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PURPOSE: How to measure brain globotriaosylceramide (Gb3) accumulation in Fabry Disease (FD) patients in-vivo is still an open challenge. The objective of this study is to provide a quantitative, non-invasive demonstration of this phenomenon using quantitative MRI (qMRI). METHODS: In this retrospective, monocentric cross-sectional study conducted from November 2015 to July 2018, FD patients and healthy controls (HC) underwent an MRI scan with a relaxometry protocol to compute longitudinal relaxation rate (R1) maps to evaluate gray (GM) and white matter (WM) lipid accumulation. In a subgroup of 22 FD patients, clinical (FAbry STabilization indEX -FASTEX- score) and biochemical (residual α-galactosidase activity) variables were correlated with MRI data. Quantitative maps were analyzed at both global ("bulk" analysis) and regional ("voxel-wise" analysis) levels. RESULTS: Data were obtained from 42 FD patients (mean age = 42.4 ± 12.9, M/F = 16/26) and 49 HC (mean age = 42.3 ± 16.3, M/F = 28/21). Compared to HC, FD patients showed a widespread increase in R1 values encompassing both GM (pFWE = 0.02) and WM (pFWE = 0.02) structures. While no correlations were found between increased R1 values and FASTEX score, a significant negative correlation emerged between residual enzymatic activity levels and R1 values in GM (r = -0.57, p = 0.008) and WM (r = -0.49, p = 0.03). CONCLUSIONS: We demonstrated the feasibility and clinical relevance of non-invasively assessing cerebral Gb3 accumulation in FD using MRI. R1 mapping might be used as an in-vivo quantitative neuroimaging biomarker in FD patients.
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Enfermedad de Fabry , Imagen por Resonancia Magnética , Trihexosilceramidas , Humanos , Enfermedad de Fabry/diagnóstico por imagen , Enfermedad de Fabry/metabolismo , Masculino , Femenino , Adulto , Imagen por Resonancia Magnética/métodos , Trihexosilceramidas/metabolismo , Estudios Transversales , Estudios Retrospectivos , Estudios de Casos y Controles , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Persona de Mediana Edad , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismoRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD) is the most common heritable multifocal cystic disease encountered in clinical practice, and it is usually diagnosed in patients with family history by the evidence of markedly enlarged kidneys with multiple bilateral cysts at ultrasound (U.S.), computed tomography (CT) scan, or magnetic resonance imaging (MRI). In most cases, genetic testing is not required. Though ADPKD diagnosis is often straightforward, misdiagnosis is possible. Here we present a case of ADPKD misdiagnosis, followed by a review of the most important kidney heritable multifocal cystic diseases. Our case report demonstrates that ADPKD can be erroneously diagnosed when other kidney heritable multifocal cystic diseases occur without their distinguishing manifestations and when there is no genetic characterization among the relatives. A proper diagnosis of heritable diseases is crucial, as it allows an appropriate management of family members who carry disease allele, apart from patient management. Therefore, we suggest a careful differential diagnosis with possible molecular genetic analysis in presentations with familial cystic kidneys and suspicious clinical and radiological features.
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Riñón Poliquístico Autosómico Dominante , Humanos , Riñón Poliquístico Autosómico Dominante/diagnóstico , Ultrasonografía , Tomografía Computarizada por Rayos X , Imagen por Resonancia Magnética , Diagnóstico DiferencialRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder with an estimated prevalence between 1 : 1,000 and 1 : 2,500. Until a few decades ago, ADPKD was considered an untreatable disease, relentlessly progressing towards end-stage renal disease because of the lack of specific interventions. In the last decade, some aberrant molecular pathways involved in ADPKD development have been identified, and controlled clinical trials have been conducted to investigate the potential role of active drugs on these pathophysiological mechanisms such somatostatin and tolvaptan. Somatostatin analogues have been shown to be effective not only in ADPKD, but also in polycystic liver disease (PLD) with beneficial effect on cardiac function and a better cost/benefit profile; the only somatostatin analogue currently available for clinical use is octreotide long-acting release (octreotide-LAR), and it is approved only in Italy. On the contrary, tolvaptan is authorized worldwide and has received more attention in the last years, even if its clinical use is widely limited by aquaresis tolerability. The aim of this review is to investigate the advantages and drawbacks of somatostatin analogues and tolvaptan in the treatment of ADPKD.
