The diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) and, despite all the progress in this field, central nervous system infiltration (CNSi) still occurs at ...an incidence of 2–10%. The objective of the present study was to evaluate the Central Nervous System International Prognostic Index (CNS-IPI) score in daily practice regarding the reproducibility in a heterogeneous cohort apart from a clinical trial.
Primary DLBCL patients were eligible for this study, between January 2007 and January 2017. All patients were treated with rituximab-based chemotherapy, mostly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The CNSi was diagnosed by liquor (positive cytology and/or immunophenotype), computerized tomography, magnetic resonance image and/or fluorodeoxy-glucose-positron emission tomography, requested only in symptomatic patients when the CNSi was clinically suspected. The CNS-IPI was assessed by graphical comparison and calibration.
After applying the inclusion/exclusion criteria, 322 patients were available for the analysis. The median follow-up was 60 months and the median age was 58 years. Seven patients experienced CNSi, characterizing an incidence of 2.17% (7/322). Comparing groups of patients with and without CNSi, we observed that the lactate dehydrogenase (LDH), number of extranodal sites, IPI, kidney/adrenal and absence of complete response were statistically different. The CNS-IPI model stratified patients in a three-risk group model as low-, intermediate- and high-risk. In our cohort, using the same stratification, we obtained an equivalent the 2-year rate of CNS relapse of 0.0%, 0.8% and 13.8%, respectively.
Our study reinforces the reproducibility of the CNS-IPI, specifically apart from clinical trials, and suggests the CNS-IPI score as a tool to guide therapy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic lymphocytic leukaemia (CLL) has a highly variable clinical course. In addition to biological factors, socioeconomic factors and health system characteristics may influence CLL outcome. Data ...from the Brazilian Registry of CLL were analyzed to compare clinical and treatment‐related characteristics in patients with CLL, from public or private institutions. A total of 3326 patients from 43 centres met the eligibility criteria, of whom 81% were followed up at public hospitals and 19% at private hospitals. The majority were male (57%), with a median age of 65 years. Comparing public and private hospitals, patients in public hospitals were older, had more advanced disease at diagnosis, and more frequently had elevated creatinine levels. All investigated prognostic markers were evaluated more often in private hospitals. First‐line treatment was predominantly based on chlorambucil in 41% of the cases and fludarabine in 38%. Anti‐CD20 monoclonal antibody was used in only 36% of cases. In public hospitals, significantly fewer patients received fludarabine‐based regimens and anti‐CD20 monoclonal antibodies. Patients from public hospitals had significantly worse overall survival (71% vs. 90% for private hospitals, p < 0.0001) and treatment‐free survival (32% vs. 40%, for private hospitals, p < 0.0001) at seven years. Our data indicate striking differences between patients followed in public and private hospitals in Brazil. A worse clinical condition and lack of accessibility to basic laboratory tests and adequate therapies may explain the worse outcomes of patients treated in public institutions.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cardiovascular comorbidities and immune-response dysregulation are associated with COVID-19 severity. We aimed to explore the key immune cell profile and understand its association with disease ...progression in 156 patients with hypertension that were hospitalized due to COVID-19. The primary outcome was progression to severe disease. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and immune cell subsets associated with the primary outcome. Obesity; diabetes; oxygen saturation; lung involvement on computed tomography (CT) examination; the C-reactive protein concentration; total lymphocyte count; proportions of CD4+ and CD8+ T cells; CD4/CD8 ratio; CD8+ HLA-DR MFI; and CD8+ NKG2A MFI on admission were all associated with progression to severe COVID-19. This study demonstrated that increased CD8+ NKG2A MFI at hospital admission, in combination with some clinical variables, is associated with a high risk of COVID-19 progression in hypertensive patients. These findings reinforce the hypothesis of the functional exhaustion of T cells with the increased expression of NKG2A in patients with severe COVID-19, elucidating how severe acute respiratory syndrome coronavirus 2 infection may break down the innate antiviral immune response at an early stage of the disease, with future potential therapeutic implications.
Comorbidities such as obesity, hypertension, and diabetes are associated with COVID-19 development and severity, probably due to immune dysregulation; however, the mechanisms underlying these ...associations are not clear. The immune signatures of hypertensive patients with obesity with COVID-19 may provide new insight into the mechanisms of immune dysregulation and progression to severe disease in these patients.
