Long-term safety and effectiveness of levodopa-carbidopa intestinal gel infusion

Levodopa-carbidopa intestinal gel () infusion has demonstrated to improve motor fluctuations. The aim of this study is to assess the long-term safety and effectiveness of infusion in advanced Parkinson's disease () patients with motor fluctuations and its effect in nonmotor symptoms. Adverse events () and their management, clinical motor, and nonmotor aspects were assessed up to 10 years. Thirty-seven patients were treated with ; in three subsets of patients, specific batteries of tests were used to assess cognitive and behavior assessment for 6 months, quality of sleep for 6 months, and quality of life and caregiver burden for 1 year. There was a high number of , but manageable, most of mild and moderate severity. All patients experienced significant improvement in motor fluctuations with a reduction in mean daily off time of 4.87 hr after 3 months (n = 37) to 6.25 hr after 9 years (n = 2). Diskynesias remained stables in 28 patients (75.7%) and improved in 5 patients (13.5%). There was no neuropsychological deterioration, but an improvement in attentional functions, voluntary motor control, and semantic fluency. Quality of sleep did not worsen, and there was an improvement in the subjective parameters, although overnight polysomnography did not change. There was a significant sustained improvement of 37% in -Q39 after 3 months and to 1 year, and a significant reduction in caregiver burden of 10% after 3 months. infusion is a safe and efficacious treatment for the control of motor fluctuations, and for improvement or nonworsening of nonmotor aspects, long-term sustained, and feasible for use in routine care

Prognosis assessment of early-stage chronic lymphocytic leukemia: Are we ready to predict clinical evolution without a crystal ball?

On behalf ofGrupo Español de Leucemia Linfática Crónica and Grupo Cooperativo Español de Citogenética Hematológica.[Background]: The discovery of new biologic variables with high prognostic effect has been accompanied by the emergence of different prognostic indexes (PIs) to assess the time to first treatment in patients with early-stage (Binet A) chronic lymphocytic leukemia (CLL). The present study compared the prognostic value of 5 PIs: CLL international prognostic index (CLL-IPI), Barcelona-Brno, international prognostic score-A (IPS-A), CLL-01, and a tailored approach.[Patients and Methods]: We applied the 5 PIs to a cohort of 428 unselected patients with Binet A CLL from a multicenter Spanish database with clinical and biologic information available. The predictive value of the scores was assessed using Harrell’s concordance index (C index) and area under the receiver operating characteristic curve (AUC).[Results]: We found a significant association between time to first treatment and risk subgroups for all 5 PIs used. The most accurate PI was the IPS-A (C-index, 0.72; AUC, 0.76), closely followed by CLL-01 (C-index, 0.69; AUC, 0.70), CLL-IPI (C-index, 0.69; AUC, 0.69), Barcelona-Brno (C-index, 0.67; AUC, 0.69), and the tailored approach (C-index, 0.61 and 0.58; AUC, 0.58 and 0.54).[Conclusions]: The concordance between the PIs was low (44%), suggesting that although all these PIs improve clinical staging and help physicians in routine clinical practice, it will be necessary to harmonize larger cohorts of patients to define the best PI for treatment decision-making in the real world.The present study was supported by the Spanish Fondo de Investigaciones Sanitarias (grants PI15/01471 and PI18/01500), Instituto de Salud Carlos III, European Regional Development Fund (Una manera de hacer Europa), Consejería de Educación, Junta de Castilla y León (grant SA271P18), Proyectos de Investigación del SACYL (grants GRS1847/A/18 and GRS1653/A17), Fundación Memoria Don Samuel Solórzano Barruso (grant FS/23-2018), Red Temática de Investigación Cooperativa en Cáncer (grant RD12/0036/0069), Centro de Investigación Biomédica en Red de Cáncer (grant CIBERONC CB16/12/00233), and Synthetic Lethality for Personalized Therapy-based Stratification in Acute Leukemia (grant ERAPERMED2018-275); and Instituto de Salud Carlos III (grant AC18/00093). M.H.S. holds a Sara Borrell postdoctoral contract (CD19/00222) from the Spanish Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, European Regional Development Fund (El Fondo Social Europeo invierte en tu future). A.E.R.V. is supported by a research grant from the Fundación Española de Hematología y Hemoterapia. M.Q.Á. is fully supported by the Ayuda predoctoral de la Junta de Castilla y León from the Fondo Social Europeo (PhD scholarship JCYL EDU/529/2017). C.P.C. is a recipient of a PFIS grant (FI19/00191) from Instituto de Salud Carlos III, cofounded by Fondo Social Europeo (El Fondo Social Europeo invierte en tu future).Peer reviewe

Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations and clinical impact

Recent evidence suggests that complex karyotype (CK) defined by the presence of 653 chromosomal aberrations (structural and/or numerical) identified by chromosome banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges towards routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with 655 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcome, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and or TP53 mutations, TP53abs) and the expression of somatically hypermutated (M-CLL) or unmutated (U-CLL) immunoglobulin heavy variable genes (IGHV). Thus, they contrasted CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs and IGHV gene somatic hypermutation status, we propose a novel hierarchical model where patients with high-CK exhibit the worst prognosis, while M-CLL lacking CK or TP53abs as well as CK with +12,+19 show the longest overall survival. In conclusion, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with 655 chromosomal aberrations emerges as prognostically adverse, independently of other biomarkers. Prospective clinical validation is warranted before finally incorporating high-CK in risk stratification of CLL

Chromosome banding analysis and genomic microarrays are both useful but not equivalent methods for genomic complexity risk stratification in chronic lymphocytic leukemia patients

Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3- 4 and ¿5 abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (kappa=0.507; P<0.001). Discordant classification was obtained in 100 patients (29.4%), including 3% classified in opposite risk groups. Most discrepancies were technique-dependent and no greater correlation in the number of abnormalities was achieved when different filtering strategies were applied for GM. Nonetheless, both methods showed a similar concordance index for prediction of time to first treatment (TTFT) (CBA: 0.67 vs. GM: 0.65) and overall survival (CBA: 0.55 vs. GM: 0.57)

TP53 abnormalities are underlying the poor outcome associated with chromothripsis in chronic lymphocytic leukemia patients with complex karyotype

Simple Summary Chromothripsis, a genomic event that generates massive chromosomal rearrangements, has been described in 1-3% of CLL patients and is associated with poor prognostic factors (e.g., TP53 abnormalities and genomic complexity). However, previous studies have not assessed its role in CLL patients with complex karyotypes. Herein, we aimed to describe the genetic characteristics of 33 CLL patients with high genomic complexity and chromothripsis. Moreover, we analyzed the clinical impact of chromothripsis, comparing these patients against a cohort of 129 patients with complex karyotypes not presenting this catastrophic event. Nine cases were also assessed via the novel cytogenomic methodology known as optical genome mapping. We confirmed that this phenomenon is heterogeneous and associated with a shorter time to first treatment. Nonetheless, our findings suggested that TP53 abnormalities, rather than chromothripsis itself, underlie the dismal outcome. Chromothripsis (cth) has been associated with a dismal outcome and poor prognosis factors in patients with chronic lymphocytic leukemia (CLL). Despite being correlated with high genome instability, previous studies have not assessed the role of cth in the context of genomic complexity. Herein, we analyzed a cohort of 33 CLL patients with cth and compared them against a cohort of 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic ..

