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1.
Br J Haematol ; 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811025

ABSTRACT

European LeukemiaNet refined their risk classification of acute myeloid leukaemia (AML) in 2022 (ELN 2022) according to the two new myeloid classifications published the same year. We have retrospectively assessed the prognostic value of the ELN 2022 in 120 AML patients undergoing allogeneic haematopoietic cell transplantation (allo-HCT), including 99 in first complete response (CR1) from 2011 to 2021 in our centre. Adverse risk patients (Adv) presented inferior outcome in terms of overall survival (OS) and leukaemia-free survival (LFS) (OS [p = 0.003], LFS [p = 0.02]), confirmed in multivariate analysis (hazard ratio [HR] for OS = 2.00, p = 0.037). These results were also seen in patients allografted in CR1. Further analysis identified a subgroup named adverse-plus (AdvP), including complex karyotype, MECOM(EVI1) rearrangements and TP53 mutations, with worse outcomes than the rest of groups of patients, including the Adv (HR for OS: 3.14, p < 0.001, HR for LFS: 3.36, p < 0.001), with higher 2-year cumulative incidence of relapse (p < 0.001). Notably, within this analysis, the outcome of Adv and intermediate patients were similar. These findings highlight the prognostic value of ELN 2022 in patients undergoing allo-HCT, which can be improved by the recognition of a poor genetic subset (AdvP) within the Adv risk group.

2.
Clin. transl. oncol. (Print) ; 26(4): 872-879, Abr. 2024. ilus, graf
Article in English | IBECS | ID: ibc-VR-50

ABSTRACT

Purpose: Local recurrence of prostate cancer after low-dose rate brachytherapy is a clinical problem with limited salvage treatment options. This prospective study evaluated the tolerability and outcome of salvage external beam radiation therapy (S-EBRT) for locally recurrent prostate cancer after primary low-dose rate prostate brachytherapy (LDR-BT). Materials and methods: Between October 2012 and 2022, 18 patients with biopsy-proven locally recurrent prostate cancer after primary LDR-BT and received S-EBRT. We evaluated biochemical failure (BF), overall survival (OS) and acute/late gastrointestinal and urinary toxicities (CTCAE v5.0 or CTCAE v4, only before 2017). Results: Median follow-up was 32 months (range, 5–124). The median age was at S-EBRT 68 years (range 59–79). 34% (6/18) were low risk, 44% (8/18) intermediate risk, 5% (1/18) high risk, and 17% (3/18) not specified. All patients were treated with IMRT/VMAT and received 60 Gy (2.5 Gy/fraction) to the prostate and 40% (7/18) 55.2 Gy (2,3 Gy/fx) to the seminal vesicles. 56% received ADT The 3-year OS and biochemical relapse-free survival after S-EBRT were 100% and 89%, respectively, with a median PSA nadir 0,035 ng/mL (0,01–0,34). Acute cystitis was present in 72% (13/18) of patients (27% of Grade > 2). Urethritis was present in 78% (14/18) patients (16% of cases Grade > 3), and acute rectitis occurred in 22% (4/18) of patients (no cases Grade > 3). Conclusions: Our data suggest that the treatment of locally recurrent prostate cancer with S-EBRT could provide adequate disease control safely and be used as an additional treatment in the natural history of prostate cancer patients. However, the results are still early and the sample is small; larger studies with longer follow-up would be mandatory.(AU)


Subject(s)
Humans , Male , Female , Small Doses , Brachytherapy , Prostatic Neoplasms , Radiotherapy , Neoplasm Recurrence, Local , Prospective Studies , Retrospective Studies
3.
Article in English | MEDLINE | ID: mdl-38362680