Hypertensive patients were selected prospectively from a multicenter registry of adults hospitalized with COVID-19 and stratified according to obesity (BMI ≥ 30 kg/m²). Clinical data including baseline characteristics, complications, treatment, and 46 immune markers were compared between groups. Logistic regression was performed to identify variables associated with the risk of COVID-19 progression in each group.
The sample comprised 213 patients (89 with and 124 without obesity). The clinical profiles of patients with and without obesity differed, suggesting potential interactions with COVID-19 severity. Relative to patients without obesity, patients with obesity were younger and fewer had cardiac disease and myocardial injury. Patients with obesity had higher EGF, GCSF, GMCSF, interleukin (IL)-1ra, IL-5, IL-7, IL-8, IL-15, IL-1β, MCP 1, and VEGF levels, total lymphocyte counts, and CD8
CD38
mean fluorescence intensity (MFI), and lower NK-NKG2A MFI and percentage of CD8
CD38
T cells. Significant correlations between cytokine and immune cell expression were observed in both groups. Five variables best predicted progression to severe COVID-19 in patients with obesity: diabetes, the EGF, IL-10, and IL-13 levels, and the percentage of CD8
HLA-DR
CD38
cells. Three variables were predictive for patients without obesity: myocardial injury and the percentages of B lymphocytes and HLA-DR
CD38
cells.
Our findings suggest that clinical and immune variables and obesity interact synergistically to increase the COVID-19 progression risk. The immune signatures of hypertensive patients with and without obesity severe COVID-19 highlight differences in immune dysregulation mechanisms, with potential therapeutic applications.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
Myocardial injury is common in hypertensive patients with 2019 coronavirus disease (COVID-19). Immune dysregulation could be associated to cardiac injury in these patients, but the underlying ...mechanism has not been fully elucidated.
Methods
All patients were selected prospectively from a multicenter registry of adults hospitalized with confirmed COVID-19. Cases had hypertension and myocardial injury, defined by troponin levels above the 99th percentile upper reference limit, and controls were hypertensive patients with no myocardial injury. Biomarkers and immune cell subsets were quantified and compared between the two groups. A multiple logistic regression model was used to analyze the associations of clinical and immune variables with myocardial injury.
Results
The sample comprised 193 patients divided into two groups: 47 cases and 146 controls. Relative to controls, cases had lower total lymphocyte count, percentage of T lymphocytes, CD8
+
CD38
+
mean fluorescence intensity (MFI), and percentage of CD8
+
human leukocyte antigen DR isotope (HLA-DR)
+
CD38
–
cells and higher percentage of natural killer lymphocytes, natural killer group 2A (NKG2A)
+
MFI, percentage of CD8
+
CD38
+
cells, CD8
+
HLA-DR
+
MFI, CD8
+
NKG2A
+
MFI, and percentage of CD8
+
HLA-DR
–
CD38
+
cells. On multivariate regression, the CD8
+
HLA-DR
+
MFI, CD8
+
CD38
+
MFI, and total lymphocyte count were associated significantly with myocardial injury.
