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Despite high complete remission (CR) rates with frontline therapy, relapses are frequent in adults with T-cell acute lymphoblastic leukemia (T-ALL) with limited salvage options. We analyzed the outcomes and prognostic factors for CR to salvage therapy and overall survival (OS) of patients with R/R T-ALL included in two prospective measurable residual disease-oriented trials. Seventy-five patients (70 relapsed, 5 refractory) were identified. Relapses occurred in bone marrow, isolated or combined in 50 patients, and in the central nervous system (CNS; isolated or combined) in 20. Second CR was attained in 30/75 patients (40%). Treatment with FLAG-Ida and isolated CNS relapse were independently associated with a higher CR rate after first salvage therapy. The median OS was 6.2 (95% confidence interval [CI], 3.9–8.6) months, with a 4-year OS probability of 18% (95% CI, 9%–27%). No differences in survival were observed according to the treatment with hematopoietic stem cell transplantation in patients in CR after first salvage therapy. Multivariable analysis showed a ≥12-month interval between first CR and relapse, CR after first salvage therapy and isolated CNS relapse as favorable prognostic factors for OS with hazard ratios (HR) (95% CI) of 1.931 (1.109–3.362), 2.958 (1.640–5.334), and 2.976 (1.157–7.655), respectively. This study confirms the poor outcomes of adults with R/R T-ALL among whom FLAG-Ida was the best of the rescue therapies evaluated. Late relapse, CR after first rescue therapy and isolated CNS relapse showed prognostic impact on survival. More effective rescue therapies are needed in adults with R/R T-ALL., La Caixa" Foundation and ISCIII, Grant/ Award Number: PI19/01828; Generalitat de Catalunya (GRC), Grant/Award Number: 2017 SGR288

The authors analyzed the incidence of sexual dysfunction (SD) with different selective serotonin reuptake inhibitors (SSRIs; fluoxetine, fluvoxamine, paroxetine, and sertraline) and hence the qualitative and quantitative changes in SD throughout time in a prospective and multicenter study. Outpatients (192 women and 152 men; age = 39.6 +/- 11.4 years) under treatment with SSRIs were interviewed with an SD questionnaire designed for this purpose by the authors and that included questions about the following: decreased libido, delayed orgasm or anorgasmia, delayed ejaculation, inability to ejaculate, impotence, and general sexual satisfaction. Patients with the following criteria were included: normal sexual function before SSRI intake, exclusive treatment with SSRIs or treatment associated with benzodiazepines, previous heterosexual or self-erotic current sexual practices. Excluded were patients with previous sexual dysfunction, association of SSRIs with neuroleptics, recent hormone intake, and significant medical illnesses. There was a significant increase in the incidence of SD when physicians asked the patients direct questions (58%) versus when SD was spontaneously reported (14%). There were some significant differences among different SSRIs: paroxetine provoked more delay of orgasm or ejaculation and more impotence than fluvoxamine, fluoxetine and sertraline (chi 2, p .05). Only 24.5% of the patients had a good tolerance of their sexual dysfunction. Twelve male patients who suffered from premature ejaculation before the treatment preferred to maintain delayed ejaculation, and their sexual satisfaction, and that of their partners, clearly improved. Sexual dysfunction was positively correlated with dose. Patients experienced substantial improvement in sexual function when the dose was diminished or the drug was withdrawn. Men showed more incidence of sexual dysfunction than women, but women's sexual dysfunction was more intense than men's. In only 5.8% of patients, the dysfunction disappeared completely within 6 months, but 81.4% showed no improvement at all by the end of this period. Twelve of 15 patients experienced total improvement when the treatment was changed to moclobemide (450-600 mg/day), and 3 of 5 patients improved when treatment was changed to amineptine (200 mg/day).