Characterizing patients with multiple chromosomal aberrations detected by FISH in chronic lymphocytic leukemia

On behalf of Grupo Español de Leucemia Linfática Crónica (GELLC) and Grupo Cooperativo Español de Citogenética Hematológica (GCECGH).We analyzed the features of chronic lymphocytic leukemia (CLL) with multiple abnormalities (MA) detected by FISH. A local database including 2095 CLL cases was used and 323 with MA (15.4%) were selected. MA was defined by the presence of two or more alterations (deletions of 13q14 (13q-), 11q22 (11q-), 17p13 (17p-) or trisomy 12 (+12)). The combination of 13q- with 11q- and 13q- with 17p-, accounted for 58.2% of the series, in contrast to 11q- with 17p- (3.7%). Patients carrying MA since diagnosis presented a short time to first therapy(TTFT) (27 months) and overall survival (OS) (76 months). The combinations including 17p- had a shorter OS (58 months) than the ones without 17p- (not reached, p =.002). Patients with a complex-FISH were the ones with worse OS (34 months). MA imply poor prognosis when they emerge at diagnosis, probably due to the high incidence of bad prognosis markers, which may be a reflection of a more complex karyotype.Peer Reviewe

A high proportion of cells carrying trisomy 12 is associated with a worse outcome in patients with chronic lymphocytic leukemia

On behalf of Grupo Español de Leucemia Linfática Crónica (GELLC), Grupo Cooperativo Español de Citogenética Hematológica (GCECGH).The prognosis of chronic lymphocytic leukemia (CLL) patients displaying trisomy 12 (+12) remains unclear. In this study, we analyzed the influence of the proportion of cells with +12, and other clinical and biologic factors, in time to first therapy (TTFT) and overall survival (OS), in 289 patients diagnosed with CLL carrying +12. Median OS was 129 months. One hundred seventy-four patients (60.2%) presented +12 in <60% of cells. TTFT and OS for this subgroup were longer than for the subgroup with +12 in ≥60% of cells, with a median TTFT of 49 months (CI95%, 39–58) vs 30 months (CI95%, 22–38) (P = 0.001); and a median OS of 159 months (CI95%, 119–182), vs 96 months (CI95%, 58–134) (P = 0.015). Other factors associated with a shorter TTFT were: Binet stage, B symptoms, lymphadenopathy, splenomegaly, high lymphocyte count, 11q-, high βmicroglobulin, and high LDH. In the multivariate analysis, clinical stage, +12 in ≥60% of cells, high lymphocyte count, B symptoms, and 11q- in addition, resulted of significance in predicting shorter TTFT. Significant variables for OS were: Binet stage, lymphadenopathy, splenomegaly, high LDH, high βmicroglobulin, 11q-, and CD38. In the multivariate analysis, only Binet stage, 11q-, and high β2microglobulin significantly predicted shorter OS. CLL with +12 entails a heterogeneous group with intermediate prognosis. However, a high proportion of cells carrying +12 separates a subgroup of patients with poor outcome.This work was partially supported by grants from the Spanish Fondo de Investigaciones Sanitarias FIS 09/01543, PI12/00281, Proyectos de Investigación del SACYL 355/A/09, COST Action EuGESMA (BM0801), Fundación Manuel Solórzano, Obra Social Banca Cívica (Caja Burgos), Fundación Española de Hematología y Hemoterapia (FEHH), and by a grant (RD12/0036/0069) from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, and European Regional Development Fund (ERDF) “Una manera de hacer Europa” and IRON-II collaborative network. The research leading to these results has received funding from the European Union Seventh Framework Programme [FP7/2007-2013] under Grant Agreement no. 306242-NGS-PTL. María HernándezSánchez is fully supported by an Ayuda Predoctoral de la Junta de Castilla y León from the Fondo Social Europeo.Peer Reviewe

Chromosome banding analysis and genomic microarrays are both useful but not equivalent methods for genomic complexity risk stratification in chronic lymphocytic leukemia patients

Data de publicació electrònica: 11-03-2021Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK, 46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity [0-2, 3-4 and ≥5 abnormalities] was also analyzed. No significant differences in the percentage of patients classified into each category were detected, but only a moderate agreement was observed between methods when focusing in individual cases (κ=0.507; p