Experts’ consensus on the definition and management of high risk multiple myeloma

High risk multiple myeloma (HRMM) at diagnosis is currently recognized according to the Revised International Staging System (R-ISS) which was set up in 2015. Since then, new clinical and biological prognostic factors have been developed, which could implement the definition of High Risk (HR) category. We conducted a survey in order to identify which additional parameters, both clinical and biological, are considered more useful for the clinical practice and to evaluate if the management of Multiple Myeloma (MM) should change on the basis of the risk category. A questionnaire, consisting of 8 statements, was submitted to 6 Italian experts, from the European Myeloma Network (EMN) Research Italy, using the Delphi method. The colleagues were asked to answer each question using a scale between 0 and 100. If a statement did not reach at least 75 out of 100 points from all the participants, it was rephrased on the basis of the proposal of the experts and resubmitted in a second or further round, until a consensus was reached among all. From the first round of the survey a strong consensus was reached regarding the opportunity to revise the R-ISS including chromosome 1 abnormality, TP53 mutation or deletion, circulating plasma cells by next generation flow and extramedullary plasmacytomas. No consensus was reached for the definition of “double hit” MM and for the application in clinical practice of treatment strategies based on the risk category. In the second round of the Delphi questionnaire, “double-hit” MM was recognized by the association of at least two high-risk cytogenetic or molecular abnormalities. Moreover, the experts agreed to reserve an intensified treatment only to specific conditions, such as plasma cell leukaemia or patients with multiple extramedullary plasmacytomas, while they admitted that there are not sufficient real word data in order to modify treatment on the basis of MRD assessment in clinical practice. This survey suggests that the definition of HRMM should be implemented by additional clinical and biological risk factors, that will be useful to guide treatment in the future

Social cognition in people with schizophrenia: A cluster-analytic approach

Background The study aimed to subtype patients with schizophrenia on the basis of social cognition (SC), and to identify cut-offs that best discriminate among subtypes in 809 out-patients recruited in the context of the Italian Network for Research on Psychoses. Method A two-step cluster analysis of The Awareness of Social Inference Test (TASIT), the Facial Emotion Identification Test and Mayer-Salovey-Caruso Emotional Intelligence Test scores was performed. Classification and regression tree analysis was used to identify the cut-offs of variables that best discriminated among clusters. Results We identified three clusters, characterized by unimpaired (42%), impaired (50.4%) and very impaired (7.5%) SC. Three theory-of-mind domains were more important for the cluster definition as compared with emotion perception and emotional intelligence. Patients more able to understand simple sarcasm (14 for TASIT-SS) were very likely to belong to the unimpaired SC cluster. Compared with patients in the impaired SC cluster, those in the very impaired SC cluster performed significantly worse in lie scenes (TASIT-LI <10), but not in simple sarcasm. Moreover, functioning, neurocognition, disorganization and SC had a linear relationship across the three clusters, while positive symptoms were significantly lower in patients with unimpaired SC as compared with patients with impaired and very impaired SC. On the other hand, negative symptoms were highest in patients with impaired levels of SC. Conclusions If replicated, the identification of such subtypes in clinical practice may help in tailoring rehabilitation efforts to the person's strengths to gain more benefit to the person

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 6410% at 3 months, 641% at 6 months, 640.1% at 12 months, 640.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 &gt;10% at 3 and 6 months, &gt;1% at 12 months, and &gt;0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR

Experts' consensus on the definition and management of high risk multiple myeloma

High risk multiple myeloma (HRMM) at diagnosis is currently recognized according to the Revised International Staging System (R-ISS) which was set up in 2015. Since then, new clinical and biological prognostic factors have been developed, which could implement the definition of High Risk (HR) category. We conducted a survey in order to identify which additional parameters, both clinical and biological, are considered more useful for the clinical practice and to evaluate if the management of Multiple Myeloma (MM) should change on the basis of the risk category. A questionnaire, consisting of 8 statements, was submitted to 6 Italian experts, from the European Myeloma Network (EMN) Research Italy, using the Delphi method. The colleagues were asked to answer each question using a scale between 0 and 100. If a statement did not reach at least 75 out of 100 points from all the participants, it was rephrased on the basis of the proposal of the experts and resubmitted in a second or further round, until a consensus was reached among all. From the first round of the survey a strong consensus was reached regarding the opportunity to revise the R-ISS including chromosome 1 abnormality, TP53 mutation or deletion, circulating plasma cells by next generation flow and extramedullary plasmacytomas. No consensus was reached for the definition of "double hit" MM and for the application in clinical practice of treatment strategies based on the risk category. In the second round of the Delphi questionnaire, "double-hit" MM was recognized by the association of at least two high-risk cytogenetic or molecular abnormalities. Moreover, the experts agreed to reserve an intensified treatment only to specific conditions, such as plasma cell leukaemia or patients with multiple extramedullary plasmacytomas, while they admitted that there are not sufficient real word data in order to modify treatment on the basis of MRD assessment in clinical practice. This survey suggests that the definition of HRMM should be implemented by additional clinical and biological risk factors, that will be useful to guide treatment in the future

