Carlos Aguilar

Different multivariate techniques for automated classification of MRI data in Alzheimer’s disease and mild cognitive impairment

Automated structural magnetic resonance imaging (MRI) processing pipelines and different multivariate techniques are gaining popularity for Alzheimers disease (AD) research. We used four supervised learning methods to classify AD patients and controls (CTL) and to prospectively predict the conversion of mild cognitive impairment (MCI) to AD from baseline MRI data. A total of 345 participants from the AddNeuroMed cohort were included in this study; 116 AD patients, 119 MCI patients and 110 CTL individuals. High resolution sagittal 3D MP-RAGE datasets were acquired and MRI data were processed using FreeSurfer. We explored the classification ability of orthogonal projections to latent structures (OPLS), decision trees (Trees), artificial neural networks (ANN) and support vector machines (SVM). Applying 10-fold cross-validation demonstrated that SVM and OPLS were slightly superior to Trees and ANN, although not statistically significant for distinguishing between AD and CTL. The classification experiments resulted in up to 83% sensitivity and 87% specificity for the best techniques. For the prediction of conversion of MCI patients at baseline to AD at 1-year follow-up, we obtained an accuracy of up to 86%. The value of the multivariate models derived from the classification of AD vs. CTL was shown to be robust and efficient in the identification of MCI converters.

Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma

Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of multiple myeloma (MM) after therapy. However, current flow-MRD has lower sensitivity than molecular methods and lacks standardization. Here we report on a novel next generation flow (NGF) approach for highly sensitive and standardized MRD detection in MM. An optimized 2-tube 8-color antibody panel was constructed in five cycles of design-evaluation-redesign. In addition, a bulk-lysis procedure was established for acquisition of ⩾107 cells/sample, and novel software tools were constructed for automatic plasma cell gating. Multicenter evaluation of 110 follow-up BM from MM patients in very good partial response (VGPR) or CR showed a higher sensitivity for NGF-MRD vs conventional 8-color flow-MRD -MRD-positive rate of 47 vs 34% (P=0.003)-. Thus, 25% of patients classified as MRD-negative by conventional 8-color flow were MRD-positive by NGF, translating into a significantly longer progression-free survival for MRD-negative vs MRD-positive CR patients by NGF (75% progression-free survival not reached vs 7 months; P=0.02). This study establishes EuroFlow-based NGF as a highly sensitive, fully standardized approach for MRD detection in MM which overcomes the major limitations of conventional flow-MRD methods and is ready for implementation in routine diagnostics.

Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia

Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 109/l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 109/l (n = 29), patients request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow‐up of 9 (range, 6–25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP < 1 year. Eleven patients were male and their median age was 59 years. They received a median of 4 previous treatment lines and 42% were splenectomized. No predictive factors of sustained response after eltrombopag withdrawal were identified. Platelet response following eltrombopag cessation may be sustained in an important percentage of adult primary ITP patients who achieved CR with eltrombopag. However, reliable markers for predicting which patients will have this response are needed. Am. J. Hematol. 90:E40–E43, 2015.

Activity and safety of lenalidomide and dexamethasone in patients with multiple myeloma requiring dialysis: a Spanish multicenter retrospective study.

