SARS-CoV-2/COVID-19 Testing: The Tower of Babel

Background and aim: Testing represents one of the main pillars of public health response to SARS-CoV-2/COVID-19 pandemic. This paper shows how accuracy and utility of testing programs depend not just on the type of tests, but on the context as well. Methods: We describe the testing methods that have been developed and the possible testing strategies; then, we focus on two possible methods of population-wide testing, i.e., pooled testing and testing with rapid antigen tests. We show the accuracy of split-pooling method and how, in different pre-test probability scenarios, the positive and negative predictive values vary using rapid antigen tests. Results: Split-pooling, followed by retesting of negative results, shows a higher sensitivity than individual testing and requires fewer tests. In case of low pre-test probability, a negative result with antigen test could allow to rule out the infection, while, in case of a positive result, a confirmatory molecular test would be necessary. Conclusions: Test performance alone is not enough to properly choose which test to use; goals and context of the testing program are essential. We advocate the use of pooled strategies when planning population-wide screening, and the weekly use of rapid tests for close periodic monitoring in low-prevalence populations

Venetoclax in combination with hypomethylating agents in previously untreated patients with acute myeloid leukemia ineligible for intensive treatment: a real-life multicenter experience

The addition of venetoclax to hypomethylating agents (HMA-V) improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive treatment. The aim of our study was to confirm data reported in literature, in a real-life multicenter experience. We retrospectively evaluated 56 naive AML patients who received HMA-V at 8 different collaborating Hematology Units in the North-East of Italy, from September 2018 to October 2020. Patients received azacitidine or decitabine at standard dose, adding venetoclax starting from cycle 1-3. The median time-to-response was 2 cycles and composite complete remission rate (CCR) was 67.9%. Thirteen out of 38 responders (34.2%) relapsed, with a median response duration of 13.7 months. Transfusion independence (TI) was obtained in 27 (87.0%) and 28 (90.3%) out of 31 patients for red blood cells and platelets, respectively. Median OS was 12.3 months (95% CI, 8.1-16.5), and median PFS was 11.3 months (95% CI, 4.6-17.9). Cytogenetic risk was the only variable impacting on survival, while no differences were observed stratifying patients by age, bone marrow blasts, WHO classification or type of HMA. In conclusion, our real-life multicenter experience indicates that HMA-V treatment allows achieving good response rates in naive AML patients, ineligible for intensive chemotherapy

Risk Factors and Outcomes of Infections by Multidrug-Resistant Gram-Negative Bacteria in Patients Undergoing Hematopoietic Stem Cell Transplantation

Abstract The objective of this study was to determine risk factors and outcomes of infections by multidrug-resistant gram-negative (MDR GN) bacteria in 241 recipients of hematopoietic stem cell transplantation (HSCT). The cumulative incidence of infections was 10.5% (95% CI, 12.0% to 25.8%), with 57% of infections occurring during the period of severe neutropenia (neutrophil count  6 /L). In multivariate analysis, allogeneic transplant and colonization with MDR GN bacteria at admission to the transplant unit were significantly associated with an increased risk of infection. Although we observed neither transplant-related mortality (TRM) nor deaths due to infections by MDR GN bacteria after autologous transplant, in the allogeneic setting a significant difference was reported in terms of overall survival (OS) and TRM between patients who developed infections and those who did not (1-year OS, 39% versus 68%; 1-year TRM, 42% versus 19%). In multivariate analysis, refractory disease and development of grades III to IV graft-versus-host disease (GVHD) were factors that affected both TRM and OS, whereas occurrence of infections by MDR GN pathogens significantly reduced OS. We conclude that eligibility to allogeneic HSCT in MDR GN bacteria carriers should be carefully evaluated together with all other factors that independently influence outcome (disease status, donor, and GVHD risk)

The baseline comorbidity burden affects survival in elderly patients with acute myeloid leukemia receiving hypomethylating agents: Results from a multicentric clinical study

Background: In older patients with acute myeloid leukemia (AML), the definition of fitness, prognosis, and risk of death represents an open question. Methods: In the present study, we tested the impact on survival of disease- and patient-related parameters in a large cohort of elderly AML patients homogeneously assigned to treatment with hypomethylating agents (HMAs). Results: In 131 patients with a median age of 76 years, we confirmed that early response (<0.001) and biology-based risk classification (p = 0.003) can select patients with better-predicted survival. However, a full disease-oriented model had limitations in stratifying our patients, prompting us to investigate the impact of baseline comorbidities on overall survival basing on a comorbidity score. The albumin level (p = 0.001) and the presence of lung disease (p = 0.013) had a single-variable impact on prognosis. The baseline comorbidity burden was a powerful predictor of patients' frailty, correlating with increased incidence of adverse events, especially infections, and predicted overall survival (p < 0.001). Conclusion: The comorbidity burden may contribute to impact prognosis in addition to disease biology. While the therapeutic armamentarium of elderly AML is improving, a comprehensive approach that combines AML biology with tailored interventions to patients' frailty is likely to fully exploit the anti-leukemia potential of novel drugs

Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters

IntroductionImmunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines.MethodsHere we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation.ResultsWe show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus.DiscussionThese data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20

The Role of Wilms’ Tumor Gene (WT1) Expression as a Marker of Minimal Residual Disease in Acute Myeloid Leukemia

The Minimal Residual Disease(MRD) monitoring in acute myeloid leukemia (AML) is crucial to guide treatment after morphologic complete remission, to define the need for consolidation with allogeneic stem cell transplantation (Allo-SCT), and to detect impending relapse allowing early intervention. However, more than 50% of patients with AML lack a specific or measurable molecular marker to monitor MRD. We reviewed the key studies on WT1 overexpression as a marker of MRD in AML patients undergoing an intensive chemotherapy program, including Allo-SCT. In addition, we provided some practical considerations on how to properly use WT1 expression as an MRD marker, considering its strengths and weaknesses. In order to achieve the best sensitivity and specificity, it is recommended to refer to the standardized method of European LeukemiaNet and its defined threshold (250 WT1 copies/104 Abelson (ABL) on Bone Marrow-BM and 50 WT1 copies/104 ABL on Peripheral Blood-PB), which has been validated in a large and multicenter cohort of patients and normal controls

Effects of disease modifying therapies on brain and grey matter atrophy in relapsing remitting multiple sclerosis

Abstract Background Progressive brain atrophy is a major feature of multiple sclerosis (MS) pathology and is actually considered a major determinant of the progressive accumulation of physical and cognitive disability in MS patients. Although brain atrophy may have different pathological substrates, several lines of evidence suggest that in disease modifying drug (DMD)-treated MS patients, the higher is the anti-inflammatory effect of the DMD the lower is the progression of brain volume loss, grey matter atrophy and the accumulation of disability. Areas covered Magnetic resonance imaging (MRI)-based measurements of inflammation (focal white matter and grey matter lesions) and neurodegeneration (decrease in brain volume, cortical and deep grey matter atrophy) are currently included among the primary or secondary end-points of Phase II and III randomized clinical trials (RCT). This review summarizes literature data on the effects of DMDs on either whole brain or grey matter atrophy emerged from RCT and from post-marketing studies. Commentary Taken all together, literature data show that DMDs are capable to reduce significantly brain inflammation and, although with different degrees of effectiveness, to slow down global brain and/or grey matter atrophy progression. Moreover, the comparison between early and delayed treatments clearly points out that the most relevant effects on brain and grey matter atrophy are observed when DMDs are initiated in the very early disease phases

The parallel analysis of phase sensitive inversion recovery (PSIR) and double inversion recovery (DIR) images significantly improves the detection of cortical lesions in multiple sclerosis (MS) since clinical onset

Double inversion recovery (DIR) detects only a minority (<20%) of cortical lesions (CL) in multiple sclerosis (MS). Phase-sensitive inversion recovery (PSIR) was suggested to be substantially superior to DIR in the detection of cortical lesions (CL). These two sequences might be complementary.To analyze CL frequency and type in MS patients having different disease duration and disability, including patients at clinical onset, and to discern more correctly the artifacts, by combining DIR and PSIR images.40 patients were enrolled in the study: 10 clinically isolated syndrome/early relapsing remitting MS (CIS/eRRMS), 24 relapsing remitting MS (RRMS), 6 secondary progressive MS (SPMS). DIR and PSIR images were jointly used to classify lesions as purely intracortical (IC), leukocortical (LC) and juxtacortical (JC).PSIR disclosed CL in 100% of the patients and was capable of identifying more than four times lesions (455.5%, p<0.00001), especially IC (mean numbers: 36.5 in CIS/eRRMS, 45.0 in RRMS and 52.3 in SPMS) and LC (mean numbers: 10.9 in CIS/eRRMS, 20.1 in RRMS and 25.3 in SPMS), compared to DIR (p<0.00001). CL number was significantly higher in SPMS compared to RRMS (p<0.0001). Artifacts were more accurately identified by comparing the two sequences.Our study confirms the higher ability of PSIR in disclosing and classifying CL. The presence of CL in all CIS patients further points out the relevance of cortical pathology in MS. Whether the parallel analysis of DIR and PSIR images may be useful for diagnostic purposes, especially when a diagnosis of MS is suspected but not confirmed by routine MRI, needs to be evaluated in larger patient series. The analysis of the cortex by DIR and PSIR may also allow a better stratification of the patients for prognostic and counseling purposes, as well as for their inclusion in clinical studies