109 research outputs found
New hopes in relapsed refractory primary central nervous system lymphoma
No full textPurpose of reviewPatients with relapsed/refractory primary central nervous system lymphoma (rrPCNSL) have poor prognosis, with a median survival after relapse of 6.8 months. In this review, we discuss the evolving landscape and the possible future directions related to this important unmet clinical need.Recent findingsThe modern two-phase approach for newly diagnosed PCNSL based on an induction using high-dose methotrexate (HD-MTX) combinations and a subsequent consolidation, has significantly improved the outcome in this setting. However, this strategy is able to cure more or less 50% of patients. rrPCNSL patients have a very poor prognosis with a reported 5-year overall survival of 18%. Late relapses (after third year) and use of high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) represent important factors associated with a better outcome in this setting. On the basis of the growing acquisition of knowledge on the molecular characteristics of PCNSL, the use of non-chemotherapeutic drugs such as bruton tyrosine kinase inhibitors (BTK-is), immunomodulatory drugs (IMiDs) and immune checkpoint blockers (ICBs) is increasing in the last years along with the introduction of novel approaches (CAR-T cells and blood - brain barrier disruption). However, despite high responses in some cases, durations are often short, translating in outcome results still unsatisfactory.SummaryTreatment of rrPCNSL patients is challenging. As no standard of care exist in this setting, it is of paramount importance to acquire new knowledge related to this condition and start multidisciplinary collaboration in order to improve pts outcome
Targeting the Blood–Brain Tumor Barrier with Tumor Necrosis Factor-α
No full textThe blood–brain tumor barrier represents a major obstacle for anticancer drug delivery to brain tumors. Thus, novel strategies aimed at targeting and breaching this structure are of great experimental and clinical interest. This review is primarily focused on the development and use of a derivative of tumor necrosis factor-α (TNF) that can target and alter the blood–brain-tumor-barrier. This drug, called NGR-TNF, consists of a TNF molecule fused to the Cys-Asn-Gly-Arg-Cys-Gly (CNGRCG) peptide (called NGR), a ligand of aminopeptidase N (CD13)-positive tumor blood vessels. Results of preclinical studies suggest that this peptide-cytokine fusion product represents a valuable strategy for delivering TNF to tumor vessels in an amount sufficient to break the biological barriers that restrict drug penetration in cancer lesions. Moreover, clinical studies performed in patients with primary central nervous system lymphoma, have shown that an extremely low dose of NGR-TNF (0.8 μg/m2) is sufficient to promote selective blood–brain-tumor-barrier alteration, increase the efficacy of R-CHOP (a chemo-immunotherapy regimen) and improve patient survival. Besides reviewing these findings, we discuss the potential problems related to the instability and molecular heterogeneity of NGR-TNF and review the various approaches so far developed to obtain more robust and homogeneous TNF derivatives, as well as the pharmacological properties of other peptide/antibody-TNF fusion products, muteins and nanoparticles that are potentially useful for targeting the blood–brain tumor barrier. Compared to other TNF-related drugs, the administration of extremely low-doses of NGR-TNF or its derivatives appear as promising non-immunogenic approaches to overcome TNF counter-regulatory mechanism and systemic toxicity, thereby enabling safe breaking of the BBTB
Radiomics-Based Machine Learning Model for Predicting Overall and Progression-Free Survival in Rare Cancer: A Case Study for Primary CNS Lymphoma Patients
No full textPrimary Central Nervous System Lymphoma (PCNSL) is an aggressive neoplasm with a poor prognosis. Although therapeutic progresses have significantly improved Overall Survival (OS), a number of patients do not respond to HD–MTX-based chemotherapy (15–25%) or experience relapse (25–50%) after an initial response. The reasons underlying this poor response to therapy are unknown. Thus, there is an urgent need to develop improved predictive models for PCNSL. In this study, we investigated whether radiomics features can improve outcome prediction in patients with PCNSL. A total of 80 patients diagnosed with PCNSL were enrolled. A patient sub-group, with complete Magnetic Resonance Imaging (MRI) series, were selected for the stratification analysis. Following radiomics feature extraction and selection, different Machine Learning (ML) models were tested for OS and Progression-free Survival (PFS) prediction. To assess the stability of the selected features, images