Management of patients with lymphoma and COVID-19: Narrative review and evidence-based practical recommendations

Patients with hematologic malignancies can be immunocompromized because of their disease, anti-cancer therapy, and concomitant immunosuppressive treatment. Furthermore, these patients are usually older than 60 years and have comorbidities. For all these reasons they are highly vulnerable to infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and have an increased risk of developing severe/critical Coronavirus disease 2019 (COVID-19) compared to the general population. Although COVID-19 vaccination has proven effective in reducing the incidence of severe/critical disease, vaccinated patients with lymphoma may not be protected as they often fail to develop a sufficient antiviral immune response. There is therefore an urgent need to address the management of patients with lymphoma and COVID-19 in the setting of the ongoing pandemic. Passive immunization with monoclonal antibodies against SARS-CoV-2 is a currently available complementary drug strategy to active vaccination for lymphoma patients, while monoclonal antibodies and antiviral drugs (remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir) have proven effective in preventing the progression to severe/critical COVID-19. In this narrative review we present the most recent data documenting the characteristics and outcomes of patients with concomitant lymphoma and COVID-19. Our ultimate goal is to provide practice-oriented guidance in the management of these vulnerable patients from diagnosis to treatment and follow-up of lymphoma. To this purpose, we will first provide an overview of the main data concerning prognostic factors and fatality rate of lymphoma patients who develop COVID-19; the outcomes of COVID-19 vaccination will also be addressed. We will then discuss current COVID-19 prophylaxis and treatment options for lymphoma patients. Finally, based on the literature and our multidisciplinary experience, we will summarize a set of indications on how to manage patients with lymphoma according to COVID-19 exposure, level of disease severity and former history of infection, as typically encountered in clinical practice

Endovascular treatment of carotid artery stenosis: evidences from randomized controlled trials and actual indications

Atherosclerotic stenosis of common and internal carotid arteries is a well-recognized risk factor for ischemic stroke, and revascularization has been proven to be the main tool of prevention, particularly for patients with stenosis- related symptoms. While for many years surgical carotid endarterectomy (CEA) has been considered the gold-standard strategy to restore vascular patency, recently the endovascular treatment through percutaneous angioplasty and stent implantation (CAS) has become a valid alternative. In the last years, interesting data about the comparison of these strategies have emerged. CAS seems to cause more peri-procedural strokes, but may also avoid many adverse events related to surgery and general anaesthesia, including peri-procedural myocardial infarction. For these reasons, it was initially considered a second-choice strategy to be adopted in patients for whom surgery was contraindicated. However, more recent trials have shown that CAS might be considered an effective alternative to CEA. Moreover, the rapid evolution of CAS technique and materials suggests its potential to improve outcome and possible superiority compared to CEA in the next future. Purpose of this review is to discuss the most recent clinical evidences concerning the treatment of carotid artery stenosis, with a special focus on the endovascular treatment

Early progression as a predictor of survival in marginal zone lymphomas: An analysis from the FIL-NF10 study

Marginal zone lymphomas (MZLs) are indolent nonfollicular B-cell lymphomas (INFLs) and have heterogeneous clinical behavior. Recently, time to progression of disease at 24 months (POD24) was identified to stratify overall survival (OS) in follicular non-Hodgkin lymphoma and in INFL. Here, we examined the ability of POD24 to predict subsequent OS in a large, international cohort of MZL as part of the NF10 prospective international registry headed by Fondazione Italiana Linfomi (FIL). POD24 was only calculated for MZL patients requiring immediate therapy and was defined as experiencing lymphoma progression within 24 months from diagnosis. Among the 1325 patients enrolled in the NF10 study, we identified 321 patients with MZL for whom immediate therapy was planned right after lymphoma diagnosis. Overall, POD24 was confirmed in 59 patients (18%). Three-year OS for patients with POD24 was 53% with a hazard ratio of 19.5 (95% confidence interval, 8.4-45) compared with patients without POD24 (3-year OS, 95%). Association of POD24 with OS was confirmed for the subgroup of splenic and extranodal MZLs. Assessment of POD24 stratifies subsequent outcome inMZL and identifies a high-risk population

Lenalidomide in Pretreated Mantle Cell Lymphoma Patients: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice (the Lenamant Study)

