Application of the Central Nervous System International Prognostic Index (CNS-IPI) score in daily practice: a retrospective analysis apart from the clinical trial at two centers in Brazil.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Bioactive Activities of the Phenolic Extract from Sterile Bracts of Araucaria angustifolia.

Sterile bracts can represent 80% of Araucaria angustifolia pinecone and are a rich source of phenolic compounds. This study aimed to optimize the extraction of the phenolic compounds from Araucaria angustifolia bracts using response surface methodology; the bioactivity properties were also investigated. The effects of the ethanol concentration, solute/solvent ratio, and temperature in relation to the phenolic composition and antioxidant activity were evaluated. The quantification and identification of the individual phenolic compounds (using high-performance liquid chromatography) and their bioactivity were evaluated. The optimized extraction conditions, which detected gallic acid, catechin, epicatechin, quercetin, and kaempferol, were obtained using 60% ethanol at a ratio of 1:38 (w/v) and a temperature of 80 °C. The extract showed high levels of phenolic classes and antioxidant activity. The extract also showed an inhibitory activity for pathogenic (approximately 80%, 10,000 µg/mL) and lactic acid (27.9%, 15,000 µg/mL) bacteria strains. The α-glucosidase inhibitory activity was approximately ten times greater than acarbose, demonstrating its high antiglycemic potential. No antioxidant and anti-inflammatory cellular activity were determined; however, a high cytotoxicity for non-tumor cells and the antiproliferative activity against the tumor cells were observed. Overall, the phenolic extract showed promising action in relation to the fight against the diseases related to oxidative stress and, hopefully, the application of the safe concentrations of the extract, based on bioavailability assays, can be verified.

Characteristics and clinical outcomes of patients with ALK-positive anaplastic large cell lymphoma: Report from the prospective international T-cell lymphoma project.

The T-cell Lymphoma Project is an international registry prospective study that enrolled patients with newly diagnosed peripheral T-cell and NK-cell lymphomas (PTCL). The main objective was to define the clinical features and outcomes, establishing a robust benchmark for future clinical trials. Seventy-four institutions from 14 countries in North America, South America, Europe, and Asia collected data on patients diagnosed and treated at their respective centers between September 2006 and February 2018. Among 1553 PTCL patients, 131 (8.4% of the total cohort) were confirmed to have anaplastic large cell lymphoma - kinase positive (ALCL, ALK+). The median age of the patients was 39 years (18-84). Sixty-five patients (66%) had advanced-stage disease, although majority (45 patients, 54%) had a low-risk International Prognostic Index (IPI) score (0-1). Of 97 patients treated with chemotherapy, 97% received anthracycline-containing regimens. The overall response rate was 81%, with 69 patients (70%) achieving complete remission. Estimated OS and PFS at 3 years were 77% (95% CI: 54%-99%) and 68% (95% CI: 46%-90%), respectively, and at 5 years were very similar, 77% of OS (95% CI: 62%-92%) and 64% of PFS (95% CI: 34%-94%). Multivariate analysis for PFS showed advanced stage (hazard ratios [HR]: 4.72, 95% CI: 1.43-23.9, p = 0.015), elevated lactate dehidrogenade (LDH) (HR 4.85; 95% CI: 1.73-13.60, p = 0.001), and Eastern Cooperative Oncology Group Performance Status scale (ECOG-PS) ≥2 (HR: 5.25; 95% CI: 1.68-16.4, p = 0.024). For OS, elevated LDH (HR: 3.77; 95% CI: 1.98-14.17, p = 0.014) and ECOG-PS ≥2 (HR: 4.59; 95% CI: 1.46-14.39, p = 0.004) were identified. In summary, although the outcome of ALK+ ALCL is superior to that of other PTCLs, it remains sufficiently favorable, given the young median age of the patients. Our results confirm the usefulness of both IPI and Prognostic Index for T-cell Lymphoma (PIT) in identifying groups of patients with different outcomes. Clinical Trials ID: NCT01142674.

Bioactive compounds recovered from apple pomace as ingredient in cider processing: monitoring of compounds during fermentation.