ABSTRACT

OBJECTIVE: The purpose of this study was to identify predictive and risk factors for the development of immune-related endocrinopathies and to analyze the incidence and characteristics of immune-related endocrinopathies in our population Design: A retrospective, single-centre cohort carried out at Gregorio Marañón Hospital between January 2018 -December 2019. METHODS: A total of 163 patients were enrolled. In January 2018 and December 2019, we treated patients who underwent ICI treatment in the Medical Oncology Department of General University Hospital Gregorio Marañón, a tertiary care public hospital in Madrid, as part of an observational, retrospective, single-center cohort study. RESULTS: Endocrinopathies were diagnosed in 19.5% of the patients (n=32). The tumours with the highest incidence of endocrinopathies were non-small cell lung cancer (25,9%), kidney cell cancer (25%) and hepatocarcinoma (20%). Among the 32 patients who developed endocrinopathy, 18,8%, 19,13%, and 21,28% received anti-CTLA-4, anti-PD-1 and anti-PDL-1, respectively. Thyroid dysfunction was the most frequent endocrinopathy (12,8%). A higher percentage of patients with negative antiTPO and antiTG antibodies developed G1 hypothyroidism compared to patients with positive antibodies who developed a higher proportion of G2 hypothyroidism. The presence of an initial phase of thyrotoxicity was not related to greater severity. We observed longer progression-free survival in patients who developed thyroid dysfunction. CONCLUSION: Pre-existing antibodies were independently associated with endocrinopathies. Moreover, our study let us conclude that the presence of thyroid autoantibodies may be related to its severity. It is important to determine anti-thyroid antibodies prior to the start of immunotherapy as a risk factor for thyroid dysfunction, which in turn is a prognostic marker.

4.
Surg Oncol ; 52: 102039, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38301449

ABSTRACT

BACKGROUND AND OBJECTIVES: Recurrent isolated pancreatic metastasis from Renal Cell Carcinoma (RCC) after pancreatic resection is rare. The purpose of our study is to describe a series of cases of relapse of pancreatic metastasis from renal cancer in the pancreatic remnant and its surgical treatment with a repeated pancreatic resection, and to analyse the results of both overall and disease-free survival. METHODS: Multicenter retrospective study of patients undergoing pancreatic resection for RCC pancreatic metastases, from January 2010 to May 2020. Patients were grouped into two groups depending on whether they received a single pancreatic resection (SPS) or iterative pancreatic resection. Data on short and long-term outcome after pancreatic resection were collected. RESULTS: The study included 131 pancreatic resections performed in 116 patients. Thus, iterative pancreatic surgery (IPS) was performed in 15 patients. The mean length of time between the first pancreatic surgery and the second was 48.9 months (95 % CI: 22.2-56.9). There were no differences in the rate of postoperative complications. The DFS rates at 1, 3 and 5 years were 86 %, 78 % and 78 % vs 75 %, 50 % and 37 % in the IPS and SPS group respectively (p = 0.179). OS rates at 1, 3, 5 and 7 years were 100 %, 100 %, 100 % and 75 % in the IPS group vs 95 %, 85 %, 80 % and 68 % in the SPS group (p = 0.895). CONCLUSION: Repeated pancreatic resection in case of relapse of pancreatic metastasis of RCC in the pancreatic remnant is justified, since it achieves OS results similar to those obtained after the first resection.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Pancreatic Neoplasms , Humans , Carcinoma, Renal Cell/surgery , Carcinoma, Renal Cell/pathology , Retrospective Studies , Pancreatectomy/methods , Pancreatic Neoplasms/pathology , Kidney Neoplasms/surgery , Kidney Neoplasms/pathology , Recurrence
5.
Cancers (Basel) ; 16(4)2024 Feb 07.
Article in English | MEDLINE | ID: mdl-38398096

ABSTRACT

Non-acute myeloid neoplasms (MNs) with NPM1 mutations (NPM1mut-MNs) pose a diagnostic and therapeutic dilemma, primarily manifesting as chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS). The classification and treatment approach for these conditions as acute myeloid leukemia (AML) are debated. We describe eight cases of atypical NPM1mut-MNs from our institution and review the literature. We include a rare case of concurrent prostate carcinoma and MN consistent with chronic eosinophilic leukemia, progressing to myeloid sarcoma of the skin. Of the remaining seven cases, five were CMML and two were MDS. NPM1 mutations occur in 3-5% of CMML and 1-6% of MDS, with an increased likelihood of rapid evolution to AML. Their influence on disease progression varies, and their prognostic significance in non-acute MNs is less established than in AML. Non-acute MNs with NPM1 mutations may display an aggressive clinical course, emphasizing the need for a comprehensive diagnosis integrating clinical and biological data. Tailoring patient management on an individualized basis, favoring intensive treatment aligned with AML protocols, is crucial, regardless of blast percentage. Research on the impact of NPM1 mutations in non-acute myeloid neoplasms is ongoing, requiring challenging prospective studies with substantial patient cohorts and extended follow-up periods for validation.