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Riñón Poliquístico Autosómico Dominante , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Tasa de Filtración Glomerular , Humanos , Octreótido/uso terapéutico , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Somatostatina/uso terapéutico , Tolvaptán/uso terapéuticoRESUMEN
Prolonged therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective in newly diagnosed acute promyelocytic leukemia (APL) but there is limited data on the efficacy of this regimen in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO therapy at the time of disease relapse. Twenty patients obtained molecular complete remission (CRm) after 2 cycles (90%). Of these, two patients underwent hematopoietic stem cell transplant (HSCT) while the remaining proceeded to receive additional cycles (up to a total of 5) of ATRA-ATO. With a median follow-up of 58 months from the time of relapse (range: 21-128 months), the 4-year OS probability was 0.85 (95% CI 0.61-0.94), DFS was 0.74 (95% CI 0.49-0.88), and EFS 0.68 (95% CI 0.45-0.83). Two patients were resistant to ATRA-ATO salvage and five relapsed at a median of 19 months. Of these, four died due to progressive disease while three relapsed achieved a new CRm after further salvage therapy. This experience confirms the potentially curative effect of prolonged ATRA-ATO therapy in relapsed APL, especially in patients with long first complete remission.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trióxido de Arsénico , Arsenicales/administración & dosificación , Terapia Combinada , Supervivencia sin Enfermedad , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Estimación de Kaplan-Meier , Leucemia Promielocítica Aguda/terapia , Masculino , Persona de Mediana Edad , Óxidos/administración & dosificación , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Terapia Recuperativa , Resultado del Tratamiento , Tretinoina/administración & dosificación , Adulto JovenRESUMEN
INTRODUCTION: Hyperkalemia, one of the most important electrolyte abnormalities of chronic kidney disease (CKD), often limits the use of renin-angiotensin-aldosterone system inhibitors and can increase in the postprandial period. In this study we report a real-world experience with the new non-adsorbed potassium binder patiromer in stage 3b-4 CKD patients. Moreover, we performed a cross-sectional analysis to evaluate, for the first time, the efficacy of patiromer in the control of postprandial potassium concentrations. METHODS: We retrospectively collected data of 40 patients at the time of patiromer initiation (T0), and after 2 (T2), 6 (T6) and 12 (T12) months of treatment. For cross sectional analysis, a blood sample was collected 2 h after the main meal for the evaluation of postprandial potassium concentrations. RESULTS: Eighty-two point five percent of patients (33/40) reached normal potassium concentrations at T2. Serum potassium significantly decreased at T2 compared to T0 (5.13 ± 0.48 vs 5.77 ± 0.41 mmol/L, respectively; p < 0.001) and the reduction remained significant during the follow-up (5.06 ± 0.36 at T6 and 5.77 ± 0.41 at T12; p < 0.001 vs T0). Renin-angiotensin-aldosterone system inhibitors were continued by 93% of patients (27/29). Adverse events were reported in 27.5% of patients and were all mild-to-moderate. Postprandial potassium concentrations did not significantly change compared to fasting state potassium measured at T12 (4.53 ± 0.33 vs 5.06 ± 0.36 mmol/L; p = 0.15). CONCLUSIONS: In a real-world setting of advanced CKD patients, patiromer is a useful treatment for hyperkalemia, since it significantly reduces serum potassium levels over the long term and is able to maintain potassium concentrations in the normal range even in the post-prandial period.
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Hiperpotasemia , Polímeros , Periodo Posprandial , Potasio , Insuficiencia Renal Crónica , Humanos , Hiperpotasemia/sangre , Hiperpotasemia/tratamiento farmacológico , Hiperpotasemia/etiología , Estudios Retrospectivos , Masculino , Femenino , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/sangre , Anciano , Potasio/sangre , Persona de Mediana Edad , Estudios Transversales , Polímeros/uso terapéutico , Resultado del Tratamiento , Factores de Tiempo , Anciano de 80 o más AñosRESUMEN
Hyperprolinemia is a rare genetic condition due to mutations in proline metabolic pathway. Type I Hyperprolinemia (HPI) typically causes neuropsychiatric disorders, and diagnosis is usually confirmed in pediatric population with suggestive neuropsychiatric involvement by elevated serum proline levels and elevated urinary proline, hydroxyproline, and glycine levels. The possible coexistence of nephropathy in patients with HPI, often specified as malformative urinary disease, is often mentioned. However, reports of HPI diagnosis due to kidney impairment do not exist in scientific literature yet. Here we present the case of a patient presenting with chronic kidney disease secondary to obstructive nephropathy who received a HPI diagnosis in adulthood. Interestingly, the family study showed the same 22q11.21 deletion and elevated blood proline levels in the father, who had no clinical anomalies. We therefore suggest, in light of the high frequency of mutations involving 22q11 and PRODH in the general population, to consider these rare alterations in patients with congenital urinary malformations, even in the presence of nuanced neurological symptoms and negative family history.