To the Editor: Lenalidomide is an immunomodulating agent that has been shown to be a highly active agent in the management of patients with multiple myeloma (MM) (1, 2), but most studies excluded patients with a serum creatinine level >2.5 mg ⁄dL. Experience with lenalidomide (3) in the management of patients with MM and renal impairment is scarce. We present the results of a retrospective study in a group of 15 patients from 11 Spanish centers with MM and severe renal impairment requiring dialysis and receiving lenalidomide-based therapy at the time of study entry. Response criteria were based on the International Myeloma Working Group (IMWG) criteria (4). Patient features at the time of inclusion are summarized in Table 1. Two patients had renal impairment requiring dialysis before myeloma diagnosis. The remaining thirteen patients developed renal failure at diagnosis or during the evolution of the disease, and it was because of MM (six patients), drug-related (two patients), secondary to underlying diabetes (two patients), and secondary to a tumoral lysis syndrome because of bortezomib (one patient). Finally, no data were available in the remaining two patients. Thirteen (86%) patients received lenalidomide at a dose of 15 mg ⁄d, three times a week after dialysis and in combination with dexamethasone (Table 1). Patients received a median of eight cycles (range, 1–28) of lenalidomide treatment. Hematological toxicity was the toxicity more frequently seen and required dose reduction in eight (53%) patients, and granulocyte-colony stimulating factor prophylaxis in seven (47%). Ten patients developed neutropenia (6 grade 3–4), and seven (47%) patients presented thrombocytopenia (1 grade 3). Finally, two (13%) patients presented grade 2 anemia. Six (40%) patients developed seven infectious episodes during the study period, five of them within the first four cycles of therapy. There were four (57%) bacteremias, two (29%) pneumonias, and one (14%) central venous line infection (Table 2). Other non-hematological complications are shown in Table 2. There were no thromboembolic complications. Overall response rate was 60% (nine patients), with four (29%) achieving complete response (CR), one (7%) patient very good partial response, and four (29%) patients partial response. Median time to best response was 4 months. With a median follow-up of 13 months (range 1–28), median progression-free and overall survival was 15 and 20 months, respectively. Among responding patients, median duration of response has not been reached. Seven (47%) patients have died because of disease progression (five patients) and of infectious complications (two patients) and eight (53%) are still alive, seven with continuous lenalidomde treatment and one off therapy because of disease progression. Renal function remained stable in all but one patient who was spared from dialysis after achieving partial response 3 months after starting treatment. Currently, there is no standard treatment for patients with MM and renal failure requiring dialysis. Results with new agents such as thalidomide and bortezomib are disparate. With thalidomide, experience is scarce and has been associated with a high incidence of hyperkaliemia in patients with serum creatinine >3 mg ⁄dL (5, 6). Better results have been reported with bortezomib-based regimens, with a response rate of 75% with 30% of CR + near CR and with a toxicity profile similar to that observed in patients with normal renal function (7). Lenalidomide has been shown to undergo substantial elimination via the kidneys, and recently, encouraging results have been reported in patients with different degrees of renal impairment (3). However, no data in patients with MM and advanced renal failure requiring dialysis are available. Our report is the first one including this high-risk subgroup of patients with MM and show a response rate of 65% with 29% of CR like that seen in patients with normal renal function (1, 2). Importantly, progression-free and overall survival was also similar to that reported in patients without significant renal failure (1, 2). Finally, among responding patients, median duration of response has not been reached, pointing that durability of response is also comparable to those of patients with MM with normal renal function in the relapsed setting (1, 2). In our series, as in other studies including lenalidomide in patients with mild renal impairment (3, 8, 9), doi:10.1111/j.1600-0609.2010.01500.x

Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut-offs.

Visual assessment of medial temporal lobe atrophy (MTA; range 0–4, from no atrophy to increasing atrophy of the choroid fissure, temporal horns and hippocampus) is a sensitive radiological marker of Alzheimers disease (AD). One of the critical elements for visual MTA assessment is the cut‐off score that determines deviation from normality.

Multivariate classification of patients with Alzheimer’s and dementia with Lewy bodies using high-dimensional cortical thickness measurements: an MRI surface-based morphometric study

ContextAlzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative dementia types. It is important to differentiate between them because of the differences in prognosis and treatment approaches.ObjectiveInvestigate if sparse partial least squares (SPLS) classification of cortical thickness measurements could differentiate between AD and DLB.MethodsTwo independent cohorts without MR-protocol alignment in Norway and Slovenia with 97 AD and DLB subjects were enrolled. Cortical thickness measurements acquired with Freesurfer were used in subsequent SPLS classification runs. The cohorts were analyzed separately and afterwards combined. The models were trained with leave-one-out cross validation and test datasets where used when available. To study the impact of MR-protocol alignment, the classifiers were additionally tested on sets drawn exclusively from the independent cohorts.ResultsThe obtained sensitivity/specificity/AUC values were 94.4/88.89/0.978 and 88.2/94.1/0.969 in the Norwegian and Slovenian cohorts, respectively. Both cohorts showed AD-associated pattern of thinning in mid-anterior temporal, occipital and subgenual cingulate cortex, whereas the pattern supportive for DLB included thinning in dorsal cingulate, posterior temporal and lateral orbitofrontal regions. When combining the cohorts, sensitivity/specificity/AUC were 82.1/85.7/0.948 for the training and 77.8/75/0.731 for the testing datasets with the same pattern-of-difference. The models tested on datasets drawn exclusively from the independent cohorts did not produce adequate accuracy.ConclusionSPLS classification of cortical thickness is a good method for differentiating between AD and DLB, relatively stable even for mixed data, but not when tested on completely independent data drawn from different cohorts (without MR-protocol alignment).