Background: Mantle cell lymphoma (MCL) has the worst prognosis of B-cell subtypes owing to its aggressive clinical disease course and incurability with standard chemo-immunotherapy. Options for relapsed MCL are limited, although several single agents have been studied. Lenalidomide is available in Italy for patients with MCL based on a local disposition of the Italian Drug Agency. Subjects, Materials, and Methods: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use in real practice. Results: Seventy patients received lenalidomide for 21/28 days with a median of eight cycles. At the end of therapy, there were 22 complete responses (31.4%), 11 partial responses, 6 stable diseases, and 31 progressions, with an overall response rate of 47.1%. Eighteen patients (22.9%) received lenalidomide in combination with either dexamethasone (n = 13) or rituximab (n = 5). Median overall survival (OS) was reached at 33 months and median disease-free survival (DFS) at 20 months: 14/22 patients are in continuous complete response with a median of 26 months. Patients who received lenalidomide alone were compared with patients who received lenalidomide in combination: OS and DFS did not differ. Progression-free survivals are significantly different: at 56 months, 36% in the combination group versus 13% in patients who received lenalidomide alone. Toxicities were manageable, even if 17 of them led to an early drug discontinuation. Conclusion: Lenalidomide therapy for relapsed MCL patients is effective and tolerable even in a real-life context. Implication for Practice: Several factors influence treatment choice in relapsed/refractory mantle cell lymphoma (rrMCL), and the therapeutic scenario is continuously evolving. In fact, rrMCL became the first lymphoma for which four novel agents have been approved: temsirolimus, lenalidomide, ibrutinib, and bortezomib. The rrMCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for rrMCL patients is effective and tolerable even in a real-life context

Guideline on carotid surgery for stroke prevention: updates from the Italian Society of Vascular and Endovascular Surgery. A trend towards personalized medicine

Background: This guideline (GL) on carotid surgery as updating of "Stroke: Italian guidelines for Prevention and Treatment" of the ISO-SPREAD Italian Stroke Organization-Group, has recently been published in the National Guideline System and shared with the Italian Society of Vascular and Endovascular Surgery (SICVE) and other Scientific Societies and Patient's Association. Methods: GRADE-SIGN version, AGREE quality of reporting checklist. Clinical questions formulated according to the PICO model. Recommendations developed based on clinical questions by a multidisciplinary experts' panel and patients' representatives. Systematic reviews performed for each PICO question. Considered judgements filled by assessing the evidence level, direction, and strength of the recommendations. Results: The panel provided indications and recommendations for appropriate, comprehensive, and individualized management of patients with carotid stenosis. Diagnostic and therapeutic processes of the best medical therapy, carotid endarterectomy (CEA), carotid stenting (CAS) according to the evidences and the judged opinions were included. Symptomatic carotid stenosis in elective and emergency, asymptomatic carotid stenosis, association with ischemic heart disease, preoperative diagnostics, types of anesthesia, monitoring in case of CEA, CEA techniques, comparison between CEA and CAS, post-surgical carotid restenosis, and medical therapy are the main topics, even with analysis of uncertainty areas for risk-benefit assessments in the individual patient (personalized medicine [PM]). Conclusions: This GL updates on the main recommendations for the most appropriate diagnostic and medical-surgical management of patients with atherosclerotic carotid artery stenosis to prevent ischemic stroke. This GL also provides useful elements for the application of PM in good clinical practice