from 23 patients scanned at three different time points were used to compute the Interclass Correlation Coefficient (ICC) and to evaluate the reproducibility of each feature for both original and normalized images. Features extracted from Z-score normalized images were significantly more stable than those extracted from non-normalized images with an improvement of about 38% on average (p-value < (Formula presented.)). The area under the ROC curve (AUC) showed that radiomics-based prediction overcame prediction based on current clinical prognostic factors with an improvement of 23% for OS and 50% for PFS, respectively. These results indicate that radiomics features extracted from normalized MR images can improve prognosis stratification of PCNSL patients and pave the way for further study on its potential role to drive treatment choice
A narrative review of consolidation strategies for young and fit patients with newly-diagnosed primary central nervous system lymphoma
No full textIntroduction: The modern treatment of patients with primary central nervous system lymphoma (PCNSL) consists of two phases: induction, currently represented by a high-dose-methotrexate-based polychemotherapy, and consolidation. The optimal consolidation therapy has not been defined yet, but several strategies, such as whole-brain radiotherapy (WBRT), high-dose chemotherapy supported by autologous stem cell transplantation (HDC/ASCT) or nonmyeloablative chemotherapy, have been addressed in important randomized trials. Areas covered: This review provides an overview of the current role of consolidation strategies in young and fit patients with newly diagnosed PCNSL. Publications in English language, peer-reviewed, from high-quality international journals, edited from 2003 to 2021 were identified on PubMed. Expert opinion: Consolidation treatment significantly improved outcomes of PCNSL. Radiotherapy had represented for years the only choice in the consolidation therapy, but large randomized trials have demonstrated that HDC/ASCT is equally effective and associated with lower neurotoxicity risk in patients younger than 65–70 years. Encouraging results have been obtained using reduced-dose WBRT, while a recent randomized trial failed to demonstrate that consolidation with nonmyeloablative chemotherapy is more effective than HDC/ASCT in PCNSL patients. A personalized consolidation treatment, driven also by a response prediction model based on radiological and molecular details, may improve the management of PCNSL patients
How we treat primary central nervous system lymphoma
No full textPrimary diffuse large B-cell (DLBCL) lymphoma of the central nervous system (CNS) (PCNSL) is a new lymphoma entity, recognized by the 2017 WHO classification of hematopoietic and lymphoid tumors. Unlike systemic DLBCL, the use of anthracycline-based chemotherapy combinations is associated with disappointing outcomes, due to low CNS bioavailability of related drugs. Therefore, international researchers investigated alternative strategies, mostly including drugs able to cross the blood–brain-barrier at low or high doses, with a progressive improvement in survival. Some effective chemotherapy combinations of high-dose methotrexate (HD-MTX) with alkylating agents and rituximab with or without cytarabine have been tested in international randomized trials and represent the induction treatment in everyday practice, with some variations among different geographical areas. In patients aged 70 years or younger, MATRix (HD-MTX/cytarabine/thiotepa/rituximab) chemotherapy followed by consolidative high-dose chemotherapy plus autologous stem cell transplantation or whole-brain irradiation has been associated with a significant improvement in overall survival. Other treatment options, such as non-myeloablative high-dose chemotherapy, oral drug maintenance, and some targeted drugs like ibrutinib or lenalidomide, are being tested in high-level international trials. These steps toward further effective treatments are motivated by an incessant search for less neurotoxic options. Thanks to international cooperation, we can affirm that PCNSL is a potentially curable tumor, especially in young patients. However, several questions remain unanswered: the optimal treatment for elderly patients as well as the management of intraocular and meningeal disease require further scientific efforts. Beside treatments, advances on molecular and radiological diagnostic tools will increase our knowledge of this disease, allowing the possibility to anticipate diagnosis and to better categorize patients' responses. This article analyzes the available literature in this setting and provides evidence-based recommendations for the management of PCNSL patients