The apple pomace-industrial residue of apple beverages manufacture-presents 42-58% of the phenolic content of fresh fruit. As the phenolic composition influences the quality of ciders, it is very relevant to monitor the evolution of these compounds during the industrial process. Therefore, this research aim was to monitor the cider composition with the addition of phenolic extract from apple pomace during the fermentation. Two treatments, S1 (without extract) and S2 (with added extract), were evaluated during 15 days of fermentation. After 15 fermentation days, the sample S2 presented an increase of 23% in total phenolic compounds and 40% in flavonoids without harm to the fermentation kinetics. Concerning the evolution of monomeric phenolic compounds, the phenolic acids in S1 and S2 presented a similar trend during the fermentation period. Enzymatic hydrolysis reactions resulted in the chlorogenic acid content decreasing, in line with increased levels of caffeic acid. Phloridzin and quercetin glycosides content showed the greatest increase in S2. The final product S2 presented higher antioxidant activity and some sensorial characteristics (astringency, bitterness and colour) were accentuated. This work shows that phenolic compounds added were maintained during the process and it did not prejudice the fermentation reactions. Therefore, this is a good alternative to valorize apple pomace and improve the functional and sensorial quality of the cider.

The impact of anti-CD20-based therapy on hypogammaglobulinemia in patients with follicular lymphoma.

Although treatment with anti-CD20 monoclonal antibodies (mAb) has improved outcomes in B-cell malignancies, it's associated with increased risk of hypogammaglobulinemia (HG). Our study aimed to determine the effects of anti-CD20 mAb on serum immunoglobulins (Ig) in follicular lymphoma (FL). Ig concentrations, infectious complications, and need for intravenous Ig were evaluated by level of exposure to anti-CD20 mAb in 380 patients. Prevalence of HG significantly differed by level of treatment exposure (p < 0.001). Single course anti-CD20 mAb was associated with rising IgG (+10.3 mg/dL/year), whereas the addition of maintenance therapy (-7.4 mg/dL/year) or multiple courses of treatment (-10.3 mg/dL/year) was associated with declining IgG. Among patients treated with anti-CD20 mAb, 45.2% developed IgG-HG and 10.3% developed symptomatic IgG-HG. Pretreatment IgG levels gradually declined in all patients, suggesting tumor burden may contribute to HG. Baseline and periodic monitoring of serum Ig is appropriate in patients with FL, including those managed with active surveillance.

Diagnosis, prevention and treatment of central nervous system involvement in peripheral t-cell lymphomas.

Non-Hodgkin lymphomas with T-cell immunophenotype encompass a heterogeneous group of infrequent neoplasms that follow variable clinical courses but prevalently include aggressive behavior and high mortality rates. The involvement of the central nervous system (CNS) is an uncommon event in T-cell lymphomas, with wide variability among the different disease entities. CNS can be affected either at initial diagnosis or at recurrence, and both forms are considered "secondary CNS T-cell lymphoma". Given the low incidence of secondary CNS T-cell lymphoma, related literature is sparse, contradictory, and primarily constituted by small case series and single case reports. However, reported studies uniformly suggest high mortality rates related to this event. Therefore, to improve our ability to identify high-risk patients and offer them successful CNS prophylaxis or timely and effective treatment once the event has occurred may prevent CNS-related T-cell lymphomas deaths. For example, some entities like aggressive adult T-cell leukemia/lymphoma, extranodal natural killer/T-cell lymphoma, and other peripheral T-cell lymphomas with involvement of two or more extranodal organs are prone to CNS dissemination and should be considered for personalized CNS prophylaxis. The level of evidence suggesting an increased risk of CNS recurrence for other T-cell lymphomas and for other risk factors is lower. Published case series show that, following the example of aggressive B-cell lymphomas, patients with T-cell lymphomas and putative increased CNS risk receive different forms of prophylaxis, mostly methotrexate and cytarabine delivered by intrathecal and/or intravenous routes, with varied success. To date, achievements in the treatment of CNS involvement in patients with aggressive B-cell lymphoma were not replicated in secondary CNS T-cell lymphomas, and identification of effective therapies remains an urgent research target. This review is focused on clinical findings, diagnosis, treatment, and prognosis of patients with T-cell lymphoma experiencing CNS dissemination either at presentation or relapse. It aims to provide logical and, oftentimes, evidence-based answers to the most common questions on the most probable risk factors to CNS involvement in patients with T-cell lymphoma, the indications and strategies to prevent this life-threating event, and the management of patients with CNS disease.