Disorganization and cognitive impairment in schizophrenia: New insights from electrophysiological findings

In subjects with schizophrenia (SCZ), the disorganization dimension is a strong predictor of real-life functioning. “Conceptual disorganization” (P2), “Difficulty in abstract thinking” (N5) and “Poor attention” (G11) are core features of the disorganization factor, evaluated using the Positive and Negative Syndrome Scale. The heterogeneity of this dimension and its overlap with neurocognitive deficits are still debated. Within the multicenter study of the Italian Network for Research on Psychoses, we investigated electrophysiological and neurocognitive correlates of disorganization and its component items to assess the heterogeneity of this dimension and its possible overlap with neurocognitive deficits. Resting state EEG was recorded in 145 stabilized SCZ and 69 matched healthy controls (HC). Spectral amplitude was averaged in ten frequency bands. Neurocognitive domains were assessed by MATRICS Consensus Cognitive Battery (MCCB). RAndomization Graphical User software explored band spectral amplitude differences between groups and correlations with disorganization and MCCB scores in SCZ. Correlations between disorganization and MCCB scores were also investigated. Compared to HC, SCZ showed increased delta, theta, and beta 1 and decreased alpha 2 activity. A negative correlation between alpha 1 and disorganization was observed in SCZ. At the item level, only “N5” showed the same correlation. MCCB neurocognitive composite score was associated with disorganization, “P2” and “N5”. Our findings suggest only a partial overlap between disorganization and neurocognitive impairment. The association of alpha 1 with the “N5” item suggests that some aspects of disorganization could be underpinned by the impairment of basic neurobiological functions that are only partially evaluated using MCCB

Disorganization and cognitive impairment in schizophrenia: New insights from electrophysiological findings

In subjects with schizophrenia (SCZ), the disorganization dimension is a strong predictor of real-life functioning. “Conceptual disorganization” (P2), “Difficulty in abstract thinking” (N5) and “Poor attention” (G11) are core features of the disorganization factor, evaluated using the Positive and Negative Syndrome Scale. The heterogeneity of this dimension and its overlap with neurocognitive deficits are still debated. Within the multicenter study of the Italian Network for Research on Psychoses, we investigated electrophysiological and neurocognitive correlates of disorganization and its component items to assess the heterogeneity of this dimension and its possible overlap with neurocognitive deficits. Resting state EEG was recorded in 145 stabilized SCZ and 69 matched healthy controls (HC). Spectral amplitude was averaged in ten frequency bands. Neurocognitive domains were assessed by MATRICS Consensus Cognitive Battery (MCCB). RAndomization Graphical User software explored band spectral amplitude differences between groups and correlations with disorganization and MCCB scores in SCZ. Correlations between disorganization and MCCB scores were also investigated. Compared to HC, SCZ showed increased delta, theta, and beta 1 and decreased alpha 2 activity. A negative correlation between alpha 1 and disorganization was observed in SCZ. At the item level, only “N5” showed the same correlation. MCCB neurocognitive composite score was associated with disorganization, “P2” and “N5”. Our findings suggest only a partial overlap between disorganization and neurocognitive impairment. The association of alpha 1 with the “N5” item suggests that some aspects of disorganization could be underpinned by the impairment of basic neurobiological functions that are only partially evaluated using MCCB

Distribution of cardiovascular disease and retinopathy in patients with type 2 diabetes according to different classification systems for chronic kidney disease: A cross-sectional analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study

