Predictive role of ITPA genetic variants in thiopurine-related myelotoxicity in Crohn's disease patients.

Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.

Determinants associated with activation in patients with oral anticoagulant treatment: A cross-sectional study.

AIMS: The terms "patient activation" and "patient empowerment" are used to describe the extent to which individuals are able to manage their own healthcare. Health outcomes and quality of life improve in patients who are more active in health care. The aim of this study was to identify sociodemographic, clinical, sociological and psychological determinants associated with activation in a group of chronically anticoagulated patients. METHODS: Cross-sectional study of patients treated with oral antivitamin-k drugs attended at a specialized outpatient anticoagulant unit between November 2021 and June 2022. The main dependent variable was the level of patient activation according to the 13-item Patient Activation Measure (PAM-13). Simple and multiple linear regression models were conducted to identify the determinants associated with PAM-13 score. RESULTS: A total of 137 patients who met all the inclusion criteria were recruited for the study. The mean age was 59.6 years (SD 13.8; range 22-86) and 60.6% were male. Sixty per cent presented a level IV of activation according to the PAM-13 scale. Mean patient activation score was 73.9 (SD 15.4). The factors independently associated with significantly lower activation were: emergency department visits in the past 12 months, intermediate social risk, anxiety symptoms, stress symptoms and low self-efficacy. CONCLUSIONS: Five determinants were found to be associated with activation. Knowing the factors that modify the level of activation can help to identify subgroups of chronic anticoagulated patients who are less likely to engage in self-management and are therefore candidates for tailored educational interventions.

Survival Outcomes and Health-Related Quality of Life in Older Adults Diagnosed with Acute Myeloid Leukemia Receiving Frontline Therapy in Daily Practice.

Acute myeloid leukemia has a poor prognosis in older adults, and its management is often unclear due to its underrepresentation in clinical trials. Both overall survival (OS) and health-related quality-of-life (HRQoL) are key outcomes in this population, and patient-reported outcomes may contribute to patient stratification and treatment assignment. This prospective study included 138 consecutive patients treated in daily practice with the currently available non-targeted therapies (intensive chemotherapy [IC], attenuated chemotherapy [AC], hypomethylating agents [HMA], or palliative care [PC]). We evaluated patients' condition at diagnosis (Life expectancy [Lee Index for Older Adults], Geriatric Assessment in Hematology [GAH scale], HRQoL [EQ-5D-5L questionnaire], and fatigue [fatigue items of the QLQ-C30 scale]), OS, early death (ED), treatment tolerability (TT) and change in HRQoL over 12 months follow-up. The median OS was 7.1 months (IC not reached, AC 5.9, HMA 8.8, and PC 1.0). Poor risk AML category and receiving just palliative care, as well as a higher Lee index score in the patients receiving active therapy, independently predicted a shorter OS. The Lee Index and GAH scale were not useful for predicting TT. The white blood cell count was a valid predictor for ED. Patients' HRQoL remained stable during follow-up.

Lupus anticoagulant is an independent risk factor for non-thrombotic in-hospital mortality in COVID-19 patients.

BACKGROUND: Thromboembolic disease is a frequent cause of death during SARS CoV-2 infection. Lupus anticoagulant (LA) appears frequently during the acute phase of infection. It is not clear whether it is merely an epiphenomenon or whether it is related to the patients' outcome. METHODS: Prospective observational cohort of 211 patients (118 women, mean age 65 years, range: 18 to 99) hospitalized for COVID-19. All patients were tested for LA at admission and retested six months after discharge. RESULTS: The LA test was positive in 128 patients (60.7%). The survival probability at 31 days was clearly worse in the LA-positive group (60%) than in the LA-negative group (90%) (P = 0.023). This notable difference in survival was confirmed by multivariate analysis (HR 3.9, 95% CI 1.04-14.5, P = 0.04). However, it was not explained by differences in thrombotic events (three in either group, P = 0.6). LA-positive patients had higher ferritin, CRP and IL-6 levels, and lower PAFI ratio and lymphocyte and platelet counts. Six months after discharge, LA was negative in the vast majority of positive cases (94%). CONCLUSION: LA is an independent predictor of in-hospital mortality in COVID-19 patients. It is associated with inflammation and disease severity but not with thromboembolic events. This marker usually disappears at six months.

Prognostic effect of VEGF gene variants in metastatic non-small-cell lung cancer patients.