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Acidosis , Errores Innatos del Metabolismo de los Aminoácidos , Humanos , Niño , Prolina Oxidasa/genética , Mutación , Prolina/genética , Prolina/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/genética , Riñón/metabolismoRESUMEN
High-dose (200 mg/m(2), MEL200) and intermediate-dose melphalan (100 mg/m(2), MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.
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Melfalán/administración & dosificación , Mieloma Múltiple/terapia , Adulto , Anciano , Algoritmos , Antígenos CD34/metabolismo , Antineoplásicos Alquilantes/administración & dosificación , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/métodos , Terapia Combinada , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Agonistas Mieloablativos/administración & dosificación , Terapia Neoadyuvante , Acondicionamiento Pretrasplante/métodos , Trasplante AutólogoRESUMEN
In order to fight the SARS-CoV-2 pandemic, mass-vaccination programs have been launched globally starting December 2020. The pace of COVID-19 vaccines development was impressive and although data from clinical trials and post-authorization studies showed acceptable safety profile, additional studies and long-term population-level surveillance are needed. A possible link between all type of vaccination and immunological diseases is perhaps one of the hottest topics in literature; correspondingly, there is growing concern over the small but growing number of case reports linking COVID-19 vaccines with the development of glomerular disease. Our group conducted a systematic review of such cases. Results showed that IgA nephropathy (IgAN) and Minimal Change Disease (MCD) are the most frequently associated glomerulopathies. Interestingly, IgAN cases are mostly flares occurring few hours after the second dose of RNA vaccines and have a good clinical outcome, while both de novo and recurring MCD can occur up to 28 days after the first or second dose of vaccines. RNA vaccines are the most common vaccine type to be associated with glomerulopathy. Of course, this may simply reflect the more widespread use of these vaccines. However, compared to traditional vaccines, they do seem produce a higher antibody response and a stronger CD8+ T- and CD4+ T-cell response, including higher production of chemokines and cytokines.
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COVID-19 , Glomerulonefritis por IGA , Nefrosis Lipoidea , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Femenino , Humanos , Masculino , Nefrólogos , SARS-CoV-2 , VacunaciónRESUMEN
Hyperkalemia is common in patients treated with renin-angiotensin-aldosterone system inhibitors (RAASis), and it represents the main cause of the large gap reported between guideline recommendations and real-world practice in chronic kidney disease (CKD). We conducted a CKD-population-based restrospective study to determine the prevalence of patients with CKD treated with RAASis, incidence of hyperkalemia in patients with CKD treated with RAASis, and proportion of patients with RAASi medication change after experiencing incident hyperkalemia. Among 809 patients with CKD analyzed, 556 (68.7%) were treated with RAASis, and RAASi prescription was greater in stages 2-4 of CKD. Hyperkalemia occurred in 9.2% of RAASi-treated patients, and the adjusted rate of hyperkalemia among patients with stage 4-5 CKD was 3-fold higher compared with patients with eGFR > 60 ml/min/1.73 m2. RAASi treatment was discontinued in 55.3% of the patients after hyperkalemia event (74.2% discontinued therapy, 3.2% received a reduced dose, and 22.6% reduced the number of RAASi drugs). This study shows that the incidence of hyperkalemia is frequently observed in patients with CKD patients with RAASis, and that rates increase with deteriorating levels of kidney function from stages 1 to 3. RAASi medication change following an episode of hyperkalemia occurred in almost half of the patients after experiencing hyperkalemia.
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Background: Gastric Diffuse large B-cell lymphoma (DLBCL) is the most common extranodal site of lymphoma's involvement (30%-40% of all extranodal lymphomas and 55%-65% of all gastrointestinal lymphomas). However, gastric localizations are also sometimes found in systemic DLBCL. Gastric complications such as bleeding, perforation, and stenosis under chemotherapy are well documented. Methods: We retrospectively analyzed 15 patients with newly diagnosed DLBCL with gastrointestinal involvement. Endoscopies were performed in these patients before and after treatment. Treatment consisted of cyclophosphamide low-dose pre-phase chemotherapy before conventional-dose chemotherapy. Results: Endoscopy at staging detected ulcers in 12 patients (80%). After low-dose pre-phase chemotherapy, GI ulcers healed in 91.6% of cases (1 ulcer detected). After the whole treatment (Low-dose pre-phase + chemotherapy) 9 patients (60%) achieved complete response, 4 patients (26.6%) partial response, 2 (13,3%) patients presented disease progression. The most frequent adverse event was neutropenia (73.3%); the most frequent non-hematological adverse event was transaminases elevation (20%). Conclusion: Cyclophosphamide low-dose pre-phase chemotherapy resulted in a safe and effective way to prevent adverse events in systemic DLBCL with gastrointestinal involvement.
