Ocena minimalnej choroby resztkowej w szpiczaku plazmocytowym

Minimal residual disease (MRD) in a patient with multiple myeloma (MM) is defined as the mini-mum levels of pathological plasma cells remaining after treatment when a patient is in complete response (CR). The ultimate aim of studying MRD is to identify patients with different prognosis and to tailor treatment for individual patients. MRD studies in MM should be recommended in young patients in CR after autologous hematopoietic stem cells transplantation and in older patients in CR after regimens including proteasome inhibitors. Bone marrow is the only recommend location to assess MRD in MM. The recommended methods of MRD testing include next generation sequencing of immunoglobulin genes or multiparametric flow cytometry (MFC), depending on the experience of each center and the possibility of study samples being available in the first 24 hours for MFC analysis. MRD should be considered as a therapeutic objective. However, there is not enough evidence for taking clinical decisions based on MRD status alone, and for this reason we encourage the design of new clinical studies to address these questions.Minimalną chorobę resztkową (MRD) u pacjenta z rozpoznaniem szpiczaka plazmocytowego defi-niuje się jako populację nowotworowych komórek plazmatycznych, która pozostała w organizmie chorego po osiągnięciu odpowiedzi całkowitej (CR). Ostatecznym celem badań MRD jest dążenie do identyfikacji chorych o odmiennym rokowaniu i indywidualizacji leczenia na tej podstawie. Ocenę MRD u chorych na szpiczaka plazmocytowego zaleca się u młodszych pacjentów, którzy osiągną CR po przeszczepieniu autologicznych krwiotwórczych komórek macierzystych oraz u chorych starszych osiągających CR po chemioterapii opartej na inhibitorach proteasomu. Powinno się oznaczać MRD wyłącznie w szpiku kostnym. Do rekomendowanych metod oceny MRD w szpiczaku plazmocytowym zalicza się sekwencjonowanie następnej generacji genów immunoglobulinowych oraz wieloparametryczną cytometrię przepływową, przy czym wybór jednej z tych metod powinien zależeć od doświadczenia danego ośrodka oraz możliwości wykonania badania cytometrycznego w czasie 24 godzin od pobrania próbki szpiku. Eradykację MRD powinna się obecnie uważać za istotny cel terapii szpiczaka plazmocytowego. Jednak, ze względu na brak wystarczających danych do podejmowania decyzji klinicznych wyłącznie na podstawie wyniku badania MRD, istnieje po¬trzeba dalszych, dobrze zaprojektowanych badań klinicznych w tym zakresie

Association of the MYH9 gene polymorphisms with chronic renal disease secondary to hypertensive nephrosclerosis, in a Caucasian population

Background: Hypertensive nephrosclerosis (HN) is a chronic kidney disease (CKD) associated to essential hypertension, but their causal relationship is controversial. New evidence suggests that MYH9 gene alterations are associated with HN in African Americans. The aim of this study is to investigate the role of this gene in Spanish Caucasians. Methods: We compare high-risk MYH9 variants of patients with HN recruited according to standard clinical criteria (CKD stages 3-5), with essential hypertensives without renal disease (estimated glomerular filtration rate (eGFR) > 60 ml/min/1,73m2 and albuminuria < 300 mg/g creatinine), and also CKD patients with HN and progressive impairment of renal function with those who were stable. Diabetics were excluded. Results: A blood sample was obtained for genetic study of 238 patients with HN-CKD and 233 hypertensive controls. The rs3752462-T and rs4821480-T (risk alleles for CKD) were more frequent in the CKD group, but without significant difference. We found no differences for these SPNs with blood pressure, creatinine, albuminuria or renal disease progression. Conclusions: The effect of two common MYH9 single nucleotide polymorphisms (SPNs) on the development of CKD secondary to HN in our Spanish Caucasian population is low or zero; in any case less than that found in other, mainly African Americans.Funding: This work was supported by grant Red de Investigación Renal-REDINREN from the Instituto Carlos III, and with funds from the Fundación Renal Iñigo Álvarez de Toledo (Iñigo Álvarez de Toledo Kidney Foundation) in the Molecular Genetics Grou

A novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia

A high proportion of patients with acute myeloid leukemia who achieve minimal residual disease negative status ultimately relapse because a fraction of pathological clones remains undetected by standard methods. We designed and validated a high-throughput sequencing method for minimal residual disease assessment of cell clonotypes with mutations of NPM1, IDH1/2 and/or FLT3-single nucleotide variants. For clinical validation, 106 follow-up samples from 63 patients in complete remission were studied by sequencing, evaluating the level of mutations detected at diagnosis. The predictive value of minimal residual disease status by sequencing, multiparameter flow cytometry, or quantitative polymerase chain reaction analysis was determined by survival analysis. The sequencing method achieved a sensitivity of 10-4 for single nucleotide variants and 10-5 for insertions/deletions and could be used in acute myeloid leukemia patients who carry any mutation (86% in our diagnostic data set). Sequencing-determined minimal residual disease positive status was associated with lower disease-free survival (hazard ratio 3.4, P=0.005) and lower overall survival (hazard ratio 4.2, P<0.001). Multivariate analysis showed that minimal residual disease positive status determined by sequencing was an independent factor associated with risk of death (hazard ratio 4.54, P=0.005) and the only independent factor conferring risk of relapse (hazard ratio 3.76, P=0.012). This sequencing-based method simplifies and standardizes minimal residual disease evaluation, with high applicability in acute myeloid leukemia. It is also an improvement upon flow cytometry- and quantitative polymerase chain reaction-based prediction of outcomes of patients with acute myeloid leukemia and could be incorporated in clinical settings and clinical trials.This study was supported by the Subdirección General de Investigación Sanitaria (Instituto de Salud Carlos III, Spain) grants PI13/02387 and PI16/01530, and the CRIS against Cancer foundation grant 2014/0120. ML holds a postdoctoral fellowship of the Spanish Ministry of Economy and Competitiveness (FPDI-2013- 16409). PRP holds a postdoctoral fellowship of the Spanish Instituto de Salud Carlos III: Contrato Predoctoral de Formación en Investigación en Salud i-PFIS (IFI 14/00008).S

Novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia

A high proportion of patients with acute myeloid leukemia who achieve minimal residual disease (MRD) negative status ultimately relapse because a fraction of pathological clones remains undetected by standard methods. We designed and validated a high-throughput sequencing method for MRD assessment of cell clonotypes with mutations of NPM1, IDH1/2 and/or FLT3-SNVs. For clinical validation, 106 follow-up samples from 63 patients in complete remission were studied by NGS, evaluating the level of mutations detected at diagnosis. The predictive value of MRD status by NGS, multiparameter flow cytometry, or quantitative PCR was determined by survival analysis. The method achieved a sensitivity of 10-4 for SNV mutations and 10-5 for insertions/deletions and could be used in acute myeloid leukemia patients who carry any mutation (86% in our diagnosis data set). NGS-determined MRD positive status was associated with lower disease-free survival (hazard ratio [HR] 3.4, p=0.005) and lower overall survival (HR 4.2, p<0.001). Multivariate analysis showed that MRD positive status by NGS was an independent factor associated with risk of death (HR 4.54, p =0.005) and the only independent factor conferring risk of relapse (HR 3.76, p =0.012). This NGS based method simplifies and standardizes MRD evaluation, with high applicability in acute myeloid leukemia. It also improves upon flow cytometry and quantitative PCR to predict acute myeloid leukemia outcome and could be incorporated in clinical settings and clinical trials.This study was supported by the Subdirección General de Investigación Sanitaria (Instituto de Salud Carlos III, Spain) grants PI13/02387 and PI16/01530, and the CRIS against Cancer foundation grant 2014/0120. M.L. holds a postdoctoral fellowship of the Spanish Ministry of Economy and Competitiveness (FPDI-2013-16409). P.R.P. holds a postdoctoral fellowship of the Spanish of Instituto de Salud Carlos III: Contrato Predoctoral de Formación en Investigación en Salud i-PFIS (IFI 14/00008).S

Hepatitis B and C virus’ infection in hemodialysed patients

Introduction: Patients subjected to hemodialysis treatment are a high risk group for hepatitis B and C infection. Objective: To identify molecular and serologic markers of hepatitis B and C viral infection in hemodialysis patients. Materials and Methods: Was performed an observational, descriptive, cross-sectional study including 103 patients with chronic kidney disease undergoing hemodialysis regime from Cuba’s Western and Central regions. The samples were received between January and April 2016 to study serologic and molecular markers of hepatitis B and C to be performed at the Gastroenterology’s Institute. Seroprevalence of anti HCV, HBsAg and Anti S was estimated, plus viral load determinations using amplification test to measuring nucleic acids DNA and RNA for hepatitis B and C respectively. Associations were evaluated using the x2 statistician. Results: 7.8% of hemodialysis patients were inactive carriers of hepatitis B. The 70.8% of patients had infection markers of hepatitis C virus; being hepatitis C hidden viremia in 18.4% of them. Conclusions: High prevalence of infection and hepatitis C hidden viremia in hemodialysis patients. Keywords: Hemodialysis patients, hepatitis B virus, hepatitis C, surface’s antigen, hidden infection.</p

Beneficial Effect of Bariatric Surgery on Abnormal MMP-9 and AMPK Activities: Potential Markers of Obesity-Related CV Risk

Bariatric surgery (BS) results in sustained weight loss and may reverse inflammation, metabolic alterations, extracellular matrix remodeling and arterial stiffness. We hypothesize that increased stiffening in omental arteries from obese patients might be associated with an increase in MMP activity and a decrease in p-AMPK, together with systemic oxidative stress and inflammation. Moreover, BS could contribute to reversing these alterations. This study was conducted with 38 patients of Caucasian origin: 31 adult patients with morbid obesity (9 men and 22 women; mean age 46 years and BMI = 42.7 ± 1.0 kg/m2) and 7 non-obese subjects (7 women; mean age 45 years and BMI = 22.7 ± 0.6 kg/m2). Seventeen obese patients were studied before and 12 months after BS. The stiffness index β, an index of intrinsic arterial stiffness, was determined in omental arteries and was significantly higher in obese patients. Levels of phosphorylated AMPK (p-AMPKThr-172) and SIRT-1 were significantly lower in peripheral blood mononuclear cells (PBMCs) from obese patients than those from non-obese patients (p &lt; 0.05) and were normalized after BS. Total and active MMP-9 activities, LDH, protein carbonyls and uric acid were higher in obese patients and reduced by BS. Moreover, there was a correlation between plasmatic LDH levels and the stiffness index β. BS has a beneficial effect on abnormal MMP-9, LDH and AMPK activities that might be associated with the development of arterial stiffness in obese patients. Since these parameters are easily measured in blood samples, they could constitute potential biomarkers of cardiovascular risk in morbid obesity

Immunogenetic characterization of clonal plasma cells in systemic light-chain amyloidosis

This study was supported by the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369; and CB16/12/00489), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI13/02196), Asociación Española Contra el Cáncer (GCB120981SAN and the Accelerator Award), CRIS against Cancer foundation grant 2014/0120, and the Black Swan Research Initiative of the International Myeloma Foundation.Peer reviewe

Mutational screening of newly diagnosed multiple myeloma patients by deep targeted sequencing

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