Background: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF's KDOQI) staging system for chronic kidney disease (CKD) is based primarily on estimated GFR (eGFR). This study aimed at assessing whether reclassification of subjects with type 2 diabetes using two recent classifications based on both eGFR and albuminuria, the Alberta Kidney Disease Network (AKDN) and the Kidney Disease: Improving Global Outcomes (KDIGO), provides a better definition of burden from cardiovascular disease (CVD) and diabetic retinopathy (DR) than the NKF's KDOQI classification.Methods: This is a cross-sectional analysis of patients with type 2 diabetes (n = 15,773) from the Renal Insufficiency And Cardiovascular Events Italian Multicenter Study, consecutively visiting 19 Diabetes Clinics throughout Italy in years 2007-2008. Exclusion criteria were dialysis or renal transplantation. CKD was defined based on eGFR, as calculated from serum creatinine by the simplified Modification of Diet in Renal Disease Study equation, and albuminuria, as measured by immunonephelometry or immunoturbidimetry. DR was assessed by dilated fundoscopy. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events.Results: Though prevalence of complications increased with increasing CKD severity with all three classifications, it differed significantly between NKF's KDOQI stages and AKDN or KDIGO risk categories. The AKDN and KDIGO systems resulted in appropriate reclassification of uncomplicated patients in the lowest risk categories and a more graded independent association with CVD and DR than the NKF's KDOQI classification. However, CVD, but not DR prevalence was higher in the lowest risk categories of the new classifications than in the lowest stages of the NKF's KDOQI, due to the inclusion of subjects with reduced eGFR without albuminuria. CVD prevalence differed also among eGFR and albuminuria categories grouped into AKDN and KDIGO risk category 1 and moderate, respectively, and to a lesser extent into higher risk categories.Conclusions: Though the new systems perform better than the NKF's KDOQI in grading complications and identifying diabetic subjects without complications, they might underestimate CVD burden in patients assigned to lower risk categories and should be tested in large prospective studies.Trial registration: ClinicalTrials.gov; NCT00715481. © 2014 Pugliese et al.; licensee BioMed Central Ltd

Pathways to functional outcome in subjects with schizophrenia living in the community and their unaffected first-degree relatives

Rationale Variables influencing real-life functioning have repeatedly been modeled in schizophrenia subjects but not systematically investigated in their unaffected first-degree relatives (SRs), in whom milder forms of deficits reported in schizophrenia have been observed, but confounders of clinical cohorts are not in play. Demonstrating that pathways to functional outcome are similar between patients and SRs would validate structural models developed in schizophrenia subjects. The present multicenter study aimed to explore whether variables associated with real-life functioning are similar in schizophrenia patients and their unaffected relatives. Methods The study sample included 921 schizophrenia patients, 379 SRs and 780 healthy controls. Structural Equation Models (SEMs) were used in patients and SRs to test associations of psychopathological dimensions, neurocognition, social cognition, resilience, perceived stigma and functional capacity with real-life functioning domains, impaired in both patients and SRs. Results Interpersonal Relationships and Work Skills were the only functional domains impaired in both patients and SRs. For both domains, functional impairment in patients was found to predict impairment in unaffected relatives, suggesting the involvement of similar illness-related vulnerability factors. In both groups variables significantly associated with Interpersonal Relationships included Social Cognition, Neurocognition, Avolition, Resilience, Disorganization, Perceived Stigma and Gender, and those significantly associated with Work Skills included Social Cognition, Neurocognition and Disorganization. Conclusions Pathways to functional outcome for Interpersonal relationships and Work skills are similar between schizophrenia patients and their unaffected first-degree relatives. These findings validate, in the absence of confounders of clinical cohorts, structural models of determinants of functional outcome in people with schizophrenia

Assessment of de novo copy-number variations in Italian patients with schizophrenia: Detection of putative mutations involving regulatory enhancer elements

Objectives: Variants appearing de novo in genes regulating key neurodevelopmental processes and/or in non-coding cis-regulatory elements (CREs), as enhancers, may increase the risk for schizophrenia. However, CREs involvement in schizophrenia needs to be explored more deeply. Methods: We investigated de novo copy-number variations (CNVs) in the whole-genomic DNA obtained from 46 family trios of schizophrenia probands by using the Enhancer Chip, a customised array CGH able to investigate the whole genome with a 300-kb resolution, specific disease loci at a ten-fold higher resolution, and which was highly enriched in probes in more than 1,250 enhancer elements selected from Vista Enhancer Browser. Results: In seven patients, we found de novo CNVs, two of which overlapped VISTA enhancer elements. De novo CNVs encompass genes (CNTNAP2, MAGI1, TSPAN7 and MET) involved in brain development, while that involving the enhancer element hs1043, also includes ZIC1, which plays a role in neural development and is responsible of behavioural abnormalities in Zic mutant mice. Conclusions: These findings provide further evidence for the involvement of de novo CNVs in the pathogenesis of schizophrenia and suggest that CNVs affecting regulatory enhancer elements could contribute to the genetic vulnerability to the disorder