6.
Orphanet J Rare Dis ; 19(1): 12, 2024 Jan 05.
Article in English | MEDLINE | ID: mdl-38183105

ABSTRACT

BACKGROUND: Hereditary fructose intolerance (HFI) is a rare metabolic disease caused by aldolase B deficiency. The aim of our study was to analyse excipient tolerability in patients with HFI and other related diseases and to design mobile and website health applications to facilitate the search for drugs according to their tolerance. RESULTS: A total of 555 excipients listed in the Spanish Medicines Agency database (July 2023) were classified as suitable for HFI patients, suitable with considerations ((glucose and glucose syrup, intravenous sucrose, oral mannitol, polydextrose, gums and carrageenans, ethanol, sulfite caramel and vanilla), not recommended (intravenous mannitol) and contraindicated (fructose, oral sucrose, invert sugar, sorbitol, maltitol, lactitol, isomaltitol, fruit syrups, honey, sucrose esters and sorbitol esters). Glucose and glucose syrup were classified as suitable with considerations due to its possible fructose content and their potential endogenous fructose production. For other related intolerances, wheat starch was contraindicated and oatmeal was not recommended in celiac disease; oral lactose and lactose-based coprocessed excipient (Cellactose®) were not recommended in lactose intolerance; and glucose, invert sugar and oral sucrose were not recommended in diabetes mellitus. The applications were named IntoMed®. Results are listed in order of tolerability (suitable drugs appear first and contraindicated drugs at the end), and they are accompanied by a note detailing their classified excipients. If a drug contains excipients within different categories, the overall classification will be the most restrictive. The apps are also able to classify substances with the same criteria if they act as active ingredients. The tools exhibited good usability (82.07 ± 13.46 points on the System Usability Scale [range: 0-100]) on a sample of HFI patients, their families and health care professionals. CONCLUSIONS: IntoMed® is a tool for finding information about the tolerability of drugs according to excipients for patients with HFI and other related intolerances, with good usability. It is a fast and reliable system that covers the current excipient legislation and expands on it with other specific information: HFI patients should be alert for excipients such as mannitol (especially in intravenous drugs), fruit syrups, honey, sulfite caramel or vanilla. Glucose might contain or produce fructose, and special precaution is needed because of potential errors in their composition.


Subject(s)
Fructose Intolerance , Humans , Excipients , Lactose , Fructose , Mannitol , Sorbitol , Glucose , Sucrose , Sulfites
7.
Ann Hematol ; 103(3): 737-747, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38263537

ABSTRACT

To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting SVT at diagnosis (n = 69, median age 43 years) or during follow-up (n = 21, median age 46 years) to a sex- and age-matched control group of PV/ET without SVT (n = 165, median age 48 years). The majority of patients presenting with SVT at diagnosis were classified as myeloproliferative neoplasm with heterozygous JAK2 mutation (87% of cases vs. 69% in PV/ET control group, p < 0.05), characterized by low JAK2 allele burden and no high-risk mutations. Despite this lower molecular complexity, patients presenting with SVT showed a higher risk of death (HR 3.0, 95% CI 1.5-6.0, p = 0.003) and lower event-free survival (HR 3.0, 95% CI 1.9-4.8, p < 0.001) than age- and sex-matched PV/ET controls. In patients presenting with SVT, molecular high-risk was associated with increased risk of venous re-thrombosis (HR 5.8, 95% CI 1.4-24.0, p = 0.01). Patients developing SVT during follow-up were more frequently allocated in molecular high-risk than those with SVT at diagnosis (52% versus 13%, p < 0.05). In the whole cohort of patients, molecular classification identified PV/ET patients at higher risk of disease progression whereas DNMT3A/TET2/ASXL1 mutations were associated with higher risk of arterial thrombosis. In conclusion, clinical and molecular characteristics are different in PV/ET patients with SVT, depending on whether it occurs at diagnosis or at follow-up. Molecular characterization by NGS is useful for assessing the risk of thrombosis and disease progression in young patients with PV/ET.