Conclusion
Our findings suggest that lymphopenia, CD8
+
CD38
+
MFI, and CD8
+
HLA-DR
+
MFI are immune biomarkers of myocardial injury in hypertensive patients with COVID-19. The immune signature described here may aid in understanding the mechanisms underlying myocardial injury in these patients. The study data might open a new window for improvement in the treatment of hypertensive patients with COVID-19 and myocardial injury.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ascidians are marine animals with a great ability to synthesize bioactive substances. This study examined the cytotoxic potential of 10 ascidians found in the coastal waters of Northeast Brazil. ...Samples of the species
Eudistoma vannamei Millar, 1977,
Eudistoma sp.,
Didemnum ligulum Monniot F., 1983,
Didemnum psammatodes (Sluiter, 1895),
Didemnum sp.,
Polysyncraton sp.,
Trididemnum sp.,
Cystodytes dellechiajei (Della Valle, 1877),
Euherdmania sp., and an unidentified species belonging to the Holozoidae family were extracted in methanol 5:1 (v/w). The extracts were tested for cytotoxicity using the brine shrimp lethality assay, sea urchin egg development assay, hemolysis assay, and MTT assay using tumor cell lines. The extract of
E. vannamei showed the highest toxicity in brine shrimp (
LD
50=34.7 μg/ml) and in all tumor cell lines tested, with an IC
50 of <2 μg/ml for CEM, 11.2 μg/ml for HL-60, 23.8 μg/ml for B16, and 14.3 μg/ml for HCT-8. In sea urchin eggs, it inhibited the cell cycle progression mainly at the blastula stage (
IC
50=74.8 μg/ml). The extract of
Euherdmania sp. also exhibited some toxicity in these assays, but at a lower potency than that of
E. vannamei. The extracts of
D. psammatodes and
Polysyncraton sp. showed a strong inhibition of the sea urchin egg cell cycle during both phases examined, first cleavage and blastula, with a possible action on the cell microfilament apparatus. The extract of
D. ligulum showed selective toxicity toward HCT-8 cells (
IC
50=35.3 μg/ml). The extract from the Holozoidae was the only one that possessed a hemolytic effect, with an IC
50 of 175.2 μg/ml. Further studies are necessary for a better characterization of the active principles of these extracts and a possible elucidation of the mechanisms of action.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose- Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been ...demonstrated to be activated in tumor samples from patients with Hodgkin Lymphoma (HL). The goal of this study was to evaluate the response, time of response, toxicity and overall survival in patients with refractory disease using everolimus out of clinical trial, in a compassionate use.
Patients and Methods- Patients were eligible if they had refractory and active Hodgkin disease. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Time to response assessement was defined by each center until progression (this was defined by each doctor, some have considered to keep the drug until clinical progression and not radiological progression of the disease). Patients could remain on drug until progression or toxicity.
Results- Thirty three patients were enrolled. Median age at the time of everolimus start was 29 years (range, 20-70). Patients had received a median of 5 prior therapies (range, 3-7) , 81% had undergone prior autologous stem cell transplant and 4 patients had undergone alogenic trasnplantation. The ORR was 51% (95% CI: 24-71%) with 14 patients achieving a PR, 3 patient achieving a CR and 10 with stable disease. Thirteen patients used the drug for more than 1 year. Patients received a median of 14 cycles of therapy and 3 remains on therappy at 36 months showing a great tolerability of the drug. The median DR for the responders (CR/PR) was 10 months. The most commons site effects were trombocitopenia and hypercholesterolemia. Three patients had pulmonar toxicity. The adverse events grade III and IV ocurred in 30% of the patients.
Conclusions- Everolimus has single-agent activity in relapsed/refractory HL, even in real lyfe and clinical practice and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant.
Off Label Use: everolimus for refractory hodgkin lymphoma.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Arenosclerins A-C and haliclonacyclamine E, new tetracyclic alkylpiperidine alkaloids isolated from the marine sponge Arenosclera brasiliensis, were subjected to antimicrobial and cytotoxic ...bioassays. Fourteen samples of microorganisms were used: Candida albicans, Staphylococcus aureus, Escherichia coli, and 12 antibiotic-resistant bacteria isolated from hospital environment. The minimum inhibitory concentration activity of each alkaloid was determined. The four compounds displayed antibacterial activity, but no antifungal activity against C. albicans. Haliclonacyclamine E and arenosclerins A and C were active against a larger number of bacteria strains than arenosclerin B. However, arenosclerins B and C presented more potent antibacterial activity. The alkaloids displayed inhibitory activity against both Gram positive and Gram negative bacteria. Cytotoxicity bioassays using the MTT method showed that these compounds present cytotoxic activity against human HL-60 (leukemia), L929 (fibrosarcoma), B16 (melanoma) and U138 (colon) cancer cell lines at concentrations between 1.5 and 7.0microg/ml. The results obtained indicated that A. brasiliensis alkaloids have a potent toxic activity. The broad cytotoxic and antimicrobial activities presented by A. brasiliensis alkaloids suggest a defensive role of arenosclerins and haliclonacyclamine E against microbial infection and/or the action of potential predators at the sponge's natural habitat.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
PDF