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study

Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19

2009

ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o n BCL2 translocations are more frequently found in the GCB subtype, whereas 18q21 locus amplification is more common in the ABC subtype of DLBCL. 3, Design and Methods Patients We studied 327 cases of previously untreated de novo DLBCL, diagnosed between January 2002 and October 2009, and collected as part of the International DLBCL Rituxan-CHOP Consortium Program Study. These cases were analyzed for Bcl-2 protein expression, and BCL2 and MYC gene abnormalities, and gene expression profiling (GEP) was performed. All cases were reviewed by a group of hematopathologists (SMM, MAP, MBM, AT, and KHY), and the diagnoses were confirmed based on World Health Organization classification criteria. Patients with transformation from low grade lymphoma, those with composite follicular lymphoma, primary mediastinal large B-cell lymphoma, primary cutaneous and primary central nervous system DLBCL were excluded from the analysis due to the unique biological features of these types of lymphoma. All patients were adults who were negative for human immunodeficiency virus and had sufficient clinical data and clinical follow-up. Patients in this study were treated with R-CHOP (n=291, 89%) or R-CHOP-like regimens (n=36, 11%; CHOP scheme adopting different anthracyclines i.e. novantrone or epirubicin). All patients with advanced stage disease received six (92%) or eight (8%) cycles, every 21 days, with or without radiotherapy for residual disease or initial bulky disease; localized cases received at least three cycles followed by radiotherapy or six cycles without radiotherapy. The current study was approved by each of the participating centers' Institutional Review Boards, and the overall collaborative study was approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center in Houston, Texas, USA. Immunohistochemistry for Bcl-2 and cut-off determination Bcl-2 protein expression was evaluated in all patients using a monoclonal anti-Bcl-2 antibody (Clone-124, Dako, Carpinteria, CA, USA) and standard immunohistochemical methods. The formalin-fixed, paraffin-embedded tissue slides underwent deparaffinization and heat-induced antigen retrieval techniques. An endogenous biotin-blocking kit (Ventana) was used to decrease background staining. Following antigen retrieval and primary antibody incubation, the reaction was completed in a Ventana ES instrument using a diaminobenzidine immunoperoxidase detection kit (Ventana). Immunoreactivity was determined without knowledge of the patients' survival, clinical data, or GEP data. The samples were analyzed independently by a group of four hematopathologists/pathologists in addition to the hematopathologist of each of the contributing centers, and disagreements were resolved by joint review at a multi-headed microscope. An average of 300-400 cells in four to five fields were counted in the tissue microarray cores. A percentage of tumor cell staining ≥50% was considered positive after receiver operating characteristic (ROC) curve analysis was implemented to assess the discriminatory accuracy of Bcl-2 protein in recognizing patients with different overall survival (OS) and progression-free survival (PFS). The 50% value was established from the analysis of the area under the ROC curve (AUROC) and had the maximum specificity and sensibility for OS and PFS discrimination in our patients (AUROC=0.564, P=0.017 for OS and AUROC=0.564, P=0.015 for PFS). 31 Gene expression profiling analysis RNA was extracted from 327 formalin-fixed, paraffin-embedded tissue samples using a HighPure Paraffin RNA Extraction Kit (Roche Applied Science). Fifty nanograms of RNA were transcribed into cDNA, linearly amplified using the WT-Ovation™ FFPE System (Nugen), and biotin-labeled using FL-Ovation™ cDNA Biotin Module V2 (Nugen) in all cases. For GeneChip hybridization, 5 μg of WT-Ovation amplified cDNA were applied to HG-U133 Plus 2.0 GeneChips (Affymetrix) and hybridized overnight. GeneChips were washed, stained, and scanned using the Fluidic Station 450 and GeneChip Scanner 3000 (Affymetrix) according to the manufacturer's recommendations. For data analysis and classification, the microarray DQN (trimmed mean of differences of perfect match and mismatch intensities with quantile normalization) signals were generated and normalized to the quantiles of beta distribution with parameters p=1.2 and q=3 as previously described. 32 A Bayesian model was also utilized to determine the class probability. The classification model was built on the 47 paired formalin-fixed, paraffin-embedded tissue sample dataset previously generated with a confidence rate of 90-100% in fresh frozen tissue and 92-100% in formalin-fixed, paraffinembedded tissue. The same methodology developed during this study has been validated and demonstrated to be applicable by using the LLMPP dataset in the Gene Expression Omnibus (GEO) database GSE#10846 that has 181 CHOP-treated and 233 R-CHOP-treated DLBCL patients with fresh-frozen samples. 3, Validation set To validate our observations in predicting survival in an independent series of cases, we analyzed a second group of 120 archival DLBCL cases studied similarly to the first cohort except for MYC analysis that was not available (GCB 49%, ABC 40%, unclassified 11%; BCL2 translocations in 18%; Bcl-2 overexpression in 54%). All these patients had been treated with R-CHOP and the same selection criteria as those for the first cohort were applied. The clinical characteristics at presentation of the patients in the validation set were not significantly different from those of the patients in the test set. Statistical analysis Following pre-defined criteria, 33 PFS was measured from the time of diagnosis to the time of progression or death from any cause. OS was measured from the time of diagnosis to last followup or death from any cause. Only patients with a follow-up of longer than 12 months were included in the survival analysis. The actuarial probabilities of PFS and OS were determined using the Kaplan-Meier method, and differences were compared using the log-rank test. A Cox proportional-hazards model was used for multivariate analysis. The χ 2 test or Mann-Whitney test was applied to assess differences between variables. The interobserver agreement for FISH was assessed using the κ statistic; a κ value of >0.75 implied excellent agreement. All statistical calculations, except for ROC and the κ statistic which were performed with SPSS 18.0 (SPSS Inc., Chicago, IL, USA), were conducted using StatView (Abacus Concepts, Berkeley, CA, USA). Results Patients' characteristics and outcome The median age of the patients at diagnosis was 62 years (range, 18-86). Their clinical characteristics are reported in BCL2 and MYC genes in the subgroups defined by gene expression profiling Sixty patients (18.3%) had DLBCL with BCL2 gene translocations, and 50 (15.3%) had BCL2 gene amplifications. The presence of BCL2 translocations was not associated with any clinical prognostic