323,724 research outputs found
Time for a new prognostic score in CLL?
No full textIn this issue of Blood, Langerbeins et al 1 evaluated the prognostic value of the current Chronic Lymphocytic Leukemia International Prognostic Index (CLL-IPI) using a pooled dataset of CLL-patients treated in first-line with targeted drugs (N=991) or chemoimmunotherapy (N=1,256).1 This work is timely, as all prognostic scores need re-evaluation as standard therapies change. The study was limited by a short median observation time (40.5 months), and the actual number of chemotherapy-free patients in the cohort receiving targeted drugs was 891 (100 patients in the targeted drug cohort had received bendamustine-debulking). Nevertheless, the authors were able to conclude that CLL-IPI retained prognostic value for progression-free survival (PFS), but with diminished discriminatory impact for the prediction of overall survival (OS).The “targeted drugs” treatments in the study by Langerbeins et al1 included combinations of anti-CD20 monoclonal antibodies with inhibitors of the B-cell receptor signaling-associated pathways (BCRi, mainly ibrutinib) and/or the BCL2 inhibitor (BCL2i) venetoclax, but only 26% of these patients had received venetoclax and ibrutinib in combination.1 The CLL-IPI score was originally generated by selecting 5 prognostic factors independently able to predict OS from 27 genetic, biochemical, and clinical parameters in patients with CLL treated in clinical trials with chemoimmunotherapy regimens in first-line between 1997 and 2010, at a time when targeted treatments were not available.2 The study describing the CLL-IPI was published in 2016 and the 5 factors were TP53 status (no abnormalities vs TP53 mutation or deletion or both), IGHV mutational status (mutated vs unmutated), serum β2-microglobulin concentration (≤3·5 mg/L vs >3·5 mg/L), clinical stage (Binet A or Rai 0 vs Binet B–C or Rai I–IV), and age (≤65 years vs >65 years). These factors were assigned a value (deleted/mutated TP53=4, unmutated IGHV=2, high β2-microglobulin =2, advanced clinical stage=1, advanced age=1) by approximating the hazard ratio (HR) value for OS risk, and a score was generated to discriminate four prognostic groups (low-risk score=0-1, intermediate=2-3, high=4-6, very-high=7-10).Langerbeins et al1 documented a significant improvement of PFS and OS in patients receiving targeted drugs compared to chemoimmunotherapy.1 The improved PFS gained using targeted treatments was observed in all CLL-IPI categories. However, the study by Langerbeins et al1 highlighted that only β2-microglobulin concentration (HR=1.7), IGHV status (HR=2.6), and TP53 status (HR=1.6) maintained prognostic value and that the relative weights of these 3 factors to PFS risk assessment were different from those calculated for OS in the 2016 study.2Langerbeins at al1 also demonstrated that the improvement gained using targeted drugs instead of chemoimmunotherapy on OS was particularly evident in the CLL-IPI high and very high-risk, but not in the low and intermediate risk groups. While there was a pair-wise significant difference between each risk group in the 2016 study,2 the current study documented a difference only between the intermediate and high-risk groups. Also, only Binet stage A vs C, β2-microglobulin, and TP53 status, but not Binet stage A vs B or B vs C and IGHV status, maintained their prognostic value for OS in the patients receiving targeted drugs with the current observation time. This suggested that, while an extension of the observation time was needed before making firm conclusions on the role of the CLL-IPI score in predicting OS, new parameters would need to be identified and weighted to predict PFS and OS in CLL in the context of targeted treatments. While there is always attention towards the role of genetic evolution,3 environmental factors explaining CLL resistance to novel treatments should also be sought.4,5 The better understanding of the main biological “drivers” of CLL, namely BCR and BCL2, and how to target them therapeutically has led to a significant improvement of the treatment strategies in CLL.6,7 The current most appealing strategies include those combining BCRi with BCL2i,8-10 which were given to only 26% of the patients in the trials considered by Langerbeins, or BCL2i with anti-CD20 antibodies.1 However, concepts are rapidly evolving and the period of observation of patients having received BCRi or BCL2i or their combinations remains short in a condition like CLL, where survivals can be measured in decades. Also, the new clinical trials with BCRi plus BCL2i combinations or BCL2i plus anti-CD20 antibody combinations will tell us if these therapeutic approaches may find a different indication for the CLL with unmutated IGHV (U-CLL) or mutated IGHV (M-CLL). U-CLL and M-CLL carry distinctive cellular origin, biology, epigenetics/genetics, and clinical behavior.6 Therefore prognostic algorithms may need to be generated separately in these 2 types of CLL. Only extended observation time and a better understanding of how to combine new targeted drugs will make it possible to identify the best prognostic factors of OS. In the interim, when combined with the outcome data in Langerbeins et al,1 the CLL-IPI remains a tool that assists prognostication for patients with CLL in the era of chemotherapy-free targeted regimens.References1. Langerbeins P, Giza A, Robrecht S, et al. Reassessing the Chronic Lymphocytic Leukemia International Prognostic Index in the era of targeted therapies. Blood. 2024.2. International CLLIPIwg. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790.3. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294.4. Chiodin G, Drennan S, Martino EA, et al. High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL. Blood Adv. 2022;6(18):5494-5504.5. Bonfiglio S, Sutton LA, Ljungstrom V, et al. BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib. Blood Adv. 2023;7(12):2794-2806.6. Stevenson FK, Forconi F, Kipps TJ. Exploring the pathways to chronic lymphocytic leukemia. Blood. 2021;138(10):827-835.7. Forconi F, Lanham SA, Chiodin G. Biological and Clinical Insight from Analysis of the Tumor B-Cell Receptor Structure and Function in Chronic Lymphocytic Leukemia. Cancers. 2022;14(3):663.8. Munir T, Cairns DA, Bloor A, et al. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med. 2024;390(4):326-337.9. Jain N, Keating M, Thompson P, et al. Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med. 2019;380(22):2095-2103.10. Niemann CU, Munir T, Moreno C, et al. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(12):1423-1433.<br/
Revisiting the definition of somatic mutational status in B-cell tumors: does 98% homology mean that a V(H)-gene is unmutated?