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Primary cutaneous CD30+ lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis. The prognosis of the disease is usually excellent but, in a minority of cases, it presents with extracutaneous involvement and aggressive behavior. The case we present-relapsed after surgical excision, immunosuppressive therapy, and conventional chemotherapy-is the first one treated with Autologous Stem Cell transplant followed by Brentuximab Vedotin consolidation, a scheme already used for high risk Hodgkin Lymphoma.
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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m6A methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML.
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Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Metiltransferasas/metabolismo , Biosíntesis de Proteínas , Adenosina/análogos & derivados , Adenosina/metabolismo , Catálisis , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular , Supervivencia Celular , Resistencia a Antineoplásicos/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Modelos Biológicos , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: The use of dasatinib and nilotinib in the treatment of patients with chronic myeloid leukemia represents a valid therapeutic option for patients resistant or intolerant to imatinib. In this multicentre study, adherence, persistence and efficacy in real life over two years of treatment were evaluated. MATERIALS AND METHODS: Adherence to treatment was calculated as the ratio between the dose received and the prescribed dose. The dose received was calculated using pharmacy refill data. The persistence with treatment was calculated as the difference between the end and the beginning of the treatment. Efficacy was assigned as Progression-Free Survival (PFS) and Events-Free Survival (EFS) and represented through the Kaplan-Meier curve. RESULTS: The number of patients analysed was 117, 70 treated with dasatinib and 47 with nilotinib. Adherence to treatment for dasatinib and nilotinib at two years was 0.91 and 0.82 respectively. Persistence at two years was 77% while the PFS was 92% for both drugs in the study. CONCLUSION: Adherence to the treatment calculated over two years showed a superiority of dasatinib over nilotinib. Nevertheless, the efficacy in terms of PFS and EFS is superimposable between the two drugs in the study.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Humanos , Mesilato de Imatinib/uso terapéutico , Italia , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas , Tiazoles/uso terapéutico , Resultado del TratamientoRESUMEN
In our opinion, the use of heparin could play a crucial role in these patients. In fact, recent studies have shown that heparin, the most commonly used anticoagulant during HD procedures, had anti-inflammatory properties and a direct antiviral action, due to its ability to prevent SARS-CoV-2 pseudovirus entry into host cells. These activities, together with its anticoagulant action, could explain the ability of heparin to ameliorate COVID-19 clinical course.
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Anticoagulantes/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Heparina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Diálisis Renal , Anticoagulantes/farmacología , COVID-19 , Heparina/farmacología , Humanos , PandemiasRESUMEN
BACKGROUND: Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis. METHODS: Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-ß, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients' characteristics and with a group of non-MM patients as controls. RESULTS: No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response. CONCLUSION: FGF-2, HGF, VEGF, and PDGF-ß plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy. TRIAL REGISTRATION: Clinical trial information can be found at the following link: NCT01063179.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Becaplermina/sangre , Factor 2 de Crecimiento de Fibroblastos/sangre , Factor de Crecimiento de Hepatocito/sangre , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Médula Ósea , Femenino , Estudios de Seguimiento , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Curva ROCRESUMEN
We report on a case of Sweet's syndrome associated with multiple myeloma, as harbinger for disease relapse.
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The World Health Organization classifies atypical chronic myeloid leukemia (aCML) as a myeloproliferative/myelodisplastic hematological disorder. The primary manifestations are leukocytosis with disgranulopoiesis, absence of basophilia and/or monocytosis, splenomegaly and absence of Philadelphia chromosome or BCR/ABL fusion. Overall 50-65% of patients demonstrate karyotypic abnormalities, although no specific cytogenetic alterations have been associated with this disease. X chromosome alterations have been rarely reported in myeloid malignancies. Although Isodicentric X, idic(X)(q13) is well known in females with myelodysplastic syndromes (MDS), little data are available on X isochromosome and its pathogenetic potential in these disorders. i(X)(p10) is observed in a variety of hematologic malignancies, both myeloid and lymphoid, as a unique abnormality, as well as part of a more complex karyotype, in females and less frequently in male patients. The present report describes the first patient with aCML, with documented isolated i(X)(p10), who developed a secondary acute myeloid leukemia (sAML).