Summary
Genetic studies in patients with Philadelphia‐negative myeloproliferative neoplasms (MPNs) are essential to establish the correct diagnosis and to optimise their management. Recently, it has ...been demonstrated that it is possible to detect molecular alterations analysing cell‐free DNA (cfDNA) in plasma samples, which is known as liquid biopsy. We have assessed the molecular profile of a cohort of 107 MPN patients 33 polycythaemia vera (PV), 56 essential thrombocythaemia (ET), 14 primary myelofibrosis (PMF) and 4 unclassifiable MPN by next‐generation sequencing (NGS) using cfDNA and paired granulocyte DNA. A high concentration of cfDNA in plasma was observed in patients with high molecular complexity, in MPL‐mutated cases, and in PMF patients. Targeted sequencing of cfDNA showed a comparable mutational profile (100% accuracy) to the one obtained in granulocytic DNA and a strong correlation was observed between the variant allele frequency (VAF) of gene mutations in both DNA sources. The median VAF detected in cfDNA (29·0%; range: 0·95–91·73%) was significantly higher than the VAF detected in granulocytes (median 25·2%; range: 0·10–95·5%), especially for MPL mutations (44·3% vs. 22·5%). In conclusion, our data support the use of cfDNA as a fast, sensitive and accurate strategy for performing molecular characterisation of MPN patients.
Objectives
In patients with essential thrombocythemia (ET), after the JAK2V617F driver mutation, mutations in CALR are common (classified as type 1, 52‐bp deletion or type 2, 5‐bp insertion). CALR ...mutations have generally been associated with a lower risk of thrombosis. This study aimed to confirm the impact of CALR mutation type on thrombotic risk.
Methods
We retrospectively investigated 983 ET patients diagnosed in Spanish and Polish hospitals.
Results
With 7.5 years of median follow‐up from diagnosis, 155 patients (15.8%) had one or more thrombotic event. The 5‐year thrombosis‐free survival (TFS) rate was 83.8%, 91.6% and 93.9% for the JAK2V617F, CALR‐type 1 and CALR‐type 2 groups, respectively (P = .002). Comparing CALR‐type 1 and CALR‐type 2 groups, TFS for venous thrombosis was lower in CALR‐type 1 (P = .046), with no difference in TFS for arterial thrombosis observed. The cumulative incidence of thrombosis was significantly different comparing JAK2V617F vs CALR‐type 2 groups but not JAK2V617F vs CALR‐type 1 groups. Moreover, CALR‐type 2 mutation was a statistically significant protective factor for thrombosis with respect to JAK2V617F in multivariate logistic regression (OR: 0.45, P = .04) adjusted by age.
Conclusions
Our results suggest that CALR mutation type has prognostic value for the stratification of thrombotic risk in ET patients.
Summary
The use of immunochemotherapy has improved the outcome of follicular lymphoma (FL). Recently, complete response at 30 months (CR30) has been suggested as a surrogate for progression‐free ...survival. This study aimed to analyse the life expectancy of FL patients according to their status at 30 months from the start of treatment in comparison with the sex and age‐matched Spanish general population (relative survival; RS). The training series comprised 263 patients consecutively diagnosed with FL in a 10‐year period who needed therapy and were treated with rituximab‐containing regimens. An independent cohort of 693 FL patients from the Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO) group was used for validation. In the training cohort, 188 patients were in CR30, with a 10‐year overall survival (OS) of 53% and 87% for non‐CR30 and CR30 patients, respectively. Ten‐year RS was 73% and 100%, showing no decrease in life expectancy for CR30 patients. Multivariate analysis indicated that the FL International Prognostic Index was the most important variable predicting OS in the CR30 group. The impact of CR30 status on RS was validated in the independent GELTAMO series. In conclusion, FL patients treated with immunochemotherapy who were in CR at 30 months showed similar survival to a sex‐ and age‐matched Spanish general population.
Since enzyme replacement therapy for Gaucher disease (MIM#230800) has become available, both awareness of and the natural history of the disease have changed. However, there remain unmet needs such ...as the identification of patients at risk of developing bone crisis during therapy and late complications such as cancer or parkinsonism. The Spanish Gaucher Disease Registry has worked since 1993 to compile demographic, clinical, genetic, analytical, imaging and follow-up data from more than 400 patients. The aims of this study were to discover correlations between patients' characteristics at diagnosis and to identify risk features for the development of late complications; for this a machine learning approach involving correlation networks and decision trees analyses was applied.
A total of 358 patients, 340 type 1 Gaucher disease and 18 type 3 cases were selected. 18% were splenectomyzed and 39% had advanced bone disease. 81% of cases carried heterozygous genotype. 47% of them were diagnosed before the year 2000. Mean age at diagnosis and therapy were 28 and 31.5 years old (y.o.) respectively. 4% developed monoclonal gammopathy undetermined significance or Parkinson Disease, 6% cancer, and 10% died before this study. Previous splenectomy correlates with the development of skeletal complications and severe bone disease (p = 0.005); serum levels of IgA, delayed age at start therapy (> 9.5 y.o. since diagnosis) also correlates with severe bone disease at diagnosis and with the incidence of bone crisis during therapy. High IgG (> 1750 mg/dL) levels and age over 60 y.o. at diagnosis were found to be related with the development of cancer. When modelling the decision tree, patients with a delayed diagnosis and therapy were the most severe and with higher risk of complications.