INTRODUCTION: Clinical and pathological characteristics are still considered prognostic markers in metastatic non-small-cell lung cancer (NSCLC) patients but they cannot explain all interindividual variability. Tumoral angiogenesis mediated by the vascular endothelial growth factor (VEGF) is critical for the progression and metastasis of the disease. We aimed to investigate the prognostic role of genetic variants within the VEGF pathway in patients with metastatic NSCLC. MATERIALS AND METHODS: We prospectively included 170 patients with metastatic NSCLC treated with first-line platinum-based chemotherapy. A comprehensive panel of single-nucleotide polymorphisms (SNPs) in genes belonging to the VEGF pathway (VEGFA, VEGFR1/FLT1, VEGFR2/KDR, GRB2, ITGAV, KISS1, KRAS, PRKCE, HIF1α, MAP2K4, MAP2K6, and MAPK11) were genotyped in blood DNA samples. SNPs were evaluated for association with overall survival (OS) and progression-free survival (PFS). RESULTS: In multivariate analyses adjusted for patient characteristics, we found that VEGFA rs2010963 and VEGFR2 rs2071559 were significantly associated with OS [Hazard Ratio (HR) 0.7 (0.5-0.9); p = 0.026 and HR 1.5 (1.1-2.3); p = 0.025, respectively]. Additionally, ITGAV rs35251833 and MAPK11 rs2076139 were significantly associated with PFS [HR 2.5 (1.4-4.3; p = 0.002 and HR 0.6 (0.5-0.9); p = 0.013, respectively]. CONCLUSION: Our findings reinforce the potential clinical value of germline variants in VEGFA and VEGFR2 and show for the first time variants in ITGAV and MAPK11 as promising prognostic markers in metastatic NSCLC patients receiving platinum-based chemotherapy.

Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype.

Although guidelines are available for hereditary hemochromatosis, a high percentage of the recommendations within them are not shared between the different guidelines. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. This final version was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles.

Long-term safety and outcome of fludarabine, cyclophosphamide and mitoxantrone (FCM) regimen in previously untreated patients with advanced follicular lymphoma: 12 years follow-up of a phase 2 trial.

Fludarabine combinations are very affective in follicular lymphoma (FL) with high rates of complete response and prolonged survival. However, late toxicities could be a concern. The aim of the present study was to analyze the long-term impact on survival, relapse and late toxicities of a trial of treatment with fludarabine, mitoxantrone and cyclophosphamide (FCM regimen) for untreated patients with advanced stage FL. One hundred and twenty patients enrolled in a phase 2 trial of treatment with FCM regimen between 2000 and 2003 were evaluated. After a median follow-up of 12 years, 52 patients eventually relapsed/progressed with 10 year progression-free survival (PFS) of 46 %. Ten patients showed histological transformation to aggressive lymphoma with a risk of transformation of 2 and 9 % at 5 and 10 years, respectively. Three patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and seven solid neoplasms with an overall risk of 3 and 8 % at 5 and 10 years, respectively. Twenty-six patients eventually died during the follow-up. Overall survival at 10 years was 83 %. In conclusion, FCM regimen allows excellent long-lasting response in previously untreated patients with FL. The incidence of late events including histological transformation and secondary neoplasia is low but not negligible.

Hemocromatosis hereditaria. Problemas en el diagnóstico y tratamiento / Hereditary hemochromatosis. Problems in diagnosis and treatment

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Polymorphisms in genes involved in the mechanism of action of methotrexate: are they associated with outcome in rheumatoid arthritis patients?

BACKGROUND: Methotrexate (MTX) is the first-line treatment option for newly diagnosed rheumatoid arthritis (RA) patients. However, 50-70% of the patients respond to treatment and 30% suffer toxicity. AIM: To identify pharmacogenetic markers of outcome in RA patients treated with MTX. PATIENTS & METHODS: We analyzed 27 genetic variants in DHFR, TYMS, MTHFR, ATIC and CCND1 genes. RESULTS: We included 124 RA patients treated with MTX monotherapy. In multivariate analyses two variants in the MTHFR gene were associated with response, rs17421511 (p = 0.024) and rs1476413 (p = 0.0086), as well as one in the DHFR gene, rs1643650 (p = 0.026). The ATIC rs16853826 variant was associated with toxicity (p = 0.039). CONCLUSION: MTHFR, DHFR and ATIC genetic variants can be considered as pharmacogenetic markers of outcome in RA patients under MTX monotherapy.

