Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) ...activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis.
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•GS expression and activity are induced by M2 stimuli, especially under starvation•Inhibition of GS activity skews M2 macrophages toward an M1-like phenotype•Metabolic rewiring by GS loss favors immunostimulatory and antiangiogenic features•GS ablation in macrophages blocks vessels, immunosuppression, and metastasis
Palmieri et al. show that inhibiting glutamine synthetase activity in M2 macrophages skews their polarization toward an HIF1α-mediated M1 state, which impairs cytotoxic T cell recruitment and angiogenesis. As a consequence of a more pronounced immunostimulatory and antiangiogenic effect, GS ablation in macrophages translates into prevention of metastasis.
Cancer patients are a population at high risk of contracting COVID-19 and, also of developing severe complications due to the infection, which is especially true when they are undergoing ...immunosuppressive treatment. Despite this, they had still to go to hospital to receive chemotherapy during lockdown. In this context, we have evaluated the psychological status of onco-hematological outpatients receiving infusion and not deferrable anti-neoplastic treatment for lymphoproliferative neoplasms, with the aim of both measuring the levels of post-traumatic symptoms, depression, and anxiety during the pandemic and also of investigating the perception of risk of potential nosocomial infection. The Impact of Event Scale-Revised (IES-R) and the Hospital Anxiety and Depression Scale (HADS) were administered to all patients. Moreover, patients were investigated about their worries regarding the impact of COVID-19 on their lives as onco-hematologic patients. Since the 2nd to the 29th April 2020 (during the first phase of the lockdown period in Italy), 77 outpatients were prospectively evaluated. They were diagnosed with non-Hodgkin's lymphoma, classical Hodgkin lymphoma, and Chronic lymphocytic leukemia/Small lymphocytic lymphoma. The mean age was 56.6 (range 22-85). We found that 36% of patients had anxiety (HADS-A), 31% depression (HADS-D), and 43% were above the cut-off for the HADS-General Scale; 36% fulfilled the diagnostic criteria for post-traumatic stress disorder (PTSD). Women and younger patients were found to be more vulnerable to anxiety and PTSD. The study firstly analyzes the psychological impact of the COVID-19 pandemic on the frail population of patients affected by lymphoproliferative neoplasms, to underly the importance of screening patients for emotional and distress conditions and then offering them psychological support.
The topic of fertility preservation in patients with a lymphoproliferative disease offers new aspects of debate, due to the introduction of novel chemotherapeutic regimens and small molecules in the ...clinical landscape. Cancer related infertility is mostly dependent on gonadotoxic treatments and fertile female patients are today addressed to the oocyte cryopreservation or to ovarian cortex fragment cryopreservation. These methods present advantages and disadvantages, which will be discussed in the present review, together with the options for male patients. The recent discovery of functional ovarian stem cells (OCSs) in woman ovarian cortex, opens new avenues offering a innovative procedure for fertility preservation through as model of regenerative medicine. Here, we review the gonadotoxic potential of “classical” chemotherapeutic treatments as well as of “novel” targeted therapies actually employed for lymphoproliferative neoplasms in young patients and revisit both the today available and future chances to preserve and restore fertility after the cancer healing.
Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. However, its effectiveness ...and safety profile in real clinical practice should be further assessed. We retrospectively evaluated 130 consecutive RRMM patients treated with KRd between December 2015 and August 2018, in 9 Hematology Departments of Rete Ematologica Pugliese (REP). The overall response rate (ORR) was 79%, with 37% complete response (CR). Treatment with KRd led to an improvement in response regardless of age, refractory disease, and number and type of previous therapies. After a median follow-up of 18 months, median PFS was 24 months and 2y-PFS was 54%. PFS was longer in patients achieving a very good partial response (VGPR) with median PFS of 32.4 months. The relapses after prior autologous transplant (ASCT) positively impact median PFS. Several baseline disease characteristics, such as III ISS scoring or elevated LDH, and prior exposure to lenalidomide were found to negatively impact PFS. Primary refractory or relapsed myeloma patients have been treated with KRd as bridge to ASCT with a great benefit. Thirty-four (83%) reached at least a partial response after KRd and 21 (61%) performed ASCT. In transplanted patients, median PFS was not reached and 2y-PFS was 100%. The treatment discontinuation rate due to adverse events (AEs) was 18%, most commonly for lenalidomide (11%). Overall, in 10% of patients, a KRd dose reduction was necessary at least once (2.5% for carfilzomib and 8% for lenalidomide). The most frequent AE was neutropenia (44%) and anemia (41%). Infections occurred in 14% of patients. Cardiovascular events occurred in 11% of patients. Elderly patients have tolerated therapy very well, without additional side effects compared to younger patients, except for cardiac impairment. Our analysis confirmed that KRd is effective in RRMM patients. It is well tolerated and applicable to the majority of patients outside clinical trials. A longer PFS was shown in patients achieving VGPR, in those lenalidomide naïve and in patients relapsing after previous ASCT. Previous ASCT should not hamper the option for KRd therapy. Accordingly, KRd should be used as bridge regimen to ASCT with remarkable improvement in response and PFS rates. Further clinical studies are needed.