Subject(s)
Polycythemia Vera , Thrombocythemia, Essential , Thrombosis , Venous Thrombosis , Humans , Adult , Middle Aged , Polycythemia Vera/complications , Polycythemia Vera/genetics , Polycythemia Vera/diagnosis , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/genetics , Thrombocythemia, Essential/diagnosis , Venous Thrombosis/genetics , Thrombosis/etiology , Thrombosis/genetics , Genomics , Disease Progression , Janus Kinase 2/genetics
8.
Clin Transl Oncol ; 26(4): 872-879, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37672205

ABSTRACT

PURPOSE: Local recurrence of prostate cancer after low-dose rate brachytherapy is a clinical problem with limited salvage treatment options. This prospective study evaluated the tolerability and outcome of salvage external beam radiation therapy (S-EBRT) for locally recurrent prostate cancer after primary low-dose rate prostate brachytherapy (LDR-BT). MATERIALS AND METHODS: Between October 2012 and 2022, 18 patients with biopsy-proven locally recurrent prostate cancer after primary LDR-BT and received S-EBRT. We evaluated biochemical failure (BF), overall survival (OS) and acute/late gastrointestinal and urinary toxicities (CTCAE v5.0 or CTCAE v4, only before 2017). RESULTS: Median follow-up was 32 months (range, 5-124). The median age was at S-EBRT 68 years (range 59-79). 34% (6/18) were low risk, 44% (8/18) intermediate risk, 5% (1/18) high risk, and 17% (3/18) not specified. All patients were treated with IMRT/VMAT and received 60 Gy (2.5 Gy/fraction) to the prostate and 40% (7/18) 55.2 Gy (2,3 Gy/fx) to the seminal vesicles. 56% received ADT The 3-year OS and biochemical relapse-free survival after S-EBRT were 100% and 89%, respectively, with a median PSA nadir 0,035 ng/mL (0,01-0,34). Acute cystitis was present in 72% (13/18) of patients (27% of Grade > 2). Urethritis was present in 78% (14/18) patients (16% of cases Grade > 3), and acute rectitis occurred in 22% (4/18) of patients (no cases Grade > 3). CONCLUSIONS: Our data suggest that the treatment of locally recurrent prostate cancer with S-EBRT could provide adequate disease control safely and be used as an additional treatment in the natural history of prostate cancer patients. However, the results are still early and the sample is small; larger studies with longer follow-up would be mandatory.


Subject(s)
Brachytherapy , Prostatic Neoplasms , Re-Irradiation , Male , Humans , Middle Aged , Aged , Brachytherapy/adverse effects , Brachytherapy/methods , Prospective Studies , Radiotherapy Dosage , Prostate-Specific Antigen , Salvage Therapy/methods , Retrospective Studies
9.
Br J Haematol ; 204(3): 892-897, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38013238

ABSTRACT

Recently modified diagnostic criteria for chronic myelomonocytic leukaemia (CMML) have lowered the cut-off for absolute monocytosis. In the largest series to date, we have analysed 313 CMML patients, including 104 with oligomonocytic (OM)-CMML. Five-year survival was longer for OM-CMML than for other patients (p < 0.001). Multivariate analysis identified OM-CMML as a favourable prognostic factor (HR 0.58; p = 0.002). The 5-year cumulative incidence of progression to classical CMML was 47%. Older age and transfusion dependence were adverse prognostic factors for OM-CMML. Our results support the inclusion of OM-CMML in the CMML category as a subtype with superior outcomes.


Subject(s)
Leukemia, Myelomonocytic, Chronic , Humans , Leukemia, Myelomonocytic, Chronic/diagnosis , Leukocytosis , Prognosis
10.
Leukemia ; 38(3): 557-569, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38017105

ABSTRACT

Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with a heterogeneous clinical behavior. In 5-10% of patients the disease transforms into a diffuse large-B cell lymphoma known as Richter transformation (RT), which is associated with dismal prognosis. Here, we aimed to establish patient-derived xenograft (PDX) models to study the molecular features and evolution of CLL and RT. We generated two PDXs by injecting CLL (PDX12) and RT (PDX19) cells into immunocompromised NSG mice. Both PDXs were morphologically and phenotypically similar to RT. Whole-genome sequencing analysis at different time points of the PDX evolution revealed a genomic landscape similar to RT tumors from both patients and uncovered an unprecedented RT subclonal heterogeneity and clonal evolution during PDX generation. In PDX12, the transformed cells expanded from a very small subclone already present at the CLL stage. Transcriptomic analysis of PDXs showed a high oxidative phosphorylation (OXPHOS) and low B-cell receptor (BCR) signaling similar to the RT in the patients. IACS-010759, an OXPHOS inhibitor, reduced proliferation, and circumvented resistance to venetoclax. In summary, we have generated new RT-PDX models, one of them from CLL cells that mimicked the evolution of CLL to RT uncovering intrinsic features of RT cells of therapeutical value.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Lymphoma, Large B-Cell, Diffuse , Humans , Animals , Mice , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Heterografts , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Clonal Evolution/genetics , Prognosis , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology
12.
Psychol Res Behav Manag ; 16: 4973-4987, 2023.
Article in English | MEDLINE | ID: mdl-38089530