Our work confirms previous observations, highlights the importance of early diagnosis and therapy and identifies new risk features such as high IgA and IgG levels for long-term complications.
The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR‐mutated. ...In low risk patients, time from diagnosis to cytoreduction was shorter in CALR‐positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR‐mutated ET than in the remaining patients (P = 0·003). In CALR‐positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR‐mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR‐mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.
Summary
Anti‐cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) have shown promise in follicular lymphoma (FL) as post‐induction therapy, by enhancing antibody‐dependent cellular ...cytotoxicity (ADCC). However, cytotoxic cells are reduced after this treatment. We hypothesised that ex vivo expanded lymphokine‐activated killer (LAK) cells administered to FL‐remission patients are safe and improve anti‐CD20 efficacy. This open, prospective, phase II, single‐arm study assessed safety and efficacy of ex vivo expanded LAK cells in 20 FL‐remission patients following rituximab maintenance. Mononuclear cells were obtained in odd rituximab cycles and stimulated with interleukin 2 (IL‐2) for 8 weeks, after which >5 × 108 LAK cells were injected. Patients were followed‐up for 5 years. At the end of maintenance, peripheral blood cells phenotype had not changed markedly. Natural killer, LAK and ADCC activities of mononuclear cells increased significantly after recombinant human IL‐2 (rhIL‐2) stimulation in all cycles. Rituximab significantly enhanced cytotoxic activity. No patients discontinued treatment. There were no treatment‐related serious adverse events. Three patients had progressed by the end of follow‐up. After a median (interquartile range) follow‐up of 59.4 (43.8–70.9) months, 85% of patients remained progression free. No deaths occurred. Quality‐of‐life improved throughout the study. Post‐induction LAK cells with rituximab seem safe in the long term. Larger studies are warranted to confirm efficacy.
Internal root resorption (IRR) is a pathologic process that occurs because of external stimuli that affect the pulp and result in the loss of dentinal tissue. The occurrence of IRR is considered ...relatively rare, and the etiology is not fully understood, although trauma is believed to be the main etiologic agent. The current study presented a case report of spontaneous remission of an IRR lesion diagnosed during orthodontic treatment. The lesion was characterized by a circular and delimited radiolucent image, located in the apical third of the root canal of the maxillary right lateral incisor diagnosed during orthodontic treatment. After the diagnosis, clinical and radiographic follow-up was performed without any intervention. The follow-up radiographic images showed loss of contour definition and reduction in the size of the lesion. At the end of orthodontic treatment, 27 months after diagnosis, the space of the lesion had been filled by tissue with similar radiopacity to the adjacent dentin, and the tooth did not change its color and response to mechanical and thermal stimuli. Eight years after the end of the treatment, the maxillary right lateral incisor still presented normal responses to vitality tests and color stability; therefore, it was impossible to notice the root canal space. The reported patient presents a possible behavior of the IRR characterized by spontaneous remission of the lesion. However, nonendodontic treatment after diagnosis should not be the routine therapy adopted for IRR because of the potential risk to the tooth.
•Internal root resorption lesions are generally asymptomatic.•They are often detected during routine radiological examinations.•Early diagnosis allowed observation and spontaneous regression of the resorption.•The space gradually filled with less organized tissue.
Management of Gaucher disease (GD) is challenging due to its wide genotypic and phenotypic variability and changing clinical manifestations due to effective treatment. Sixteen face‐to‐face meetings ...with experts were held in order to discuss daily clinical practice and identify controversies regarding the management of GD. With this information, a questionnaire with 93 recommendations for different clinical scenarios was designed, and a Delphi survey among 86 physicians with experience in GD was conducted. Consensus was reached on 73 out of the 93 items. Recommendations on follow‐up of adult and pediatric patients were in line with current guidelines, and underscored the importance of a patient‐tailored approach. For the follow‐up of stable patients receiving long‐term treatment, consensus was reached on the importance of multidisciplinary care that involves pediatricians, internal medicine, and primary care, specialized radiologists, orthopedic surgeons, and hematologists when required. Degree of pain, use of painkillers and antidepressants, and quality of life should be evaluated at every follow‐up visit or at least once per year. In general, a closer follow‐up was recommended for untreated patients or patients who underwent a treatment change (every 3 months during the first year) and during pregnancy. For pregnant patients, hemostasis and risk of hemorrhage should be assessed, but no consensus was reached for initiation of treatment in asymptomatic pregnant patients. Lastly, recommendations on how to adapt GD management during a COVID‐19 pandemic were collected. This expert consensus may help decision‐making during the management of GD in specific clinical scenarios.
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