Challenging the current approaches to multiple myeloma-related bone disease: from bisphosphonates to target therapy
No full textImplications of recent molecular achievements in early diagnosis and precision treatments for primary CNS lymphoma
No full textIntroduction: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) represents a relevant challenge in onco-hematology. PCNSL has specific molecular profile and biological characteristics that distinguish it from systemic DLBCL. Several translational studies have allowed for significant improvement in the knowledge about its genomic and molecular profile. High-dose-methotrexate-based chemotherapy followed whole-brain irradiation or autologous stem cell transplantation is the most commonly used therapeutic approach in PCNSL patients. Areas covered: This work provides an overview of the new biomarkers of PCNSL, focusing on their potential diagnostic, predictive and prognostic role. Publications in English language, peer-reviewed, high-quality international journals, were identified on PubMed. Expert opinion: Early diagnosis, a better antitumor response definition and recognition of new effective treatments are important research fields aiming to improve PCNSL outcome and management. The acquisition of new molecular and genomic knowledge in PCNSL has allowed for the attainment of promising diagnostic and prognostic tools as well as the development of clinical trials with new therapeutic approaches beyond chemotherapy agents, which have demonstrated activity in refractory/relapsed PCNSL and deserve to be investigated in first-line therapy
Primary central nervous system lymphoma
No full textPrimary central nervous system lymphoma (PCNSL) is a diffuse large B cell lymphoma in which the brain, spinal cord, leptomeninges and/or eyes are exclusive sites of disease. Pathophysiology is incompletely understood, although a central role seems to comprise immunoglobulins binding to self-proteins expressed in the central nervous system (CNS) and alterations of genes involved in B cell receptor, Toll-like receptor and NF-κB signalling. Other factors such as T cells, macrophages or microglia, endothelial cells, chemokines, and interleukins, probably also have important roles. Clinical presentation varies depending on the involved regions of the CNS. Standard of care includes methotrexate-based polychemotherapy followed by age-tailored thiotepa-based conditioned autologous stem cell transplantation and, in patients unsuitable for such treatment, consolidation with whole-brain radiotherapy or single-drug maintenance. Personalized treatment, primary radiotherapy and only supportive care should be considered in unfit, frail patients. Despite available treatments, 15–25% of patients do not respond to chemotherapy and 25–50% relapse after initial response. Relapse rates are higher in older patients, although the prognosis of patients experiencing relapse is poor independent of age. Further research is needed to identify diagnostic biomarkers, treatments with higher efficacy and less neurotoxicity, strategies to improve the penetration of drugs into the CNS, and roles of other therapies such as immunotherapies and adoptive cell therapies
Terminating Evaluation of Logic Programs with Finite Three-Valued Models
No full textAs evaluation methods for logic programs have become more sophisticated, the classes of programs for which
termination can be guaranteed have expanded. From the perspective of answer set programs that include
function symbols, recent work has identified classes for which grounding routines can terminate either on
the entire program [Calimeri et al. 2008] or on suitable queries [Baselice et al. 2009]. From the perspective
of tabling, it has long been known that a tabling technique called subgoal abstraction provides good termination properties for definite programs [Tamaki and Sato 1986], and this result was recently extended
to stratified programs via the class of bounded term-size programs [Riguzzi and Swift 2013]. In this paper
we provide a formal definition of tabling with subgoal abstraction resulting in the SLG
SA algorithm. Moreover, we discuss a declarative characterization of the queries and programs for which SLG
SA terminates. We
call this class strongly bounded term-size programs and show its equivalence to programs with finite wellfounded models. For normal programs strongly bounded term-size programs strictly includes the finitely
ground programs of [Calimeri et al. 2008]. SLG
SA has an asymptotic complexity on strongly bounded termsize programs equal to the best known and produces a residual program that can be sent to an answer set
programming system. Finally, we describe the implementation of subgoal abstraction within the SLG-WAM
of XSB and provide performance results
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