferation or the survival of nucleated blood cells and that this phenotypic characteristic is critical during hematopoiesis.

Thyroid function was investigated by a TRH test in 24 clinically prepubertal children, 3–15 years old with β-thalassaemia major; in 7 of them the test was repeated once and in 2 twice at intervals of at least 12 months. Basal T4, T3, TBG and TSH levels and the TSH levels during a TRH test were determined and correlated with age and serum ferritin levels. Basal serum T4, T3 and TBG levels were lower and serum TSH levels were higher during the test and in the basal state in thalassaemia major children than in control children. These results show a compensated sub-clinical primary hypothyroidism. The transversal study did not show any significant correlation between the hormonal parameters studied and chronological age or serum ferritin levels. In contrast, the longitudinal study showed a significant correlation between pituitary-thyroidal axis function and siderosis (positive correlations between the variations of TSH levels as Δ, peak, 30 and 45 min values and the variations of serum ferritin levels). The thyroid impairment seems not to be correlated with serum ferritin levels in the transversal study because of the presence of an individual different sensitivity of the gland to the iron overload. The ferritin dependence of this impairment is shown only by longitudinal studies where individual differences in sensitivity of the gland are absent. Therefore iron chelation by desferrioxamine sc infusions, resulting in a decrease of ferritin, improves the deficient thyroid function.

Lucrezia Ferrario,1 Fabrizio Schettini,1 Angelo Avogaro,2 Chiara Bellia,3 Federico Bertuzzi,4 Graziella Bonetti,5 Antonio Ceriello,6 Marcello Ciaccio,3,7 Massimiliano Corsi Romanelli,8,9 Elena Dozio,9 Luca Falqui,10 Angela Girelli,11 Antonio Nicolucci,12 Gianluca Perseghin,13,14 Mario Plebani,15 Umberto Valentini,11 Martina Zaninotto,15 Silvana Castaldi,9,16 Emanuela Foglia1 1Centre for Health Economics, Social and Health Care Management, Università Carlo Cattaneo - LIUC, Castellanza, Italy; 2Department of Medicine, University-Hospital of Padova, Padova, Italy; 3Section of Clinical Biochemistry and Clinical Molecular Medicine, Department of Biopathology and Medical Biotechnologies, University of Palermo, Palermo, Italy; 4Diabetology Unit, Grande Ospedale Metropolitano Niguarda Hospital, Milan, Italy; 5Department of Medicine Services, Valcamonica Hospital, Esine, Italy; 6Department of Cardiovascular and Metabolic Diseases, Multimedica Research Institute, Milan, Italy; 7Department of Laboratory Medicine, University-Hospital of Palermo, Palermo, Italy; 8Service of Laboratory Medicine 1-Clinical Pathology, Policlinico San Donato, Milan, Italy; 9Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy; 10Department of Medicine, Diabetes and Endocrinology, Multimedica Research Institute, Milan, Italy; 11Diabetes Care Unit, Spedali Civili Hospital, Brescia, Italy; 12Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy; 13Department of Medicine and Surgery, Università degli Studi di Milano Bicocca, Milan, Italy; 14Department of Medicine and Rehabilitation, Unit of Metabolic Medicine, Policlinico di Monza, Monza, Italy; 15Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy; 16Fondazione Ca’ Granda Ospedale Maggiore Policlinico Research Institute of Milano, Milano, ItalyCorrespondence: Lucrezia FerrarioCentre for Health Economics, Social and Health Care Management, Università Carlo Cattaneo – LIUC, Corso Matteotti 22, Castellanza, 21053, VA, ItalyTel +39 033 1572504Fax +39 033 1572513Email lferrario@liuc.itPurpose: To investigate the glycated albumin (GA) introduction implications, as an add-on strategy to traditional glycemic control (Hb1Ac and fasting plasma glucose – FPG) instruments, considering insulin-naïve individuals with type 2 diabetes mellitus (T2DM), treated with oral therapies.Methods: A Health Technology Assessment was conducted in Italy, as a multi-dimensional approach useful to validate any innovative technology. The HTA dimensions, derived from the EUnetHTA Core Model, were deployed by means of literature evidence, health economics tools and qualitative questionnaires, filled-in by 15 professionals.Results: Literature stated that the GA introduction could lead to a higher number of individuals achieving therapeutic success after 3 months of therapy (97.0% vs 71.6% without GA). From an economic point of view, considering a projection of 1,955,447 T2DM insulin-naïve individuals, potentially treated with oral therapy, GA introduction would imply fewer individuals requiring a therapy switch (− 89.44%), with a 1.06% in costs reduction, on annual basis, thus being also the preferable solution from a cost-effectiveness perspective (cost-effectiveness value: 237.74 vs 325.53). According to experts opinions, lower perceptions on GA emerged with regard to equity aspects (0.13 vs 0.72, p-value> 0.05), whereas it would improve both individuals (2.17 vs 1.33, p-value=0.000) and caregivers quality of life (1.50 vs 0.83, p-value=0.000). Even if in the short term, GA required additional investments in training courses (− 0.80 vs 0.10, p-value = 0.036), in the long run, GA could become the preferable technology (0.30 vs 0.01, p-value=0.018) from an organisational perspective.Conclusion: Adding GA to traditional glycaemic control instruments could improve the clinical pathway of individuals with T2DM, leading to economic and organisational advantages for both hospitals and National Healthcare Systems.Keywords: glycated albumin, type 2 diabetes mellitus, T2DM, Health Technology Assessment, economic evaluation, multidimensional approach

Càncer de mama; Genòmica del càncer; Recerca translacional Cáncer de mama; Genómica del cáncer; Investigación traslacional Breast cancer; Cancer genomics; Translational research Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression. This work was supported by the grants from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement No. 847912 (to A.P.), the Instituto de Salud Carlos III-PI16/00904 (to A.P.), Pas a Pas (to A.P.), Save the Mama (to A.P.), Breast Cancer Now-2018NOVPCC1294 (to A.P.), Fundación Científica Asociación Española Contra el Cáncer-Ayuda Postdoctoral AECC 2017 (to F.B.-M.), Fundación SEOM, Becas FSEOM para Formación en Investigación en Centros de Referencia en el Extranjero 2018 (to T.P.) and PhD4MD - Departament de Salut expedient SLT008/18/00122 (to N.C.).