Out of a group of 220 acute lymphoblastic leukaemias (ALL) with phenotypic study at diagnosis, 18 were selected on which sequential studies were performed due to relapse (15 cases) or to lack of achievement of complete remission (primary resistant ALL, 3 cases). The purpose of this study was to analyse the incidence and characteristics of the possible antigenic changes with regard to the diagnosis. Along with the classic markers, a panel comprised of 20 monoclonal antibodies against lymphoid and myeloid antigens was used. Major phenotypic changes (acquisition of myeloid antigens CD13 and CD33) were found only in one case amongst the relapsing ALL (7%). Seven other patients (47%) showed minor phenotyping changes, including: 1) acquisition or loss of antigens (2 cases); 2) changes in more then 50% of any antigen's expression (4 cases); 3) both (1 case). These results might suggest that antigenic changes are rather frequent in relapsing ALL; however, none of such changes modified in our experience the phenotypic diagnosis so any change of this last should be regarded as an exceptional event. The majority of these antigenic changes consisted of the loss of maturation antigens (CD20) or acquisition of early markers (TdT, HLA-DR) or activation markers (CD38); this would mean that the relapsing blast cells show a functional status of activation and proliferation, with a phenotype more immature than that of the diagnosis, thus explaining the poorer prognosis of the patients in relapse. No phenotypic changes were found in the primary resistant ALL, which may indicate the persistence of the original cell clone without any alteration.

Meningiomas are cytogenetically heterogeneous tumors in which chromosome gains and losses frequently occur. Based on the intertumoral cytogenetic heterogeneity of meningiomas, hypothetical models of clonal evolution have been proposed in these tumors which have never been confirmed at the intratumoral cell level. The aim of this study was to establish the intratumoral patterns of clonal evolution associated with chromosomal instability in individual patients as a way to establish tumor progression pathways in meningiomas and their relationship with tumor histopathology and behavior. A total of 125 meningioma patients were analyzed at diagnosis. In all cases, multicolor interphase fluorescence in situ hybridization (iFISH) studies were performed on fresh tumor samples for the detection of quantitative abnormalities for 11 different chromosomes. In addition, overall tumor cell DNA content was measured in parallel by flow cytometry. iFISH studies were also performed in parallel on tissue sections in a subset of 30 patients. FISH studies showed that 56 (45%) of the 125 cases analyzed had a single tumor cell clone, all these cases corresponding to histologically benign grade I tumors. In the remaining cases (55%) more than one tumor cell clone was identified: two in 45 cases (36%), three in 19 (15%), and four or more clones in five cases (4%). Overall, flow cytometric analysis of cell DNA contents showed the presence of DNA aneuploidy in 44 of these cases (35%), 30% corresponding to DNA hyperdiploid and 5% to hypodiploid cases; from the DNA aneuploid cases, 35 (28%) showed two clones and 9 (7%) had three or more clones. A high degree of correlation (r ≥ 0.89; P < 0.001) was found between FISH and flow cytometry as regards the overall quantitative DNA changes detected with both techniques, the former being more sensitive. Among the cases with chromosome abnormalities, the earliest tumor cell clone observed was frequently characterized by the loss of one or more chromosomes (64% of all meningiomas); loss of either a single chromosome 22 or, less frequently, of a sex chromosome (X or Y) and del (1p) was commonly found as the single initial cytogenetic aberration (30%, 5%, and 5% of the cases, respectively). Interestingly, an isolated loss of chromosome 22 was only found as the initial abnormality in one out of 14 atypical/anaplastic meningiomas, while the same cytogenetic pattern was present in the ancestral tumor cell clone of 32% of the benign tumors. Cytogenetic patterns based on chromosome gains were found in the ancestral tumor cell clone in 4% of the patients, 2% corresponding to tetraploid tumors. Overall, cytogenetic evolution of the earliest tumor cell clones was frequently associated with tetraploidization (31%). Our results show that meningiomas are genetically heterogeneous tumors that display different patterns of numerical chromosome changes, with the presence of more than one tumor cell clone detected in almost half of the cases including all atypical/anaplastic cases. Interestingly, the pathways of intratumoral clonal evolution observed in the benign tumors were different from those observed in atypical/anaplastic meningiomas, suggesting that the latter tumors might not always represent a more advanced stage of histologically benign meningiomas.

Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) Group (Spanish Society of Hematology, SEHH)., The prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBX1 showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation)., This work was supported in part by CERCA/Generalitat de Catalunya SGR 2017 288 (GRC), a restricted grant from ‘La Caixa’ and Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms (HARMONY).