No full textIn B-cell tumors, accurate assessment of somatic mutational status has implications for defining tumor origin and, in some categories, has relevance for predicting the clinical outcome. In 1999, it was found that in chronic lymphocytic leukemia (CLL) cases carrying VH-genes with >98% homology to the closest germline (GL) gene identified a subset with a poorer prognosis, as compared to cases which had clearly undergone somatic mutation.1 Initially, the 98% cutoff was used to exclude potential polymorphic variant sequences. It was a short cut to avoid analyzing the corresponding GL gene in each patient, and is now used for assignment of mutational status in a range of B-cell tumors.
The most integrated V-base database (http://www.mrc-cpe.cam.ac.uk/v
base) describes 47 polymorphisms in 30/51 functional VH-gene segments, with nucleotide differences from GL generally of 2% variation. Aligned VH-genes readily map to the correct allele, and the 98% cutoff point seemed reasonable. However, low levels of mutations can occur in VH-genes and single-base changes (0.33–0.35% from germ line) may be important for improving the antigen recognition.2 It is possible therefore that significant changes could be occurring in cases with apparent >98% homology to GL. While it is unlikely to affect the prognostic power in CLL, it has implications for our understanding of the behavior of B-cell tumors.
One problem with assessing low levels of mutation is that of the approaching Taq error rate, and, although an increased rate may suggest somatic mutation, it can still be questioned. An indicator of the reality of base changes is identification of the same change in >1 sequence derived from separate amplification reactions. However, this parameter applies mainly to mutations occurring early in tumor development, and may not be evident from those accumulating late in the life of the clone. It has revealed genuine intraclonal heterogeneity in some cases of monoclonal gammopathy of undetermined significance, distinguishing it from the more malignant counterpart, multiple myeloma.3
For B-cell tumors with a low level (98% homology to GL sequence.4 Among these cases, only 1/5 had variants repeated in >1 clone. While lack of repeats prevents confirmation of the reality of the mutations, it might be expected if mutational events are relatively random and of low frequency. An intriguing single case of splenic marginal zone lymphoma with >99% homology also showed suggestive evidence for intraclonal heterogeneity.5
Recently, we have analyzed VH-genes in hairy cell leukemia (HCL). These tumors commonly express multiple isotypes and the majority have undergone somatic mutation in all isotype variants.6 The new finding that 2/13 HCL cases displayed germline tumor-derived VH-genes (Forconi F et al, submitted) prompted the question whether a further 3/13 cases with >98% homology were actually unmutated. Tumor VH transcripts were identified by established RT-PCR and cloning procedures described previously.6 Full sequence transcripts were analyzed and shared the same CDR3 in multiple clones. Cases 103 and 163 (Figure 1) revealed VH-genes with 98.6 and 98.2% homology to the closest germline allele, V4-31 and V1-02, respectively.6 Case 330 displayed 98.6% homology to the V2-05 gene
Analisi funzionale del servizio data streaming in LTE e studio simulativo delle relazioni tra QoE e QoS
No full textLa rete radiomobile Long Term Evolution (LTE) è la prima rete radiomobile wireless all-IP ed in quanto tale impone agli operatori di telecomunicazioni una particolare attenzione alla qualità del servizio erogato all'utente finale. Limitarsi al monitoraggio delle prestazioni di rete, potrebbe non essere sufficiente per assicurare un buon livello di qualità offerta all'utente finale nell'erogazione di un servizio. E' necessario per l'operatore, poter correlare la qualità percepita dell'utente durante la fruizione del servizio, con le prestazioni di rete. Obiettivo del lavoro di tesi è l'analisi funzionale del servizio Data Streaming in LTE e lo studio simulativo delle relazioni tra la Quality of Experience (QoE) e la Quality of Service ( QoS). L'analisi funzionale porta alla realizzazione di modelli funzionali del servizio Data Streaming LTE sulla base dei quali verrà sviluppato il modello simulativo al livello di dettaglio che consenta di operare sulle discipline di Scheduling e di Admission Control, al fine di calcolare gli effetti di tali discipline sui vari fattori QoS considerati e che saranno inseriti nel modello di correlazione QoS/QoE del servizio. Il modello può fornire uno strumento di supporto alle decisioni dell'operatore che voglia assicurare conformità nella QoE (agendo sullo Scheduling ed Admission Control) al variare delle condizioni al contorno (cadute di segmenti di rete, oscillazioni della domanda di servizio, eccetera)
Deep vein thrombosis during varicella in a child with factor V Leiden mutation and familial deficiency of protein S
No full textLa verità, tutta la verità. Tracce, dimenticanze e trappole nel ricordo autobiografico. Colloquio e testimonianza in psicologia forense.
No full text
La Compra De Oficios Como Vía De Acceso A Las Varas De Justicia. Venalidad Y Coaliciones Políticas En Un Cabildo Rioplatense: La “Casa De Los Monje” (Santa Fe, 1700-1750)
No full textFil: Barriera, Darío. Universidad Nacional de Rosario. CONICET; ArgentinaFil: Forconi, María Celeste; Universidad Nacional de Rosario. Argentin
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