Consensus opinion for the selection and use of therapeutic products for the treatment of haemophilia in Spain

The period between isolation of HIV in the early 1980s and the development of effective viral inactivation procedures able to eradicate the virus from the blood supply was long and unfortunately many recipients of blood-derived products became infected; this translated into a devastating impact on their quality of life, quality of care as well as on their life expectancy. Some years later, hepatitis C virus infection was identified as another known blood-borne disease complicating the treatment of haemophilia. Nowadays, the potential threat of emerging new pathogens has stressed the need to provide effective but primarily safe products with regard to infectious agents, as well as to regularly update therapeutic guidelines for haemophilia. The aim of the present publication was to review some of the crucial aspects related to the choice of haemostatic concentrates for the treatment of haemophilia and other inherited bleeding disorders, to analyse the current situation in the United States, Canada and European Union countries and to report the most relevant aspects of the Spanish consensus opinion of haemophilia-treating doctors for the use of therapeutic products for haemophilia recently issued. Essentially, it suggests that a gradual switch to recombinant concentrates may be a beneficial decision for patients with haemophilia and for the National Health Service.

Molecular and clinical profile of von Willebrand disease in Spain (PCM–EVW–ES): Proposal for a new diagnostic paradigm

The diagnosis of von Willebrand disease (VWD) remains difficult in a significant proportion of patients. A Spanish multicentre study investigated a cohort of 556 patients from 330 families who were analysed centrally. VWD was confirmed in 480. Next generation sequencing (NGS) of the whole coding VWF was carried out in all recruited patients, compared with the phenotype, and a final diagnosis established. A total of 238 different VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 463 were found to have VWF mutation/s. A good phenotypic/genotypic association was estimated in 96.5% of the patients. One hundred seventy-four patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred sixteen patients presented with mutations that had previously been associated with increased von Willebrand factor (VWF) clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an appropriate classification in 63 of them. The remaining seven patients presented with a VWF novel mutation pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed. These data seem to support NGS as a first line efficient and faster paradigm in VWD diagnosis.

Application of a MRI based index to longitudinal atrophy change in Alzheimer disease, mild cognitive impairment and healthy older individuals in the AddNeuroMed cohort.

Cross sectional studies of patients at risk of developing Alzheimer disease (AD) have identified several brain regions known to be prone to degeneration suitable as biomarkers, including hippocampal, ventricular, and whole brain volume. The aim of this study was to longitudinally evaluate an index based on morphometric measures derived from MRI data that could be used for classification of AD and healthy control subjects, as well as prediction of conversion from mild cognitive impairment (MCI) to AD. Patients originated from the AddNeuroMed project at baseline (119 AD, 119 MCI, 110 controls (CTL)) and 1-year follow-up (62 AD, 73 MCI, 79 CTL). Data consisted of 3D T1-weighted MR images, demographics, MMSE, ADAS-Cog, CERAD and CDR scores, and APOE e4 status. We computed an index using a multivariate classification model (AD vs. CTL), using orthogonal partial least squares to latent structures (OPLS). Sensitivity, specificity and AUC were determined. Performance of the classifier (AD vs. CTL) was high at baseline (10-fold cross-validation, 84% sensitivity, 91% specificity, 0.93 AUC) and at 1-year follow-up (92% sensitivity, 74% specificity, 0.93 AUC). Predictions of conversion from MCI to AD were good at baseline (77% of MCI converters) and at follow-up (91% of MCI converters). MCI carriers of the APOE e4 allele manifested more atrophy and presented a faster cognitive decline when compared to non-carriers. The derived index demonstrated a steady increase in atrophy over time, yielding higher accuracy in prediction at the time of clinical conversion. Neuropsychological tests appeared less sensitive to changes over time. However, taking the average of the two time points yielded better correlation between the index and cognitive scores as opposed to using cross-sectional data only. Thus, multivariate classification seemed to detect patterns of AD changes before conversion from MCI to AD and including longitudinal information is of great importance.

Safety and efficacy of splenectomy in over 65‐yrs‐old patients with immune thrombocytopenia

Few studies specifically focus on elderly splenectomized immune thrombocytopenia (ITP) patients. Older patients with ITP and excellent health are often excluded from surgery splenectomy. We aimed to compare the safety and efficacy of splenectomy in elderly and non‐elderly ITP patients and to examine the effect of age on therapeutic response.