ABSTRACT

Background: Although the use of technology is a trend, since the COVID-19 pandemic, its use has been exacerbated, especially in educational processes, causing techno-stress among teachers. Purpose: In order to contribute to the lack of validated and adapted instruments in Latin America, this study aimed to analyze the psychometric properties and factorial structure of the Spanish version of the technostress scale in a large sample of Ecuadorian teachers. Methods: A non-probabilistic intentional sample of 2850 teachers (mean age 40 years, SD= 9.65; 65% female) from various schools throughout the Ecuadorian territory was surveyed online using a cross-sectional design. Data analysis included exploratory (EFA) and confirmatory factor analysis (CFA), factorial invariance, assessment of internal consistency, sex differences in technostress scale scores and convergent validity. Results: The EFA yielded a structure of four factors: skepticism, fatigue, anxiety and inefficiency. Through CFA, the hierarchical model that included a general factor and four nested factors had a better fit, and that model remained invariant across sex, age and public and private institutions. Total omega value (ω) was 0.962 for the total scale and hierarchical omega values (ωh) were 0.886 for the general factor, as well as 0.30, 0.22, 0.12 and 0.21 for the respective nested factors (skepticism, fatigue, anxiety and inefficiency). Moreover, the Resources, Experiences, Demands for Information and Communication Technologies (RED/TIC) scores were significantly higher among women, although effect sizes of comparison of those sex differences were very small. Finally, the RED/TIC scores correlated with the Depression, Anxiety and Stress Scale (DASS-21). Conclusion: The RED/TIC scale has adequate psychometric properties in primary and high school teachers, and its use in that population is supported, which provides a valuable tool for the evaluation and detection of technostress in teachers and facilitates the investigation of this multifactorial phenomenon in Latin America.

14.
Ann Rheum Dis ; 82(12): 1594-1605, 2023 12.
Article in English | MEDLINE | ID: mdl-37666646

ABSTRACT

BACKGROUND: The vacuoles, E1-enzyme, X linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease (AID) due to postzygotic UBA1 variants. OBJECTIVES: To investigate the presence of VEXAS syndrome among patients with adult-onset undiagnosed AID. Additional studies evaluated the mosaicism distribution and the circulating cytokines. METHODS: Gene analyses were performed by both Sanger and amplicon-based deep sequencing. Patients' data were collected from their medical charts. Cytokines were quantified by Luminex. RESULTS: Genetic analyses of enrolled patients (n=42) identified 30 patients carrying UBA1 pathogenic variants, with frequencies compatible for postzygotic variants. All patients were male individuals who presented with a late-onset disease (mean 67.5 years; median 67.0 years) characterised by cutaneous lesions (90%), fever (66.7%), pulmonary manifestations (66.7%) and arthritis (53.3%). Macrocytic anaemia and increased erythrocyte sedimentation rate and ferritin were the most relevant analytical abnormalities. Glucocorticoids ameliorated the inflammatory manifestations, but most patients became glucocorticoid-dependent. Positive responses were obtained when targeting the haematopoietic component of the disease with either decitabine or allogeneic haematopoietic stem cell transplantation. Additional analyses detected the UBA1 variants in both haematopoietic and non-haematopoietic tissues. Finally, analysis of circulating cytokines did not identify inflammatory mediators of the disease. CONCLUSION: Thirty patients with adult-onset AID were definitively diagnosed with VEXAS syndrome through genetic analyses. Despite minor interindividual differences, their main characteristics were in concordance with previous reports. We detected for the first time the UBA1 mosaicism in non-haematopoietic tissue, which questions the previous concept of myeloid-restricted mosaicism and may have conceptual consequences for the disease mechanisms.