Time from diagnosis to 2nd treatment is a promising surrogate for overall survival in patients with advanced stage follicular lymphoma.

It is difficult to demonstrate an overall survival (OS) benefit in trials of immediate therapy vs observation in follicular lymphoma (FL). Time to 2nd treatment (TT2T) may be a preferred endpoint. We identified 584 consecutive patients at our institution with advanced stage FL grade 1-3 A for whom intention was observation (n = 248) or therapy (n = 338). Median time to 1st treatment (TT1T), TT2T, and OS were estimated (subdistribution function). Modified Kendall's tau (mKτ) was used to assess correlation between survival endpoints. Among initially observed patients, median TT1T was 3.3 years, TT2T was 12.1 years, 10-year treatment-free survival was 23%, and 10-year OS was 82%. TT2T was strongly correlated with OS following initial observation (mKτ 0.46, p = .004) or therapy (mKτ 0.53, p < .0001), while duration of observation was not. TT2T is a potential surrogate for OS. Given the outstanding survival in this population, early intervention trials should focus on identifying high risk patients.

How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation

ABSTRACT: The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation.

The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

Peripheral T-Cell Lymphomas: Incorporating New Developments in Diagnostics, Prognostication, and Treatment Into Clinical Practice-PART 2: ENKTL, EATL, Indolent T-Cell LDP of the GI Tract, ATLL, and Hepatosplenic T-Cell Lymphoma.

The World Health Organization classification for peripheral T-cell lymphomas (PTCLs) continues to evolve based on genetic and clinical distinctions of each entity. In Part 1, an overview was provided of PTCL not otherwise specified, follicular T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma (ALCL), and breast implant-associated ALCL. In Part 2, this review is extended to extranodal natural killer (NK)/T-cell lymphoma, enteropathy-associated T-cell lymphoma, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, adult T-cell leukemia/lymphoma, and hepatosplenic T-cell lymphoma. Each NK/T-cell malignancy has its own signature, requiring knowledge of the appropriate diagnostic, prognostic, and therapeutic considerations when caring for afflicted individuals. Future directions will depend on discoveries that further our understanding of each disease and clinical trials that test the latest treatment options.

Peripheral T-Cell Lymphomas: Incorporating New Developments in Diagnostics, Prognostication, and Treatment Into Clinical Practice-PART 1: PTCL-NOS, FTCL, AITL, ALCL.

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of diseases, with low incidence and unique epidemiology and pathobiology; they are usually clinically aggressive, with poor outcomes. There have been significant advances in our understanding of the molecular and signaling alterations seen in these malignancies. These observations have led to novel therapeutic strategies that have had a meaningful impact on outcomes. This two-part series highlights the most important aspects of PTCLs and describes current treatment options and investigative opportunities. Part 1 will cover PTCL not otherwise specified, follicular T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma (ALCL), and breast implant-associated ALCL. Part 2 will cover extranodal natural killer/T-cell lymphoma, enteropathy-associated T-cell lymphoma, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, adult T-cell leukemia/lymphoma, and hepatosplenic T-cell lymphoma.

Transformed follicular lymphoma.

Follicular Lymphoma (FL) is the second most common type of non-Hodgkin lymphoma and is considered to be the prototype of indolent lymphomas. Histologic transformation into an aggressive lymphoma, which is expected to occur at a rate of 2 to 3% each year, is associated with rapid progression, treatment resistance, and poor prognosis. Recent modifications to the physiopathologic mechanism of transformed follicular lymphoma (t-FL) have been proposed, including genetic and epigenetic mechanisms as well as a role for the microenvironment. Although t-FL is considered a devastating complication, as it is associated with treatment-refractory disease and a dismal outcome, recent data in the rituximab era have suggested that not only is the prognosis less severe than reported in the previous literature but the risk of transformation is also lower. Thus, this study aimed to review the most recent research on t-FL in an attempt to better understand the clinical meaning of transformation from FL to diffuse large B cell lymphoma (DLBCL) and the impact of current treatment strategies on the curability of this intriguing subentity of lymphoma.