variable at diagnosis, except for Ann Arbor Stage (70% versus 49% with stage III-IV, P=0.004), as shown in The OS and PFS rates of patients with BCL2 translocations were similar to those of patients without BCL2 translocations, irrespectively of MYC status. When we restricted the analysis to the GCB subtype, patients with BCL2 translocations alone, in the absence of MYC breaks, had a significantly worse outcome than GCB patients without BCL2 translocations (3-year PFS of 53% versus 76%, respectively; P=0.0002). The outcome of patients with BCL2 rearranged GCB subtype was similar to that of the patients with the ABC subtype of DLBCL (52%, P=0.30), but still better than that of the patients with double hit lymphomas (P<0.0001, The presence of MYC breaks alone in the 19 patients without concomitant BCL2 translocations was not associated with impaired PFS (P=0.70) or OS (P=0.66) in the whole cohort, but was associated with inferior OS (P=0.03), but not PFS (P=0.22), in patients with GCB-DLBCL (only 9 with isolated MYC breaks). As shown in BCL2 gains were not prognostic in any of the subgroups of patients. Particular consideration of high-level amplifications was of no additional prognostic value. Bcl-2 protein expression, clinical characteristics, fluorescence in situ hybridization and gene expression profiling None of the common clinical characteristics of our patients at the time of presentation was significantly associated with Bcl-2 protein expression except age, with older patients more often being Bcl-2 positive (≥60 years old, P=0.02). Bcl-2 protein expression in GEP-and FISHdefined subgroups is shown in © F e r r a t a S t o r t i F o u n d a t i o n patients without the BCL2 translocation (range, 0-100%; median 60%). Bcl-2 protein expression was significantly associated with worse PFS (P=0.01) and OS (P=0.02) in the whole cohort, but when patients were divided according to GEPdefined subtypes, we observed that higher Bcl-2 expression was associated with significantly inferior PFS in the GCB subgroup (P=0.04), but not in the ABC subgroup (P=0.57), as shown in Multivariate analysis Multivariate analysis of all 137 patients with the GCB subtype of DLBCL showed that BCL2 translocations (HR 0.40, 95% CI: 0.18-0.89; P=0.02), but not Bcl-2 expression (HR 1.01, 95% CI: 0.45-2.21; P=0.98), MYC breaks (HR 0.25, 95% CI: 0.10-0.59; P=0.001), and IPI score (HR 0.41, 95% CI: 0.20-0.84; P=0.01), were independently associated with patients' outcome. Results were not modified after each molecular feature was computed with age as a continuous parameter. C. Visco et al. 258 haematologica | 2013; 98(2) Overall survival Progression-free survival Four-hundred and forty-four genes were found to be differentially expressed (>1.5 fold and P<0.005) in DLBCL patients with or without BCL2 translocations including both GCB and ABC subtypes. In the GCB group, however, only 43 genes were differentially expressed among patients with and without BCL2 translocations ( Interestingly, a number of genes overexpressed in the BCL2 translocated group are involved in the control of angiogenesis and the inflammatory response (AIMP1, PPIA, and ALOX), while others are involved in promoting apoptosis or regulating B-cell signaling (STK17A, RAL-GPS2, NCOA3, STRBP, and ZNF117). 35-37 C. Visco et al. 260 haematologica | 2013; 98(2) © F e r r a t a S t o r t i F o u n d a t i o n Discussion We addressed the clinical impact of BCL2 aberrations and their relationship to Bcl-2 protein expression in a large series of patients with DLBCL homogeneously treated with R-CHOP, with known MYC gene status and molecularly characterized according to GEP analysis. We were able to establish the role of the BCL2 gene in different subtypes of DLBCL, irrespectively of concomitant MYC aberrations. We found that isolated BCL2 translocations, in the absence of MYC breaks, were associated with a poor outcome in the subset of patients with GCB-DLBCL, and that the prognosis of these patients was similar to that of patients with ABC-DLBCL. The concomitant presence of MYC breaks (double hit lymphoma) further worsened the outcome of these patients. The role of Bcl-2 protein expression appeared dependent on its association with BCL2 translocations, as outlined by multivariate analysis and survival curves As determined by FISH break apart probe analysis, the overall frequency of BCL2 translocations in de novo DLBCL was 18.3%. The BCL2 translocations were almost exclusively associated with GCB-DLBCL, found in 34.5% of cases The impact of BCL2 translocations on survival in our series could not be explained by differences in the clinical features of the patients because there was no association between the presence of BCL2 translocations and IPI risk groups (P=0.90, A C B FIGURE A COLORI SOLO ONLINE © F e r r a t a S t o r t i F o u n d a t i o n with isolated BCL2 or MYC lesions. Confirming previous findings, In this series, Bcl-2 protein was overexpressed in half of the patients with GCB-DLBCL and in 72% of patients with ABC-DLBCL 18,39 However, Bcl-2 overexpression had prognostic value only in the GCB subtype, as already observed by others in the era of R-CHOP therapy. Iqbal et al. 22 Secondly, Bcl-2 protein expression in Iqbal's study was significantly associated with adverse clinical prognostic factors (stage III-IV, elevated lactate dehydrogenase, high IPI risk group) in GCB-DLBCL, which was not the case in our study. Finally, no mention was made about exclusion of possibly confounding DLBCL subtypes such as double hit lymphoma, primary cutaneous or primary central nervous system DLBCL. We also acknowledge that different findings in the literature regarding BCL2 rearrangements or protein expression could very well be related to lack of uniformity between different studies in terms of Bcl-2 staining and scoring. Moreover, patients' characteristics in the different series, differences in the management of the cases as they were not in clinical trials, data collection regarding outcome, and sometimes short follow-up times may also have contributed to different results. Our GEP analysis revealed that patients with BCL2 translocations substantially differed with respect to important recurrent oncogenic events, which may contribute to the adverse outcome of the subgroup of GCB-DLBCL patients with BCL2 translocations. Up-regulation of the BCL11A gene occurred exclusively in the group of patients with BCL2 translocations We confirm that the outcome of GCB-DLBCL patients should be interpreted in the context of abnormalities of the MYC and BCL2 genes. While the MYC rearrangement is quite rare, it is rarely found as the sole genetic abnormality, and its clinical relevance is mainly related to a double hit mechanism, BCL2 rearrangements are present in a considerable fraction of patients with the GCB subtype who have similar outcomes to those of patients with the ABC subtype. Our results confirm that the GCB and ABC subtypes of DLBCL have distinct pathogeneses, and support the rationale for further classification of different subgroups. © F e r r a t a S t o r t i F o u n d a t i o n Funding CV is a hematologist supported by Sa