Subject(s)
Arthritis , Mosaicism , Adult , Humans , Male , Female , Cytokines/genetics , Ferritins , Glucocorticoids , Mutation
16.
Cancers (Basel) ; 15(15)2023 Jul 31.
Article in English | MEDLINE | ID: mdl-37568719

ABSTRACT

Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic classification of MF considering whether it is primary or secondary. One-hundred seventy-five patients, 81 with primary MF (PMF) and 94 with secondary MF (SMF) were hierarchically allocated into eight molecular groups. We found that TP53 disruption/aneuploidy (n = 16, 9%) was more frequent (12% versus 6%) and showed higher allele burden (57% versus 15%, p = 0.01) in SMF than in PMF, and was associated with shorter survival (median 3.5 years). Mutations in chromatin/spliceosome genes (n = 72, 41%) represented the most frequent genomic group in PMF. Homozygous JAK2 mutation (n = 40, 23%) was enriched with old patients with SMF after long-standing polycythemia vera, whereas MF with heterozygous JAK2 mutation (n = 22, 13%) was similarly distributed among PMF and SMF. MF with CALR mutation (n = 19, 11%) predominated in post-essential thrombocythemia MF. The remaining genomic groups were infrequent. TP53 disruption, chromatin/spliceosome mutation, and homozygous JAK2 mutation were associated with significantly shorter survival and higher risk of progression. In conclusion, genomic classification reveals different pathogenic pathways between PMF and SMF and provides relevant information regarding disease phenotype and outcomes.

17.
Life Sci Alliance ; 6(11)2023 11.
Article in English | MEDLINE | ID: mdl-37562845

ABSTRACT

Splicing factor 3B subunit 1 (SF3B1) is involved in pre-mRNA branch site recognition and is the target of antitumor-splicing inhibitors. Mutations in SF3B1 are observed in 15% of patients with chronic lymphocytic leukemia (CLL) and are associated with poor prognosis, but their pathogenic mechanisms remain poorly understood. Using deep RNA-sequencing data from 298 CLL tumor samples and isogenic SF3B1 WT and K700E-mutated CLL cell lines, we characterize targets and pre-mRNA sequence features associated with the selection of cryptic 3' splice sites upon SF3B1 mutation, including an event in the MAP3K7 gene relevant for activation of NF-κB signaling. Using the H3B-8800 splicing modulator, we show, for the first time in CLL, cytotoxic effects in vitro in primary CLL samples and in SF3B1-mutated isogenic CLL cell lines, accompanied by major splicing changes and delayed leukemic infiltration in a CLL xenotransplant mouse model. H3B-8800 displayed preferential lethality towards SF3B1-mutated cells and synergism with the BCL2 inhibitor venetoclax, supporting the potential use of SF3B1 inhibitors as a novel therapeutic strategy in CLL.


Subject(s)
Antineoplastic Agents , Leukemia, Lymphocytic, Chronic, B-Cell , Mice , Animals , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , RNA Splicing Factors/genetics , RNA Precursors , Phosphoproteins/genetics , Mutation/genetics , RNA Splice Sites , Transcription Factors/genetics
18.
Blood Adv ; 7(19): 5799-5811, 2023 10 10.
Article in English | MEDLINE | ID: mdl-37450374

ABSTRACT

Germ line predisposition in acute myeloid leukemia (AML) has gained attention in recent years because of a nonnegligible frequency and an impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germ line variants (GVs) in 288 genes related to cancer predisposition in 47 patients with available paired, tumor-normal material, namely bone marrow stroma cells (n = 29), postremission bone marrow (n = 17), and saliva (n = 1). These patients correspond to 2 broad AML categories with heterogeneous genetic background (AML myelodysplasia related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia, or strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, 6 affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41, and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21, and CSF3R). We did not find differences in clinical characteristics nor outcome between carriers of GVs vs noncarriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.


Subject(s)
Hematologic Neoplasms , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Humans , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/genetics , Hematologic Neoplasms/epidemiology , Myelodysplastic Syndromes/genetics , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/epidemiology , Germ-Line Mutation , Genotype , DNA Helicases/genetics
19.
Curr Oncol ; 30(6): 5201-5213, 2023 05 23.
Article in English | MEDLINE | ID: mdl-37366878

ABSTRACT

In recent years, major advances in the understanding of acute myeloid leukemia (AML) pathogenesis, together with technological progress, have led us into a new era in the diagnosis and follow-up of patients with AML. A combination of immunophenotyping, cytogenetic and molecular studies are required for AML diagnosis, including the use of next-generation sequencing (NGS) gene panels to screen all genetic alterations with diagnostic, prognostic and/or therapeutic value. Regarding AML monitoring, multiparametric flow cytometry and quantitative PCR/RT-PCR are currently the most implemented methodologies for measurable residual disease (MRD) evaluation. Given the limitations of these techniques, there is an urgent need to incorporate new tools for MRD monitoring, such as NGS and digital PCR. This review aims to provide an overview of the different technologies used for AML diagnosis and MRD monitoring and to highlight the limitations and challenges of current versus emerging tools.