Sistemática diagnóstica en la hiperferritinemia / Systematic approach to the diagnosis of hyperferritinemia

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Alternativas al tratamiento habitual de la hemocromatosis hereditaria / Alternatives to the current treatment of hereditary hemochromatosis

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Pharmacogenetic analysis in the treatment of Hodgkin lymphoma.

About 15-20% of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy ± radiotherapy still die following relapse or progressive disease. The outcome might be influenced by gene polymorphisms influencing chemotherapy metabolism. We studied 126 patients with HL treated with the ABVD regimen. We analyzed glutathione S-transferases (GSTT1, GSTM1 and GSTP1), cytochromes P450 (CYP3A4 and CYP2D6), UGT1A1 and BLMH gene polymorphisms and their association with clinical and outcome variables. Patients with a GSTM1 genotype associated with extensive or ultrahigh activity had a probability of 93.8% to achieve a complete response, while the remainder of the patients had a probability of 82.3% (p = 0.04). This variable maintained its statistical significance in multivariate analysis (hazard ratio 3.7, 95% confidence interval 1-13, p = 0.05). Patients with an extensive or ultrahigh GSTM1 genotype had better prognostic factors than those with poor or intermediate genotypes (hemoglobin level, p = 0.003; serum albumin, p = 0.05; and International Prognostic Score, p = 0.038). Thus, in the treatment of HL, clinical determinants might be more relevant than the pharmacogenetic parameters analyzed to date.

Síndrome mielodisplásico en el paciente mayor: valoración geriátrica integral y recomendaciones terapéuticas / Myelodysplastic syndrome in the elderly: comprehensive geriatric assessment and therapeutic recommendations

La edad de presentación de los síndromes mielodisplásicos (SMD) suele ser alrededor de los 70 años. A pesar de esto, la mayor parte de los ensayos clínicos se restringen a sujetos más jóvenes, con lo cual el tratamiento de los pacientes mayores con SMD no siempre es el mejor. El paciente mayor presenta características fisiológicas que lo diferencian del adulto, y esto condiciona el tratamiento farmacológico. En este sentido, la valoración geriátrica integral (VGI) cobra especial importancia. Este artículo recoge las conclusiones de la I Reunión de Especialistas de la Sociedad Española de Medicina Geriátrica y de la Sociedad Española de Hematología y Hemoterapia, y propone la implantación de instrumentos de la VGI que ayuden en el proceso de toma de decisiones del paciente mayor con SMD. Los resultados se centrarán en el diagnóstico, pronóstico, tratamiento y manejo de los efectos adversos en este grupo de pacientes (AU)

The onset of myelodysplastic syndromes (MDS) is usually around the age of 70. Despite this, most clinical trials are restricted to younger subjects. Thus, the management of elderly patients with MDS is not always optimal. Physiologically, elderly patients show characteristics that differ from those of younger patients and that condition their pharmacological treatment. In this regard, the comprehensive geriatric assessment (CGA) becomes particularly important. This document gathers conclusions from the 1st Meeting of Members of the Sociedad Española de Medicina Geriátrica and the Sociedad Española de Hematología y Hemoterapia, with the objective of proposing the establishment of CGA instruments to assist in the decision-making process of elderly patients with MDS. The results of this consensus document will focus on the diagnosis, prognosis, treatment and management of adverse events in this age group (AU)

[Myelodysplastic syndrome in the elderly: comprehensive geriatric assessment and therapeutic recommendations]. / Síndrome mielodisplásico en el paciente mayor: valoración geriátrica integral y recomendaciones terapéuticas.

The onset of myelodysplastic syndromes (MDS) is usually around the age of 70. Despite this, most clinical trials are restricted to younger subjects. Thus, the management of elderly patients with MDS is not always optimal. Physiologically, elderly patients show characteristics that differ from those of younger patients and that condition their pharmacological treatment. In this regard, the comprehensive geriatric assessment (CGA) becomes particularly important. This document gathers conclusions from the 1(st) Meeting of Members of the Sociedad Española de Medicina Geriátrica and the Sociedad Española de Hematología y Hemoterapia, with the objective of proposing the establishment of CGA instruments to assist in the decision-making process of elderly patients with MDS. The results of this consensus document will focus on the diagnosis, prognosis, treatment and management of adverse events in this age group.