An Open-Source, Low-Cost Apparatus for Conductivity Measurements Based on Arduino and Coupled to a Handmade Cell

Electrical conductivity is one of the main parameters for the characterization of water solutions and for the monitoring of water sources. In this paper, we describe a very inexpensive prototype for conductivity measurements based on Arduino UNO R3 coupled to an open-source circuit board with only passive components. We designed the printed circuit board (PCB) and the suitable handmade cell using stainless-steel electrodes and wrote the freeware management software; the assembly of the prototype, including a temperature probe, and results were relatively simple. In order to allow for replicates, the instrument design, schematics, and software are available with an open-source license. Thirty-one bottles of spring waters with conductivities of between 15.2 and 2000 µS cm−1 were tested using both this prototype and a commercial conductivity meter. Data correlation produced an equation that allowed us to obtain the conductivity value, starting with the value furnished by the Arduino apparatus in arbitrary units. The prototype is accurate enough (inaccuracy lower than 6% excluding very low conductivity values) and precise (RSD% of about 5%). Even if a lot of commercial instruments for conductivity are available, we propose a prototype built with the aim of lowering the cost of measurements, while ensuring that they remain useful for lab or in situ application, as well as for continuous water monitoring/management systems. A further aim was to propose the building of the instrument as a laboratory exercise; this can help students to better understand basic theoretical concepts regarding conductivity, electronic components, and the acquisition and treatment of analytical data

Iron stains on paper. Can electrophoretic removal become an effective alternative to chemical cleaning?

Research in restoration and conservation is directed vs. more sustainable working materials, methods and technologies. Electrophoretic removal, from porous material, of undesired stains due to charged species is theoretically an interesting alternative to chemical cleaning methods, but the lack of specific and comprehensive research work leads to controversial opinions about the efficiency and the needed harmfulness for the treated objects. In this work paper, samples with artificial rust stains were subjected to electrophoretic cleaning treatments in mineral water as electrolyte. Treatments were carried out either in a bath by complete sample immersion between the distanced electrodes or by sample wetting and sandwiching between the electrodes. Evaluation of cleaning efficiency and treatment effects was based on colour change measurements (image analysis of scanned paper samples before and after the treatment and by colorimetric data via spectrophotometric measurements), investigation of morphological changes by SEM observations and folding endurance measurements