Subject(s)
Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Neoplasm, Residual/diagnosis , Neoplasm, Residual/genetics , Neoplasm, Residual/therapy , Prognosis , High-Throughput Nucleotide Sequencing/methods , Mutation
20.
Cir. Esp. (Ed. impr.) ; 101(6): 397-407, jun. 2023. tab, graf
Article in English | IBECS | ID: ibc-222015

ABSTRACT

Introduction: It remains unclear whether liver resection is justified in patients with non-colorectal non-neuroendocrine liver metastases (NCNNLM). A single-center study was conducted to analyse overall survival (OS), disease-free survival (DFS), and potential prognostic factors in patients with different types of NCNNLM. Method: A retrospective analysis of all patients who underwent liver resection of NCNNLM from January 2006 to July 2019 was performed. Results: A total of 62 patients were analyzed. 82.3% presented metachronous metastases and 74.2% were unilobar. The most frequent primary tumor site (PTS) were breast (24.2%), urinary tract (19.4%), melanoma (12.9%), and pancreas (9.7%). The most frequent primary tumor pathologies were breast carcinoma (24.2%), non-breast adenocarcinoma (21%), melanoma (12.9%) and sarcoma (12.9%). The most frequent surgical procedure performed was minor hepatectomy (72.6%). R0 resection was achieved in 79.5% of cases. The major complications’ rate was 9.7% with a 90-day mortality rate of 1.6%. The 1, 3 and 5-year OS/DFS rate were 65%/28%, 45%/36% and 46%/28%, respectively. We identified the response to neoadjuvant therapy and PTS as possible prognostic factors for OS (P =0.06) and DFS (P =0.06) respectively. Conclusion: Based on the results of our series, NCNNLM resection produces beneficial outcomes in terms of OS and DFS. PTS and the response to neoadjuvant therapy could be the main prognostic factors after resection. (AU)


Introducción: No está totalmente aclarado si la resección hepática está justificada en pacientes con metástasis hepáticas no colorrectales no neuroendocrinas (MHNCNN). Hemos realizado un estudio en un solo centro para analizar la supervivencia global (SG), la supervivencia libre de enfermedad (SLE) y posibles factores pronósticos en pacientes con diferentes tipos de MHNCNN. Método: Se realizó un análisis retrospectivo de todos los pacientes que se sometieron a resección hepática de MHNCNN desde enero de 2006 hasta julio de 2019. Resultados: Se analizaron un total de 62 pacientes. El 82,3% presentó metástasis metacrónicas y el 74,2% fueron unilobares. El sitio original del tumor primario (STP) más frecuente fue mama (24,2%), tracto urinario (19,4%), melanoma (12,9%) y páncreas (9,7%). Las histopatologías tumorales primarias más frecuentes fueron el carcinoma de mama (24,2%), el adenocarcinoma no mamario (21%), el melanoma (12,9%) y el sarcoma (12,9%). El procedimiento quirúrgico realizado con mayor frecuencia fue la hepatectomía menor (72,6%). La resección R0 se logró en el 79,5% de los casos. La tasa de complicaciones mayores fue del 9,7% con una tasa de mortalidad a los 90 días del 1,6%. La tasa de SG / SLE a 1, 3 y 5 años fue de 65% / 28%, 45% / 36% y 46% / 28%, respectivamente. Identificamos la respuesta a la terapia neoadyuvante y el STP como posibles factores pronósticos de SG (p = 0,06) y SLE (p = 0,06) respectivamente. Conclusión: Según los resultados de nuestra serie, la resección de MHNCNN produce resultados beneficiosos en términos de SG y SLE. El STP y la respuesta a la terapia neoadyuvante podrían ser los principales factores pronósticos tras la resección. (AU)


Subject(s)
Humans , Male , Female , Middle Aged , Liver Neoplasms , Neoplasm Metastasis , Retrospective Studies , Hepatectomy , Melanoma
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