OBJECTIVE: The objective of this study was to evaluate the efficacy of rescue fractional microablative CO2 laser treatment in women with severe symptoms and sexual dysfunction related to lichen sclerosus not responsive to long-term ultra-potent topical corticosteroid treatment. METHODS: Consecutive eligible women with lichen sclerosus referred to our unit who received fractional microablative CO2 laser treatment after failure of ultra-potent topical corticosteroid treatment were enrolled in the study. The diagnosis was confirmed by histological assessment in all cases. Patients underwent two cycles of CO2 laser every 30 to 40 days. The severity of lichen sclerosus-related symptoms, sexual function, and procedure discomfort were evaluated with a visual analog scale in the same individual at baseline, after completion of each treatment cycle. Follow-up visits were scheduled during each treatment cycle and at least 1 month after completion of the treatment. The Friedman ANOVA test was used to evaluate differences in the visual analog scale scores of each symptom during treatment. RESULTS: A total of 100 patients with vulvar lichen sclerosus were screened, 40 of whom fulfilled the eligibility criteria. We found a significant improvement in vulvar itching (χ [2] = 31,182, P

Elevated plasma concentrations of endogenous thrombin generation markers and thrombotic events have been reported in children with leukemia. The aim of this study was to evaluate the effects of cancer and its treatment on thrombin generation (TAT levels) in children with acute lymphoblastic leukemia (ALL). The authors evaluated 32 children (23 M, 9 F) aged between 1 and 15 years (mean 6) affected by ALL (immunophenotypic subgroups: 16 common, 7 T, and 9 pre-B type). In all patients TAT levels at onset and after 5-6 doses of L-asparaginase were evaluated. TAT levels were higher in patients both at onset (13.04 +/- 10.90 ng/L) and after the 5-6 doses of L-asp (19.41 +/- 11.05 ng/L) with respect to controls (4 +/- 1 ng/L) (p < .001 and p < .001). TAT levels after 5-6 doses of L-asp were higher than those at onset (p < .001). Factorial ANOVA showed that at onset there was a significant effect of leukemia immunophenotypic subgroups upon TAT levels (p < .05) and no effect of inherited thrombotic risk factors. These results indicate that in children with ALL an important role is played by acquired thrombotic risk factors, among which the indirect cancer procoagulant activity has its importance.

Acute leukaemias are characterized by non-random chromosomal aberrations which are often strictly related to the inactivation of tumour suppressor genes (TSGs). Alterations at the short arm of chromosome 9 have been reported in a remarkable percentage of acute lymphoblastic leukaemias (ALL) and have been suggested to cause the loss of activity of the putative TSG, p16 INK4A (MTS1/CDKN2) gene. In order to evaluate the correlation between this gene inactivation and visible cytogenetic abnormalities, we have investigated p16 INK4A homozygous gene deletions in 10 paediatric acute leukaemias of different cell lineages which demonstrated karyotype aberrations involving chromosome 9. Moreover, the dimension of the genetic alteration was evaluated by studying the loss of heterozygosity of two highly polymorphic markers of chromosome 9p, namely α-interferon (IFNA) and D9S104, and the deletion of 5'-methylthioadenosine phosphorylase (MTAPase) gene. Finally, the deletion of a gene belonging to p16 INK4A family, the p18 gene, was analysed in these acute leukaemias. Our results demonstrated that : (i) the biallelic loss of p16 INK4A gene is strictly related to a specific immunophenotype, namely ALL of T-cell lineage ; (ii) no significant correlation exists between alterations at chromosome 9p level and the homozygous deletions of p16 INK4A gene ; and (iii) p18 gene was not deleted in the examined cases. These findings suggest a possible correlation between the T-lymphocyte phenotype and the expression of p16 INK4A gene. Moreover, the absence of MTAPase activity seems to be a valuable marker of p16 INK4A gene inactivation, thus indicating that the deleted chromosomal area on 9p21 very frequently involves the MTAPase gene.

To determine the incidence of homozygous deletions of the newly identified tumour suppressor gene, CDK4I, molecular genomic DNA analyses by PCR technique were performed on primary neoplastic cells from 22 childhood acute leukaemias obtained at presentation. The blast cells derived in all the analysed cases from bone marrow. We found that none of acute myeloblastic leukaemias (four cases) showed the CDK4I alteration, whereas 6/13 (46%) common acute lymphoblastic leukaemias (ALLs) displayed homozygous deletions. Moreover, and even more important, all the blasts purified from ALLs derived from early lymphoid precursors (three early-T ALLs and two pre-B ALLs) showed the absence of CDK4I gene. When the entire coding sequence of the CDK4I gene from samples without homozygous deletions was analysed by the single-strand conformational polymorphism method, no point mutations were identified. These results demonstrate that CDK4I gene deletions are very frequent and probably early events in childhood acute leukaemias of lymphoid origin and especially in early-T and pre-B ALLs. Moreover, the molecular mechanism of the loss of function of the gene is correlated, at least in childhood ALLs, almost exclusively to deletions and not to point mutations.