Everolimus as a single agent in refractory or relapsed Hodgkin's lymphoma: the Brazilian Named Patient Program Experience

Abstract Background Despite all the scientific progress that has been made on understanding the disease, prognosis for patients with relapsed and refractory Hodgkin's lymphoma remains poor and the treatment is palliative in the majority of the cases. Thus, the aim of this study was to present the results on the compassionate use of everolimus in a group of patients who were monitored at nine different centers in Brazil. Methods A 10-mg oral dose of everolimus was given to each patient daily. Response time was evaluated from the beginning of medication use until loss of response, toxicity or medical decision to cease treatment. Results Thirty-three patients were evaluated. The median age at the beginning of medication administration was 29 years. Patients had received a median of five prior therapies. Overall response rate was 45.4%, with 13 patients achieving partial response, two achieved clinical response, 14 remained with stable disease, two had disease progression, and two were not evaluated. Patients received a median of 14 cycles. Progression-free survival was nine months, and overall survival was estimated to be 36 months. Three patients used the medication for more than four years. The most frequently reported adverse events were thrombocytopenia and hypercholesterolemia. Three patients had pulmonary toxicity. Grade III and IV adverse events occurred in 39% of the patients. Conclusion Everolimus was found to provide a response in a group of patients with refractory or relapsed Hodgkin's lymphoma who had adequate tolerability to the drug.

Everolimus as a single agent in refractory or relapsed Hodgkin's lymphoma: the Brazilian Named Patient Program Experience.

BACKGROUND: Despite all the scientific progress that has been made on understanding the disease, prognosis for patients with relapsed and refractory Hodgkin's lymphoma remains poor and the treatment is palliative in the majority of the cases. Thus, the aim of this study was to present the results on the compassionate use of everolimus in a group of patients who were monitored at nine different centers in Brazil. METHODS: A 10-mg oral dose of everolimus was given to each patient daily. Response time was evaluated from the beginning of medication use until loss of response, toxicity or medical decision to cease treatment. RESULTS: Thirty-three patients were evaluated. The median age at the beginning of medication administration was 29 years. Patients had received a median of five prior therapies. Overall response rate was 45.4%, with 13 patients achieving partial response, two achieved clinical response, 14 remained with stable disease, two had disease progression, and two were not evaluated. Patients received a median of 14 cycles. Progression-free survival was nine months, and overall survival was estimated to be 36 months. Three patients used the medication for more than four years. The most frequently reported adverse events were thrombocytopenia and hypercholesterolemia. Three patients had pulmonary toxicity. Grade III and IV adverse events occurred in 39% of the patients. CONCLUSION: Everolimus was found to provide a response in a group of patients with refractory or relapsed Hodgkin's lymphoma who had adequate tolerability to the drug.

Disseminated infection with Lacazia loboi and immunopathology of the lesional spectrum.

The pathogenesis of lacaziosis continues to be obscure, and works have investigated the blood systemic immune response or the dermal immune response in restricted lesions in different body regions. Some authors describe that the inflammatory infiltrate in lacaziosis lesions showed a predominance of macrophages followed by CD45RO(+), CD4(+), and CD8(+) T cells; CD57(+) natural killer cells; S-100(+) cells; and CD20(+) B lymphocytes. A 54-year-old man and living in the State of Para, Amazon region, Brazil, was seen with a lesion on the left lower limb, which had started as a small nodular area 18 years ago. The lesion showed progressive growth and disseminated to other parts of the body. Our findings showed that dermal immune response differs depending on the type of lesions and clinical presentation, with presence of CD1a(+), FXIIIa(+), CD45(+), CD4(+), CD8(+), and S-100(+) cells and cytokine profile with expression of interleukin 1 ß, tumor necrosis factor α, transforming growth factor ß, IL-10, and interferon γ.