Polycythemia vera (PV) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow, ...mainly due to a Janus kinase 2 gene mutation (JAK2
). Givinostat, a histone-deacetylase inhibitor that selectively targets JAK2
cell growth, has demonstrated good efficacy and safety in three phase 1/2 studies in patients with PV. This manuscript focuses on the 4-year mean (2.8 year median) follow-up of an open-label, long-term study that enrolled 51 patients with PV (out of a total of 54 with MPN) who received clinical benefit from givinostat in these previous studies or on compassionate use, and who continued to receive givinostat at the last effective and tolerated dose. The primary objectives are to determine givinostat's long-term safety and tolerability, and efficacy evaluated by the investigators according to internationally recognized response criteria. During follow-up, only 10% of PV patients reported Grade 3 treatment-related adverse events (AEs), while none had Grade 4 or 5 treatment-related AEs. The overall response rate for the duration of follow-up was always greater than 80% in patients with PV. In conclusion, givinostat demonstrated a good safety and efficacy profile in patients with PV, data supporting long-term use in this population.
Summary Background Chemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone ...is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma. Methods This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18–75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3·5 g/m2 on day 1 (n=40) or methotrexate 3·5 g/m2 on day 1 plus cytarabine 2 g/m2 twice a day on days 2–3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00210314. Findings All randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6–30) and 46% (31–61), respectively, (p=0·006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25–55) and 69% (55–83), respectively, (p=0·009). Grade 3–4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 92% vs six 15%). Four patients died of toxic effects (three vs one). Interpretation In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone. Funding Swiss Cancer League.
The unstructured nature of Real-World (RW) data from onco-hematological patients and the scarce accessibility to integrated systems restrain the use of RW information for research purposes. Natural ...Language Processing (NLP) might help in transposing unstructured reports into standardized electronic health records. We exploited NLP to develop an automated tool, named ARGO (Automatic Record Generator for Onco-hematology) to recognize information from pathology reports and populate electronic case report forms (eCRFs) pre-implemented by REDCap. ARGO was applied to hemo-lymphopathology reports of diffuse large B-cell, follicular, and mantle cell lymphomas, and assessed for accuracy (A), precision (P), recall (R) and F1-score (F) on internal (n = 239) and external (n = 93) report series. 326 (98.2%) reports were converted into corresponding eCRFs. Overall, ARGO showed high performance in capturing (1) identification report number (all metrics > 90%), (2) biopsy date (all metrics > 90% in both series), (3) specimen type (86.6% and 91.4% of A, 98.5% and 100.0% of P, 92.5% and 95.5% of F, and 87.2% and 91.4% of R for internal and external series, respectively), (4) diagnosis (100% of P with A, R and F of 90% in both series). We developed and validated a generalizable tool that generates structured eCRFs from real-life pathology reports.
Advances in diagnosis and treatment of hematological malignancies has boosted attention on optimal follow-up care of survivors after cancer. To collect evidence that could inform the development of ...an optimal model for Italian hematology centers and the scientific community, Fondazione Italiana Linfomi (FIL) commissioned an analysis of the international follow-up approaches for long-term survivors after classical Hodgkin lymphoma (cHL) or diffuse large B-cell lymphoma (DLBCL). FIL set up multidisciplinary teams, representing all different skills relevant for cancer survivors. They conducted a series of systematic reviews focused on three main aspects: incidence of long-term toxicity; comparison of old or standard therapies and more recent ones; and evidence on specific follow-up approaches. The teams applied this framework to cardiological, endocrine-metabolic, neurological/cognitive, and psychological disorders, secondary cancers, fertility preservation, and lifestyles. Each team conducted comprehensive literature searches on PubMed, Embase and Cochrane Library databases up to 2020. Screening followed the PRISMA statement for reporting systematic reviews. The reviews report the results of this wide project covering the main areas of late toxicity and conditions in the long-term survival of cHL and DLBCL patients and their follow-up. From a clinical point of view, the series confirmed that the evidence on follow-up tended to focus on solid tumors with scant evidence on hematological malignancies.
The potential for visually detectable clinical signs of anaemia and their correlation with the severity of the pathology have supported research on non-invasive prevention methods. Physical ...examination for a suspected diagnosis of anaemia is a practice performed by a specialist to evaluate the pallor of the exposed tissues. The aim of the research presented herein is to quantify and minimize the subjective nature of the examination of the palpebral conjunctiva, suggesting a method of diagnostic support and autonomous monitoring. Here we describe the methodology and system for extracting key data from the digital image of the conjunctiva, which is also based on analysis of the dominant colour classes. Effective features have been used herein to establish the inclusion of each image in a diagnosis probability class for anaemia. The images of the conjunctiva were taken using a new low cost and easy to use device, designed to optimize the properties of independence from ambient light. The performance of the system was tested either by extracting manually the palpebral conjunctiva from images or by extracting them in a semi-automatic way based on the SLIC Superpixel algorithm. Tests were conducted on images obtained from 102 people. The dataset was unbalanced, since many more samples of healthy people were available, as often happens in the medical field. The SMOTE and ROSE algorithms were evaluated to balance the dataset, and some classification algorithms for assessing the anaemic condition were tested, yielding very good results. Taking a photo of the palpebral conjunctiva can aid the decision whether a blood sample is needed or even whether a patient should inform a physician, considerably reducing the number of candidate subjects for blood sampling. It also could highlight the suspected anaemia, allowing screening for anaemia in a large number of people, even in resource-poor settings.
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